Preparation of sulfonamide-containing antimicrobial agents and substrate treatment compositions containing sulfonamide-containing antimicrobial agents

Abstract

A quaternary ammonium sulfonamide compound of formula (I): wherein R = (II), C 1 ‑C 3 Straight or branched alkyl, R 1 and R 2 are the same or different and are selected from C 1 To C 18 Straight or branched alkyl, R 3 and R 4 are the same or different and are selected from C 1 To C 4 Straight or branched alkyl, CF 3 , OR 5 , where R 5 It is C 1 To C 8 Straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X = halogen, and Y = (III), wherein R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and are selected from C 1 To C 6 A straight chain or branched chain alkyl group, a benzophenone selected from substituted benzophenone and unsubstituted benzophenone, a method for preparing the compound and an antimicrobial surface coating composition of the compound.

Description

Technical Field

[0001] The present invention relates to dual action antimicrobial compounds and compositions for treating substrates, especially surfaces, to reduce, preferably inhibit, microbial growth and biofouling on the treated substrates. Background Art

[0002] One of the main challenges facing the healthcare industry is to control infection and reduce the spread of microorganisms such as fungi, bacteria and viruses. A few microorganisms have the ability to attach to surfaces, such as porous surfaces, and proliferate to form colonies called biofilms. The use of antibiotics to treat infectious diseases caused by biofilms has become one of the biggest milestones in the history of medicine. However, after the widespread use of these antibiotics and other chemicals for disinfection purposes, some strains of microorganisms (such as bacteria) have developed resistance to them. For an increasing number of clinically important microorganisms (an example is pathogens), there is a lack of effective treatment or only one or two antibiotics, which are difficult to administer, expensive and / or have growing toxic side effects. In addition, when growing on surfaces as biofilms, microorganisms are generally more persistent, and it is now known that most infections involve biofilms. Biofilms also pose a significant threat to the contamination of food processing equipment and the deterioration of other products susceptible to microbial invasion.

[0003] Bacterial infections are spread in two different ways in the hospital environment: external contamination or internal contamination from implants. Patients can acquire external infections through contact with surfaces such as door handles, pens, telephones, healthcare worker uniforms (HCWU), stethoscopes, or sterile packaging that has been colonized by microorganisms. Hospital-acquired infections (HAIs) caused by contact with pathogenic microorganisms affect approximately 2 million people and cause more than 100,000 deaths in the United States each year. Such infections require additional hospitalization for 10-20 days, costing the already strained U.S. healthcare system approximately $25,000-30,000 per infection, totaling billions of dollars per year.

[0004] The second way for patients with bacterial infections is through hospital invasive support equipment, such as intravascular lines and implanted medical devices, such as artificial prostheses, cardiovascular implants and catheters. Implantation-related infections (IAI) occur in more than one million patients and cost an estimated $3 billion per year in the U.S. For example, about 10-50% of patients with implanted catheters have the risk of developing urinary tract infections (UTIs) causing additional medical expenses. The rise in the frequency and severity of HAI and IAI can be attributed to the reduced antibiotic efficacy of resistant strains of pathogens found in surface biofilms.

[0005] The formation of biofilms includes three stages. Initially, the bacteria reversibly adhere to the surface through the polysaccharides and adhesion proteins on the bacterial membrane (the first stage). Under appropriate conditions, the bacteria then firmly adhere to the surface (the second stage), followed by the secretion of a protective polymer matrix (biofilm, the third stage), at which stage the bacteria generally show a significant increase in resistance to antibiotics compared to non-adherent bacteria. As a result, once an infection occurs, it is difficult to treat. Therefore, it is necessary to actively seek strategies to prevent bacterial contamination or destroy adsorbed microorganisms that cause biofilm formation.

[0006] One way to prevent biofilm formation, which can potentially cause damage or infection, is to use antimicrobial coatings on surfaces that are not susceptible to the development of resistance by the target microorganisms. These coatings have bacteriostatic (inhibiting) or bactericidal (killing) properties, and thus result in a preventative strategy compared to disinfection, which is reactive, often performed after some damage or infection has already occurred. Relative to traditional antibiotics, bacteria are less likely to develop resistance to antimicrobial coatings, which physically inhibit microorganisms rather than chemically. This important distinction, and the associated alarming rate at which the number of effective antibiotics has decreased, is the primary reason for the rapid growth of interest in these antimicrobial coatings in recent years.

[0007] Quaternary ammonium compounds ("QACs") have gained attention as surfactants with antimicrobial activity. QACs consist of an irreversibly positively charged quaternary nitrogen atom, in which typically at least one substituent is a long aliphatic chain. The synthesis of these compounds involves a Menxiu Gold reaction (i.e., reaction with a tertiary amine of an alkyl halide) and subsequent quaternization of the tertiary amine.

[0008] Without being bound by any particular theory, the mode of action of QACs that kill bacteria is multi-step. First, QACs are adsorbed to the bacterial cell wall. Second, the long hydrophobic alkyl chains of QACs react with the phospholipid bilayer of the bacterial cell membrane and change its fluidity and structure, which adds stress to the cell wall. Finally, the stress added to the cell wall agitates the bilayer, expelling cytoplasmic material and ultimately causing cell death.

[0009] Polymeric antimicrobial coatings have the advantages of being chemically stable, non-toxic, and non-volatile, making them more effective, selective, and environmentally safe than conventional antimicrobial coatings, which rely on chemical leaching from the substrate. Over the past 35 years, it has become common practice to dissolve antimicrobial coatings into thermoplastic polymer solutions. In addition, solvents commonly used to dissolve antimicrobial agents into thermoplastic polymers include tetrahydrofuran ("TUF") and dimethylformamide ("DMF"). These solvents have the ability to attack polymeric surfaces, including those of polyurethanes, polyisoprenes, butyl rubber, polycarbonates, and the like. This tends to distort the surface, altering the integrity of the material at the surface, which in turn can ultimately increase the resistance of microbial cells to the antimicrobial component and the attachment of other microorganisms when the concentration of the antimicrobial component drops below the threshold required for inhibition. Moreover, once the prior art coatings are applied to a surface, a drying time of almost 24 hours is required to completely evaporate the solvent from the surface.

[0010] The development of antimicrobial coatings is limited by the availability of suitable antimicrobial agents that can be incorporated into thermoplastic polymers. Silver is a common preparation that can be used in elemental and salt forms. However, the technology for incorporating silver into polymer materials is lacking, expensive, and not environmentally friendly. Moreover, the performance of silver is weak, requiring up to eight hours to reach an antimicrobial effective level, and discoloration is common in silver-treated materials. Therefore, there is a long-term need for a low-cost, durable and effective composition that eliminates microorganisms and prevents biofilm formation without these harmful side effects. In an effort to increase the stability of antimicrobial films on polymer surfaces, antimicrobial agents are irreversibly covalently attached to the desired surface. Methods for grafting antimicrobial agents to polymer surfaces have been developed, typically using functionalized surfaces and / or antimicrobial molecules. However, some of these functionalization techniques are expensive and require a large number of synthetic methods. Recently, there have been reports on systems involving the photoactivation of photosensitive groups. Benzophenone is a popular photoreactive group and is often used in fragrances and cosmetics. There have been reports on systems involving the photoactivation of photosensitive groups. Benzophenone is a popular photoreactive group and is often used in fragrances and cosmetics.

[0011] The first quaternary ammonium phosphate compounds (quaternary ammonium phosphates) were disclosed as synthetic detergents in the early 1950s in U.S. Pat. No. 2,774,786 and Dutch Patent NL 79189. In these patented synthesis reactions, the final product can only be isolated as the sodium salt of phosphobetaine after hydrolysis of the phosphate with HCl followed by treatment with NaHCO3. In a similar synthesis (Germanaud et al., Bulletin de la Societe Chimique de France, 1988, 4, 699-704), quaternary ammonium phosphates are disclosed as betaines separated by purification on anion exchange resins. The products disclosed in the patents have no spectral characterization, while Germanaud's purification is expensive and the product is not isolated as phosphoric acid.

[0012] Phosphate monolayers for surface antimicrobial treatment have been shown to outperform thiol self-assembled monolayers (SAMs) in durability, long-term stability, and surface coverage, particularly on titanium and stainless steel. Thiol-based SAMs lack substrate specificity (mainly reserved for gold surfaces) and long-term stability required for biomedical applications (i.e., implants). Over time, thiol-based SAMs oxidize to sulfonates that lack affinity for gold and are removed from the surface.

[0013] It has been observed that Listeria increases biofilm production when the environment becomes more unstable or less ideal for active growth (Nilsson, R., Ross, T. and Bowman, J. (2011) Variability in biofilm production by Listeria monocytogenes correlated to strain origin and growth conditions. International Journal of Food Microbiology 150. Pages 14-24). It appears that Listeria use biofilm production as a form of defense, and their ability to survive appears to be linked to the maturation of the biofilm and their resistance to antimicrobials.

[0014] Biofilms allow for cellular interactions of essential cells as well as protection from harmful environments. Listeria biofilms have a simple structure and can form mature colonies after 24 hours, which is the incubation period of the large droplet test.

[0015] In general, actively growing Listeria cells are sensitive to quaternary ammonium compounds (QACs), even over a wide temperature and pH range and at relatively short exposure times. In contrast, mature biofilms appear to be more resistant to QACs, suggesting that components of mature biofilms, potentially extracellular polymeric substances (EPS), may provide protection against QACs. This behavior is unique to Listeria strains, but other microorganisms may have similar mechanisms for surviving exposure to antimicrobials.

[0016] In addition to biofilm maturation, it appears that other factors such as high pH and smooth attachment surfaces can affect the antimicrobial efficacy of QACs against Listeria monocytogenes (Yang, H., Kendall, P., Medeiros and L., Sofos, J. (2009) Efficacy of sanitizing agents against Listeria monocytogenes biofilms on high-density polyethylene cutting board surfaces. Journal of Food Protection, Vol. 72, No. 5, Pages 990-998). Exposure of non-lethal doses of sanitizers to colonies may lead to resistance of microbial communities over time (Feliciano, L., Li, J., Lee, J., Pascall, M. (2012) Efficacies of sodium hypochlorite and quaternary ammonium sanitizers for reduction of norovirus and selected bacteria during ware-washing operations. PLOS ONE, Vol 7, Issue 12. E50273). The Listeria strain isolated may be one that has already established these resistances.

[0017] In order to prevent the formation of biofilms, a variety of strategies have been used in the past to make surfaces inhospitable to bacteria. For example, small molecule monolayers or polymer films that are "grafted" to or "grown" from surfaces have been widely used to prepare antimicrobial surfaces and garments. These existing monolayer or polymer coatings include, for example, non-biofouling coatings, which are passive strategies that rely on using hydrophobic or zwitterionic films to prevent bacterial adhesion but do not kill invading bacteria. The second type of antimicrobial film kills contacting microorganisms by releasing biocides or immobilizing biocides. The third type of antimicrobial film utilizes a combination strategy of including non-biofouling and biocidal components to the coating. Currently, there are no known environmentally safe sulfonamide quaternary ammonium salt coatings that protect surfaces from biofouling.

[0018] US Patent No. 3,697,402 teaches photocurable thiol-terminated polyolefin polymers that, when applied to a surface and exposed to ultraviolet ("UV") light, form solid products useful as sealants, coatings, adhesives, and the like.

[0019] US Patent No. 4948819 teaches water soluble quaternary ammonium methacrylate coatings with photoactive linking molecules useful as UV curable coatings. US Patent No. 5714360 teaches a chemical crosslinker XYX, where X is a photoreactive group and Y is a nitrogen-containing group used to attach the chemical compound to other compounds or substrates.

[0020] JC Tiller et al. (Proceedings of the National Academy of Sciences, 2001, 98, 5981) teach a surface coating composition of polyvinyl pyrrolidone ("PVP")-QAC, wherein the surface is a pre-functionalized glass surface and the PVP-QAC is bound to the functional group. The surface needs to be pre-functionalized with an acyl chloride compound to allow the coating to bind to the glass surface.

[0021] US Patent Application Publication No. 2006 / 0147413 teaches a water-soluble photoactivated polymer bonded to biomaterials such as proteins, genes, vectors and cells via reactive groups for delivering molecular therapeutics.

[0022] US Patent Application Publication No. 2007 / 0231291 teaches polymeric QAC-polyethyleneimine for preventing bacterial and fungal attack on surfaces. International Patent Application Publication No. WO 2010 / 065421 teaches UV-cured coatings containing a rheology modifier or an antimicrobial agent, wherein the antimicrobial agent is not covalently attached to the coating polymer.

[0023] International Patent Application Publication No. WO2010 / 096444 teaches UV curable polyethyleneimine polymers that can be attached to a pre-functionalized surface that imparts antimicrobial activity to the surface. The surface was functionalized by reacting the surface with 7-octenyltrichlorosilane.

[0024] VP. Dhende et al. (Application of Material Interfaces, 2001, 3, 2830) teach a UV curable polyethyleneimine copolymer that can be attached to a pre-functionalized surface that imparts antimicrobial activity to the surface. The surface was functionalized by reacting it with octyltrichlorosilane.

[0025] International Patent Application Publication No. WO2011 / 139817 teaches a UV-curable vinyl substituted polyethyleneimine that can be attached to a pre-functionalized surface and impart antimicrobial activity to the surface. The surface was functionalized by reacting the surface with 7-octenyltrichlorosilane.

[0026] Mustafa Baris Yagci (“Self-Stratifying Antimicrobial Coatings”, doctoral thesis, January 16, 2012) teaches, inter alia, a surface coating of QAC-bonded polyurethanes.

[0027] Lawrence CA et al., Journal of the American Pharmaceutical Association, 1948, 37 , 424-428 teach quaternary ammonium compounds with sulfonamide functional groups and their antimicrobial activity modification. Specifically, the compounds include a para-substituted benzene ring, one end of which contains the sulfonamide function and the other constitutes a quaternary ammonium site. The absence of a linking group in the compound precludes covalent attachment of the compound to a substrate.

[0028] Song D. et al., European Journal of Medicinal Chemistry, 2013, 69, 670-677 teach quaternary ammonium sulfonamides and their use as anticancer drugs.

[0029] International Patent Application Publication No. WO 2014 / 089680 teaches UV-curable benzophenone-terminated quaternary ammonium compounds and their use as antimicrobial surface treatments.

[0030] International Patent Application Publication No. WO 2014 / 127451 teaches quaternary ammonium multidentate phosphate compounds and their use as durable antimicrobial surface treatments.

[0031] US Patent No. 5,104,649 teaches biocide-treated polymers and surfaces in which the antimicrobial agent is attached to the surface by a multi-step process.

[0032] U.S. Patent Application Publication No. 2007 / 0287750 teaches polycationic sulfonamide compounds useful for treating disease.

[0033] US Patent Application Publication No. 2013 / 0255061 teaches systems and methods for coating polymer surfaces, particularly medical devices, with biocide compounds.

[0034] U.S. Patent Application Publication No. 2015 / 0175812 teaches antimicrobial polymers for touch-sensitive surfaces, wherein the polymers contain pendant antimicrobial groups.

[0035] International Patent Application Publication No. WO2013 / 019918 teaches that sulfonyl quaternary ammonium compounds are covalently attached to a fabric surface having OH groups via sulfur-oxygen bonds.

[0036] Therefore, there is a long-standing need for a durable and environmentally safe antimicrobial quaternary ammonium sulfonamide for surface treatment and a method for making the same. Summary of the invention

[0037] Brief description of the invention

[0038] In one aspect of the present disclosure, there is provided a quaternary ammonium sulfonamide compound of formula (I):

[0039]

[0040] in,

[0041]

[0042] C1-C3 straight or branched chain alkyl,

[0043] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0044] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0045] 1 is 1, 2, 3, 4, 5, 6, 7 or 8,

[0046] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0047] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X = halogen, and

[0048]

[0049] Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched chain alkyl groups, and the phenyl ring of benzophenone may be substituted or unsubstituted.

[0050] In a preferred embodiment, halogen is selected from Cl, Br and I. In the preferred embodiment, R1 and R2 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably a methyl group. In a preferred embodiment, R3 and R4 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably a methyl group. In a preferred embodiment, 1 is selected from 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably a methyl group. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably a methyl group. In a preferred embodiment, R9 and R 10 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl.

[0051] In another aspect of the present disclosure, there is provided a method for preparing a quaternary ammonium sulfonamide of formula (I):

[0052]

[0053] It comprises the compound of formula (II) With alkyl halide of formula (III) Reaction, where

[0054]

[0055] C1-C3 straight or branched chain alkyl,

[0056] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0057] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0058] 1 is 1, 2, 3, 4, 5, 6, 7 or 8,

[0059] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0060] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, X = halogen, and

[0061]

[0062] Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched chain alkyl groups, and wherein the phenyl ring of the benzophenone may be substituted or unsubstituted.

[0063] In a preferred embodiment, halogen is selected from Cl, Br and I. In the preferred embodiment, R1 and R2 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is selected from 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R9 and R 10 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl.

[0064] In a preferred embodiment, the method can occur in at least one polar aprotic solvent, and the polar aprotic solvent is preferably selected from the group consisting of dichloromethane (DCM), dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile (ACN) and combinations thereof, more preferably ACN. The method can be carried out at an elevated temperature up to the reflux temperature of the at least one polar aprotic solvent. The reaction duration can be from the formation of partial product to the completion of the reaction, preferably from about 2 hours to about 48 hours, more preferably from about 3 hours to about 12 hours. The final product can be preferably purified by washing, more preferably by washing with a dialkyl ether, especially diethyl ether. The final product can be dried, preferably at about 10 -3 In a preferred embodiment, wherein Y is selected from benzophenone, the drying step is preferably carried out in the absence of light. In a preferred embodiment, wherein Y is selected from silane, the drying step is preferably carried out in the absence of moisture.

[0065] In another aspect of the present disclosure, there is provided a method for preparing a compound of formula (II),

[0066]

[0067] It comprises the compound of formula (IV) With the compound of formula (V) reaction, preferably in the presence of a base, wherein

[0068]

[0069] C1-C3 straight or branched chain alkyl,

[0070] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0071] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0072] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0073] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0074] The aryl ring in R may be substituted or unsubstituted.

[0075] Preferably, the optional base is selected from an amine, preferably an alkylamine or pyridine, more preferably a trialkylamine, most preferably triethylamine. In a preferred embodiment, R1 and R2 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0.

[0076] In a preferred embodiment, the method can occur in a polar aprotic solvent, preferably selected from the group consisting of ACN, DMF, THF, DCM and combinations thereof, preferably DCM. Adding the reactants can occur at a temperature of about -20°C to about 10°C, more preferably from about -10°C to about 5°C, most preferably at about 0°C. The reaction can be carried out at about 0°C to about room temperature, and from the formation of some product to the completion of the reaction, preferably from about 2 hours to about 8 hours, more preferably from about 3 hours to about 6 hours.

[0077] In another aspect of the present disclosure, there is provided an antimicrobial substrate treatment, preferably substrate coating, more preferably a surface coating composition comprising at least one compound of formula (I) and an environmentally friendly carrier,

[0078]

[0079] in

[0080]

[0081] C1-C3 straight or branched chain alkyl,

[0082] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0083] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0084] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0085] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0086] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0087] wherein the aryl ring in R may be substituted or unsubstituted,

[0088] X = halogen, and

[0089]

[0090] Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched alkyl, wherein the phenyl ring of the benzophenone may be substituted or unsubstituted. In a preferred embodiment, halogen is selected from the group consisting of Cl, Br and I, in a preferred embodiment, R1 and R2 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R9 and R 10 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl.

[0091] In a preferred embodiment, the environmentally friendly carrier is water, preferably a mixture of water, preferably a mixture of distilled water and at least one alkanol, preferably, the alkanol is selected from the group consisting of methanol, ethanol, isopropanol and combinations thereof, wherein the alkanol is preferably methanol or ethanol, and the water is preferably distilled water. In a preferred embodiment, the mixture of alkanol and water has a ratio of alkanol to water from about 5:95 to about 80:20: more preferably from about 10:90 to about 75:35, most preferably from about 10:90 to about 70:30. In a preferred embodiment, when the alkanol is methanol, the ratio of alkanol to water is from about 30:70 to about 70:30. In a preferred embodiment, when the alkanol is ethanol, the ratio of alkanol to water is from about 10:90 to about 40:60. In a preferred embodiment, the concentration of the antimicrobial quaternary ammonium sulfonamide in the composition is at least about 0.1%, preferably from about 0.5% to about 2%, more preferably from about 0.75% to about 1.5%, and most preferably from about 0.75% to about 1.25%.

[0092] In another aspect of the present disclosure, there is provided a method for treating, in particular coating, a substrate with an antimicrobial agent, the method comprising the steps of: (i) contacting the substrate with an antimicrobial composition comprising at least one compound of formula (I) and an environmentally friendly carrier.

[0093]

[0094] in,

[0095]

[0096] C1-C3 straight or branched chain alkyl,

[0097] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0098] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0099] 1 is 1, 2, 3, 4, 5, 6, 7 or 8,

[0100] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0101] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0102] wherein the aryl ring in R may be substituted or unsubstituted,

[0103] X = halogen, and

[0104]

[0105] Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched alkyl, wherein the phenyl ring of the benzophenone may be substituted or unsubstituted, (ii) drying the treated substrate, in one embodiment, allowing it to dry passively, in another embodiment actively, and (iii) optionally irradiating the treated substrate.

[0106] In a preferred embodiment, the halogen is selected from Cl, Br and I. In a preferred embodiment, R1 and R2 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is selected from 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R9 and R 10 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl.

[0107] In another preferred embodiment, the substrate can be a porous or non-porous substrate, and in yet another preferred embodiment, the substrate can be a surface. In a preferred embodiment, passive drying can include allowing the treated substrate, preferably the coated substrate, and more preferably the coated surface to dry at room temperature. More preferably, the temperature of room temperature is from about 15°C to about 30°C, and most preferably from about 20°C to about 25°C. In a preferred embodiment, active drying can include allowing the treated substrate, preferably the coated substrate, and more preferably the coated surface to dry at a temperature above room temperature and at a pressure equal to or lower than room pressure. More preferably, the temperature above room temperature is at least 40°C. More preferably, the pressure equal to room pressure or the pressure below room pressure is about 10 -3 mmHg to about 760 mmHg.

[0108] In another aspect of the present disclosure, there is provided a method for treating, preferably coating, a substrate, preferably a surface, with an antimicrobial agent, the method comprising the steps of: (i) contacting the substrate, preferably the surface, with an antimicrobial composition comprising a compound of formula (I) and an environmentally friendly carrier,

[0109]

[0110] in,

[0111]

[0112] C1-C3 straight or branched chain alkyl,

[0113] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0114] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0115] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0116] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0117] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0118] wherein the aryl ring in R may be substituted or unsubstituted,

[0119] X = halogen, and

[0120]

[0121] Wherein the phenyl ring of the benzophenone may be substituted or unsubstituted, (ii) drying the treated substrate, preferably the coated substrate, preferably the coated surface, in one embodiment, allowing passive drying, or actively drying in another embodiment, and (iii) optionally irradiating the treated substrate, preferably the coated substrate, more preferably the coated surface. In a preferred embodiment, the halogen is selected from Cl, Br and I. In a preferred embodiment, the substrate, preferably the surface, may be a porous or non-porous substrate, preferably a porous or non-porous surface. Preferably, the substrate, more preferably the surface, is a polymer or non-cellulose fiber. Preferably, the substrate, more preferably the surface, may include, but is not limited to, polymers such as polyethylene, polypropylene, acrylonitrile-butadiene-styrene, polyurethane, polyvinyl chloride, or nylon articles, such as food trays, molded bedding, tables and chairs and various furniture, disposable syringes, plastic handles for household appliances, bathroom fixtures, blinds, etc. Depending on the article or substrate, preferably the surface to be treated, especially to be coated, the skilled person will take the necessary steps to ensure that the composition substantially treats, preferably coats the substrate, especially the surface, preferably completely coats the substrate, more preferably completely coats the surface. For example, the article may require only one application of the composition, or the article may require multiple applications of the composition to ensure that the article is substantially treated, preferably substantially coated. In a preferred embodiment, the irradiation step comprises irradiating, preferably with UV light, the treated, preferably coated substrate, more preferably the coated surface.

[0122] In yet another aspect of the present disclosure, there is provided a method for treating, in particular coating, a substrate, in particular a surface, with an antimicrobial agent, the method comprising the steps of contacting the substrate, preferably the surface, with an antimicrobial composition comprising a compound of formula (I) and an environmentally friendly carrier, preferably under stirring and heating,

[0123]

[0124] in,

[0125]

[0126] C1-C3 straight or branched chain alkyl,

[0127] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0128] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0129] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0130] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0131] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0132] wherein the aryl ring in R may be substituted or unsubstituted,

[0133] X = halogen, and

[0134]

[0135] wherein R6, R7 and R8 are identical or different and are selected from C1 to C6 straight or branched alkyl, (ii) drying the treated substrate, preferably the coated substrate, more preferably the coated surface, and washing the treated substrate, preferably the coated substrate, more preferably the coated surface. Preferably, the washing step can be carried out using water. In a preferred embodiment, the halogen is selected from the group consisting of Cl, Br and I. In a preferred embodiment, R1 and R2 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is selected from 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. The substrate can be a porous or non-porous substrate. Preferably, the substrate, more preferably, the surface, can include, but is not limited to glass, cellulosic materials, cotton, and cotton blended products such as textiles, clothing, towels, bandages, outdoor fabrics, etc. In a preferred embodiment, heating is by a radiant heat source to produce a treatment temperature from about 30°C to about 80°C, more preferably from about 35°C to about 75°C, and most preferably about 40°C. In a preferred embodiment, stirring is performed once for about 3 minutes to about 5 minutes, most preferably about 4 minutes. Depending on the article or substrate to be treated, especially to be coated, those skilled in the art will take the necessary steps to ensure that the composition is basically treated, preferably coated with the substrate, especially the surface, preferably completely coated with the substrate, especially the surface. For example, the article may require only one coating of the composition, or the article may require multiple coatings of the composition to ensure that the article is basically treated, preferably basically coated.

[0136] In another aspect of the present disclosure, there is provided a method for treating a substrate, particularly a surface, with an antimicrobial agent, comprising the steps of: (i) contacting the substrate, preferably a heated substrate, more preferably a heated surface, with an antimicrobial composition comprising a compound of formula (I) and an environmentally friendly carrier;

[0137]

[0138] in,

[0139]

[0140] C1-C3 straight or branched chain alkyl,

[0141] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0142] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0143] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0144] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0145] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0146] wherein the aryl ring of R is substituted or unsubstituted,

[0147] X = halogen, and

[0148]

[0149] Among them, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched alkyl, (ii) optionally then further heating the substrate and (iii) drying the substrate. Preferably, the heating is radiant heating. In a preferred embodiment, the halogen is selected from Cl, Br and I. In a preferred embodiment, R1 and R2 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is selected from 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R9 and R 10 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl. The substrate may be a porous or non-porous substrate.

[0150] In a preferred embodiment, the antimicrobial coating composition can be applied to a given substrate, preferably a surface, preferably by dipping, spraying or aerosol spraying with a solution of about 1 to about 20 mM of a phosphate compound for a certain period of time so as to coat, preferably substantially coat, more preferably completely coat the substrate, preferably the surface. In one embodiment, the coating method can be repeated so as to coat an additional layer of the phosphate antimicrobial. Preferably, the antimicrobial coating composition can be applied to various substrates, such as, but not limited to, minerals, metals, metal oxides or metal alloys of aluminum, copper, iron, steel, titanium, zirconium and silicon (silicon dioxide), etc. More preferably, the substrate is selected from a metal or a metal oxide. Most preferably, the substrate is a metal.

[0151] In a preferred embodiment, the environmentally friendly carrier is water, preferably a mixture of water and at least one alkanol, the alkanol being selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, wherein the alkanol is preferably selected from methanol and ethanol, and the water is distilled water. In a preferred embodiment, the mixture of at least one alkanol and water has an alkanol to water ratio of from about 5:95 to about 80:20, more preferably from about 10:90 to about 75:35, and most preferably from about 10:90 to 70:30. In a preferred embodiment, when the alkanol is methanol, the alkanol to water ratio is from about 30:70 to about 70:30. In a preferred embodiment, when the alkanol is ethanol, the alkanol to water ratio is from about 10:90 to about 40:60.

[0152] In yet another aspect of the present disclosure, a test flow device is provided, preferably made of plastic, for evaluating antimicrobial quaternary ammonium sulfonamide coated substrates at a solid / liquid interface. In a preferred embodiment, the plastic can be exposed to a single or multiple bacterial strains that are typically capable of forming biofilms under controlled conditions and evaluated for growth or death of colony forming units.

[0153] In yet another aspect, an antimicrobial quaternary ammonium sulfonamide for reducing microbial growth at a solid / gas interface is provided. In a preferred embodiment, the microbial growth may be attributed to a group of microorganisms consisting of bacteria, fungi and viruses.

[0154] According to yet another aspect of the present disclosure, there is provided a substrate, preferably a surface, treated, preferably coated, with an antimicrobial agent as defined herein. In a preferred embodiment, the substrate, preferably a surface, may be porous or non-porous.

[0155] According to another aspect of the present disclosure, there is provided a method for reducing the growth of at least one microorganism on a substrate treated with an antimicrobial composition comprising at least one compound of formula (I) and an environmentally friendly carrier.

[0156]

[0157] in,

[0158]

[0159] C1-C3 straight or branched chain alkyl,

[0160] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0161] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0162] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0163] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0164] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0165] The aryl group of R may be substituted or unsubstituted

[0166] X = halogen, and

[0167]

[0168] Among them, R6, R7, R8, R9 and R 10 are identical or different and are selected from C1 to C6 straight or branched alkyl groups, wherein the phenyl group of benzophenone may be substituted or unsubstituted. In a preferred embodiment, halogen is selected from the group consisting of Cl, Br and I. In a preferred embodiment, R1 and R2 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is selected from 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R9 and R10 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl.

[0169] According to yet another aspect of the present disclosure, there is provided a method for reducing the growth of at least one microorganism on a substrate, preferably on a surface, treated with an antimicrobial composition, the antimicrobial composition comprising a 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide, 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(4-methylphenylsulfonamide)propyl)propan-1-ammonium bromide, 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonamide)propyl)propan-1-ammonium bromide, 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonamide)propyl)propan-1-ammonium bromide, At least one compound of the group consisting of methyl-N-(3-(naphthalene-1-sulfonamide)propyl)propan-1-ammonium bromide, N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide, N,N-dimethyl-3-(4-methylphenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide, N,N-dimethyl-3-(phenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide, N,N-dimethyl-3-(naphthalene-1-sulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide and combinations thereof. In a preferred embodiment, the at least one microorganism is selected from the group consisting of Listeria monocytogenes, Arthrobacter, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, and combinations thereof.

[0170] According to another aspect of the present disclosure, there is provided a use of an antimicrobial composition comprising a compound of formula (I):

[0171]

[0172] in,

[0173]

[0174] C1-C3 straight or branched chain alkyl,

[0175] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0176] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0177] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0178] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0179] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0180] The aryl group of R may be substituted or unsubstituted

[0181] X = halogen, and

[0182]

[0183] Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched alkyl groups, wherein the phenyl group of benzophenone may be substituted or unsubstituted to protect the substrate from biofouling. In a preferred embodiment, the halogen is selected from Cl, Br and I. In a preferred embodiment, R1 and R2 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R3 and R4 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, 1 is 1, 2 or 3, more preferably 1. In a preferred embodiment, R5 is selected from methyl, ethyl, n-propyl or isopropyl groups, more preferably methyl. In a preferred embodiment, m is selected from 1, 2 or 3, more preferably 2. In a preferred embodiment, n is selected from 0, 1, 2 or 3, more preferably 0. In a preferred embodiment, R6, R7 and R8 are the same and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably methyl. In a preferred embodiment, R9 and R 10 are identical and are selected from methyl, ethyl, n-propyl or isopropyl, more preferably isopropyl. In a preferred embodiment, the biofouling is caused by a biofilm.

[0184] According to yet another aspect of the present disclosure, there is provided a quaternary ammonium disulfonamide compound of formula (VI):

[0185]

[0186] Where R 11 and R 12Same or different, and selected from the following groups

[0187]

[0188] and X is halogen.

[0189] In a preferred embodiment, halogen is selected from the group consisting of Cl, Br and I. In a preferred embodiment, R 11 and R 12 are the same and are

[0190] In another aspect of the present disclosure, there is provided a use of a compound of formula (I) for reducing bacterial growth on a solid / gas interface.

[0191]

[0192] in,

[0193]

[0194] C1-C3 straight or branched chain alkyl,

[0195] R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group,

[0196] R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide,

[0197] l is 1, 2, 3, 4, 5, 6, 7 or 8,

[0198] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17,

[0199] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18,

[0200] wherein the aryl ring of R may be substituted or unsubstituted,

[0201] X = halogen, and

[0202]

[0203] Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 linear or branched alkyl groups, wherein the phenyl group of the benzophenone may be substituted or unsubstituted.

[0204] Further and other aspects will be apparent to the skilled reader. BRIEF DESCRIPTION OF THE DRAWINGS

[0205] Figure 1 Shown are images of polymer samples before (light color) and after (dark color) treatment with a benzophenone-anchored sulfonamide quaternary antimicrobial compound.

[0206] Figure 2 Shown are images of cotton fabric samples before (light color) and after (dark color) treatment with a benzophenone-anchored sulfonamide quaternary antimicrobial compound.

[0207] Figure 3 Shown is a graph of the log (colony forming units) change in dry surface over time for untreated control and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide treated polystyrene and N,N-dimethyl-3-(4-methylphenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride treated cotton exposed to Arthrobacter.

[0208] Figure 4 Shown is a graph of the log (colony forming units) change in dry surface over time for untreated control and cotton treated with N,N-dimethyl-3-(phenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride, N,N-dimethyl-3-(4-methylphenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride, N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium chloride and N,N-dimethyl-3-(naphthalene-1-sulfenamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride exposed to Arthrobacter.

[0209] Figure 5 Shown is a graph of the log (colony forming units) change over time of dry surface for untreated control and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonamide)propyl)propan-1-ammonium bromide and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonamide)propyl)propan-1-ammonium bromide treated polyethylene exposed to Arthrobacter.

[0210] Figure 6Shown is a graph of the log (colony forming units) change in the dry surface over time for untreated control and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide treated polyethylene exposed to Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus).

[0211] Figure 7 Shown are images of polyethylene samples before (control) and after (treated) treatment with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide containing a trace amount (0.05% w / v) of a fluorophore.

[0212] Figure 8 Shown is a graph of the log (colony forming units) change over time of dry surface for untreated control and polyethylene treated with the antimicrobial compound 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide containing 0.05% w / v fluorophore exposed to Arthrobacter.

[0213] Fig. 9 Shown are graphs of log (colony forming units) changes in the solid-liquid interface over time and planktonic cell survival for untreated control and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide-treated polyethylene test tubes exposed to Arthrobacter.

[0214] Fig.10 Shown are graphs of the log (colony forming units) change over time at the solid-liquid interface and biofilm cell survival for untreated control and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide treated polyethylene tubes exposed to Arthrobacter. DETAILED DESCRIPTION OF THE INVENTION

[0216] A range of alkyl and aryl UV and thermally cured quaternary ammonium sulfonamide antimicrobials can be prepared by conventional and microwave synthesis. Common to all UV curable compounds are sulfonamide bonds, quaternary ammonium sites and benzophenone linker segments. In addition, compounds containing silane linkers (preferably attached to porous substrates, etc.) or phosphate linkers (preferably attached to metal substrates, etc.) can be prepared using similar techniques.

[0217] These materials can be designed to have dual functionality: 1) functional anchoring groups that are selectively grafted to porous or non-porous substrates, and 2) quaternary ammonium charges and sulfonamide bonds for attracting bacteria (preferably harmful bacteria) and killing them (e.g., by mechanical methods operating at the solid / air interface).

[0218] The term quaternary ammonium sulfonamide refers to a quaternary ammonium compound substituted with a sulfonamide group RS(=O)2-, wherein C1-C3 straight chain or branched alkyl, wherein the aromatic ring in R can be substituted or unsubstituted, wherein R3 and R4 are the same or different and are selected from C1 to C4 straight chain or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight chain or branched alkyl or polyethylene oxide, and the sulfonamide fragment is connected to the quaternary ammonium nitrogen center through a carbon atom chain, preferably a saturated chain, more preferably a three-carbon chain, and most preferably a saturated three-carbon chain.

[0219] The term polar aprotic solvent refers to a solvent that has a dipole moment, but no acidic hydrogens. Non-limiting examples include acetonitrile, dimethylformamide, dimethyl sulfoxide, and dichloromethane.

[0220] Currently disclosed quaternary ammonium sulfonamide compounds utilize covalent bonding to be connected to metals (phosphate bonds), plastics (UV curable benzophenone bonds) or textiles and glass (silane connections), and the sulfonamide functionality is accompanied by quaternary ammonium salts that impart antimicrobial properties to these materials. Antimicrobial coating compositions of these compounds can be formulated as alcohol-based, water / alcohol or water-based formulations. Using such solvent systems makes these compositions nontoxic, low cost, minimally impacted on the environment and can be applied by electrospray or traditional coating techniques.

[0221] These preparations do not require a photoinitiator to graft the quaternary ammonium sulfonamide compound to a substrate. These antimicrobial coating compositions can be sprayed, aerosolized or applied to non-porous and porous surfaces, dried, and then actively grafted or cured (covalently linked) to these substrates by low heat, air or ultraviolet irradiation to form a self-assembled monolayer. These cured antimicrobial coatings form a durable bond with difficult-to-bond surfaces, resulting in the inhibition of biofilm formation at the solid / air interface. The solid / air interface is where many biofilms and harmful bacteria that can reside therein exist. These formulations are non-leaching and water-based, and can provide effective preventive protection against harmful bacteria. These compounds work at the solid / air interface, where dry-tolerant pathogenic bacteria can survive and individual or colonizing bacteria thrive.

[0222] The antimicrobial quaternary ammonium sulfonamide compounds of the present disclosure can be applied to protect a variety of porous and non-porous substrates, preferably surfaces. In one embodiment, the benzophenone attachment compound can be attached to, for example, polymers, including polyethylene and polypropylene; the silane attachment compound can be attached to, for example, cellulosic fibers and textiles including cotton and cotton blends; and the phosphate attachment compound can be attached to, for example, metal and metal oxide substrates, composites and glass. The substrate attached to the terminated sulfonamide containing quaternary ammonium salt forms a protective self-assembled monolayer that is 1-2 molecules thick on the substrate. These protective coatings may find application where an antimicrobial substrate is needed, particularly biomedical applications.

[0223] In a preferred embodiment, coating of the polymer substrate is achieved by first dissolving the quaternary ammonium salt in a 10:90 ethanol:water solution, followed by electrostatic spraying (2x), and a short 30 second UV cure cycle.

[0224] Microbiological evaluation of the antimicrobial quaternary ammonium sulfonamide coated substrates of the present disclosure revealed that they were highly effective.

[0225] Reference Figure 1 The presence of benzophenone-anchored sulfonyl polystyrene, polyethylene, polyvinyl chloride and polyetheretherketone samples was confirmed with bromophenol blue indicator. Dark samples indicated the presence of benzophenone-anchored quaternary ammonium sulfonamide, and light samples were untreated samples.

[0226] Reference Figure 2 The presence of silane-anchored quaternary ammonium sulfonamide on cotton fabric samples can be confirmed by bromophenol blue indicator. Light-colored samples indicate untreated; dark-colored samples indicate treated.

[0227] Reference Figure 3 , untreated and treated with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide polystyrene, and untreated and treated with N,N-dimethyl-3-(4-methylphenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide cotton, were inoculated with Arthrobacter spp. All bacteria on both treated samples were eliminated within three hours compared to the control. The data are shown in Example 34.

[0228] Reference Figure 4Cotton, untreated and treated with N,N-dimethyl-3-(phenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide, N,N-dimethyl-3-(4-methylphenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide or N,N-dimethyl-3-(naphthalene-1-sulfenamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide, was inoculated with Arthrobacter spp. All bacteria on all four samples were cleared within three hours compared to the control.

[0229] Reference Figure 5 Polyethylene samples of untreated and treated with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1-sulfenylamide)propyl)propan-1-ammonium bromide or 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonylamide)propyl)propan-1-ammonium bromide were inoculated with Arthrobacter spp. All bacteria in both samples were eliminated within three hours compared to the control. The data are shown in Example 34.

[0230] Reference Figure 6 Untreated and treated polyethylene samples with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide were inoculated with Escherichia coli or Staphylococcus aureus. All bacteria were eliminated within three hours compared to the control. See Example 34 for data.

[0231] Reference Figure 7 , The presence of 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide containing a trace amount (0.05% w / v) of fluorescent group on polyethylene samples was determined by UV imaging. Dark samples show no treatment; glowing samples show treatment.

[0232] Reference Figure 8 Polyethylene samples, untreated and treated with 0.05% w / v of the fluorescent group 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide, were inoculated with Arthrobacter. All bacteria were eliminated within three hours compared to the control. See Example 34 for data.

[0233] Reference Fig. 9The interior of a polyethylene tube was inoculated with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide and inoculated with Arthrobacter and planktonic cells. Samples were collected after 48 hours of incubation and agitation. The growth medium and inoculum were washed off and evaluated for the presence of biofilm. The test was retested to determine whether the antimicrobial activity persisted after repeated exposure. In both cases, planktonic cells were completely eliminated. The data are shown in Example 35.

[0234] Reference Fig.10 , and Fig. 9 The same test was used to evaluate the survival of biofilm cells. Biofilm cells were eradicated after 48 hours. See Example 35 for data.

[0235] The following non-limiting examples are provided.

[0236] Abbreviations:

[0237] ACN-Acrylonitrile

[0238] DCM-dichloromethane

[0239] Et2O-diethyl ether

[0240] Et3N-triethylamine

[0241] QAC, QUAT - Quaternary Ammonium Compounds

[0242] TSB-Tryptone Soybean

[0243] General Method 1 Aromatic sulfonamide drug precursors

[0244] To a flame-dried round-bottom flask containing 40-50 ml of anhydrous DCM equipped with a stirring bar on an ice bath, 1.0 equivalent of sulfonyl chloride was added, followed by 1.5 equivalents of Et3N, and 1.5 equivalents of 3-(dimethylamino)propylamine were added dropwise. The reaction mixture was removed from the ice bath and stirred at room temperature for the indicated time. The reactants were then transferred to a separatory funnel and extracted with 30-70 ml of distilled water. Volatiles and / or solvents were removed from the organic phase using a rotary evaporator and then precipitated at 10 °C for 30 min. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then quenched with water and the mixture was concentrated to a 4% ethanol. The evaporation reaction mixture was stirred at room temperature for 10 min. The evaporation reaction mixture was then quenched with water and the mixture was concentrated to a 4% ethanol. The evaporation reaction mixture was then quenched to a 5% ethanol. The evaporation reaction mixture was quenched to a 5% ethanol. The mixture was concentrated to a 5% ethanol. The mixture was concentrated to a 5% ethanol. -3 Dry under vacuum at 370 mmHg.

[0245]

[0246] Scheme 1: General reaction for aromatic sulfonamide precursors

[0247] Conventional method 2 Aliphatic sulfonamide

[0248] Into a flame-dried round-bottom flask containing 40-50 ml of anhydrous DCM equipped with a stirring bar on an ice bath, 1.0 equivalent of 3-(dimethylamino)propylamine was added, followed by dropwise addition of the corresponding sulfonyl chloride (1.0 equivalent). The reaction mixture was taken out from the ice bath and stirred at room temperature for 3-5 hours. After completion, the reaction solvent was evaporated using a rotary evaporator, and the resulting residue was then dissolved in an appropriate amount of potassium carbonate solution (0.05 M) and extracted with 40-60 ml of DCM. Volatiles and / or solvents were removed from the organic phase using a rotary evaporator and then dried over 10 °C. -3 Dry under vacuum at 370 mmHg.

[0249]

[0250] Scheme 2: General reaction of aliphatic sulfonamide precursors

[0251] General Method 3 Sealed Tube Menschutkin Quaternization

[0252] In a 20 mL scintillation / microwave vial, add 1.0 equivalent of sulfonamide, followed by 1.0-1.5 equivalents of the corresponding linker (silane, phosphate, or benzophenone) and a magnetic stir bar, and seal with a screw cap. The reaction mixture is heated at 110°C using an oil bath for 3-48 hours. The reaction mixture is prepared by adding Et2O (10-30 mL) directly to the reaction mixture, followed by decantation (Et2O wash × 3) and evaporation at 10 -3 Dry under vacuum at 370 mmHg.

[0253]

[0254] Scheme 3: General reaction of Menschutkin quaternization DETAILED DESCRIPTION

[0255] Synthesis of Aromatic Sulfonamides

[0256]

[0257] Example 1 N-(3-(Dimethylamino)propyl)benzenesulfonamide (1):

[0258] This compound was synthesized according to General Method 1 using benzenesulfonyl chloride (1.4 mL, 11.32 mmol), triethylamine (2.4 mL, 16.99 mmol, 1.5 eq) and 3-(dimethylamino)propylamine (2.1 mL, 16.99 mmol, 1.5 eq) in DCM (30 mL) for 4 hours to give a clear solution. The solution was then extracted with distilled water (40 mL) and the extracted organic layer was dried on a rotary evaporator to give a yellow-green oil which was heated to 10 °C. -3Further drying under vacuum at 100 mmHg afforded the product as a pale yellow waxy solid with a yield of 98% (2.69 g). 1 H NMR (CDCl3, 400MHz, δ): 7.68 (dd, 2H, J 3-2 =8.3Hz, H3), 7.40-7.30 (m, 3H, H1and H2), 2.86 (t, 2H, J 6-7 =5.8Hz, H6)), 2.11(t, 2H, J 8-7 =5.9Hz, H8), 1.98 (s, 6H, H9), 1.45-1.36 (m, 2H, H7)ppm; 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 140.20(C4), 132.33(C1), 128.99(C2), 126.96(C3 ), 59.13(C8), 45.28(C9), 44.05(C6), 25.12(C7)ppm.HRMS-ESI-TOF(m / z): [M + +H + ]C 11 H 19 Calculated value for N2O2S1, 243.3458, measured value, 243.1162.

[0259]

[0260] Example 2 N-(3-(Dimethylamino)propyl)-4-methylbenzenesulfonamide (2):

[0261] This compound was synthesized according to General Method 1 using p-toluenesulfonyl chloride (10.505 g, 55.10 mmol), triethylamine (11.5 mL, 82.65 mmol, 1.5 eq) and 3-(dimethylamino)propylamine (10.4 mL, 82.65 mmol, 1.5 eq) in DCM (100 mL) for 4 h to give a milky white solution. The solution was then washed with distilled water (100 mL) and the organic layer was extracted with a rotary evaporator to give a light yellow oil which was heated to 10 °C. -3 Further drying under vacuum at 200 mmHg afforded the product as a pale white waxy solid in 98% yield (13.85 g). 1 H NMR (CDCl3, 400MHz, δ): 7.73 (d, 2H, J 4-2 =8.3Hz, H4), 7.29(d, 2H, J 2-4 =7.9Hz, H2), 3.03(t, 2H, J 7-8=5.8Hz, H7), 2.42(s, 3H, H1), 2.29(t, 2H, J 9-8 =5.8Hz, H9), 2.16(s, 6H, H10), 1.62-1.53(m, 2H, H8)ppm; 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 142.83(C5), 137.11(C3), 129.44(C2), 126.88(C4), 58.7 6(C9), 45.15(C10), 43.65(C7), 25.23(C8), 21.32(C1)ppm.HRMS-ESI-TOF(m / z): [M + +H + ]C 12 H 21 Calculated value for N2O2S1, 257.3723, measured value, 257.1322.

[0262]

[0263] Example 3 N-(3-(Dimethylamino)propyl)-2,4,6-trimethylbenzene (3):

[0264] This compound was synthesized according to General Method 1 using 2,4,6-trimethylbenzene-1-sulfonyl chloride (2 g, 9.14 mmol), triethylamine (1.9 mL, 13.72 mmol, 1.5 eq) and 3-(dimethylamino)propylamine (1.7 mL, 13.72 mmol, 1.5 eq) in DCM (50 mL) for 3 h to give a clear solution. The solution was then extracted with distilled water (75 mL) and the extracted organic layer was dried on a rotary evaporator to give a clear oil which was heated to 10 °C. -3 Further drying under vacuum at 0.1 mmHg afforded the product as a pale white waxy solid in a yield of 98.5% (2.56 g). 1 H NMR (CDCl3, 400MHz, δ): 7.04 (br.s, 1H, H7), 6.93 (s, 2H, H3), 2.94 (t, 2H, J 8-9 =5.7Hz, H8), 2.61(s, 6H, H4), 2.32(t, 2H, J 10-9 =5.6Hz, H10), 2.27(s, 3H, H1), 2.18(s, 6H, H11), 1.69-1.56(m, 2H, H9)ppm; 13 C{ 1H}NMR (CDCl3, 100MHz, δ): 141.74(C6), 139.07(C2), 133.80(C5), 131.87(C3), 59.66(C10 ), 45.48(C11), 43.72(C8), 24.99(C9), 22.88(C4), 20.95(C1)ppm.HRMS-ESI-TOF(m / z): [M + +H + ]C 14 H 25 Calculated value for N2O2S1, 285.4255, measured value, 285.1643.

[0265]

[0266] Example 4 N-(3-(Dimethylamino)propyl)-2,4,6-triisopropylbenzenesulfonamide (4):

[0267] This compound was synthesized according to General Method 1 using 2,4,6-triisopropylbenzene-1-sulfonyl chloride (2 g, 6.60 mmol), triethylamine (1.4 mL, 9.91 mmol, 1.5 eq) and 3-(dimethylamino)propylamine (1.2 mL, 9.91 mmol, 1.5 eq) in DCM (50 mL) for 3 hours to give a clear solution. The solution was then extracted with distilled water (75 mL) and the organic layer was dried on a rotary evaporator to give a light green oil which was heated to 10 °C. -3 Further drying under vacuum at 100 mmHg afforded the product as a pale white waxy solid in 97% yield (2.36 g). 1 H NMR (CDCl3, 400MHz, δ): 7.15 (s, 2H, H4), 4.23-4.11 (m, 2H, H6), 3.08 (t, 2H, J 9-10 =5.9Hz, H9), 2.89 (m, 1H, H2), 2.60-2.40 (br.m, 2H, H11), 2.30 (br.s, 6H, H12), 1.83-1.66 (br.m, 2H, H10), 1.29-1.22 (br.m, 18H, H1and H1a)ppm; 13 C{ 1H}NMR (CDCl3, 100MHz, δ): 152.48(C7), 150.45(C5), 132.57(C3), 123.79(C4), 59.03(C11), 45.28(C12 ), 42.93(C9), 34.25(C2), 29.74(C6), 25.61(C10), 25.10(C1a), 23.73(C1)ppm.HRMS-ESI-TOF(m / z): [M + +H + ]C 20 H 37 Calculated value for N2O2S1, 369.5850, measured value, 369.2570.

[0268]

[0269] Example 5 N-(3-(Dimethylamino)propyl)naphthalene-1-sulfonamide (5):

[0270] This compound was synthesized according to General Method 1 using naphthalene-1-sulfonyl chloride (4 g, 18.04 mmol), triethylamine (3.8 mL, 27.06 mmol, 1.5 eq) and 3-(dimethylamino)propylamine (3.4 mL, 27.06 mmol, 1.5 eq) in DCM (50 mL) for 3 hours to give a clear solution. The solution was then extracted with distilled water (50 mL) and the organic layer was dried on a rotary evaporator to give a yellow-green oily extract which was then heated to 10 °C. -3 Further drying under vacuum at 0.1 mmHg afforded the product as a pale white waxy solid in a yield of 99.7% (5.27 g). 1 H NMR (CDCl3, 400MHz, δ): 8.67 (d, 1H, J 1-2 =8.5Hz, H1), 8.25(d, 1H, J 8-7 =6.2Hz, H8), 8.05(d, 1H, J 6-7 =8.2Hz, H6), 7.95(d, 1H, J 4-3 =7.8Hz, H4), 7.65 (m, 1H, H2), 7.59 (m, 1H, H3), 7.52 (t, 1H, H7), 2.95 (t, 2H, J 12-13 =5.6Hz H12), 2.21(t, 2H, J 14-13 =5.6Hz, H 14), 2.12 (s, 6H, H15), 1.55 (m, 2H, H13)ppm; 13 C{ 1H}NMR (CDCl3, 100MHz, δ): 134.85(C9), 134.45(C5), 133.96(C4), 129.79(C6), 129.16(C2), 128.42(C10), 128.21(C3), 126.82(C8), 124.76(C7), 124.28(C1), 59.80(C14), 45.56(C15), 44.77(C12), 24.68(C13)ppm.HRMS-ESI-TOF(m / z): [M + +H + ]C 15 H 21 Calculated value for N2O2S1, 293.4044, found value, 293.1319.

[0271] Synthesis of Aliphatic Sulfonamides

[0272] Example 6 N-(3-(Dimethylamino)propyl)methanesulfonamide (6):

[0273]

[0274] This compound was synthesized according to General Method 2 using methanesulfonyl chloride (1.4 mL, 17.46 mmol) and 3-(dimethylamino)propylamine (2.2 mL, 17.46 mmol, 1.5 eq) in DCM (50 mL) for 4 h and extracted with K2CO3 (0.05 M, 40 mL) to give a clear oil which was heated at 10 -3 Dry under vacuum at 100 mmHg. Yield: 65% (2.05 g). 1 H NMR (CDCl3, 400MHz, δ): 3.23 (t, 2H, H3), 2.91 (s, 3H, H1), 2.43 (t, 2H, H5), 2.22 (s, 6H, H6), 1.77-1.65 (m, 2H, H4)ppm; 13 C{ 1 H} NMR (CDCl3, 100MHz, δ): 59.26 (C5), 45.37 (C6), 44.08 (C3), 39.70 (C1), 25.72 (C4) ppm.

[0275]

[0276] Example 7 N-(3-(Dimethylamino)propyl)ethanesulfonamide (7):

[0277] This compound was synthesized according to General Method 2 using ethanesulfonyl chloride (0.7 mL, 7.78 mmol) and 3-(dimethylamino)propylamine (1.5 mL, 11.67 mmol, 1.5 eq) in DCM (50 mL) for 4 h and extracted with K2CO3 (0.05 M, 50 mL) to give a clear oil which was heated at 10 -3 Dry under vacuum at 100 mmHg. Yield: 61% (0.92 g). 1 H NMR (CDCl3, 400MHz, δ): 3.19 (t, 2H, J 4-5 =5.8Hz, H4), 3.0(q, 2H, J 2-1 =7.4Hz, H2), 2.42(t, 2H, J 6-5 =5.8Hz, H6), 2.22(s, 6H, H7), 1.75-1.64(m, 2H, H5), 1.34(t, 3H, J 1-2 =7.4Hz, H1)ppm; 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 59.33 (C6), 46.05 (C2), 45.41 (C7), 44.11 (C4), 25.91 (C5), 8.35 (C1) ppm. HRMS-ESI-TOF (m / z): [M + +H + ]C7H 19 Calculated value for N2O2S1, 195.1162, measured value, 195.1167.

[0278]

[0279] Example 8 N-(3-(Dimethylamino)propyl)butane-1-sulfonamide (8):

[0280] This compound was synthesized according to General Method 2 using butanesulfonyl chloride (1.7 mL, 12.77 mmol) and 3-(dimethylamino)propylamine (2.4 mL, 19.15 mmol, 1.5 eq) in DCM (50 mL) for 4 h and extracted with K2CO3 (0.05 M, 50 mL) to give a clear oil which was heated at 10 -3 Dry under vacuum at 370 mmHg. Yield: 81% (2.31 g). 1 H NMR (CDCl3, 400MHz, δ): 3.15 (t, 2H, J 6-7 =5.9Hz, H6), 2.94(t, 2H, J 4-3 =7.9Hz, H4), 2.38(t, 2H, J 8-7=5.9Hz, H8), 2.18 (s, 6H, H9), 7.78-1.61 (m, 4H, H), 1.48-1.34 (m, 2H, H2), 0.91 (t, 3H, J 1-2 =7.3Hz, H1)ppm; 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 59.08(C8), 51.56(C4), 45.38(C9), 43.83(C6), 26.05(C3), 25.70(C7), 21.54(C2), 13.63(C1)ppm.HRMS-ESI-TOF(m / z): [M + +H + ]C9H 23 Calculated value for N2O2S1, 223.1475, found value, 223.1480.

[0281]

[0282] Example 9 N-(2-(Dimethylamino)propyl)-N,N-dimethylsulfonamide (9):

[0283] This compound was synthesized according to General Method 2 using N,N-dimethylsulfamoyl chloride (1.5 mL, 13.93 mmol) and 3-(dimethylamino)propylamine (2.6 mL, 20.89 mmol, 1.5 eq) in DCM (50 mL) for 4 h and extracted with K2CO3 (0.05 M, 50 mL) to give a clear oil which was heated at 10 -3 Dry under vacuum at 100 mmHg. Yield: 79.8% (2.33 g). 1 H NMR (CDCl3, 400MHz, δ): 3.11 (t, 2H, J 3-4 =6.0Hz, H3), 2.75(s, 6H, H1), 2.38(t, 2H, J 5-4 =6.0Hz, H5), 2.19(s, 6H, H6), 1.69-1.61(m, 2H, H4)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 59.24 (C5), 45.39 (C6), 44.31 (C3), 38.00 (C1), 25.62 (C4) ppm. HRMS-ESI-TOF (m / z): [M + +H + ]C7H 20 Calculated value for N3O2S1, 210.1271, found value, 210.1276.

[0284] Example 9A 3-(((1-S,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methylsulfonylamino)-N,N-dimethylpropan-1-ammonium chloride:

[0285]

[0286] This compound was synthesized according to General Method 1 using (1S)-(+)-camphorsulfonyl chloride (20.938 g, 83.75 mmol) and 3-(dimethylamino)propylamine (10.5 mL, 83.75 mmol, 1.0 eq) in DCM (50 mL) at room temperature for 3 hours to give a light yellow cloudy precipitate. The mixture was evaporated on a rotary dryer to give a yellow oil which solidified to the camphoramine hydrochloride salt as a light off-white hard solid in a pressurized vacuum system. Yield: 100% (26.151 g, 83.5 mmol). 1 HNMR (CDCl3, 400MHz, δ): 5.44(s, 1H), 4.33(s, 4H), 3.69(s, 4H), 3.44(s, 4H), 2.77(s , 4H), 2.71 (s, 4H), 2.52-2.48 (m, 8H), 2.43-2.06 (m, 37H), 2.10 (d, J=2.3Hz, 9H), 2.10 (d, J = 2.3 Hz, 7H), 2.04 (s, 5H), 1.86 (s, 3H), 1.74-1.64 (m, 8H), 1.59 (s, 3H), 1.34 (s, 3H), 1.04 (s, 3H, H1), 0.87 (s, 3H, H1) ppm; consistent with the literature value (Eur. J. Pharm. Sci. 65 (2014) 29-37).

[0287] General Procedure for Menschutkin Quaternization 4

[0288] 1.0 equivalent of a tertiary amine-containing sulfonamide and 1.0-1.5 equivalents of the corresponding terminally functionalized (silane, phosphorus or benzophenone) halide were mixed in ACN and heated for 3-48 hours using Method 3. The reaction vial was cooled to room temperature and the crude product was purified as described in Method 3.

[0289] Synthesis of QAC-based organosilanes

[0290]

[0291] Example 10N, N-dimethyl-3-(phenylsulfonylamino)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride (1a):

[0292] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)benzenesulfonamide (1.0 g, 4.13 mmol) and (3-chloropropyl)trimethoxysilane (1.1 mL, 6.19 mmol, 1.5 eq) were used in ACN (3 mL) for 4 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg afforded a transparent golden brown viscous oil. Yield: 97.5% (1.77 g). 1 H NMR (CDCl3, 400MHz, δ): 8.39 (br.S, 1H, H5), 7.96 (d, 2H, H3), 7.54-7.341 (m, 3H, H1&H2), 3.69-3.62 (m, 2H, H8), 3.51 (s, 9H, H13 ), 3.37-3.30 (t, 2H, H10), 3.21 (s, 6H, H9), 3.03-2.96 (m, 2H, H6), 2.12-2.015 (m, 2H, H7), 1.80-1.68 (m, 2H, H11), 0.59 (t, 2H, J 12 - 11 =7.8Hz, H12)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 139.86(C4), 132.41(C1), 129.14(C2), 127.20(C3), 65.94(C10) , 62.45(C8), 51.10(C9), 50.72(C13), 39.93(C6), 22.61(C7), 16.45(C11), 5.57(C12)ppm. 29 Si 1 H} NMR (79.4MHz, CDCl3, δ): -44.41ppm.

[0293]

[0294] Example 11 N,N-dimethyl-3-(4-methylphenylsulfonylamino)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride (2a):

[0295] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)-4-methylbenzenesulfonamide (1.0 g, 3.90 mmol) and (3-chloropropyl)trimethoxysilane (1.1 mL, 5.85 mmol, 1.5 eq) were used in ACN (3 mL) for 3.5 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10-3 Drying in a vacuum of 1 mmHg afforded a clear golden brown gummy oil. Yield: 97% (1.67 g). 1 H NMR (CDCl3, 400MHz, δ): 8.18 (br.s, 1H, H6), 7.85 (d, 2H, J 4-2 =7.9Hz, H4), 7.29(d, 2H, J 2-4 =7.7Hz, H2), 3.75-3.62 (m, 2H, H9), 3.55 (s, 9H, H14), 3.41-3.32 (m, 2H, H11), 3.25 (s, 6H, H10), 3 .08-2.94(m,2H,H7),2.40(s,3H,H1),2.15-2.05(m,2H,H8),1.84-1.58(m,2H,H12),0.63(t,2H,J 4-2 =7.7Hz, H13)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 143.08(C5), 136.85(C3), 129.70(C2), 127.85(C4), 65.82(C11), 62.4 5(C9), 51.10(C14), 50.70(C10), 39.91(C7), 22.66(C1), 21.46(C8), 16.44(C12), 5.57(C13)ppm. 29 Si 1 H}NMR(79.4MHz, CDCl3, δ): -44.37ppm.HRMS-ESI-TOF(m / z): [M + -Cl - ]C 18 H 35 Calculated value for N2O5S1Si1, 419.6309, found value, 419.2026.

[0296]

[0297] Example 12 N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium chloride (3a):

[0298] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide (2.0 g, 7.03 mmol) and (3-chloropropyl)trimethoxysilane (1.9 mL, 10.55 mmol, 1.5 eq) were used in ACN (3 mL) for 4.5 hours to give a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg afforded a clear golden brown gummy oil. Yield: 92.6% (3.27 g). 1 HNMR (CDCl3, 400MHz, δ): 7.74 (t, 1H, J 7-8 =6.0Hz, H7), 6.90 (s.2H, H3), 3.70 (t, 2H, J 8-9 =7.9Hz, H8), 3.53 (s, 9H, H15), 3.40-3.33 (m, 2H, H12), 3.25 (s, 6H, H11), 3.02-2.94 (m, 2H, H10), 2.62(br.s, 6H, H4), 2.25(s, 3H, H1), 2.14-2.04(m, 2H, H9), 1.83-1.72(m, 2H, H13), 0.62(t, 2H, J 14-13 =7.9Hz, H14)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 142.01(C6), 139.22(C5), 133.83(C2), 132.01(C3), 66.06(C12), 62.51(C10) , 51.22(C11), 50.81(C15), 39.33(C8), 23.28(C4), 22.88(C1), 20.95(C9), 16.57(C13), 5.70(C14)ppm. 29 Si 1 H}NMR(79.4MHz, CDCl3, δ): -44.43ppm.HRMS-ESI-TOF(m / z): [M + -Cl - ]C 20 H 39 N2O5S1Si1, calculated value, 447.6840, found value, 447.2357.

[0299]

[0300] Example 13 N,N-dimethyl-3-(naphthalene-1-sulfonylamino)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride (5A):

[0301] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (0.5 g, 2.21 mmol) and (3-chloropropyl)trimethoxysilane (0.6 mL, 3.31 mmol, 1.5 eq) in ACN (3 mL) for 5 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of 1 mmHg afforded a clear golden brown gummy oil. Yield: 78.8% (0.85 g). 1H NMR (CDCl3, 400 MHz, δ): 8.83 (d, 1H, J8-7 = 8.6 Hz, H8), 8.47 (t, 1H, J11-12 = 5.7 Hz, H11), 8.20 (d, 1H, J6-7 = 7.3 Hz, Hs6), 7.99 (d, 1H, J1-2 = 8.1 Hz, H1), 7.87 (d, 1H, J4-3 = 8.1 Hz, H4), 7.74-7.65 (m, 1H, H 7), 7.55-7.46(m, 2H, H3&H2), 3.51-3.46(m, 11H, H14&H19), 3.22-3.16(m, 2H, H16), 3.09-3.01(m, 8 H, H12&H15), 1.98-1.86 (m, 2H, H13), 1.68-1.54 (m, 2H, H17), 0.51 (t, 2H, J18-17=7.8Hz, H18)ppm.1 3C{1H}NMR (CDCl3, 100MHz, δ): 135.12(C9), 134.16(C5), 133.91(C1), 129.07(C6), 128.8(C4), 128 .56(C7), 128.12(C10), 127.02(C3), 125.30(C8), 124.31(C2), 65.84(C16), 62.32(C14), 50.92(C1 5), 50.69 (C19), 39.79 (C12), 22.81 (C13), 16.33 (C17), 5.48 (C18) ppm.29Si{1H}NMR (79.4MHz, CDCl3, δ): -44.49ppm.HRMS-ESI-TOF (m / z): [M+-Cl-]C21H35N2O5S1Si1 calculated value, 455.2030, found value, 455.2018.

[0302]

[0303] Example 14 3-(Ethylsulfonylamino)-N,N-dimethyl-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride (7a):

[0304] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)ethanesulfonamide (1.0 g, 5.15 mmol) and (3-chloropropyl)trimethoxysilane (1.4 mL, 7.72 mmol, 1.5 eq) in ACN (3 mL) for 5 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg afforded a clear golden brown gummy oil. Yield: 86.0% (1.73 g). 1 H NMR (CDCl3, 400MHz, δ): 7.63 (s, 1H, H3), 3.75-3.47 (m, 11H, H6&H1), 3.39-3.31 (m, 2H, H8), 3.25-3. 15(m, 8H, H7&H4), 3.07-2.98(m, 2H, H2), 2.19-2.02(m, 2H, H5), 1.88-1.69(m, 2H, H9), 1.31(td, 3H, J 1-2 =7.3Hz, J 1-1a =3.4Hz, H1&H1a), 0.62(t, 2H, J 10-9 =7.8Hz, H10)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 65.89(C8), 62.40(C6), 51.18(C7), 50.81(C11) , 46.37(C2), 40.09(C4), 23.58(C5), 16.54(C9), 8.28(C1), 5.73(C10)ppm. 29 Si 1 H} NMR (79.4MHz, CDCl3, δ): -44.51ppm.

[0305]

[0306] Example 15 3-(Butylsulfonylamino)-N,N-dimethyl-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride (8a)

[0307] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)butanesulfonamide (1.0 g, 4.50 mmol) and (3-chloropropyl)trimethoxysilane (1.2 mL, 6.75 mmol, 1.5 eq) were used in ACN (3 mL) for 5 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 5) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg afforded a clear golden brown gummy oil. Yield: 60.0% (1.13 g). 1 H NMR (CDCl3, 400MHz, δ): 7.62 (br.s, 1H, H5), 3.67-3.60 (m, 2H, H8), 3.51 (s, 9H, H13), 3.36-3.29 (m, 2H, H4), 2.15-2.04 (m, 2H, H7), 1.83-1.66 (m, 4H, H11&H3), 1.41-1.33 (m, 2H, H2), 0.87 (td, J 1-2 =7.3Hz, J 1-1a =3.1Hz, H1&H1a), 0.60(t, 2H, J 12-11 =7.3Hz, H12)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 65.82(C10), 51.81(C4), 51.12(C9), 50.74(C13), 40.04 (C6), 25.38(C3), 23.50(C7), 21.58(C2), 16.50(C11), 13.62(C1), 5.68(C12)ppm. 29 Si 1 H}NMR(79.4MHz, CDCl3, δ): -44.50ppm.HRMS-ESI-TOF(m / z): [M + -Cl - ]C 15 H 37 Calculated for N2O5S1Si1, 385.2187, found, 385.2185, found, 385.2185.

[0308]

[0309] Example 16 3-((N,N-dimethylamino)amino)-N,N-dimethyl-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride (9a)

[0310] Synthesis of organophosphorus based on QAC

[0311]

[0312] Example 17 3-(Diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(phenylsulfonamide)propyl)propan-1-ammonium bromide (1b):

[0313] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)benzenesulfonamide (1.0 g, 4.13 mmol) and diisopropyl(3-bromopropyl)phosphate (1.10 mL, 4.13 mmol, 1 eq.) were used in ACN (3 mL) for 4 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg gave a light yellow fluffy / gelatinous powder. Yield: 86.0% (1.87 g). 1 H NMR (CDCl3, 400MHz, δ): 7.94 (d, 2H, J 3-2 =6.5Hz, H3), 7.65(t, 1H, J 5-6 =5.9Hz, H5), 7.54-7.46(m, 3H, H1&H2), 4.70-4.57(m, 2H, H13), 3.73-3.65(m, 2H, H8), 3.64-3.56(m, 2H, H10), 3.27(s, 6H, H9), 3.02(dd, 2H, J 6-5 =11.3Hz, J 6-7 =5.6Hz, H6), 2.16-1.94(m, 4H, (H7, H11, &ACN)), 1.79(dt, 2H, J 12-P =17.7Hz, H8, J 12-11 =7.2Hz, H12), 1.28(dd, 12H, J 14-P =6.2Hz, H8, J 14-13 =1.7Hz, H14)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 139.57(C4), 132.59(C2), 129.23(C1), 127.19(C3), 70.82(d, 2 J 13-P =6.7Hz, C13), 6.74(d, 3 J 10-P =15.1Hz, C10), 62.41(C8), 51.28(C9), 39.89(C6), 24.12(d, J 14-P =4.5Hz, C14), 23.99(d,,J 14-P=4.0Hz, C14), 23.82&22.38(d,J 12-P =144.3Hz, C12), 22.68(C7), 16.67(C11)ppm. 31 P{ 1 H}NMR (CDCl3, 121.45MHz, δ): 27.36ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 20 H 38 Calculated value for N2O5P1S1, 449.2234, found value, 449.2232.

[0314]

[0315] Example 18 3-(Diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(4-methylphenylsulfonylamido)propyl)propan-1-ammonium bromide (2b):

[0316] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)-4-methylbenzenesulfonamide (0.50 g, 1.95 mmol) and diisopropyl(3-bromopropyl)phosphate (0.50 mL, 1.95 mmol, 1 eq) in ACN (3 mL) for 3 h to obtain a light yellow solution with some precipitate formation. Purification was performed using Et2O (10 mL x 3) and the mixture was stirred at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy white powder. Yield: 89.5% (0.95 g). 1 H NMR (CDCl3, 400MHz, δ): 7.78 (d, 2H, J 4-2 =8.2Hz, H4), 7.55(t, 1H, J 6-7 =5.8Hz, H6), 7.28-7.23(m, 2H, H2and CDC13), 4.72-4.49 (m, 2H, H14), 3.72-3.63 (m, 2H, H9), 3.62-3.54 (m, 2H, H11), 3.25 (s, 6 H, H10), 3.00-2.90 (m, 2H, H7), 2.36 (s, 3H, H1), 2.16-1.90 (m, 4H, H8&H12), 1.75 (dt, 2H, J 13-P =17.8Hz, J 13-12 =7.1Hz, H13), 1.25(dd, 12H, J 15-P =56.15Hz, J 15-14 =2.1Hz, H15)ppm. 13 C{1 H}NMR (CDCl3, 100MHz, δ): 143.25(C5), 136.46(C3), 129.74(C2), 127.22(C4), 70.71(d, 2 J 14-P =6.7Hz, C14), 63.67(d, 3 J 11-P =15.8Hz, C11), 62.42(C9), 51.17(C10), 39.86(C7), 24.10(d, J 15-P =4.5Hz, C15), 23.97(d, J 15-P =4.0Hz, C15), 23.79&22.36(d,J 13-P =144.1Hz, C13), 22.52(C8), 21.47(C1), 16.69(d, 2 J 12-P =4.1Hz, C12)ppm. 31 P{ 1 H}NMR (CDCl3, 121.45MHz, δ): 27.15ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 21 H 40 Calculated value for N2O5P1S1, 463.5909, found value, 463.2394.

[0317]

[0318] Example 19 3-(Diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonylamido)propyl)propan-1-ammonium bromide (3b):

[0319] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzene (0.50 g, 1.76 mmol) and diisopropyl(3-bromopropyl)phosphate (0.40 mL, 1.76 mmol, 1 eq) were used in ACN (3 mL) for 4 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg gave a light yellow fluffy / gelatinous powder. Yield: 71.0% (0.71 g). 1 H NMR (CDCl3, 400MHz, δ): 7.14 (t, 1H, J 7-8=6.0Hz, H7), 6.92 (s, 2H, H3), 4.71-4.57 (m, 2H, H15), 3.84-3.75 (m, 2H, H10), 3.74-3.60 (m, 2H, H12), 3.32 (s, 6H, H11), 3.01 (dd, 2H, J 8-7 =11.2Hz, J 8-9 =5.6Hz, H8), 2.63(s, 6H, H4), 2.27(s, 3H, H1), 2.22-2.00(m, 4H, H9&H13), 1.81(dt, 2H, J 14-P =17.8Hz, J 14-13 =7.0Hz, H14), 1.30(d, 12H, J 16-15 =6.2Hz, H16)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 142.11(C6), 139.07(C2), 133.33(C5), 132.00(C3), 70.80(d, 2 J 15-P =6.7Hz, C15), 63.68(d, 2 J 12-P =15.0Hz, C112), 62.35(C10), 51.32(C11), 39.20(11C8), 24.13(d, J 16-P =4.5Hz, C16), 24.00(d, J 16-P =4.0Hz, C16), 23.81&22.38(d,J 14-P =144.3Hz, C14), 23.22(C4), 22.68(C9), 20.89(C1), 16.76(C13)ppm. 31 P{ 1 H}NMR (CDCl3, 121.45MHz, δ): 27.16ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 23 H 44 Calculated value for N2O5P1S1, 491.2703, found value, 491.2693.

[0320]

[0321] Example 20 3-(Diisopropoxyphosphoryl)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonylamino)propyl)propan-1-ammonium bromide (5b):

[0322] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (0.50 g, 4.13 mmol) and diisopropyl(3-bromopropyl)phosphate (0.50 mL, 3.42 mmol, 1 eq) in ACN (3 mL) for 5.5 hours to give a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg gave a light yellow fluffy / gelatinous powder. Yield: 77.4% (0.77 g). 1 H NMR (CDCl3, 400MHz, δ): 8.82 (d, 1H, J 8-7 =8.7Hz, H8), 8.20(d, 1H, J 6-7 =7.3Hz, H6), 8.02(d, 1H, J 1-2 =8.3Hz, H1), 7.92-7.84(m, 2H, H4&H11), 7.73-7.62(m, 1H, H7), 7.57-7.48(m, 2H, H3&H2 ), 4.69-4.50(m, 2H, H19), 3.62-3.47(m, 4H, H14&H16), 3.12(s, 6H, H15), 3.03(dd, 2H, J 12-11 =11.2Hz, J 12-13 =5.6Hz, H12), 2.08-1.82 (m, 7H, (ACN, H13&H17)), 1.71 (dt, 2H, J 18-P =17.5Hz, J 18-17 =7.2Hz, H18), 1.12(t, 12H, J 20-19 =6.0Hz, H2O)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 134.63(C9), 134.18(C5), 13.14(C1), 129.37(C6), 128.9 2(C4), 128.63(C7), 128.03(C10), 127.08(C3), 125.17(C8), 124.36(C2), 70.80(d, 2 J 19-P =6.7Hz, C19), 63.60(d, 3 J 16-P =15.1Hz, C16), 62.36(C14), 51.14(C15), 39.74(C12), 24.12(d, J 20-P =4.5Hz, C20), 23.99(d, J20-P =4.0Hz, C20), 23.74&22.31(d,J 18-P =144.5Hz, C18), 22.68(C13), 16.65(d, 2 J 17-P =144.3Hz, C17)ppm. 31 P{ 1 H}NMR (CDCl3, 121.45MHz, δ): 27.19ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 24 H 40 Calculated value for N2O5P1S1, 499.2390, found value, 499.2385.

[0323]

[0324] Example 21 3-(Diisopropoxyphosphoryl)-N-(3-(ethylsulfonylamido)propyl)-N,N-dimethylpropan-1-ammonium bromide (7b):

[0325] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)ethanesulfonamide (0.25 g, 1.29 mmol) and diisopropyl(3-bromopropyl)phosphate (0.30 mL, 1.29 mmol, 1 eq) in ACN (3 mL) for 5 h to obtain a viscous golden brown solution. It was purified using Et2O (10 mL x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg afforded a white colloidal powder. Yield: 86.0% (0.53 g). 1 H NMR (CDCl3, 400MHz, δ): 7.08 (t, 1H, J 3-4 =5.8Hz, H3), 4.76-4.54(m, 2H, H11), 3.74(t, 2H, J 6-5 =7.6Hz, H6), 3.63(t, 2H, J 8-9 =7.9Hz, H8), 3.35-3.16 (m, 8H, H7&H4), 3.07 (q, 2H, J 2-1 =7.4Hz, H2), 2.27-2.13(m, 2H, H5), 2.12-1.96(m, 2H, H9), 1.82(dt, 2H, J 10-P =17.4Hz, J 10-9 =7.2Hz, H10), 1.44-1.24(m, 15H, H1&H12)ppm. 13 C{ 1H}NMR (CDCl3, 100MHz, δ): 70.74(d, 2 j 11-p =6.7Hz, C11), 63.75(d, 3 J 8-P =15.7Hz, C8), 62.36(C6), 51.20(C7), 46.22(C2), 39.97(C4), 24.12(d, J 12-P =4.5Hz, C12), 23.98(d, J 12-P =4.0Hz, C12), 23.86&22.43(d, 2 j 10-P =144.3Hz, C10), 23.36(C5), 16.74(C9), 8.24(C1)ppm. 31 P{ 1 H}NMR (CDCl3, 121.45MHz, δ): 27.05ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 16 H 38 Calculated value for N2O5P1S1, 401.2234, found value, 401.2235.

[0326]

[0327] Example 22 3-(Butylsulfonylamino)-N-(3-(diisopropoxyphosphoryl)propyl)-N,N-dimethylpropan-1-ammonium bromide (8b):

[0328] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)butane-1-sulfonamide (0.50 g, 2.25 mmol) and diisopropyl(3-bromopropyl)phosphate (0.60 mL, 2.25 mmol, 1 eq) were used in ACN (3 mL) for 3 hours to obtain a viscous golden brown solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 -3 Drying in a vacuum of mmHg gave a light yellow sticky powder. Yield: 82.0% (0.94 g). 1 H NMR (CDCl3, 400MHz, δ): 7.07 (t, 1H, J 3-4 =6.1Hz, H5), 4.69(qd, 2H, J 13-P =12.4Hz, J 13-14 =6.2Hz, H13), 3.78(t, 2H, J 8-7 =7.8Hz, H8), 3.66(t, 2H, J10-11 =8.4Hz, H10), 3.33(s, 6H, H9), 3.28(dd, 2H, J 6-5 =12.0Hz, J 6-7 =6.0Hz, H6), 3.29(t, 2H, J 4-3 =8.4Hz, H4), 2.24-2.15 (m, 2H, H7), 2.15-2.03 (m, 2H, H11), 1.89-1.75 (m, 4H, H3&H12), 1.45 (dq, 2H, J 2-3 =14.7, J 2-1 =7.3, H2), 1.38-1.29 (m, 12H, H14), 0.96 (t, 3H, J 1-2 =7.4Hz, H1)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 70.77(d, 2 J 13-P =6.7Hz, C13), 63.73(d, 3 J 10-P =15.5Hz, C10), 62.36(C8), 51.72(C4), 51.25(C9), 39.98(C6), 25.35(C3), 24.14(d, J 14-P =4.5Hz, C14), 24.00(d, J 14-P =4.0Hz, C14), 23.87&22.43(d,J 12-P =144.4Hz, C12), 23.37(C7), 21.51(C2), 16.73(d, 2 J 11-P =4.2Hz, C11), 13.62(C1)ppm. 31 P{ 1 H}NMR (CDCl3, 121.45MHz, δ): 27.22ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 18 H 42 Calculated value for N2O5P1S1, 429.2547, found value, 429.2543.

[0329]

[0330] Example 23 3-(Diisopropoxyphosphoryl)-N-(3-((N,N-dimethylamino)amino)propyl)-N,N-dimethylpropan-1-ammonium bromide (9b):

[0331] This compound was synthesized by the following steps: N-(2-(dimethylamino)propyl)-N,N-dimethylsulfonamide (0.50 g, 2.39 mmol) and diisopropyl(3-bromopropyl)phosphate (0.6 mL, 2.39 mmol, 1 eq) were reacted in ACN (3 mL) for 3 h to give a viscous light yellow solution. The product was purified using Et2O (10 mL x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a light yellow fluffy / gelatinous powder. Yield: 91.7% (1.09 g). 1 H NMR (CDCl3, 400MHz, δ): 7.02 (t, 1H, J 2-3 =5.9Hz, H2), 4.62(qd, 2H, J 10-P =12.4Hz, J 10-11 =6.2Hz, H10), 3.66(t, 2H, J 5-4 =7.9Hz, H5), 3.59(t, 2H, J 7-8 =8.2Hz, H7), 3.26(s, 6H, H6), 3.14(dd, 2H, J 3-2 =12.0Hz, J 3-4 =6.0Hz, H3), 2.75 (s, 6H, H1), 2.20-2.06 (m, 2H, H4), 2.05-1.97 (m, 2H, H8), 1.78 (dt, 2H, J 9-P =17.4Hz, J 9-8 =7.2Hz, H9), 1.31-1.20(m, 12H, H11)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 70.78(d, 2 J 10-P =6.6Hz, C10), 63.74(d, 3 J 7-P =15.4Hz, C7), 62.44(C5), 51.24(C6), 40.19(C6), 38.15(C1), 24.13(d, J 11-P =4.5Hz, C11), 24.06(d, J 11-P =4.0Hz, C11), 23.87&22.44(d,J 9-P =144.0Hz, C9).22.84(C4), 16.74(C8)ppm. 31 P{ 1H}NMR (CDCl3, 121.45MHz, δ): 27.27ppm. HRMS-ESI-TOF (m / z): [M + -Br - ]C 16 H 39 Calculated value for N3O5P1S1, 416.2343, found value, 416.2341.

[0332] Synthesis of benzophenone based on QAC

[0333]

[0334] Example 24 3-(4-Benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonylamino)propyl)propan-1-ammonium bromide (1c):

[0335] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)benzenesulfonamide (0.921 g, 3.8 mmol) and 4-(3-bromopropoxy)benzophenone (1.29 g, 4.0 mmol) were reacted in ACN (10 mL) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 mL x 3) and then stirred at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy light yellow powder. Yield: 82% (1.74 g). 1 H NMR (CDCl3, 400MHz, δ): 7.96-7.89 (m, 2H, H3), 7.86-7.77 (m, 1H, H5), 7.74-7.62 (m, 4 H, H15&H19), 7.57-7.49(m, 1H, H21), 7.49-7.37(m, 5H, (H1, H2, & H20)), 6.89(d, 2H, J 14-15 =8.9Hz, H14), 4.11(t, J 12-11 =5.3Hz, H12), 3.79-3.56(m, 4H, H8&H10), 3.27(s, 6H, H9), 3.06-2.92(m, 2H, H6), 2.36-2.19(m, 2H, H11), 2.19-1.97(m, 2H, H7)ppm. 13 C{ 1H}NMR (CDCl3, 100MHz, δ): 195.58(C17), 161.80(C13), 139.64(C1), 137.99(C 4), 132.71(C18), 132.51(C15), 132.19(C21), 130.60(C16), 139.75(C2), 129 .32(C19), 128.35(C20), 127.22(C3), 114.31(C14), 64.68(C12), 62.44(C8), 62.06(C10), 39.98(C6), 23.08(C11), 22.75(C7)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C 27 H 33 Calculated value of N2O4S, 481.2156, measured value, 481.2155.

[0336]

[0337] Example 25 3-(4-Benzoylphenoxy)-N,N-dimethyl-N-(3-(4-methylphenylsulfonylamino)propyl)propan-1-ammonium bromide (2c):

[0338] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)-4-methylphenylsulfonamide (1.05 g, 4.1 mmol) and 4-(3-bromopropoxy)benzophenone (1.417 g, 4.44 mmol) were reacted in ACN (10 ml) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 ml x 3) and then heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy light yellow powder. Yield: 80% (1.88 g). 1 H NMR (CDCl3, 400MHz, δ): 7.80 (d, 2H, J 4-2 =8.2Hz, H4), 7.73-7.65(m, 4H, H16&H20), 7.56-7.59(m, 1H, H22), 7.42(t, J 4-2 =7.2Hz2H,H22),7.21(d,2H,J 2-4 =8.2Hz, H2), 6.89(d, 2H, J 15-16 =8.8Hz, H15), 4.12(t, 2H, J 13-12=5.4Hz, H13), 3.79-3.59(m, 4H, H9&H11), 3.29(s, 6H, H10), 3.07-2.90(m, 2H, H7), 2.35-2.23(m, 5H, H1&H12), 2.19-2.03(m, 2H, H8)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 195.57(C18), 161.82(C14), 143.50(C3), 138.05(C5), 13 6.53(C19), 132.54(C16), 132.19(C22), 130.69(C17), 129.90(C20), 129.80(C2), 1 28.36(C21), 127.34(C4), 114.32(C15), 64.71(C13), 62.53(C9), 62.11(C11), 51.6 2(C10), 40.01(C7), 23.15(C12), 22.75(C8), 21.57(C1)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C 28 H 35 Calculated value of N2O4S, 495.2312, measured value, 495.2319.

[0339]

[0340] Example 26 3-(4-Benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide (3c):

[0341] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)-2,4,6-trimethylphenyl)sulfonamide (0.853 g, 3.0 mmol) and 4-(3-bromopropoxy)benzophenone (1.0 g, 3.13 mmol) were reacted in ACN (10 ml) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 ml x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy white powder. Yield: 67% (1.20 g). 1 H NMR (CDCl3, 400MHz, δ): 7.76 (d, 2H, J 17-16 =8.7Hz, H17), 7.72(d, 2H, J 21-22 =7.2Hz, H21), 7.56(t, 2H, J 23-22=7.4Hz, H23), 7.49-7.41(m, 2H, H22), 7.22(t, 1H, J 4-2 =6.2Hz, H7), 6.94(t, 2H, J 16-17 =6.0Hz, H16), 6.90(s, 2H, H3), 4.21(t, 2H, J 14-13 =5.4Hz, H14), 3.90-3.80 (m, 2H, H10), 3.80-3.68 (m, 2H, H12), 3.37 (s, 6H, H11), 3.04 (dd, 2H, J 8-7 =11.4Hz, J 8-9 =5.7Hz, H8), 2.63(s, 6H, H4), 2.43-2.32(m, 2H, H13), 2.25(s, 3H, H1), 2.23-2.13(m, 2H, H9)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 195.63(C19), 161.81(C15), 142.40(C5), 139.24(C2), 1 38.15(20), 133.41(C6), 132.66(C17), 132.22(C23), 132.18(C3), 130.91(C18), 12 9.90(C21), 128.39(C22), 64.72(C14), 62.68(C10), 62.29(C12), 51.77(C11), 39.3 6(C8), 23.42(C4), 23.27(C13), 23.05(C9), 21.03(C1)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C 30 H 39 Calculated value of N2O4S, 523.2625, measured value, 523.2636.

[0342]

[0343] Example 27 3-(4-Benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-triisopropylphenylsulfonamide)propyl)propan-1-ammonium bromide (4c):

[0344] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)-2,4,6-triisopropylbenzenesulfonamide (0.379 g, 1.03 mmol) and 4-(3-bromopropoxy)benzophenone (0.329 g, 1.03 mmol) in ACN (10 ml) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 ml x 3) and stirred at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy white powder. Yield: 92% (0.65 g). 1 HNMR (CDCl3, 400MHz, δ): 7.78-765 (m, 4H, H18&H22), 7.57-7.49 (m, 1H, H24), 7.43 (t, 2H, J 23-22 =7.5Hz, H23), 7.12(s, 2H, H4), 7.06(t, 1H, J 8-9 =6.1Hz, H8), 6.93(d, 2H, J 17-18 =8.9Hz, H17), 4.20(t, 2H, J 15-14 =5.5Hz, H15), 4.16-4.05 (m, 2H, H6), 3.90-3.81 (m, 2H, H11), 3.80-3.69 (m, 2H, H13), 3.39 (s, 6H, H12), 3.10 (dd, 1H, J 9-8 =11.3Hz, J 9-10 =5.7Hz, H9), 2.91-2.79 (m, 2H, H2), 2.45-2.31 (m, 2H, H14), 2.28-2.14 (m, 2H, H10), 1.21 (dd, 18H, J 1-2 =6.8Hz, J 1a-6 =2.3Hz, H1&H1a)ppm. 13 C{ 1H}NMR (CDCl3, 100MHz, δ): 195.55(C20), 161.75(C16), 152.76(C3), 150.33(C7), 138.01( C21), 132.50(C18), 132.06(C24), 131.96(C5), 130.66(C19), 129.74(C22), 128.24(C23), 123.88(C4), 114.22(C17), 64.67(C15), 62.49(C11), 62.03(C13), 51.66(C12), 39.47(C9) , 34.10(C2), 29.54(C6), 25.12(C1), 23.14(C14), 23.07(C10)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C 36 H 51 Calculated value of N2O4S, 607.3564, measured value, 607.3555.

[0345]

[0346] Example 28 3-(4-Benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonamido)propyl)propan-1-ammonium bromide (5c):

[0347] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (0.584 g, 2.0 mmol) and 4-(3-bromopropoxy)benzophenone (0.702 g, 2.2 mmol) were reacted in ACN (10 mL) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 mL x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy white powder. Yield: 82% (1.0 g). 1 H NMR (CDCl3, 400MHz, δ): 8.80 (d, 1H, J 1-2 =8.7Hz, H1), 8.15(d, 1H, J 8-7 =7.3Hz, H8), 7.96(s, 1H, H11), 7.91(d, 1H, J 6-7 =8.3Hz, H6), 7.78(d, 1H, J 4-3 =8.2Hz, H4), 7.70-7.55(m, 4H, (H2, H25, & H21)), 7.51(t, 2H, J 27-26=7.4Hz, H27), 7.46-7.34(m, 4H, (H3, H26, & H7), 6.77(d, 2H, J 20-21 =8.7Hz, H20), 4.00-3.85 (m, 2H, H18), 3.59-3.37 (m, 4H, H14&H16), 3.19- 2.91(m, 8H, H15&H12), 2.17-1.99(m, 2H, H17), 1.97-1.76(m, 2H, H13)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 195.59(C23), 161.77(C19), 138.04(C24), 134.85(C9), 134.21(C6), 132.50(C25), 132.20(C27), 130.56(C10), 129.80(C2), 129.36(C8), 129.05(C4), 128.76(C21), 128.37(C7), 128.00(C22), 127.18(C3), 125.20(C1), 124.52(C26), 114.25(C20), 64.59(C18), 62.42(C14), 62.10(C16), 51.42(15), 39.83(C12), 22.92(C17&C13)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C 31 H 35 Calculated value of N2O4S, 531.2312, measured value, 531.2328.

[0348]

[0349] Example 29 3-(4-Benzoylphenoxy)-N-(3-(ethylsulfonamido)propyl)-N,N-dimethylpropan-1-ammonium bromide (7c):

[0350] This compound was synthesized by the following steps: using N-(3-(dimethylamino)propyl)ethanesulfonamide (0.250 g, 1.29 mmol) and 4-(3-bromopropoxy)benzophenone (0.411 g, 1.29 mmol) in ACN (10 mL) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 mL x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy light yellow powder. Yield: 77% (0.52 g). 1H NMR (CDCl3, 400MHz, δ): 7.78 (d, 2H, J 13-12 =8.7Hz, H13), 7.72(d, 2H, J 17-18 =7.4Hz, H17), 7.56(t, 2H, J 19-18 =7.4Hz, H19), 7.50-7.40 (m, 2H, H18), 7.12 (t, 1H, J 3-4 =6.0Hz, H3), 6.98(d, 2H, J 12-13 =8.8Hz, H12), 4.21(t, 2H, J 10-9 =5.3Hz, H10), 3.86-3.75 (m, 2H, H6), 3.75-3.65 (m, 2H, H8), 3.35 (s, 6H, H7), 3.31-3.22 (m, 2H, H4), 3.07 (q, 2H, J 2-3 =7.3Hz, H2), 2.43-2.29(m, 2H, H9), 2.27-2.13(m, 2H, H5), 1.34(t, 3H, J 2-3 =7.4Hz, H1)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 195.55(C15), 161.66(C11), 137.94(C16), 132.55(C13), 132.16(C19), 130.83(C14), 129.78(C17), 128.29(C18), 114 .22(C12), 64.57(C10), 62.46(C6), 62.17(C8), 51.61(C7), 46.44(C2), 3 9.95(C4), 23.64(C5), 23.11(C9), 8.27(C1)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C 23 H 33 Calculated value of N2O4S, 433.2156. Measured value, 433.2153.

[0351]

[0352] Example 30 3-(4-Benzoylphenoxy)-N-(3-(butylsulfonamido)propyl)-N,N-dimethylpropan-1-ammonium bromide (8c):

[0353] This compound was synthesized by the following steps: N-(3-(dimethylamino)propyl)butane-1-sulfonamide (0.324 g, 1.46 mmol) and 4-(3-bromopropoxy)benzophenone (0.466 g, 1.46 mmol) were reacted in ACN (10 ml) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 ml x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy light yellow powder. Yield: 73% (0.58 g). 1 H NMR (CDCl3, 400MHz, δ): 7.74 (d, 2H, J 15-14 =8.7Hz, H15), 7.69(d, 2H, J 19-20 =7.1Hz, H19), 7.54(t, 1H, J 21-20 =7.4Hz, H21), 7.47-7.38 (m, 2H, H20), 7.10 (t, 1H, J 5-6 =5.6Hz, H5), 6.96(d, 2H, J 14-15 =8.8Hz, H14), 4.18(t, 1H, J 12-11 =5.2Hz, H12), 3.79-3.61(m, 2H, H8&H10), 3.33(s, 6H, H9), 3.27-3.20(m, 2H, H6), 3.10-2.96( m, 2H, H4), 2.42-2.25 (m, 2H, H11), 2.25-2.07 (m, 2H, H7), 1.80-1.65 (m, 2H, H3), 1.38 (dq, 2H, J 2-3 =14.6Hz, J 2-1 =7.4Hz, H2), 0.87(t, 3H, J 1-2 =7.3Hz, H1)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 195.56(C17), 161.17(C13), 137.89(C18), 132.50 (C15), 132.16(C21), 130.62(C16), 129.71(C19), 128.29(C20), 114.27(C14 ), 64.67(C12), 62.30(C8), 61.96(C10), 51.79(C4), 51.56(C9), 25.37(C3), 23.55(C7), 23.05(C11), 21.51(C2), 13.64(C1)ppm.HRMS-ESI-TOF(m / z): [M + -Br - ]C25 H 37 Calculated value of N2O4S, 461.2469, measured value, 461.2458.

[0354]

[0355] Example 31 3-(4-Benzoylphenoxy)-N-(3-((N,N-dimethylamino)amino)propyl)-N,N-dimethylpropan-1-ammonium bromide (9c):

[0356] This compound was synthesized by the following steps: N-(2-(dimethylamino)propyl)-N,N-dimethylsulfonamide (0.232 g, 1.11 mmol) and 4-(3-bromopropoxy)benzophenone (0.354 g, 1.11 mmol) were reacted in ACN (10 ml) for 48 hours to give a viscous light yellow solution. The product was washed with Et2O (10 ml x 3) and heated at room temperature for 10 min. -3 Drying in a vacuum of mmHg gave a fluffy light yellow powder. Yield: 60% (0.36 g). 1 H NMR (CDCl3, 400MHz, δ): 7.70 (d, 2H, J 12-11 =8.7Hz, H12), 7.65(d, 2H, J 16-17 =7.2Hz, H16), 7.51(t, 1H, J 18-17 =7.4Hz, H18), 7.44-7.36 (m, 2H, H17), 7.03-6.87 (m, 3H, H11&H2), 4.15 (t, 2H, J 9-8 =4.7Hz, H9), 3.71-3.53(m, 4H, H5&H7), 3.28(s, 6H, H6), 3.20-3.12(m, 2 H, H3), 2.72 (s, 6H, H1), 2.37-2.22 (m, 2H, H8), 2.19-2.02 (m, 2H, H4)ppm. 13 C{ 1 H}NMR (CDCl3, 100MHz, δ): 195.62(C14), 161.88(C9), 137.87(C15), 132.50(C12), 132.17(C18), 130.49(C13), 129.73(C16), 128.30(C17) , 114.35(C11), 64.82(C9), 62.24(C5), 61.76(C7), 51.62(C6), 40.18(C3), 38.15(C1), 23.06(C4), 22.97(C8)ppm.HRMS-ESI-TOF(m / z): [M+ -Br - ]C 23 H 34 Calculated value of N3O4S, 448.2265, measured value, 448.2262.

[0357] Example 31A N-(3-(4-benzoylphenoxy)propyl)-3-((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methylsulfonylamino)-N,N-dimethylpropan-1-ide-1-ammonium, bromide salt:

[0358]

[0359] This compound was synthesized by the following steps: 1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)-N-(3-(dimethylamino)propyl)methanesulfonamide (1.32 g, 4.187 mmol) and 4-(3-bromopropoxy)benzophenone (1.403 g, 4.39 mmol, 1.05 eq) were refluxed in EtOAc (10 mL) for 3 hours to give a viscous light yellow oil. After purification, a fluffy white powder was obtained. Yield: 58% (1.535 g), mp = 33-34°C. 1 H NMR (CDCl3, 400MHz, δ): δ7.80-7.73 (m, 2H, H3), 7.73-7.58 (m, 2H, H7), 7.48 (s, 1H, H1), 7.43-7.37 (m, 2H, H2) , 7.09-6.95 (m, 2H, H8), 4.04-4.00 (m, 2H, H10), 3.69 (s, 1H, H18), 3.54-3.39 (m, 5H, H18, H12, H14), 3.36-3.3 2(m, 6H, H13), 2.76 (d, J=7.4Hz, 2H, H16), 2.36 (s, 1H,), 2.22-2.18 (m, 2H, H11), 2.11 (s, 1H,), 2.03 (dd, J=19 .1, 0.6Hz, 4H), 1.83 (s, 1H, H25), 1.59 (s, 1H, H24), 1.34 (s, 1H, H24), 1.11 (s, 3H, H22), 1.08 (m, 3H, H22)ppm.

[0360] Example 32 Application and curing of benzophenone-anchored antimicrobial agent to test surface

[0361] A 1% (w / v) solution of a benzophenone-anchored sulfonamide quaternary ammonium salt antimicrobial agent was prepared by dissolving the desired antimicrobial compound in an ethanol:water mixture between 10:90 and 40:60, depending on the solubility of the antimicrobial compound. Emphasis was placed on reducing the ethanol content at the application site. Each test sample, consisting of a 25 mm (±5 mm) x 25 mm (±5 mm) x 1 mm plastic material, was coated by setting an ESS AD-LG electrospray device at 150 kPa, which applied the compound uniformly over the test surface at the pressure. After application, the coated surface was allowed to air dry and then subjected to a UV curing step in which the surface was exposed to UV light at an intensity of 5000 mW for 1 minute. This coating and curing step was repeated a second time to ensure adequate coverage of the compound, which was confirmed using bromophenol blue staining, which visualizes surface-bound sulfonamide quaternary ammonium salts. Polystyrene and polyethylene materials were provided by VWR International, polyvinyl chloride was sourced from Home Depot, and polyetheretherketone was sourced from Drake Plastics. Figure 1 Treated and untreated samples are shown.

[0362] Example 33 Application and curing of silicone-anchored antimicrobial agent to test surface

[0363] A 1% (w / v) solution of a silicone-anchored sulfonamide quaternary ammonium salt antimicrobial agent was prepared by dissolving the desired antimicrobial compound in a methanol:water mixture between 30:70 and 70:30, depending on the solubility of the antimicrobial compound. Emphasis was placed on reducing the methanol content at the application site. Coating of the test samples was performed by gentle heating and agitation of the cotton samples in the coating solution at 40°C for 5 minutes. After application, the coated surface was allowed to air dry and then rinsed with water. The coating quality of the treated cotton samples can be confirmed by bromophenol blue staining, which visualizes the surface-bound sulfonamide quaternary ammonium salt. The cotton fabric was provided by META Labware. Figure 2 Treated and untreated cotton samples are shown.

[0364] Example 34 Testing the antibacterial effect of solid-gas interface

[0365] Large-droplet inoculation method (Ronan E et al., Biofouling 2013, 29, 1087-1096)

[0366] Many pathogens can remain viable on inanimate surfaces for extended periods of time. The long-term survival of pathogens in inanimate environments poses a significant risk of infection spread and contamination in high-risk environments such as hospital wards or food processing plants. Large droplet inoculation methods were developed to simulate the deposition of bacterial species on exposed surfaces and determine the dry viability of these cells.

[0367] For these tests, small surface coupons were first treated with the antimicrobial agents described above. Bacterial test species were grown overnight in a shaker and the cultures were washed twice with sterile water replacing the growth medium. 100 μL aliquots of the prepared cultures were then inoculated onto multiple coated surfaces and allowed to air dry in a biosafety cabinet. Drying typically occurred 2-3 hours after inoculation, and viable cells were counted immediately and 24 hours after drying. For counting, inoculated coupons were inactivated in triplicate and placed into separate 5 mL tubes containing 0.9% saline recovery fluid. Each coupon was vigorously stirred for 1 minute using a benchtop vortex to transfer cells from the test surface to the collection fluid.

[0368] A range of bacterial species were used in these tests.

[0369] Arthrobacter, a Gram-positive laboratory strain originally isolated from indoor air, was used in most of the testing because it is known to be highly resistant to desiccation and was therefore used as a model for a desiccation-tolerant pathogen. Efficacy testing against, for example, Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) was also performed because both contain pathogenic strains and are closely associated with major nosocomial outbreaks. Figure 3 It was shown that 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamido)propyl)propan-1-ammonium bromide treated polystyrene and N,N-dimethyl-3-(4-methylphenylsulfonamido)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride treated cotton showed excellent resistance against Arthrobacter within 3 hours. The following is the bacterial reduction data tabulated:

[0370]

[0371] Figure 4It was shown that cotton treated with N,N-dimethyl-3-(phenylsulfonylamino)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride, N,N-dimethyl-3-(4-methylphenylsulfonylamino)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride, N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonylamino)propyl)propan-1-ammonium chloride and N,N-dimethyl-3-(naphthalene-1-sulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium chloride demonstrated excellent resistance against Arthrobacter within 3 hours. The following is the bacterial reduction data tabulated:

[0372]

[0373] Figure 5 It was shown that 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonamido)propyl)propan-1-ammonium bromide and 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonamido)propyl)propan-1-ammonium bromide treated polyethylene demonstrated excellent resistance against Arthrobacter within 3 hours. The following is the bacterial reduction data tabulated:

[0374]

[0375]

[0376] Figure 6 It was shown that 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamido)propyl)propan-1-ammonium bromide treated polyethylene demonstrated excellent resistance to E. coli and Staphylococcus aureus within 3 hours. The following is a tabulated bacterial reduction data:

[0377]

[0378] Figure 7 Polyethylene samples showing the inclusion of trace amounts (0.05% w / v) of fluorescent groups were coated with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide. Figure 8 It was shown that 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide containing 0.05% w / v fluorescent group showed excellent resistance against Arthrobacter within 3 hours. The following is the bacterial reduction data tabulated:

[0379] Polyethylene control A(cfu) B(cfu) C(cfu) average error 0 hours (load) 4.63E+08 4.63E+08 4.63E+08 4.63E+08 0 3 hours 4.20E+06 8.55E+06 9.10E+06 7.28E+06 2.68E+06 Polyethylene treatment A(cfu) B(cfu) C(cfu) average error 0 hours (load) 4.63E+08 4.63E+08 4.63E+08 4.63E+08 0 3 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0

[0380] Example 34 Testing the antibacterial effect at a static solid-liquid interface

[0381] Static Biofilm Test

[0382] The inside of the polyethylene test tube is coated with a sulfonamide quaternary ammonium antimicrobial agent similar to that in Example 32. The test tube is filled with 2.7 mL of growth medium (3 g / L TSB), and 300 μL of Arthrobacter bacterial culture is inoculated into the medium. After 48 hours of cultivation and stirring, the floating cells are sampled by removing 100 μL aliquots from each tube. After 48 hours, the liquid in each tube is completely removed so that the biofilm attached to the inside of the tube can be evaluated. In order to test biofilm attachment, the test tube is first gently rinsed in a saline solution to remove any loosely attached or residual floating cells. Then, 1 ml of saline solution is added to each tube, and the tube is shaken vigorously for 1 minute to transfer the biofilm cells to the recovery liquid. Then the serial dilutions of this collected liquid are plate counted. The planktonic and biofilm colony counts from the three replicate coated tubes are averaged and compared with the test colony counts of the uncoated control tubes performed in parallel.

[0383] After 14 days of exposure to ambient air, the tubes used above were subjected to the second static biofilm test described above without re-application of the antimicrobial agent. This test was performed to determine whether the antimicrobial effect of the coating persisted after repeated exposure.

[0384] Fig. 9 It was shown that polyethylene tubes treated with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonylamino)propyl)propan-1-ammonium bromide inoculated with Mycobacterium spp. showed excellent resistance to planktonic cells within 48 hours. The following is a tabulated bacterial reduction data:

[0385]

[0386]

[0387] Fig.10 It is shown that the polyethylene tubes treated with 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonamido)propyl)propan-1-ammonium bromide showed excellent resistance to the development of biofilm. The bacterial reduction data are tabulated below:

[0388] Initial biofilm control A(cfu) B(cfu) C(cfu) average error 0 hours (load) 7.75E+08 7.75E+08 7.75E+08 7.75E+08 0.00E+00 48 hours 9.00E+04 1.10E+05 6.20E+05 2.73E+05 3.00E+05 Initial biofilm treatment A(cfu) B(cfu) C(cfu) average error 0 hours (load) 7.75E+08 7.75E+08 7.75E+08 7.75E+08 0.00E+00 48 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 Biofilm control again A(cfu) B(cfu) C(cfu) average error 0 hours (load) 8.00E+08 8.00E+08 8.00E+08 8.00E+08 0.00E+00 48 hours 8.90E+06 7.20E+06 6.70E+06 7.60E+06 1.15E+06 Testing biofilm treatment again A(cfu) B(cfu) C(cfu) average error 0 hours (load) 8.00E+08 8.00E+08 8.00E+08 8.00E+08 0.00E+00 48 hours 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00

[0389] Many changes could be made in the preferred embodiment described above without departing from the scope thereof; it is intended that all matter contained herein shall be interpreted as illustrative and not limiting.

Claims

1. A quaternary ammonium sulfonamide compound of formula (I): in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, or OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched chain alkyl groups; The quaternary ammonium sulfonamide compounds of formula (I) are useful as antimicrobial agents.

2. The compound of claim 1, wherein X is Br.

3. The compound of claim 1, wherein X is Cl.

4. The compound of claim 1, wherein R1 and R2 are the same and are methyl.

5. The compound according to any one of claims 1 to 4, wherein 6. The compound according to any one of claims 1 to 4, wherein 7. A compound according to any one of claims 1 to 4, wherein 8. A method for preparing a quaternary ammonium sulfonamide of formula (I): It comprises the compound of formula (II) Reaction with an alkyl halide of formula (III), in or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, or OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched chain alkyl groups; The quaternary ammonium sulfonamide compounds of formula (I) are useful as antimicrobial agents.

9. An antimicrobial substrate treatment composition comprising a compound of formula (I) and an environmentally friendly carrier in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, or OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched chain alkyl groups; The compounds of formula (I) are useful as antimicrobial agents.

10. A method for treating a substrate with an antimicrobial agent, the method comprising the steps of: i) contacting the substrate with an antimicrobial composition comprising at least one compound of formula (I) and an environmentally friendly carrier in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and Among them, R6, R7, R8, R9 and R 10 are the same or different and are selected from C1 to C6 straight or branched chain alkyl groups, (ii) passively or actively drying the treated substrate, and (iii) optionally irradiating the treated substrate; The compounds of formula (I) are useful as antimicrobial agents.

11. A method for treating a substrate with an antimicrobial agent, the method comprising the steps of: (i) contacting the substrate with an antimicrobial composition comprising a compound of formula (I) and an environmentally friendly carrier in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and (ii) passively or actively drying the treated substrate, and (iii) irradiating the treated substrate; The compounds of formula (I) are useful as antimicrobial agents.

12. A method for treating a substrate with an antimicrobial agent, the method comprising the steps of: i) contacting the substrate with an antimicrobial composition comprising a compound of formula (I) in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, or OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and Stir and heat at the same time, ii) drying the substrate; and iii) washing the treated substrate; The compounds of formula (I) are useful as antimicrobial agents.

13. A method for treating a substrate with an antimicrobial coating, the method comprising the steps of: i) contacting the heated substrate with a composition comprising a compound of formula (I) in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, or OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and as well as ii) drying the substrate; The compounds of formula (I) are useful as antimicrobial agents.

14. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with the antimicrobial substrate treatment composition of claim 9.

15. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(2,4,6-trimethylphenylsulfonyl)propyl)propan-1-ammonium bromide.

16. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(4-methylphenylsulfonyl)propyl)propan-1-ammonium bromide.

17. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(phenylsulfonylamino)propyl)propan-1-ammonium bromide.

18. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising 3-(4-benzoylphenoxy)-N,N-dimethyl-N-(3-(naphthalene-1-sulfonamide)propyl)propan-1-ammonium bromide.

19. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising N,N-dimethyl-3-(trimethoxysilyl)-N-(3-(2,4,6-trimethylphenylsulfonamide)propyl)propan-1-ammonium bromide.

20. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising N,N-dimethyl-3-(4-methylphenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide.

21. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising N,N-dimethyl-3-(phenylsulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide.

22. A method of reducing the growth of at least one microorganism on a substrate comprising treating the substrate with an antimicrobial composition comprising N,N-dimethyl-3-(naphthalene-1-sulfonamide)-N-(3-(trimethoxysilyl)propyl)propan-1-ammonium bromide.

23. The method of any one of claims 14 to 22, wherein the at least one microorganism is selected from the group consisting of Listeria monocytogenes, Arthrobacter, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, and combinations thereof.

24. Use of an antimicrobial composition comprising a compound of formula (I) for protecting a substrate from microbial contamination: in, or C1-C3 straight or branched chain alkyl, R1 and R2 are the same or different and are selected from C1 to C 18 Straight or branched alkyl group, R3 and R4 are the same or different and are selected from C1 to C4 straight or branched alkyl, CF3, or OR5, wherein R5 is C1 to C8 straight or branched alkyl or polyethylene oxide, l is 1, 2, 3, 4, 5, 6, 7 or 8, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, when l is 1, m is not 2, and n is not 0; X = halogen, and The compounds of formula (I) are useful as antimicrobial agents.

25. Use of a compound as claimed in claim 1 for reducing bacterial growth at a solid / air interface.

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