Epi-pleuromutilin and tiamulin triazole derivatives

Abstract

The present invention provides e / zz'-pleuromutilin triazole derivatives and e / zz'-tiamulin triazole derivatives with antibacterial activity.

Description

EPI-PLEUROMUTILIN AND TIAMULIN TRIAZOLE DERIVATIVESCROSS-REFERENCE TO RELATED APPLICATIONSThis application relies on the disclosure of and claims priority to and the benefit of the filing date of U.S. Provisional Application No. 63 / 693,630 filed September 11, 2024, the disclosure of which is hereby incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTIONField of the InventionThe present invention relates to the field of organic synthesis, specifically epi-pleuromutilin and epi-tiamulin triazole derivatives. The present disclosure further relates to epi-pleuromutilin and epi-tiamulin triazole derivatives for antibacterial compositions, such as pharmaceutical compositions.Description of Related ArtAntimicrobial resistance (AMR) is a threat to world health, demanding effective treatments to prevent 1.3 million annual deaths (Murray, C.J. et al., Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis, The Lancet, 399 (2022), 629-655) and mitigate the forecasted tens of millions of deaths per year (No time to wait: Securing the future from drug-resistant infections; Interagency Coordination Group on Antimicrobial Resistance: 2019). One approach to increase the number of available treatment options is the iterative improvement of established antibiotics to increase effectiveness, for example, using semi-synthesis of natural products. This process has yielded 78 out of 126 new small molecule antimicrobials from 1981-2019 (Newman, D. J. and Cragg, G. M, Natural Products as Sources of New Drugs over the Nearly Four Decades from 01 / 1981 to 09 / 2019 Journal of Natural Products, 83 (2020) 770-803) and a minimum of 65% of antibiotic prescriptions in the US, such as azithromycin and amoxicillin (Centers for Disease Control and Prevention. Outpatient antibiotic prescriptions United States, 2021), which are created in this fashion.While purely synthetic approaches have provided critical antibiotics, such as linezolid, and promising new resistance breakers (e.g., cresomycin), the chief drawbacks of this method are concerns about synthetic length, scalability, and starting material availability. These obstacles are often combatted by targeting structures with planarity and / or low dimensionality, which can prevent maximal contact with specific binding sights and lower selectivity, and by sourcing starting materials from non-renewable feedstocks, which contributes to the strain on natural resources.In contrast, semi-synthesis typically starts from complex, fermentation-derived scaffolds with high degrees of 3-dimensionality (e.g., rings, high sp3:sp2 ratio, stereocenters) which confers selectivity and potency. Additionally, many starting materials can be renewably mass produced via microbial fermentation.Despite semi-synthesis's success as a drug discovery method, it is challenging to implement due to the orthogonal modification of functional groups. Specifically, it can be challenging to access the desired location while leaving other portions of the molecule intact. However, new methods of highly selective functionalization are continually reported in the literature.Developing antibiotics that have not yet had resistance mechanisms develop or have a low propensity for resistance development is especially important, and one example antibiotic class is the pleuromutilin class. However, continued development of pleuromutilin via semisynthesis can succumb to these above pitfalls. Substitution at the C22 position of pleuromutilin 1, especially via a thiol ether, has been well explored, producing several medically (Rittenhouse, S. et al., "Selection of retapamulin, a novel pleuromutilin for topical use," Antimicrob. Agents Chemother. 50 (2006) 3882-3885; Hunt, A., “FDA approves new antibiotic to treat community-acquired bacterial pneumonia,” FDA News Release, August 19, 2019) and veterinary (Czok, R. et al. "Antibiotic compositions for treating coccidiosis," US Patent No. 4,148,890, 1979) relevant drugs, but giving limited returns on continued exploration of this site of the molecule. Other functional groups, specifically the C3 ketone, C11 alcohol, and carbonyl of the C14 ester, were shown to be critical to at least one binding configuration (Egger, H. and Reinshagen, H., “New pleuromutilin derivatives with enhanced antimicrobial activity," J. Antibiot. 29 (1976) 915-922). Recent total synthesis efforts support that maintaining the integrity of the tricyclic mutilin core may be important to some binding configurations (Goethe, O. et al., "Total synthesis of structurally diverse pleuromutilin antibiotics," Nature Chemistry 14 (2022) 1270-1277).Building on these findings, a computationally supported strategy was implemented to synthesize libraries of triazole pleuromutilin derivatives (FIG. 1) focusing either on the traditional C22 position or the sole remaining functionality, the C19-C20 vinyl group attached to the C12 position (Breiner, L.M. et al., “Synthesis, testing, and computational modeling of pleuromutilin 1,2,3-triazole derivatives in the ribosome," Tetrahedron Chem 4 (2022) 100034). Triazoles were selected as a core functionality due to their ease of assembly, their ability to sample a wide array of chemical space, and their growing acceptance as medicinally relevant pharmacophores (Lengerli, D. et al., “The 1,2,3-triazole ‘all-in-one' ring system in drug discovery: a good bioisostere, a good pharmacophore, a good linker, and a versatile synthetic tool,” Expert Opin. Drug Discov. 17 (2022) 1209-1236), as well as their potential to engage in pi-stacking and hydrogen-bonding interactions with the nucleotide of the ribosome. The C22 azido could not be synthesized using established methods, a novel approach was employed to directly create C20 triazoles in one step in line with doing semisynthesis. While the C22 derivatives generally retained activity when compared to pleuromutilin, the C20 derivatives were inactive. Computational studies investigating the binding of these compounds to the ribosome showed that the tricyclic mutilin core of both the C20 and C22 series bound in the pocket normally occupied by pleuromutilin. However, to optimally contact the pocket normally inhabited by the C14 thioglycolate arm of tiamulin 2 (Breiner, 2022), the C20 triazolyl-functionalized series shifted, twisting the hydrophobic core of the derivatives out of the proper orientation, and disrupting key hydrogen bonding contacts of the C3 ketone, C11 alcohol, and the carbonyl of the C14 ester.While these results demonstrated that the functionalization of C20 on native pleuromutilin with triazoles did not enhance activity, close inspection of our computational findings showed that the C12 methyl group, rather than the C12 vinyl group, was better positioned for derivatization. Supporting this approach, Nabriva Therapeutics had previously demonstrated that epimerization of C12 and subsequent oxidative scission of the C19 / C20 bond followed by reductive amination could give rise to active derivatives (Thirring, K. et al., US9,701,628, 2017). These epimerized compounds not only retained the activity of the parent antibiotic (lefamulin 3) against Gram-positive organisms, but also gained activity against Gram-negative pathogens. A need remains for highly active pleuromutilin derivatives, and C12-epimerized pleuromutilins are a promising class of compounds.SUMMARY OF THE INVENTIONAspects of embodiments of the invention include Aspect 1, which is a compound or pharmaceutically acceptable salt thereof according to formula(I):(I)wherein: R is selected from direct attachment, or attachment through one or more heteroatom (such as N, S, or O), with one or more of (C1-C10)alkyl, aryl, phenyl, biphenyl, (C2 C10)alkenyl, alkynyl, amine, amide, alcohol, ether, thiol, thioether, sulfoxide, sulfamate, sulfamide, triazole, amino acids, sugars, carbocycles, heterocycles, halo, OH, NH2, SH, S(CH2)2NE12, CN, NO2, H, and combinations thereof; R' is selected from H, F, Cl, Br, I, CH2OH, (CH2)2OH, (CH2)3OH, C(CH3)2OH, CH2NH2, (CH2)2NH2, (CH2)5CH3, CH2OCH2(C6H5), C6H5 (phenyl), CH2(C6H5), CH2O(C6H5), C6H4C6H5 (biphenyl), (C1-C10)alkyl, aryl, (C2-C10)alkenyl, alkynyl, amine, amide, alcohol, ether, thiol, thioether, sulfoxide, sulfamate, sulfamide, triazole, amino acids, sugars, carbocycles, heterocycles, OH, NH2, SH, CN, NO2, S(CH2)2NEt2, and combinations thereof; any alkyl, alkenyl, or aryl is optionally substituted by 1-4 substituents independently selected from the group consisting of F, Cl, Br, OH, CF3, O-CF3, acetyl, (C1- C6)alkyl, O-(C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C6-C10)aryl, and CN; and any aryl optionally contains one or more heteroatom in the ring, such as N, O, or S.Aspect 2 is the compound or pharmaceutically acceptable salt of Aspect 1, wherein R is OH or S(CH2)2NEt2; and R' is selected from CH2OH, (CH2)2OH, (CH2)3OH, C(CH3)2OH, CH2NH2, (CH2)2NH2, (CH2)5CH3, CH2OCH2(C6H5), C6H5 (phenyl), CH2(C6H5), CH2O(C6H5), and C6H4C6H5 (biphenyl).Aspect 3 is a pharmaceutical composition comprising one or more compound or pharmaceutically acceptable salt thereof of Aspect 1 or 2 and one or more pharmaceutically acceptable excipient.Aspect 4 is a method of treating a disease in a patient comprising administering to a subject a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any of Aspects 1-3.Aspect 5 is the method of Aspect 4, wherein the disease is a bacterial infection.Aspect 6 is the method of Aspect 5, wherein the bacteria is a gram-positive bacteria.Aspect 7 is the method of Aspect 5, wherein the bacteria is a gram-negative bacteria.Aspect 8 is the method of Aspect 5, wherein the bacteria is selected from the group consisting of: S. aureus, MRSA, VRSA, E. coli, VRE, C. difficile, N. gonnorhoeae, and E. faecium.BRIEF DESCRIPTION OF THE DRAWINGSThe accompanying drawings illustrate certain aspects of implementations of the present disclosure and should not be construed as limiting. Together with the written description the drawings serve to explain certain principles of the disclosure.FIG. 1 is a table showing the chemical structures of compounds belonging to the pleuromutilin class of antibiotics and derivatization sites.FIG. 2 is a drawing showing the synthetic pathway for epimerized, hydroazidated intermediates, according to embodiments of the invention.FIG. 3 is a drawing showing the structures and yields of 12-epi-20-triazolyl pleuromutilin and tiamulin derivatives, according to embodiments of the invention.FIGS. 4A-C are illustrations showing binding interactions of compounds according to embodiments of the invention. FIG. 4A shows key binding interactions of derivatives 9, 14, 15, and 16. FIG. 4B shows key binding interactions of derivatives 17, 22, 23, and 24. FIG. 4C shows available binding areas derived from the empty receptor cavity with compounds 23 and 24 docked.FIG. 5 is a drawing showing the structures and yields of aromatic 12-epi-20-triazolyl pleuromutilin and tiamulin derivatives, according to embodiments of the invention.FIGS. 6A-F are illustrations showing docking poses of aromatic derivatives (25-32). FIG. 6A shows phenyl derivatives (25 and 29). FIG. 6B shows benzyl derivatives (26 and 30). FIG. 6C shows phenoxymethylene derivatives (27 and 31). FIG. 6D shows biphenyl derivatives (28 and 32). FIG. 6E shows C22 alcohol derivatives (25-28). FIG. 6F shows an overlay of C22 S(CH2)2NEt2 derivatives (29-32).FIG. 7 is a graph showing the in vitro cytotoxicity evaluation of several derivatives against monkey kidney fibroblast cells (Vero cells).FIG. 8 is a graph showing the in vitro cytotoxicity evaluation of several derivatives against human endocervical epithelial cells (ME-180).DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS OF THE INVENTION22-O-Tosylpleuromutilin (4, FIG. 2) was synthesized from pleuromutilin (1) in 92% yield following established literature procedures (see WO2017 / 151492A1) while suppressing formation of the C22-chloro byproduct (Breiner, 2022). To generate the epimerized derivatives, an improved version (US9,701,628) of an early finding by Berner (Berner, H. et al., “Mitt.: Konfigurationsumkehr der Vinylgruppe am Kohlenstoff 12 durch reversible Retro-En-Spaltung," Monatshefte fr Chemie Chemical Monthly 117 (1986) 1073-1080) that showed alkyl zinc reagents can invert the C12 position of 4 was adapted. The alkyl zinc reacts with the secondary alcohol of 4, coordinating the vinyl group and enabling a retro-Barbier type reaction. This results in the opening of the eight-membered ring between C11 and C12. Upon reclosure, thermodynamic epimerization of the C12 center yielded a mixture of 4 and C12 epimer 5 while avoiding generation of cyclopropanoid byproducts seen in other methods (Berner, 1986). This reaction is a thermodynamic process, and a ratio of 47:53 of 4 to epimer 5 was achieved as assessed by NMR, in accord with literature values (US9,701,628). Multiple rounds of chromatography enabled over 90% recovery of the epimer 5, a 48% yield. Tiamulin 2 could be epimerized with even higher conversion (2:3 tiamulin:epi-tiamulin as assessed by NMR). However, chromatographic separation of tiamulin from its epimer was extremely inefficient, and as such, a late-stage divergent strategy was required to access pleuromutilin-type (C22 = OH) and tiamulin-type (C22 = S(CH2)2NEt2) triazole derivatives from a common intermediate.With 5 in hand, a radical anti-Markovnikov hydroazidation using 2-iodosobenzoic acid (IBA) as a catalyst (Li, H. et al., “Direct intermolecular anti-Markovnikov hydroazidation of unactivated olefins,” J. Am. Chem. Soc. 141 (2019) 9415-9421) was performed to generate C20-azido intermediate 6. The presence of the tosylate was not only tolerated, a surprising result considering the potentially nucleophilic environment generated by the excess azide reagent added, it appeared to aid in the formation of the hydroazide, enabling 6 to be accessed in a yield of 54%, an improvement compared to the same reaction performed on native pleuromutilin (32%) (Breiner, 2022). The tosylate essentially serves as a protecting group for the primary alcohol of native pleuromutilin. This masking prevents the primary alcohol from reacting with TMSN3 in a silylation reaction, which following subsequent hydrolysis and regeneration of the problematic alcohol, would catalytically consume the azidation reagent and decrease the yield (Breiner, 2022). The results suggest radical azidation conditions can be more widely applied in the presence of reactive functional groups to add diversity via click chemistry in medicinal chemistry and natural products derivatization.After installation of the azide handle 6, the synthesis diverged to generate epi-pleuromutilin or epi-tiamulin triazoles. The pleuromutilin series (to be derived from 7) was prepared by first deprotecting the tosylate of 6 to reveal the C22 alcohol 7. Deprotection was achieved under mild conditions by first displacing the tosylate with formate, followed by solvolysis of the resulting formate ester. This process proceeded in quantitative yield and did not require purification, although recrystallization from benzene proved facile, even on scales as small as 100 mg. For creation of the epi-tiamulin series to be based on hydroazide 8, common intermediate 6 was subjected to a freshly generated solution of N,N-diethyl-(2-amino)ethanethiol furnishing 8 in good yield (74%). These results surpass those reported previously (CN104447449A) for generating tiamulin (~54%), an increase that could be attributed to using higher amounts of reactants and longer reaction times. Both processes were completed in high yield under mild conditions to maintain the integrity of the azide for the diversifying cycloaddition reaction.To achieve the triazole derivatives, advanced intermediates (7 and 8, FIG. 3) were subjected to copper-catalyzed azide / alkyne cycloaddition (CuAAC) conditions using the procedure established by Sharpless (Himo, F. et al., “Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates,” J. Am. Chem. Soc. 127 (2005) 210-216). Some reagents showed poor solubility in the highly polar water:tert-butanol solvent system, but heating the mixture to 70 °C enabled production of both series in good to excellent yields. As with previous cycloadditions (Breiner, 2022), use of an alkyne containing a free amine reduced yields (13-14, 21-22, FIG. 3), likely because of the primary amine interacting with the copper and slowing the rate of reduction from Cu2+ to the active Cu¹+ species (Zhang, C.X. et al., “Copper(I)-dioxygen reactivity of [(L)Cu(I)]+ (L = tris(2-pyridylmethyl)amine): kinetic / thermodynamic and spectroscopic studies concerning the formation of CuO2 and Cu2-02 adducts as a function of solvent medium and 4-pyridyl ligand substituent variations, Inorg. Chem. 42 (2003) 1807-24) or via Cu2+ catalyzing the oxidation of the amines in the presence of O2 (Kim, J. et al., "Copper(II)-Catalyzed Aerobic Oxidation of Amines: Divergent Reaction Pathways by Solvent Control to Imines and Nitriles," Asian Journal of Organic Chemistry 8 (2019) 1674-1679). Despite these challenges, all compounds were obtained in sufficient quantities for biological testing. There was no appreciable difference in the efficiency of CuAAC with the C22 hydroxide 7 versus the diethylaminoethane thiol 8, demonstrating the general robustness of this approach.The pleuromutilin (9-16) and tiamulin (17-24) epi-C12-triazole compounds were tested against four Staphylococcus aureus strains (8810 and three Methicillin-resistant), two Escherichia coli variants (1061 and TolC efflux pump knockout), two vancomycin-resistant Enterococcus faecium, Enterococcus faecalis, Shigella flexneri, Salmonella enterica, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa in broth microdilution assays to determine their minimum inhibitory concentrations (MIC).Within the epi-pleuromutilin series (Table 1), homolygated alcohols (9-11) and amines (13 and 14) lost activity in the S. aureus strains, showing activities at least 8-fold less potent than 1. This effect was not as severe in the E. coli strains, especially efflux pump TolC knockout strain, E. coli AtolC, against which all were within 2-fold activity of 1. Against the wild-type E. coli, the amines retained activity while the alcohols did not, likely because of greater uptake due to attraction at physiological pH between the ammoniums of 13 and 14 and the cell membrane of the Gram-negative bacteria (Khondker, A. and Rheinstädter, M.C., "How do bacterial membranes resist polymyxin antibiotics?" Commun. Biol. 3 (2020) 77; Qiu, H. et al., “The Mechanisms and the Applications of Antibacterial Polymers in Surface Modification on Medical Devices," Front. Bioeng. Biotechnol. 8 (2020) 910). Against VRE strains, activity of the linear alcohols and amines was comparable to 1. The branched chain alcohol 12 generally matched the activity of the other alcohols. Testing of longer aliphatic and aromatic chains showed that hexyl derivative 15 retained activity in the S. aureus and VRE strains, but lost activity in E. coli when TolC was present, suggesting this modification made the compound more susceptible to efflux. Of the epi- pleuromutilin triazole species, the most active was benzyl ether derivative 16, with a 2-fold to 4- plus-fold increase against S. aureus strains, including several MRSA types. The activity of 16 against E. coli 1061 was the same as with 1, with a 4-fold increase in the TolC knockout. Activity of 16 against VRE was also promising, showing comparable or improved values relative to 1.For the epi-tiamulin series, the alcohol (17-19, 20) and amine (21 and 22) triazole derivatives also generally showed a loss in activity against the tested strains. However, it was not as drastic as in the epi-pleuromutilin series. In the case of the E. coli TolC, these derivatives mostly retained activity, suggesting that efflux may be responsible for their loss of activity against the other strains. The hexyl derivative (23) lost activity against the MRSA strains and E. coli but retained activity against susceptible S. aureus and the TolC knockout, suggesting that efflux or other adaptations attenuate its activity. Activity of 23 against the VRE strains was variable. As with the pleuromutilin series, the benzyl ether derivative 24 had the best activity, comparable or slightly improved relative to the tiamulin parent compound. Overall, the tiamulin analogs were generally more potent than their pleuromutilin counterparts, possibly due to slight differences in the ribosome structure of the different organisms (Schierholz, L. et al., “A Conserved Ribosomal Protein Has Entirely Dissimilar Structures in Different Organisms," Mol. Biol. Evol. 41 (2024) msad254) or because of unrecognized context specificity (Syroegin, E.A. et al., "Structural basis for the context-specific action of the classic peptidyl transferase inhibitor chloramphenicol," Nat. Struct. Mol. Biol. 29 (2022) 152-161) in terms of protein production.While most compounds were inactive against the variety of Gram-negative strains tested, of note was the activity of tiamulin amine triazole derivatives 21 and 22. These two compounds were the most potent against E. coli and also inhibited S. flexneri at 32 µg / mL. As evidenced by activity against the E. coli TolC knockout, all compounds demonstrated ribosome inhibition. The increase in activity of 21 and 22 likely results from enhanced uptake, with the additional amine group increasing the positive charge at physiological pH and making them more attractive to the negatively charged outer membrane of Gram-negative bacteria, such as S. flexneri and E. coli. Compounds 13 and 14 showed a similar enhancement, though it was not as pronounced. These findings, supported by literature precedent (see US 2016 / 0332963), suggest that there is chemical space to explore for the inhibition of Gram-negative pathogens using pleuromutilin derivatives.The epimeric synthetic intermediates (5, 6, 7, and 8) created during the synthesis of the various triazole series also generally retained high activity against S. aureus strains.Table 1. Minimum inhibitory concentrations (MIC) of the initial series of compounds in nine organisms. All MIC values are in µg / mL. Compounds were inactive against two strains of Enterococcus faecalis, Salmonella enterica, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Compounds 21 and 22 showed activity against Shigella flexneri at 32 µg / mL.Compound | S. aureus 8810 | MRSA NRS 123 (USA400) | MRSA NRS 384 (USA300) | VRSA VRS 10 (USA100) | E. coli BW 25113 | E. coli JW 51103 AtolC | VRE | Ε. faecium HM-965--- | --- | --- | --- | --- | --- | --- | --- | ---9 | 16 | >32 | 8 | 16 | 32 | >64 | 1 | 4 | 110 | 16 | 16 | 4 | 8 | 8 | >64 | 1 | 4 | 0.511 | 16 | 32 | 4 | 8 | 16 | >64 | 2 | 4 | 112 | 16 | 32 | 8 | 8 | 1 | >64 | 2 | 16 | 213 | 32 | >32 | 16 | 32 | 32 | >64 | 0.5 | 4 | 114 | 16 | >32 | 16 | 32 | 32 | >64 | 1 | 16 | 115 | 1 | 2 | 0.5 | 1 | 8 | >64 | 1 | 2 | 116 | 0.5 | 1 | 0.25 | 0.25 | 0.25 | >64 | 0.25 | 1 | 0.51 | 2 | 2 | 0.5 | 1 | 0.5 | >64 | 0.5 | 8 | 0.517 | 4 | 32 | 2 | 4 | 4 | >64 | 0.5 | 2 | 0.518 | 4 | 8 | 1 | 2 | 2 | >64 | 0.5 | 2 | 0.519 | 4 | 16 | 1 | 2 | 2 | >64 | 0.5 | 2 | 0.520 | 4 | 16 | 2 | 4 | 4 | >64 | 1 | 4 | 121 | 8 | 32 | 8 | 16 | 16 | 64 | 0.25 | 4 | 422 | 4 | 32 | 4 | 8 | 16 | 64 | 0.125 | 4 | 223 | 1 | 4 | 8 | 8 | 1 | >64 | 2 | 1 | 124 | 0.5 | 2 | 0.25 | 0.5 | 0.5 | >64 | 0.25 | 0.5 | 0.252 | 1 | 2 | 0.5 | 0.5 | 0.5 | >64 | 0.125 | 2 | 0.255 | 0.5 | 0.5 | 1 | 1 | 0.5 | >64 | 2 | 2 | 16 | 0.5 | 1 | 2 | 4 | 1 | >64 | 1 | >32 | 27 | 2 | 2 | 1 | 2 | 1 | >64 | 0.25 | 8 | 18 | 2 | 4 | 2 | 4 | 1 | >64 | 0.25 | 2 | 1Activity against the tolC knockout E. coli strain was sub micromolar for all four derivatives, but activity was completely abolished for 5 and 6 against MC1061, suggesting the tosylate substituent helps with recognition for this efflux pump. Activity against VRE was approximately at the level of pleuromutilin except for 6, which was inactive against one strain.The most active derivatives from each series were the benzyloxymethylene-terminated triazole compounds (16 and 24) followed by the more variable aromatic toluenesulfonate intermediates 5 and 6. The aromatic functionality of these compounds may make favorable contacts with the nucleoside rich ribosome, thus increasing their potency. Among these compounds, 16 was generally the most potent showing activities of ≤0.25 ug / mL, especially against a subset of MRSA strains. Compound 24 was nearly as potent and tended to have a slight advantage against VRE strains. These results are in stark contrast compared to the non-C12 epimerized analog (Breiner, 2022) of 16, which was previously found to be inactive (MIC ≥64 ug / mL) against all tested organisms, as were all other non-epimerized C20 triazoles. The high activity of 16 and 24 conclusively demonstrates that the C12 vinyl group is a suitable site for derivatization, provided that the geometry of the pendant triazole is in a suitable orientation, a consideration that was not immediately apparent based on analysis of the crystal structure of the tiamulin parent (Schlünzen, F. et al., Harms, Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin," Mol. Microbiol. 54 (2004) 1287-1294).To learn about how the various triazole arms influence binding and to guide continuing derivatization, the inventors' ribosome docking methodology (Breiner, 2022; Gannett, C. et al., "Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead," ACS Medicinal Chemistry Letters 15 (2024) 362-368) was applied to these series of epi-C12 triazole derivatives. Pleuromutilin class antibiotics bind to the 50S ribosomal subunit in the peptidyl transferase center (PTC) with the tricyclic mutilin core binding in a hydrophobic pocket near the A-site and C14 substituents extending toward the P-site. Together, these factors inhibit peptide bond formation by hindering movement of the aminoacylated 3'-end of the A-site tRNA to the P-site (Schlünzen, 2004; Paukner, S. and Riedl, R., “Pleuromutilins: Potent drugs for resistant bugs-Mode of action and resistance," Cold Spring Harb. Perspect. Med. 7 (2017) a027110). The two epimerized series bind similarly, but differences in the composition of the new triazole substituents off epi-C12 and the interplay of these substituents with the C22 hydroxy (pleuromutilin) or diethylaminoethyl sulfide (tiamulin) affect their computed binding affinities.The pleuromutilin series (9 – 16, FIG. 4A) binds into the A-site pocket, closely overlapping their mutilin cores with that of the original co-crystalized tiamulin with binding differences mainly occurring due to the new epi-C12 triazole arm. While the C14 arm of tiamulin (black sticks) bends towards C-2046 and U-2564, the new arm formed by the 12-epi-triazoles extends in a different direction reaching towards A-2482 and A-2040, A-2041, and A-2042.The terminal alcohol groups of 9-12 are in the right proximity to interact with A-2040, A-2041, and A-2042 as hydrogen-bond acceptors. The triazole ring of 9, 10, and 12 show parallel-displaced pi-stacking interactions with A-2482. Interaction fingerprint graphs show that A-2482 is a new, high-frequency interaction that is present in all-triazole-containing compounds but not observed in regular tiamulin binding. Compound 11 also exhibited this interaction in fingerprint graphs; however, the increased length of its alkoxy chain caused the triazole to shift and share hydrogen bonds with the nearby rRNA phosphate backbone instead of pi-stacking.The triazoles of amines 13 and 14 also show high frequency pi-stacking interactions with A-2482. The terminal amino group is flexible enough to participate in hydrogen-bonding interactions with the group of adenine residues that bind 9-12, but molecular visualization and interaction frequency graphs suggest that because of their cationic state at physiological pH, the amines of 13 and 14 prefer to hydrogen-bond to the sugar base of G-2484 (not shown).The observations made for docking pleuromutilin series 9-14 reflected their experimentally measured MICs in comparison to pleuromutilin. They maintained the same high- frequency interactions as the co-crystalized mutilin core but shifted slightly in the binding site to enable contact of the triazole arm. New interactions by the C12 triazole arm generate additional binding, and the alcohol derivatives, 9-12, were predicted to perform slightly better than the terminal amine derivatives because as better hydrogen bond acceptors they interacted more strongly with A-2040, A-2041, and A-2042, a result that matched the MIC values. On the other hand, while the triazole of 15 shows typical pi-stacking interaction with A-2482, its alkyl chain is not able to engage in any polar interactions, instead making various non-polar interactions with nucleotides of the underlying ribosome.The best pleuromutilin series derivative was benzyloxymethyl triazole 16. It bound following the same trends as 9-14; however, it maintained a better alignment of the mutilin core. Derivative 16 also shows higher binding efficacy than 9-14because of the ether in its C12 triazole arm and its aromatic terminus. The ether is better able to accept hydrogen bonds from A-2040, A- 2041, and A-2042 than the alcohols or amines of 9-14, which can also flip to hydrogen-bonding donating interactions. In addition to pi-stacking of the triazole by A-2482 shared with other derivatives, the longer total length of the arm enables the terminal phenyl group to reach further into this new pocket of the A-site and undergo staggered pi-stacking with G-2039 and G-2555.The tiamulin triazole series (17-24, FIG. 4B) also bound into the A-site pocket, showing good overlap between their mutilin cores and the core position of the original co- crystalized tiamulin. The binding of the C14 thioglycolate arms of the derivatives mimic that of co-crystalized tiamulin, contacting C-2046 and U-2564. The epi-C12 triazole arms of the tiamulin series coordinate near A-2482 and A-2040 – A-2042, exhibiting the same binding contacts as the corresponding modifications to the pleuromutilin series. The tiamulin series was predicted to have a higher inhibitory efficacy than the pleuromutilin series because they were able to maintain the original binding contacts of the C14 thioglycolate arm of tiamulin while also adding new, strong interactions from the C12 triazole arm.These results mirror the experimentally derived activity (Table 1). Also matching the experimental results was the identification of the top two compounds, the aromatic benzyloxymethyl triazoles 16 and 24. Analysis of the docking results suggested that these compounds bind strongly because of the interaction of the ether as a hydrogen-bond acceptor with A-2040, A-2041, and A-2042, the triazole interacting with A-2482, and because of the pi-stacking with G-2039 and G-2555. The terminal aromatic portion of the benzyloxymethyl triazoles in particular seemed to show enhanced efficacy by reaching into a new region of the binding pocket. Analysis of the space available (FIG. 4C) suggested that aromatic groups would fill space in a new region and have good interactions with the underlying nucleotides and that there was additional accessible space around the hexyl chain of derivatives 15 and 23.Based on these results, the available space of this new binding region merited investigation. As compounds comprising the oxa-functionality and aromaticity off the triazole both showed potential, a series of aromatic triazoles of both pleuromutilin and tiamulin were synthesized (FIG. 5, compounds 25-28 and 29-32, respectively) to test these functionalities. These compounds were synthesized in the same manner as the other triazole derivatives (FIG. 3). After hydroazidation of 5 furnished 6 and divergence via hydrolysis or aminothiolation, CuAAC of 7 and 8 (FIG. 5) gave the pleuromutilin (25-28) and tiamulin (29-32) series, respectively, in yields ranging from 46-80%. Combined with the top derivatives 16 and 24 (inset) from the initial series, these compounds enable a SAR testing length and oxa-functionality of 12-epi-20-triazole mutilins terminated with an aromatic group.These series of aromatic C12-epi-pleuromutilin and -tiamulin triazole derivatives were tested against a variety of pathogens (Table 2). Compared to pleuromutilin and tiamulin, the aromatic derivatives were essentially equipotent against Gram-negative pathogens but showed significant increases in activity against Gram-positive strains. In contrast to the initial derivatives, where the tiamulin triazole series generally outperformed the pleuromutilin triazole series, the aromatic pleuromutilin triazoles were more effective against S. aureus strains (including MRSA), especially 25 and 28, which showed ng / mL activities. This activity suggests that a more rigid orientation of aromatic functionality is preferred for S. aureus activity and that larger functionality, such as biphenyl 28, is accommodated and active. The tiamulin variants outperformed their pleuromutilin counterparts against VRE with the original benzyloxymethyl derivative 24 and phenyl derivative 29 showing activities ranging from equivalent to 4-fold improved relative to the tiamulin parent. For flexible chains, inclusion of oxygen functionality in the chain extending off the triazole may also be important as the benzyl triazoles 26 and 30 saw a loss of potency relative to 16, 27, 24, and 31.Table 2. Minimum inhibitory concentrations (MIC) of the aromatic compound series. All MIC values are in µg / mL. Compounds were inactive against Enterococcus faecalis, Shigella flexneri, Salmonella enterica, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa.Compound | S. aureus 8810 | MRSA | MRSA NRS 123 (USA400) | MRSA NRS 384 (USA300) | VRSA VRS 10 (USA100) | E. coli BW 25113 (wt) | E. coli JW 51103 (AtolC) | VRE | E. faecium HM-965--- | --- | --- | --- | --- | --- | --- | --- | --- | ---25 | 0.25 | 0.5 | 0.25 | 0.25 | 0.25 | >64 | 0.5 | 2 | 0.526 | 2 | 4 | 0.5 | 1 | 1 | >64 | 0.5 | 8 | 127 | 0.5 | 1 | 0.25 | 0.25 | 0.25 | >64 | 0.25 | 2 | 0.2528 | 0.25 | 0.5 | 0.25 | 0.25 | 0.5 | >64 | 4 | 1 | 0.2516 | 0.5 | 1 | 0.25 | 0.25 | 0.25 | >64 | 0.25 | 1 | 0.51 | 2 | 2 | 0.5 | 1 | 0.5 | >64 | 0.5 | 8 | 0.529 | 0.5 | 2 | 0.25 | 0.5 | 0.25 | >64 | 0.25 | 0.5 | 0.2530 | 1 | 4 | 1 | 2 | 1 | >64 | 0.5 | 1 | 0.531 | 0.5 | 2 | 0.25 | 0.25 | 0.25 | >64 | 0.25 | 1 | 0.532 | 1 | 4 | 1 | 2 | 2 | >64 | 4 | 1 | 1624 | 0.5 | 2 | 0.25 | 0.5 | 0.5 | >64 | 0.25 | 0.5 | 0.252 | 1 | 2 | 0.5 | 0.5 | 0.5 | >64 | 0.125 | 2 | 0.25Docking of these aromatic series confirmed favorable interactions with additional nucleotides (FIG. 6). Derivative 25 (FIG. 6A) showed unique docking poses due to its short aromatic modification. The mutilin core is still centralized in the same region of the A-site as with the tiamulin and pleuromutilin triazole series 9-24, but it is rotated more extremely allowing the epi-C12 extension to form new contacts. In this orientation, the C3 ketone of the mutilin core is less than 3 Å away from hydrogen bond-donating groups on G-2044, C-2046, and A-2430. Interaction fingerprints showed that these are high frequency interactions conserved from tiamulin binding. The C11 hydroxyl is coordinated by donating a hydrogen bond to A-2482. Because of its shorter length, 25 cannot pi-stack with G-2039 like 16; however, its more extreme orientation allows its phenyl group to pi-stack with A-2041. The triazole group continues to show either hydrogen bond interactions or pi-stacking interactions with A-2040, A-2041, A-2042, and A-2482 that were not present with tiamulin. Derivative 29 bound with a less extreme rotation of its mutilin core than 25 due to contacts of its substituted C14 thioglycolate arm. The new triazole arm off of epi-C12 is still able to reach into the new region of the pocket and pi-stack the phenyl group with A-2041. The triazole group is, again, in range to show either hydrogen bond interactions or pi- stacking interactions with A-2040, A-2041, A-2042, and A-2482.The predicted binding pose of 26 (FIG. 6B) is very similar to that of 25, with the C3 ketone being able to accept hydrogen bonds from A-2430 or C-2431 (not shown). It showed a lack of interactions with the C11 hydroxyl, which may explain its decrease in efficacy compared to other aromatic modifications. Derivative 30 mimics 26 in terms of activity, but its mutilin core bound in a different manner during docking studies. The triazole of 26 potentially pi-stacks with A-2482, while the triazole of 30 pi-stacks with this nucleotide. The benzyl groups of both derivatives participate in T-shaped pi-stacking with A-2041 and favor other nonpolar interactions. The different geometry of the benzyl chain and its inability to participate as a hydrogen bond acceptor prevent it from effectively accessing the same binding pockets as 25 or 16, further contributing to the lower efficacy of these derivatives.Docking of 27 and 31 (FIG. 6C) predicted that they bind very similarly to 16 and 24, which is likely why they share almost identical efficacies. These compounds bind differently than the other aromatic derivatives in this SAR, folding into a separate cleft in the ribosome. Binding to this different region is driven by interactions of the ether oxygen and flexibility of the aromatic substituent off the triazole. Unlike 25 and 28, which are rigid, the flexible benzyloxymethylene of 16 and phenoxymethylene of 27 twist to favorably pi-stack with G-2039 and G-2555 (not shown). The ether oxygen serves as a hydrogen-bond acceptor with A-2040, A-2041, and A-2042, in contrast to other flexible derivatives (26 and 30) that lack this functionality.Derivatives 28 and 32 (FIG. 6D) were predicted to bind similarly to 15 due to the long length and neutral character of the modifications and in the same region as 25-26 and 29-30. The triazole maintains pi-stacking with A-2482 and appears to hydrogen bond to the phosphate backbone. The biphenyl rings are in range to pi-stack with A-2041, A-2042, and C-2589. The accommodation and activity of the biphenyl suggests that continued optimization of phenyls 25 and 29 or biphenyls 28 and 32 can take advantage of interactions in this new binding region to continue enhancing potency of new epi-C12 pleuromutilin triazole derivatives.These analyses focus on the lowest energy binding poses. The deviations adopted by these poses from the static ligand shown in the crystal structure does not mean a different mechanism of action is in play. Other top poses match that of tiamulin. This diversity highlights the dynamic nature of ligand binding to the ribosome and how a synergistic combination of computational modeling and medicinal chemistry is critical to expanding our abilities to model this complex organelle and to develop more effective antibiotics that target it. Of note, both the ether-containing derivatives 16, 24, 27, and 31 and phenyl triazole derivatives 25, 28, 29, and 32 are highly potent but bind in different regions (FIGS. 6E-F), suggesting multiple avenues for further derivatization. In several docking poses of active derivatives, the tiamulin side chain is significantly distorted or displaced. This result, coupled with the similar activity between corresponding members of the aromatic pleuromutilin (16, 25-28) and tiamulin (24, 29–32) series suggests that potential gains from contacts provided by the new C12 triazole arm may dominate over the effect of the previously optimized thioglycolate arm.Cytotoxicity data was collected for the top hits, the initial benzyloxymethylene triazoles 16 and 24 and the highly active phenyl triazoles 25 and 29, to ensure their viability as potential lead compounds. In monkey kidney fibroblast cells (FIG. 7), compounds 16 and 25 exhibited no cytotoxicity at the highest tested concentration of 64 µg / mL. The corresponding epi- tiamulins 24 and 29, however, demonstrated toxicity at concentrations of 32-64 ug / mL. Neither pleuromutilin nor tiamulin were cytotoxic at any measure concentration.In the human endocervical epithelial cell line ME-180 (FIG. 8), the overall trends were the same, but all compounds except 16—including pleuromutilin and tiamulin-began to exhibit toxicity at least at the highest dose tested. Compared to pleuromutilin and tiamulin, which began exhibiting toxicity at 32 µg / mL and 16 ug / mL, respectively, compound 16 showed no toxicity up to 64 µg / mL. Compound 25 was slightly more toxic than pleuromutilin and tiamulin at 64 µg / mL, but nontoxic at concentrations of 32 µg / mL or less. Compounds 24 and 29, however, began showing toxicity at 16 µg / mL.The high activity of 16 and 25 (0.25 – 2 µg / mL, Tables 1 and 2) against drug resistant Gram-positive pathogens versus their low cytotoxicity indicates a selectivity index suitable for human use. The lower toxicity of 16, 25, and tiamulin relative to disubstituted derivatives 24 and 29 suggest that simultaneous substitution of both the C22 and C20 positions with respective thioether and triazole-aromatic pendant groups somehow contributes to toxicity, at least with tiamulin-type thioethers. Furthermore, the strong efficacy demonstrated by 16 and 25, which is at a similar level to their tiamulin counterparts (24 and 29), suggests that refining the C22 position after optimizing the triazole constituent could lead to further enhancements in activity.In summary, epimerization of the C12 position of pleuromutilin and functionalization of the vinyl group as substituted triazoles via anti-Markovnikov hydroazidation results in active pleuromutilin (C22 hydroxy) and tiamulin (C22 thioglycolate) type derivatives displaying 4- to 8-fold potency increases relative to pleuromutilin and tiamulin. Top compounds demonstrate especially promising activity against drug-resistant S. aureus strains with no increase in cytotoxicity relative to pleuromutilin and tiamulin. Molecular docking analysis suggests that the increase in activity is due to the aromatic triazole derivatives accessing a new binding site in the ribosome capable of accommodating large aromatic functional groups. Based on these results, benzyloxymethylene and phenyl triazole 12-epi-pleuromutilins 16 and 25 can serve as lead compounds for a series of SAR studies directed at identifying a new class of pleuromutilin-type antibiotics.Improving the function of natural product-derived antibiotics is a challenging and arduous process, especially when targeting complex structures, such as the bacterial ribosome (Wu, K.J.W. et al. An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance, Science 383 (2024) 721-726). Through the incorporation of insights achieved using molecular docking (Breiner, 2022), another potential derivatization site was identified on pleuromutilin that is amenable to diversification via a divergent semisynthesis. To access this location, the C12 position of tosyl pleuromutilin (4, FIG. 2) was epimerized in a nearly quantitative recovery. The resulting epi-tosylate 5 was subsequently activated as the azido (6) in a single step via an optimized anti-Markovnikov hydroazidation protocol that was superior to previous efforts using pleuromutilin (Breiner, 2022). To access the epi-tiamulin series, the C22 tosylate of 6 was displaced using a combination of diethylamine and thiirane to gain the substituted thioglycolate (8) and subsequently converted to various triazoles using CuAAC (FIG. 3). For the epi- pleuromutilin series, the C22 tosylate of 6 was essentially a protecting group that could be quantitatively cleaved via the formate ester in the presence of the azido under mild conditions with no purification required. The resulting compound 7 also converted well to various triazoles using CUAAC.Testing of the resulting libraries showed that an aromatic substituent off the triazole was most active (Table 1). Molecular docking to assess binding affinity was in accord with these findings, and analysis of the computational data suggested that the aromatic and long aliphatic substituents were accessing new binding regions (FIGS. 4A-C). Based on this analysis, a limited SAR study focused on the size of aromatic substituents was completed (FIG. 5). Testing of the resulting library showed sub-microgram per milliliter potency with phenyltriazole pleuromutilin derivative 25 (Table 2) and toxicity levels comparable to pleuromutilin and tiamulin (FIGS. 7 and 8). para-Phenyl 25 (that is, biphenyl 28) was also highly active. In conjunction with computational analysis (FIGS. 6A-F), these results indicate that there are accessible pharmacophore binding sites around the phenyl group of 25 and the benzyl group of 16 suggesting they can serve as lead compounds for developing new classes of pleuromutilin-type antibiotics. Considering that the tiamulin counterparts (24 and 29) of benzyloxymethylene 16 and phenyl 25 had only equivalent activity, there are non-neutral interactions between the C14 ester and the epi-C12 triazole chains that influence binding leading us to conclude there are underlying interactions with the ribosome yet to be exploited. Accordingly, stepwise refinement of C22 substitution after optimization of the epi-C12 triazoles is expected to yield derivatives with even higher potency.In embodiments, one or more pharmaceutical composition is prepared using one or more of the pleuromutilin and / or tiamulin derivatives disclosed herein. In embodiments, the pharmaceutical composition is administered to a human or animal for the purpose of treating a bacterial infection. In embodiments, the pharmaceutical composition is administered orally or dermally. In embodiments, the pharmaceutical composition comprises an effective amount of the compound to kill one or more strain of bacteria.As used herein, “pharmaceutical compositions" include one or more compound according to formula (I) and, optionally, one or more pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof.In embodiments, the pharmaceutical compositions may be administered in either single or multiple doses by oral administration. Administration may be by way of any one or more of capsule, tablet, gel, spray, drops, solution, suspensions, syrups, or the like.As used herein, “treating” or “treatment” means complete cure or incomplete cure, or it means that the symptoms of the underlying disease or associated conditions are at least reduced and / or delayed, and / or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced, delayed and / or eliminated. It is understood that reduced or delayed, as used in this context, means relative to the state of the untreated disease, including the molecular state of the untreated disease, not just the physiological state of the untreated disease.The term "effective amount" refers to an amount that is sufficient to affect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the patient being treated (e.g., human or animal, male or female), the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.The term "about" used herein in the context of quantitative measurements means the indicated amount ±10%. For example, with a ±10% range, "about 5 mg" can mean 4.5-5.5 mg.The present invention has been described with reference to particular embodiments having various features. In light of the disclosure provided above, it will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention without departing from the scope or spirit of the invention. One skilled in the art will recognize that the disclosed features may be used singularly, in any combination, or omitted based on the requirements and specifications of a given application or design. When an embodiment refers to "comprising" certain features, it is to be understood that the embodiments can alternatively "consist of" or "consist essentially of any one or more of the features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Likewise, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.It is noted in particular that where a range of values is provided in this specification, each value between the upper and lower limits of that range is also specifically disclosed. The upper and lower limits of these smaller ranges may independently be included or excluded in the range as well. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered as exemplary in nature and that variations that do not depart from the essence of the invention fall within the scope of the invention. Further, all of the references cited in this disclosure are each individually incorporated by reference herein in their entireties and as such are intended to provide an efficient way of supplementing the enabling disclosure of this invention as well as provide background detailing the level of ordinary skill in the art.

Claims

1. A compound or pharmaceutically acceptable salt thereof according to formula (I):(I)wherein:R is selected from direct attachment, or attachment through one or more heteroatom (such as N, S, or O), with one or more of the following: (C1-C10)alkyl, aryl, phenyl, biphenyl, (C2-C10)alkenyl, alkynyl, amine, amide, alcohol, ether, thiol, thioether, sulfoxide, sulfamate, sulfamide, triazole, amino acids, sugars, carbocycles, heterocycles, polycycles, halogens, OH, NH2, SH, S(CH2)2NEt2, CN, NO2, and H;R' is selected from direct attachment, or attachment through one or more heteroatom (such as N, S, or O), with one or more of the following: H, F, Cl, Br, I, CH2OH, (CH2)2OH, (CH2)3OH, C(CH3)2OH, CH2NH2,(CH2)2NH2,(CH2)5CH3, CH2OCH2(C6H5), C6H5 (phenyl), CH2(C6H5), CH2O(C6H5), C6H4C6H5 (biphenyl), (C1-C10)alkyl, aryl, (C2-C10)alkenyl, alkynyl, amine, amide, alcohol, ether, thiol, thioether, sulfoxide, sulfamate, sulfamide, triazole, amino acids, sugars, carbocycles, heterocycles, OH, NH2, SH, CN, NO2, and S(CH2)2NEt2;any alkyl, alkenyl, aryl, carbocycle, polycycle, amine, thioether, or heterocycle is optionally substituted by 1-4 substituents independently selected from the group consisting of F, Cl, Br, amines, amides, OH, ethers, esters, CF3, O-CF3, acetyl, (C1-C6)alkyl, O-(C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C5-C10)aryl, amino acids, sugars, carbocycles, heterocycles, polycycles, SH, thioethers, CN, NO2;any aryl optionally contains one or more heteroatom in the ring, such as N, O, or S; andany amine optionally comprises two substituents which can be the same or different.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein:R is OH or S(CH2)2NEt2; andR' is selected from CH2OH, (CH2)2OH, (CH2)3OH, C(CH3)2OH, CH2NH2, (CH2)2NH2, (CH2)5CH3, CH2OCH2(C6H5), C6H5 (phenyl), CH2(C6H5), CH2O(C6H5), and C6H4C6H5 (biphenyl).

3. A pharmaceutical composition comprising one or more compound or pharmaceutically acceptable salt thereof of claim 1 or 2 and one or more pharmaceutically acceptable excipient.

4. A method of treating a disease in a patient comprising:administering to a subject a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 or 2.

5. The method of claim 4, wherein the disease is a bacterial infection.

6. The method of claim 5, wherein the bacterial infection comprises a gram-positive bacteria.

7. The method of claim 5, wherein the bacterial infection comprises a gram-negative bacteria.

8. The method of claim 5, wherein the bacterial infection comprises bacteria selected from the group consisting of: S. aureus, MRSA, VRSA, E. coli, VRE, C. difficile, N. gonnorhoeae, and E. faecium.

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