A METHOD FOR PRODUCING ANTIFUNGAL SMALL MOLECULES WITH A NEW CHEMICAL SKELETON.

Abstract

The invention relates to a method for producing pentacyclic antifungal small molecules with a benzoxazine core, obtained by condensation and intramolecular ring-closure reactions of 2-aminophenol derivatives containing different functional groups and substitution patterns with acenaphthylene-1,2-dione, used in the fields of pharmaceutical and medicinal chemistry, particularly in the treatment of infections caused by multidrug-resistant fungal pathogens (especially Candida auris), as disinfectants in the disinfection of hospital surfaces, and as antiseptic agents in wound antisepsis.

Description

ANTIFUNGAL SMALL MOLECULES WITH A NEW CHEMICAL SKELETON PRODUCTION METHOD Technical Area The invention has implications for the fields of pharmaceutical and medicinal chemistry, the pharmaceutical industry, and medical microbiology. in applications especially against multidrug-resistant fungal pathogens (particularly Candida In the treatment of infections caused by (Auris auria), antifungal agents are used on hospital surfaces. as a disinfectant in disinfection and as an antiseptic agent in wound antisepsis with the new antifungal small molecules used and the method of producing these molecules It is related. The invention specifically relates to 2-aminophenols containing different functional groups and substitution patterns. Condensation and intramolecular ring closure of its derivatives with acenaphthylene-1,2-dione. pentacyclic with a benzoxazine core obtained by reacting it It is related to the method of producing antifungal small molecules. State of the Art Recent increase in the incidence of fungal infections (particularly Candida auris infection) A dramatic increase has been observed worldwide in recent years. Behind this increase... resistance or multiple resistance developed by various fungi to antifungal agents This includes acquired resistance in the case of Candida auris, as well as resistance to some antifungals. The observation of intrinsic resistance to the virus (93% fluconazole resistance) also made the treatment problematic. This leads to failure. It is necessary to prevent the failures observed in treatment. New alternatives need to be presented. Agents used in current technology (antifungals, disinfectants, and antiseptic agents) Due to insufficient target specificity, there is a conflict between therapeutic efficacy and safety. It has a narrow window. This situation concerns long-term or high-dose use. It is limiting. In addition, most of the existing molecular skeletons have similar effects. Because it relies on these mechanisms, the risk of cross-resistance is high, and new chemicals... The need for classrooms is increasing. 35 2 Due to its increasing incidence and multiple antifungal resistance worldwide, Candida auris, Candida auris poses a serious threat to public health. Therefore, it is a global concern. It has been included in the World Health Organization's list of fungal pathogens of medical importance. Its ability to survive on surfaces for a long time, its biofilm formation, and its resistance to antifungals. Resistance to disinfectants and antiseptic agents creates fertile ground for hospital-acquired outbreaks. is preparing. The limited availability of current antifungal options, pan-resistant isolates Presence and resistance to common disinfectants, treatment with disinfection-sterilization This leads to failures in the processes. Therefore, an effective, low-toxicity and There is an urgent need for new antifungal agents and disinfectants that can overcome resistance mechanisms. It is needed. In conclusion, the existence of the above problems and the inadequacy of the current solutions, This has made it necessary to make improvements in the technical field. Purpose of the Invention The present invention eliminates the aforementioned disadvantages and contributes to the relevant technical field. antifungal small molecules with a novel chemical skeleton that brings new advantages It relates to the production method and areas of use. The main aim of the invention is to develop resistant fungi through a unique chemical framework. Potentially effective against pathogens, structurally distinctive and improvable. The goal is to produce antifungal small molecules. The aim of the invention is to create derivatives containing different functional groups and substitution patterns. Through systematic synthesis, it exhibits antifungal activity against host cells. antifungal microorganisms that allow for the optimization of the balance between cytotoxicity and microorganisms. The goal is to create molecules. Another aim of the invention is to combat multidrug-resistant fungal pathogens (especially Candida auris) The goal is to develop new, effective antifungal small molecules. Another aim of the invention is to create a new chemical that differs from existing classes of antifungal drugs. The goal is to develop antifungal small molecules with a built-in skeleton. 35 Another aim of the invention is to be used in pharmaceutical formulations (cream, gel, ointment, tablet, 3 antifungal that can be used both in capsules and in disinfectant / antiseptic compositions. The goal is to create small molecules. Another purpose of the invention is in surface disinfection and biofilm generation. Highly stable antifungal that can be used to remove contamination. The goal is to create small molecules. Another objective of the invention is to develop selective antifungal activity with a low toxicity profile. The goal is to identify small antifungal molecules that can demonstrate this. Another aim of the invention is to create an alternative target that can overcome resistance mechanisms. The goal is to identify antifungal small molecules that have specific interactions. Another aim of the invention is to create a product that is easy to synthesize, scalable, and can be produced with high yields. The goal is to produce antifungal small molecules. Another aim of the invention is to create a novel structural platform that differs from existing antifungal agents. The goal is to introduce small antifungal molecules. Another aim of the invention is to identify candidates with the potential to delay the development of resistance. Antifungal small molecules that allow the identification of molecules to place. Another aim of the invention is to improve the safety profile through compounds with increased selectivity. The goal is to develop antifungal small molecules that promote healing. Another aim of the invention is to make it suitable for further pharmaceutical development and preclinical studies. The goal is to identify antifungal small molecules that make it possible to identify potential candidates. To fulfill all the purposes mentioned above and those that can be derived from the detailed explanation. The invention is based on the following principles: in the fields of pharmaceutical and medicinal chemistry, in the pharmaceutical industry and in the medical field. In microbiology applications, especially multidrug-resistant fungal pathogens (particularly In the treatment of infections caused by Candida auris, antifungal agents are used in hospitals. disinfectant for surface disinfection and antiseptic agent for wound antisepsis 35 is the method of producing antifungal small molecules used, 4 a) Add 1 mmol of a suitable 2-aminophenol to a 50 mL reaction vessel. addition of the derivative, b) The reaction is carried out in an inert atmosphere by passing nitrogen gas through the reaction vessel. to be carried out under, c) As solvent to the reaction medium, 10–50 per 1 mmol of starting material. absolute alcohol or C1–C4 alcohol (1-propanol, 2-propanol, at a concentration of mL / mmol) by adding 1-butanol, 2-butanol, isobutanol or tert-butanol) and the mixture, homogenization by mixing with a magnetic stirrer, d) Adding 1 mmol of acenaphthylene-1,2-dione to the reaction vessel, e) Moles of 2-aminophenol derivative used as a starting material in the mixture Adding 0.05–0.5 equivalents of acidic catalyst depending on the amount, f) Stirring the mixture to complete the reaction. g) The solid product formed at the end of the reaction settles and the precipitate is filtered. separation from the reaction medium, h) Recrystallization of the raw product in 70–100% ethanol. purification by subjecting it to i) Obtaining the final compound by drying the pure crystalline product under suitable conditions. It is related to including the process steps. Detailed Description of the Invention This detailed description explains the production method of the antifungal small molecules that are the subject of the invention. preferred alternatives, solely for the purpose of better understanding the subject and It is explained in a way that will not create any limiting effects. The invention relates to the reconciliation of 2-aminophenol derivatives with acenaphthylene-1,2-dione in a suitable solvent medium. obtained by subjecting to condensation and intramolecular ring closure reactions. new pentacyclic antifungal small molecules with a benzoxazine core This relates to the production method of (AcBOx-1– AcBOx-7). The resulting compounds are (AcBOx-1– AcBOx-7 presents a unique chemical skeleton not previously reported in the literature. and potential antifungal activity against multidrug-resistant fungal pathogens This indicates that the aforementioned AcBOx-1–AcBOx-7 expressions refer to the synthesized compounds. They represent laboratory code names, each with its respective chemical structure. It has been defined. 35 X: O, S R: H, Cl, MeO, Me R : H, NO , Me AcBOx-1: AcBOx-2: AcBOx-3: AcBOx-4: AcBOx-5: 6 AcBOx-6: AcBOx-7: Structural diversity of compounds (AcBOx-1–AcBOx-7) as starting materials This is achieved through chemical variations of the 2-aminophenol derivatives used. variations; heteroatom isostere changes (O, S, NH), halogen substitutions (F, (Cl, Br) and electron-donating (OMe, Me) or electron-withdrawing (NO₂, CN, CF₃) groups Its presence in different locations includes modifications. This diversity is due to substitution. the effect of patterns and electronic properties on antifungal efficacy It creates a broad structure-effect relationship that allows for its evaluation. The compounds (AcBOx-1–AcBOx-7) covered by this invention exhibit antifungal activity and host... enabling the optimization of the balance between cytotoxicity and cellular resistance It possesses structural features that enhance selectivity and improve its safety profile. It contributes to the development of antifungal candidate molecules. Furthermore, these compounds... both in pharmaceutical formulations (cream, gel, ointment, tablet, capsule) and Stability and solubility suitable for use in disinfectant and antiseptic compositions. It has the following characteristics. The solvent system used within the scope of this invention improves reaction yield and product purity. To enhance its effect, it contains C1–C4 alcohols. C1–C4 alcohols include methanol and ethanol. 1‑propanol, 2‑propanol (isopropanol), 1‑butanol, 2‑butanol, isobutanol and tert‑butanol This refers to low molecular weight aliphatic alcohols. These solvents are used in the reaction. increasing the solubility of their components, condensation and ring closure They ensure that the reactions proceed in a controlled manner and at the end of the reaction They are preferred because they facilitate the settling of the product. The resulting AcBOx-1–AcBOx-7 compounds could overcome resistance mechanisms. 7 They have alternative target interactions, biofilm-derived surface their use in removing contamination and in further pharmaceutical development Because they are suitable for the processes, they are used in both medical and industrial applications. It is of a nature that can be evaluated. The production method for the AcBOx-1–AcBOx-7 compounds covered by this invention is as follows: It includes the following steps: a) Preparation of the starting material: In a 50 mL reaction vessel, add 1 mmol of a suitable 2-aminophenol derivative. is added. The 2-aminophenol derivative used determines the structure of the resulting AcBOx compound. is the determining fundamental component. Within the scope of this invention, a 2-aminophenol derivative is the fundamental component. Heteroatom isostere transformations (O, S, or NH) of the 2-aminophenol structure, halogen substitutions (F, Cl or Br), electron-donating groups (OMe or Me), electron-withdrawing groups groups (NO₂, CN or CF₃) and the presence of the substituent at position 4- or 5- It refers to modified derivatives. Synthesis Method: b) Creating an anaerobic environment: The reaction is carried out under an inert atmosphere by passing nitrogen gas through the reaction vessel. its implementation is ensured. c) Addition of solvent: As solvent, 10–50 units per 1 mmol of starting material are added to the reaction medium. absolute alcohol (methanol or ethanol) or C1-C4 alcohol (1-propanol, at a concentration of mL / mmol, 2-propanol, 1-butanol, 2-butanol, isobutanol or tert-butanol) are added. The mixture, The mixture is homogenized by stirring with a magnetic stirrer at a speed range of 200–800 rpm. d) Addition of acenaphthylene-1,2-dione: One mmol of acenaphthylene-1,2-dione is added to the reaction vessel. This compound, It acts as the main carbonyl component in the formation of the benzoxazine core. 8 e) Addition of an acidic catalyst: To initiate the reaction and accelerate the condensation / cyclization mechanism. moles of 2-aminophenol derivative used as a starting material in the mixture for this purpose Depending on the amount, 0.05–0.5 equivalents of acidic catalyst are added. The aforementioned acidic catalyst... Glacial acetic acid was used as a catalyst. f) Conducting the reaction: The mixture should be stored at a temperature range of 15–30 °C, preferably at room temperature (20–25 °C), for 6–24 hours. The reaction is completed by stirring preferably for 10-14 hours. This is achieved through condensation and intramolecular ring closure during this process. A pentacyclic benzoxazin backbone is formed. g) Sedimentation and separation of the product: The solid product formed at the end of the reaction precipitates. The precipitate is filtered away from the reaction medium. They leave. h) Purification: The raw product is subjected to recrystallization in 70–100% ethanol. It is purified. This process increases the purity of the product and ensures that it is obtained in crystalline form. The crystallization process can be carried out in a temperature range of 0–25 °C. i) Drying: The pure crystalline product is dried under suitable conditions to obtain the final AcBOx compound. The method described in the invention is based on a 2-aminophenol derivative used as a starting material. as AcBOx ‑1, AcBOx ‑2, AcBOx ‑3, AcBOx ‑4, AcBOx ‑5, AcBOx ‑6 or AcBOx ‑7 It enables the production of one of the compounds with high yield and purity. AcBOx-1 and AcBOx-7 compounds are used in a wide range of antifungal applications. These compounds can be used in both human and veterinary medicine, either systemically or orally. Topical antifungal treatments can be considered. Compounds; tablets, capsules, in topical formulations such as suspensions, creams, ointments, gels, sprays or lotions It can be used in concentrations of 0.001%–10%. 35 Compounds (AcBOx-1–AcBOx-7), enhancing efficacy, targeted distribution and It can be integrated into the following advanced pharmaceutical systems for controlled release: 9  Nanoemulsion systems  Liposomal delivery systems  Polymeric nanoparticles  Controlled release systems AcBOx compounds have the potential to create synergistic effects with existing antifungal agents. It has and can be used in combination with the following medications:  Azoles (fluconazole, voriconazole)  Echinocandins  Amphotericin B AcBOx compounds are used in medical and environmental applications such as surface disinfection and wound antisepsis. It can be used as an antifungal agent in applications. AcBOx compounds are used in the treatment of animal fungal infections and in farms. It can be used in fungal disinfection applications in animals. The compounds (AcBOx-1–AcBOx-7) obtained by the method described in this invention have antifungal properties. Efficacy was screened using well diffusion tests. Different Candida auris strains (28 strains) The antifungal effects of the compounds in question were determined using the well diffusion test. This has been investigated. In the conducted study, these compounds were found in all Candida auris strains. It has been determined that it exhibits antifungal activity on the following compounds (AcBOx-1– Well diffusion test showing the antifungal activity (inhibition zones) of AcBOx-7. The results are shown. (One well was used for each compound.)

Claims

1. In the field of pharmaceutical and medicinal chemistry, in the drug industry and in the medical field. in microbiology applications, especially multidrug-resistant fungal pathogens (especially in the treatment of infections caused by Candida auris) antifungal agent, disinfectant and wound disinfectant in hospital surfaces antifungal small molecules used as antiseptic agents in antisepsis It is a production method, and its characteristic is; a) Add 1 mmol of a suitable substance to a 50 mL reaction vessel. Addition of a 2-aminophenol derivative, b) By passing nitrogen gas through the reaction vessel, the reaction becomes inert. conducted under the atmosphere, c) As solvent to the reaction medium, per 1 mmol of starting material, Absolute alcohol or C1–C4 alcohol (1-propanol, at a concentration of 10–50 mL / mmol, 2-propanol, 1-butanol, 2-butanol, isobutanol or tert-butanol) the mixture is added and stirred homogeneously with a magnetic stirrer. to be brought into being, d) Adding 1 mmol of acenaphthylene-1,2-dione to the reaction vessel, e) The 2-aminophenol derivative used as a starting material in the mixture Adding 0.05–0.5 equivalents of acidic catalyst according to the molar amount, f) Stirring the mixture to complete the reaction. g) The solid product formed at the end of the reaction settles and the precipitate is filtered. separation from the reaction medium, h) Recrystallization of the crude product in 70–100% ethanol. purification by subjecting it to a process, i) Obtaining the final compound by drying the pure crystalline product under suitable conditions. to be done It includes the steps of the process.

2. A method for producing antifungal small molecules in accordance with Claim 1, characterized by: In the aforementioned step (a), the 2-aminophenol derivative is converted into the basic 2-aminophenol heteroatom isostere changes in structure (O, S or NH), halogen substitutions (F, Cl or Br), electron-donating groups (OMe or Me), electrons attractor groups (NO₂, CN or CF₃) and at the 4- or 5-position of the substituent It contains modified derivatives with the presence of 35. 11 3. A method for producing antifungal small molecules in accordance with Claim 1, characterized by: In step (c) mentioned, the absolute alcohol contains methanol or ethanol.

4. A method for producing antifungal small molecules in accordance with Claim 1, characterized by: In the mentioned (c) process step, the mixture is stirred with a magnetic stirrer at 200–800 rpm This involves a mixing process step within the specified speed range.

5. A method for producing antifungal small molecules in accordance with Claim 1, characterized by: The acidic catalyst added to the mixture in the mentioned (e) process step is glacial. It contains acetic acid.

6. A method for producing antifungal small molecules in accordance with Claim 1, characterized by: In the mentioned (f) process step, the mixture is kept at a temperature range of 15–30°C for 6–24 hours. It involves the process of mixing them.

7. A method for producing antifungal small molecules in accordance with Claim 1, characterized by: In the mentioned (f) process step, the crystallization process takes place in the temperature range of 0–25°C. It includes the process step of carrying out the execution.

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