ABSTRACT
1,3-Oxazolidine-2-one is an important heterocyclic ring participating in the chemical structure of many drugs. In this research, 22 new amide/sulfonamide/thiourea derivatives (1-22) were obtained by the reaction of (S)-4-(4-aminobenzyl)-2(1H)-1,3-oxazolidinone with 4-substituted benzoyl chlorides, 4-substituted benzene sulfonyl chlorides, and 4-substituted phenyl isothiocyanates. The structures of all synthesized compounds were clarified by FT-IR, NMR, and mass spectroscopic and elemental analysis techniques. The synthesized compounds were screened for their antimicrobial activity. Antimicrobial susceptibility and cellular physiology were evaluated using the microbroth dilution assay and the flow cytometry method. As a result, it was determined that compound 16 displayed better antimicrobial activity than chloramphenicol against Gram-positive bacteria, especially Staphylococcus aureus. In order to understand the mechanism of effect of the compounds on the cell membrane, fluorescence microscopy was used. Cell membrane damage of the Gram positive bacteria treated with compound 16 was observed as a result of intense staining with propidium iodide. In addition, genotoxicity, cytotoxicity, and absorption, distribution, metabolism, and excretion (ADME) parameters of compound 16 were examined and it was found as non-mutagenic and non-cytotoxic at the concentration at which it showed antimicrobial activity. According to the calculated ADME parameters and drug likeness scores, the compounds can be good drug candidates, especially compound 16.
Subject(s)
Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/pharmacology , Sulfonamides/pharmacology , Thiourea/pharmacology , Amides/chemistry , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Membrane/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Gram-Positive Bacteria/cytology , Male , Mice , Microbial Sensitivity Tests , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Microsomes, Liver/microbiology , Molecular Structure , NIH 3T3 Cells , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Rats , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Structure-Activity Relationship , Sulfonamides/chemistry , Thiourea/chemistrySubject(s)
Anti-Bacterial Agents/pharmacology , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacology , Drug Design , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida/classification , Candida/drug effects , Cell Survival/drug effects , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase Inhibitors/chemical synthesis , Drug Evaluation, Preclinical , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutagenicity Tests , NIH 3T3 Cells , Phenylpropionates/chemical synthesis , Species Specificity , Spectrum Analysis/methodsABSTRACT
Owing to the growing need for antifungal agents, we synthesized a new series 2-((5-(4-(5-substituted-1H-benzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol-3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives, which were tested against Candida species. The synthesized compounds were characterized and elucidated by FT-IR, ¹H-NMR, 13C-NMR and HR-MS spectroscopies. The synthesized compounds were screened in vitro anticandidal activity against Candida species by broth microdiluation methods. In vitro cytotoxic effects of the final compounds were determined by MTT assay. Microbiological studies revealed that compounds 5m, 5o, 5r, 5t, 5y, 5ab, and 5ad possess a good antifungal profile. Compounds 5w was the most active derivative and showed comparable antifungal activity to those of reference drugs ketoconazole and fluconazole. Cytotoxicity evaluation of compounds 5m, 5o, 5r, 5w, 5y, 5ab and 5ad showed that compounds 5w and 5ad were the least cytotoxic agents. Effects of these two compounds against ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of ergosterol level in C. albicans. Compounds 5w and 5d inhibited ergosterol biosynthesis concentration dependently. A fluorescence microscopy study was performed to visualize effect of compound 5w against C. albicans at cellular level. It was determined that compound 5w has a membrane damaging effect, which may be related with inhibition of biosynthesis of ergosterol.
