Hülya Karaca Gençer

New Benzimidazole-1,2,4-Triazole Hybrid Compounds: Synthesis, Anticandidal Activity and Cytotoxicity Evaluation

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.

Synthesis and initial biological evaluation of substituted 1-phenylamino-2-thio-4,5-dimethyl-1H-imidazole derivatives

In this work, some new 2-[(4,5-dimethyl-1-(arylamino)-1H-imidazol-2-yl)thio]-1-(aryl)ethanone derivatives were synthesized and investigated for their antibacterial, antifungal and anticancer activities. Toxicity of the most effective compounds was established by performing Brine-Shrimp lethality assay. Antifungal activity of the compounds was found to be higher than antibacterial and anticancer activities of the compounds.

New 1,4-dihydro[1,8]naphthyridine derivatives as DNA gyrase inhibitors

Owing to the growing need for novel antibacterial agents, we synthesized a novel series of fluoroquinolones including 7-substituted-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid derivatives, which were tested against clinically relevant Gram positive and Gram negative bacteria. Chemical structures of the synthesized compounds were identified using spectroscopic methods. In vitro antimicrobial effects of the compounds were determined via microdilution assay. Microbiological examination revealed that compounds 13 and 14 possess a good antibacterial profile. Compound 14 was the most active and showed an antibacterial profile comparable to that of the reference drugs trovafloxacin, moxifloxacin, and ciprofloxacin. A significant MIC90 value (1.95μg/mL) against S. aureus ATCC 25923, E. coli ATCC 35218, and E. coli ATCC 25922 was recorded for compound 14. We observed reduced metabolic activity associated with compounds 13 and 14 in the relevant bacteria via a luminescence ATP assay. Results of this assay supported the antibacterial potency of compounds 13 and 14. An E. coli DNA gyrase inhibitory assay indicated that compound 14 is a potent inhibitor of E. coli DNA gyrase. Docking studies revealed that there is a strong interaction between compound 14 and the E. coli DNA gyrase enzyme. Genotoxicity and cytotoxicity evaluations of compounds 13 and 14 showed that compound 14 is non-genotoxic and less cytotoxic compared to the reference drugs (trovafloxacin, moxifloxacin, and ciprofloxacin), which increases its biological importance.

Design, synthesis, and evaluation of novel 2-phenylpropionic acid derivatives as dual COX inhibitory-antibacterial agents

Abstract A series of 2-(4-substitutedmethylphenyl)propionic acid derivatives (6a–6m) were synthesized, characterized and evaluated for cyclooxygenase (COX) enzyme inhibitory and antimicrobial activity. Test compounds that exhibited good COX inhibition and antibacterial activity were further screened for their cytotoxicity and genotoxicity. Compounds 6h and 6l showed better COX-1 and COX-2 inhibition when compared to ibuprofen. Inhibition potency of these compounds against COX-2 was very close to that of nimesulide. The compounds 6d, 6h, 6l and 6m displayed promising antibacterial property when compared to chloramphenicol. However, the compound 6l was emerged as the best dual COX inhibitory-antibacterial agent in this study. The ADME prediction of the compounds revealed that they may have a good pharmacokinetic profile. Docking results of the compounds 6h and 6l with COX-1 (PDB ID: 1EQG) also exhibited a strong binding profile.

Synthesis of Some New Thiazole Derivatives and Their Biological Activity Evaluation

New 2-(4-arylpiperazine-1-yl)-N-[4-(2-(4-substituted phenyl)thiazol-4-yl)phenyl]acetamide derivatives were synthesized and evaluated for their antimicrobial and anticholinesterase activities. Acetylcholinesterase inhibitory activities of the compounds were found weak contrary to expectations. It is unlikely that antifungal activity of the compounds was found significant, especially against Candida parapsilosis.

A New Series of Pyrrole-Based Chalcones: Synthesis and Evaluation of Antimicrobial Activity, Cytotoxicity, and Genotoxicity

In an effort to develop new potent antimicrobial and anticancer agents, new pyrrole-based chalcones were designed and synthesized via the base-catalyzed Claisen-Schmidt condensation of 2-acetyl-1-methylpyrrole with 5-(aryl)furfural derivatives. The compounds were evaluated for their in vitro antimicrobial effects on pathogenic bacteria and Candida species using microdilution and ATP luminescence microbial cell viability assays. MTT assay was performed to determine the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, C6 rat glioma, and NIH/3T3 mouse embryonic fibroblast cell lines. 1-(1-Methyl-1H-pyrrol-2-yl)-3-(5-(4-chlorophenyl)furan-2-yl)prop-2-en-1-one (7) and 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(2,5-dichlorophenyl)furan-2-yl)prop-2-en-1-one (9) were found to be the most potent antifungal agents against Candida krusei and therefore these compounds were chosen for flow cytometry analysis and Ames MPF assay. ATP bioluminescence assay indicated that the antifungal activity of compounds 7 and 9 against C. krusei was significantly higher than that of other compounds and the reference drug (ketoconazole), whereas flow cytometry analysis revealed that the percentage of dead cells treated with compound 7 was more than that treated with compound 9 and ketoconazole. According to Ames MPF assay, compounds 7 and 9 were found to be non-genotoxic against TA98 and TA100 with/without metabolic activation. MTT assay indicated that 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(2-nitrophenyl)furan-2-yl)prop-2-en-1-one (3) showed more selective anticancer activity than cisplatin against the HepG2 cell line. On the other hand, 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(4-nitrophenyl)furan-2-yl)prop-2-en-1-one (1) was found to be more effective and selective on the A549 cell line than cisplatin.

Synthesis, Antituberculotic, and Cytotoxic Properties of New Hydrazone Derivatives Bearing Pyrimidine-Alkylsulfanyl Moiety

GRAPHICAL ABSTRACT Abstract A series of N’-(arylidene)-4-[(pyrimidine-2-yl)thio]butanohydrazide derivatives (3a-3m) has been synthesized and investigated for their antituberculotic and cytotoxic activity. The antitubercular activities of the newly synthesized compounds were tested against Mycobacterium tuberculosis H37Rv strain by MABA (Microplate Alamar Blue Assay) method and cytotoxic properties were tested against NIH/3T3 and A549 cell lines by MTT method. The title compounds have been exhibited moderate antitubercular activity. Compound 3m, titled N’-(4-nitrobenzylidene)-4-[(pyrimidine-2-yl)thio]butanohydrazide showed promising cytotoxic activity when compared with the standard drug.

Synthesis and Biological Evaluation of Some Novel Dithiocarbamate Derivatives

18 novel dithiocarbamate derivatives were synthesized in order to investigate their inhibitory potency on acetylcholinesterase enzyme and antimicrobial activity. Structures of the synthesized compounds were elucidated by spectral data and elemental analyses. The synthesized compounds showed low enzyme inhibitory activity. However, they displayed good antimicrobial activity profile. Antibacterial activity of compounds 4a, 4e, and 4p (MIC = 25 μg/mL) was equal to that of chloramphenicol against Klebsiella pneumoniae (ATCC 700603) and Escherichia coli (ATCC 35218). Most of the compounds exhibited notable antifungal activity against Candida albicans (ATCC 10231), Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), and Candida parapsilosis (ATCC 7330). Moreover, compound 4a, which carries piperidin-1-yl substituent and dimethylthiocarbamoyl side chain as variable group, showed twofold better anticandidal effect against all Candida species than reference drug ketoconazole.

Design and evaluation of biological activities of 1,3-oxazolidinone derivatives bearing amide, sulfonamide, and thiourea moieties

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.