Ulviye Acar Çevik

Design, synthesis, and AChE inhibitory activity of new benzothiazole-piperazines.

In the current study, 14 new benzothiazole-piperazine compounds were designed to meet the structural requirements of acetylcholine esterase (AChE) inhibitors. The target compounds were synthesised in three steps. Structures of the newly synthesised compounds (7-20) were confirmed using IR, 1H NMR, 13C NMR, and HRMS methods. The inhibitory potential of the compounds on AChE (E.C.3.1.1.7, from electric eel) was then investigated. Among the compounds, 19 and 20 showed very good activity on AChE enzyme. Kinetics studies were performed to observe the effects of the most active compounds on the substrate-enzyme relationship. Cytotoxicity studies, genotoxicity studies, and theoretical calculation of pharmacokinetics properties were also carried out. The compounds 19 and 20 were found to be nontoxic in both of the toxicity assays. A good pharmacokinetics profile was predicted for the synthesised compounds. Molecular docking studies were performed for the most active compounds, 19 and 20, and interaction modes with enzyme active sites were determined. Docking studies indicated a strong interaction between the active sites of AChE enzyme and the analysed compounds.

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.

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.

Anticholinesterase activity screening of some novel dithiocarbamate derivatives including piperidine and piperazine moieties

GRAPHICAL ABSTRACT ABSTRACT The present study was undertaken to synthesize some novel lipophilic piperazine and piperidinedithiocarbamates and investigate their inhibitory potencies against cholinesterase enzymes. In the synthetic studies, 44 new compounds were isolated. The structures of the synthesized compounds were confirmed by spectroscopic analyses. Enzymatic studies were carried out using modified Ellmans assay against Acetylcholinesterase (AChE) and Butrylcholinesterase (BChE) enzymes, and it was observed that some of the compounds selectively inhibit AChE. Theoretical ADME predictions were calculated for selected compounds in the series. Enzyme kinetics and molecular docking studies were performed for the most active compound C41 and nature of inhibition and interactions between enzyme and ligand were explained.

Synthesis and Antidepressant Activity Profile of Some Novel Benzothiazole Derivatives

Within the scope of our new antidepressant drug development efforts, in this study, we synthesized eight novel benzothiazole derivatives 3a–3h. The chemical structures of the synthesized compounds were elucidated by spectroscopic methods. Test compounds were administered orally at a dose of 40 mg/kg to mice 24, 5 and 1 h before performing tail suspension, modified forced swimming, and activity cage tests. The obtained results showed that compounds 3c, 3d, 3f–3h reduced the immobility time of mice as assessed in the tail suspension test. Moreover, in the modified forced swimming tests, the same compounds significantly decreased the immobility, but increased the swimming frequencies of mice, without any alteration in the climbing frequencies. These results, similar to the results induced by the reference drug fluoxetine (20 mg/kg, po), indicated the antidepressant-like activities of the compounds 3c, 3d, 3f–3h. Owing to the fact that test compounds did not induce any significant alteration in the total number of spontaneous locomotor activities, the antidepressant-like effects of these derivatives seemed to be specific. In order to predict ADME parameters of the synthesized compounds 3a–3h, some physicochemical parameters were calculated. The ADME prediction study revealed that all synthesized compounds may possess good pharmacokinetic profiles.

Design and Synthesis of New Benzothiazole Compounds as Selective hMAO-B Inhibitors

In the current work a new class of novel benzothiazole-hydrazone derivatives was designed and synthesized as hMAO-B inhibitors. Structures of the obtained compounds (3a–3j) were characterized by IR, 1H-NMR, 13C-NMR, and HRMS spectroscopic methods. The inhibitory activity of compounds (3a–3j) against hMAO-A and hMAO-B enzymes was evaluated by using an in vitro fluorometric method. According to activity results, some of the synthesized compounds displayed selective and significant hMAO-B enzyme inhibitor activity. Compound 3e was the most active derivative in the series with an IC50 value of 0.060 µM. Furthermore, cytotoxicity of compound 3e was investigated and found to be non-cytotoxic. Absorption, distribution, metabolism, and excretion (ADME) and blood-brain barrier (BBB) permeability predictions were performed for all compounds. It was determined that these compounds may have a good pharmacokinetic profiles. Bınding modes between the most active compound 3e and the hMAO-B enzyme were analyzed by docking studies. It was observed that there is a strong interaction between compound 3e and enzyme active site.

Synthesis and Anticandidal Activity Evaluation of New Benzimidazole-Thiazole Derivatives

Azole-based antifungal agents constitute one of the important classes of antifungal drugs. Hence, in the present work, 12 new benzimidazole-thiazole derivatives 3a–3l were synthesized to evaluate their anticandidal activity against C. albicans, C. glabrata, C. krusei, and C. parapsilopsis. The structures of the newly synthesized compounds 3a–3l were confirmed by IR, 1H-NMR, 13C-NMR, and ESI-MS spectroscopic methods. ADME parameters of synthesized compounds 3a–3l were predicted by an in-slico study and it was determined that all synthesized compounds may have a good pharmacokinetic profile. In the anticandidal activity studies, compounds 3c and 3d were found to be the most active compounds against all Candida species. In addition, cytoxicity studies showed that these compounds are nontoxic with a IC50 value higher than 500 µg/mL. The effect of compounds 3c and 3d on the ergosterol level of C. albicans was determined by an LC-MS-MS method. It was observed that both compounds cause a decrease in the ergosterol level. A molecular docking study including binding modes of 3c to lanosterol 14α-demethylase (CYP51), a key enzyme in ergosterol biosynthesis, was performed to elucidate the mechanism of the antifungal action. The docking studies revealed that there is a strong interaction between CYP51 and the most active compound 3c.

Synthesis and evaluation of new benzimidazole derivatives with hydrazone moiety as anticancer agents

Abstract Objectives: Cancer is one of the leading causes of death throughout the world. Current therapy options suffer from the major limitations of side effects and drug resistance. Thus, continuing search for newer and safer anticancer drugs remains critically important. From this point of view, in the present study benzimidazole-hydrazone derivatives were synthesized by aiming at the identification of new chemical entities as potent anticancer agents. Material and methods: A series of 12 new compounds of 4-(5(6)-substituted-1H-benzimidazol-2-yl)-N′thiophen/furan-2-yl-methylene) benzohydrazide derivatives were synthesized. The structures of the obtained compounds were elucidated using by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. In vitro cytotoxic activity of the compounds against A549, MCF-7 and NIH/3T3 cell lines was evaluated by MTT assay. Results: Among the tested compounds, compound 3e showed higher cytotoxicity against MCF-7 human breast cancer cells when compared with cisplatin. Also, it has lower cytotoxicty against healthy cell line, NIH/3T3. Conclusions: It was determined that compound 3e showed inhibition towards MCF-7. Considering the substituent effect on cytotoxic activity, compound 3e bearing 2-methylthiophene has attracted attention with its higher anticancer activities.

Synthesis and antimicrobial activities of some novel thiazole compounds

Abstract Objective: The advent of resistant pathogenic microorganisms against current antimicrobial drugs prompted scientists to investigate novel molecules with new mechanisms. In this paper, some new 2-[2-[4-(ethyl/phenyl)cyclohexylidene]hydrazinyl]-4-(4-substitutedphenyl)thiazole (2a–2o) derivatives were synthesized and studied for their antimicrobial activities. Materials and methods: The title compounds (2a–2o) were obtained via the reaction of 4-(ethyl/phenyl)cyclohexane-1-one with appropriate phenacyl bromide in ethanol at room temperature. The chemical structures of the compounds were elucidated by FT-IR, 1H-NMR, 13C-NMR, HRMS and elemental analysis. Antimicrobial activity of the compounds was measured by using broth microdilution method. Chloramphenicol and ketoconazole were used as reference drugs. Results: Among the synthesized compounds, 2-[2-(4-phenylcyclohexylidene)hydrazinyl]-4-phenylthiazole (2h) and 2-[2-(4-phenylcyclohexylidene)hydrazinyl]-4-(4-chlorophenyl)thiazole (2l) have been found to exhibit potency almost four-fold better than ketoconazole against C. albicans with MIC90 value of 1.95. Conclusion: The current study contributed to the knowledge of the antimicrobial activity of thiazole bearing compounds.