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Carbonic anhydrase (CA) enzymes are a common catalytic enzyme in many organisms. Vertebrates and invertebrates have different CA isoforms. Sixteen different isozymes of the α-CA isoform found in vertebrates have been identified so far. The main task of this enzyme is to catalyze the reversible conversion of carbon dioxide into bicarbonate and hydrogen ions in the body. It is widely distributed in many organs and tissues. They are involved in important physiological processes such as pH and CO2homeostasis, biosynthetic reactions such as gluconeogenesis, lipogenesis, ureagenesis, bone resorption, calcification, tumorigenicity, and electrolyte secretion. As a result of the literature research, it has been determined that the most effective inhibitor of the carbonic anhydrase enzyme is sulfonamides. The R group in the general molecular structure of R-SO2–NH2generally consists of aromatic or heteroaromatic ring systems. The sulfonamides interact strongly with the Zn2+ions in the active site of the enzyme. In this study, 10 sulfonamide derivatives were synthesized. Analyses of the obtained compounds are evaluated by using 1H NMR, 13C NMR and HRMS spectroscopic methods. The inhibition effect of the obtained compounds on the carbonic anhydrase enzyme was investigated by means of in vitrokit method. For the selected compounds, docking studies were performed and the enzyme active sites and binding points were determined. It was revealed that the strongest interaction with CA enzymes (CA-I, CA-II, CA-IX, CA-XII) active sites was observed with the compound 2e.

AbstractBreast cancer is the most frequent female cancer and second cause of cancer-related deaths among women around the world. Two thirds of breast cancer patients have hormone-dependent tumors, which is very likely be treated with hormonal therapy. Aromatase is involved in the biosynthesis of estrogen thus a critical target for breast cancer. In this study, in order to identify new aromatase enzyme inhibitors, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and MS spectra analyses. In the in vitroanticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5aexhibited the most potent activity with IC50values of 5.165 ± 0.211 μM and 5.995 ± 0.264 μM against MCF-7 and HepG2 cell lines. Compound 5awas included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5cwas also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 cell line. In vitro,enzymatic inhibition assays of aromatase enzyme were performed for compound 5aacting on the MCF-7 cell line. For compound 5a, in silicomolecular docking and dynamics simulations against aromatase enzyme was performed to determine possible protein-ligand interactions and stability. DFT study was performed to evaluate the quantum mechanical and electronic properties of compound 5a. Finally, the theoretical ADME properties of the potential aromatase inhibitor compound 5awere analyzed by calculations.Communicated by Ramaswamy H. Sarma

In this study, novel pyridine-containing thiazolyl hydrazone derivatives were synthesized. Structure determinations of the compounds were performed using 1H NMR, 13C NMR and HRMS techniques. The biological activities of the compounds were evaluated against MAO enzymes by in vitrofluorometric method. As a result of activity studies, compound 3ashowed selective inhibitory activity against MAO-B enzyme with IC50= 0.088 + 0.003 µM. The selectivity index of this compound is greater than 1136. Molecular docking studies were carried out using 2V5Z crystal. It has been observed that docking studies and activity studies are in harmony.

In this study, two novel series of thiazolylhydrazone derivatives containing 4-ethylpiperazine (3a–3f) and 4-methoxyphenylpiperazine (3g–3l) side chains were synthesized and their structures were characterized by spectral (1H NMR, 13C NMR, and MS spectra) analyses. In vitroinhibitory activities of synthesized compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined by Ellman method. According to the results, all compounds showed a weak inhibitory effect on AChE, while promising results were obtained on BChE. Among the synthesized compounds, the activities of the derivatives carrying 4-ethylpiperazine (3a–3f) structure were found to be more effective than the compounds carrying 4-methoxyphenyl piperazine (3g–3l) derivatives. Especially, compound 3fbearing the nitro substituent was found to be the most promising compound on BChE in the series. The absorption, distribution, metabolism, and excretion (ADME) parameters of the synthesized compounds were predicted by using the SwissADME server. The potential binding mode and stability of compound 3fwith BChE were investigated by the molecular docking and dynamics simulations. The results showed that 3fwas strongly bound up with BChE with the optimal conformation; in addition, their binding free energy reached −167.936 ± 13.109 kJ/mol.

MAO-A inhibitors are used in the treatment of depression. There are many studies showing that the thiazolyl-hydrazone structure is a pharmacophore structure for the MAO enzyme. In previous studies by our team, activity studies were carried out with thiazolyl-hydrazone derivatives containing pyrrolidine, morpholine, and piperazine. All of them were displayed MAO-A selective inhibition profile. Additionally, derivatives containing piperazine ring were most active. For this purpose, thiazolyl-hydrazone derivatives containing piperazine were synthesized, but this time an active group, formyl group, was added to the piperazine ring as a substituent. Based on this view, new thiazolyl-hydrazone compounds were synthesized, characterized, and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitrofluorometric method. The structure of the compound was tried to be fully elucidated using 2D NMR technique. The compound including 2,4-dimethyl substituent (3i) were found to be the most effective agents in the series against MAO-A enzyme with the IC50value of 0.080 ± 0.003 µM. The docking study of compound 3irevealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.

The synthesis of new N-(5-substituted-1,3,4-thiadiazol-2-yl)-2-[(5-(substituted amino)-1,3,4-thiadiazol-2-yl)thio]acetamide derivatives and investigation of their anticancer activities were the aims of this work. All the new compounds’ structures were elucidated by elemental analyses, IR, 1H NMR, 13C NMR and MS spectral data. Anticancer activity studies of the compounds were evaluated against MCF-7 and A549 tumor cell lines. In addition, with the purpose of determining the selectivity of cytotoxic activities, the most active compound was screened against a noncancer NIH3T3 cell line (mouse embryonic fibroblast cells). Among the tested compounds, compound 4y(N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-((5-(p-tolylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide), showed promising cytotoxic activity against MCF7 cancer cell with an IC50value of 0.084 ± 0.020 mmol L−1and against A549 cancer cell with IC50value of 0.034 ± 0.008 mmol L−1, compared with cisplatin. The aromatase inhibitory activity was evaluated for compound 4yon MCF-7 cell line showing promising activity with IC50of 0.062 ± 0.004 mmol L−1.

Inhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2kwith IC50values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50= 0.021 ± 0.001 µM). Then, these compounds were subject to further in silicoaromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50= 4.664 μM) and compound 6bwas proven to be the most active compound (IC50= 0.060 μM). Moreover, it was seen that compound 6bshowed a similar inhibition profile to that of clorgyline (IC50= 0.048 μM). The inhibition profile was found to be reversible and competitive for compound 6bwith MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6band MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.

Background: The lack of selectivity and development of drug-resistance encourage researchers to search for novel, more efficient and multi-targeted agents with less toxicity. Objective: In this paper, a series of novel chalcone derivatives bearing diverse heterocycles have been synthesized and evaluated for their antiproliferative activity against A549 (Human Lung Adenocarcinoma) and C6 (Rat Brain Glioma) cells. Method: Structures of the title compounds (3-18) were verified by FT-IR, 1H NMR, 13C NMR, HRMS spectral data and elemental analyses. Antiproliferative activities of the compounds were evaluated using MTT assay, BrdU method, and flow cytometric analysis. Results: Compounds 9 and 15 were revealed as the most promising cytotoxic agents due to their selectivity towards A549 cells with lower IC50 values (IC50=0.05 μM and IC50=0.0316 μM) than cisplatin (IC50=0.06 μM). Flow cytometric analysis of compounds 9 and 15 showed that they affected lung cancer cells by the apoptotic pathway. Conclusion: It is concluded that this study will contribute to the research of novel antiproliferative agents.

Background: In this study, benzothiazole-piperazine compounds were synthesized by condensing the functional groups of donepe-zil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer’s disease, with the aim of obtaining new and potent anti-Alzheimer agents. Methods: Initially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman’s method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer’s disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icv) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (1, 5, and 10 mg/kg) on learning and memory parameters of icvSTZ-injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test. Results: The compounds B2-B5and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2and B3at 10 mg/kg doses and compounds B4and B5at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities. Conclusion: Results of the present study revealed that compounds B2-B5repaired the parameters related to the learning and memory deficits of icvSTZ-injected rats. Potencies of these test compounds were comparable to the activity of DNP.

The discovery of DNA topoisomerases has added a new dimension to the study of anticancer drugs. Bisbenzimidazole derivatives are important compounds known as DNA topoisomerase I inhibitors. In the present study, some symmetrical bisbenzimidazole derivatives were synthesized and investigated for their anticancer activity. Anticancer activity screening was applied on HT-29 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines by investigation of cytotoxicity, analysis of DNA synthesis, and DNA fragmentation assays. One of the seven compounds tested showed signifi cant cytotoxicity in both cell lines and caused DNA degradation in the HT-29 cell line.

The mutagenicities of 2,2’-(di-3-hydroxyphenyl)-1H,1H’-[5,5’]-bisbenzimidazole, 2,2’-(di- 4-hy droxyphenyl)-1H,1H’-[5,5’]-bisbenzimidazole, 2,2’-(di-3-methoxyphenyl)-1H,1H’-[5,5’]- bisbenzimidazole, 2,2’-bis-(4-nitrophenyl)-1H,1H’-[5,5’]-bisbenzimidazole, 2,2’-bis-(3-nitrophenyl)- 1H,1H’-[5,5’]-bisbenzimidazole, 2,2’-bis-(4-methylphenyl)-1H,1H’-[5,5’]-bisbenzimidazole, 2,2’-(di-4-methoxyphenyl)-1H,1H’-[5,5’]-bisbenzimidazole, and 2,2’-bis-(3-me thylphenyl)- 1H,1H’-[5,5’]-bisbenzimidazole were studied in vitro using two strains of Salmonella typhimurium with frameshift mutation (TA98) and base-pair substitution mutation (TA100) as the plate incorporation assay in the absence of metabolic activation. These compounds are currently used to treat cancer. 4-Nitrophenyl and 3-nitrophenyl compounds were found to be mutagenic on both strains of Salmonella. A clear mutagenic response was seen in nitro-bound derivatives. The mutagenic response in Salmonella test strains (TA98, TA100) and structures of molecules suggest that nitro-bound molecules could be mutagenic.

A series of N-[1-(((3,4-diphenylthiazol-2(3H)-ylidene)amino)methyl)cyclopentyl]acetamide derivatives (4a-4i) were synthesized in good yield and assayed for their inhibitory potency against monoamine oxidase (MAO) isoforms. Structures of newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR, and mass spectroscopic methods. The inhibitory activity of compounds (4a-4i) against hMAO-A and hMAO-B enzymes was elucidated by using in vitro fluorometric method using Amplex Red® reagent. In the hMAO-A inhibition assay, compounds 4a, 4b, 4c, and 4i exhibited similar activity with standard drug moclobemide (IC50 = 6.061 ± 0.262 µM) with IC50 values of 7.06 ± 0.18 µM, 6.56 ± 0.20 µM, 6.78 ± 0.15 µM, and 7.09 ± 0.17 µM, respectively. According to hMAO-B inhibition results, compounds 4a, 4b, and 4c displayed significant activity with IC50 values of 0.42 ± 0.012 µM, 0.36 ± 0.014 µM, and 0.69 ± 0.020 µM, respectively. In the wake of all these results, it was understood that compound 4b was found to be the most potent derivative in the series against both isoforms and selective as MAO-B inhibitor. The cytotoxicity test was performed for compounds 4a, 4b, and 4c, and it was found that these compounds were noncytotoxic at the concentration of their IC50 values. Also, enzyme kinetic and docking studies of compound 4b were performed against MAO-B. It was observed that 4b showed a reversible and noncompetitive inhibition type. The important binding modes of this compound with active site of hMAO-B were shown owing to in silico studies.

Due to anticandidal importance of azole compounds, a new series of benzimidazole-triazole derivatives (5a–5s) were designed and synthesized as ergosterol inhibitors. The chemical structures of the target compounds were characterized by spectroscopic methods. The final compounds were screened for antifungal activity against Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 22019), and Candida albicans (ATCC 24433). Compounds 5i and 5s exhibited significant inhibitory activity against Candida strains with MIC50 values ranging from 0.78 to 1.56 μg/mL. Cytotoxicity results revealed that IC50 values of compounds 5i and 5s against NIH/3T3 are significantly higher than their MIC50 values. Effect of the compounds 5i and 5s against ergosterol biosynthesis was determined by LC-MS-MS analysis. Both compounds caused a significant decrease in the ergosterol level. The molecular docking studies were performed to investigate the interaction modes between the compounds and active site of lanosterol 14-α-demethylase (CYP51), which is as a target enzyme for anticandidal azoles. Theoretical ADME predictions were also calculated for final compounds.

Some hydrazone derivatives were synthesized and their potential anticholinesterase activities were examined. A series of eleven new compounds of N′-(2,4-disubstitutedbenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide derivatives were obtained via reaction of 2-[4-(4-nitrophenyl)piperazin-1-yl]acetohydrazide with aromatic aldehydes. The chemical structures of the compounds were enlightened by FT-IR, 1H-NMR, 13C-NMR, and HRMS (ESI) spectral data. The inhibition potency of the compounds 3a–k against AChE and BuChE was measured and evaluated using a modification of Ellman’s spectrophotometric method. Among the tested compounds, compound 3c was assigned to be the most active derivative. Galantamine was used as a standard drug.

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.

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.