Synthesis, anticholinesterase activity, molecular docking, and molecular dynamic simulation studies of 1,3,4-oxadiazole derivatives.

Two new series of 1,3,4-oxadiazoles bearing pyridine and thiazole heterocycles (4a-h and 5a-h) were synthesized (2,5-disubstituted-1,3,4-oxadiazoles). The structures of these newly synthesized compounds were confirmed by 1 H nuclear magnetic resonance (NMR), 13 C NMR, high-resolution mass spectrometric and Fourier transform infrared spectroscopic methods. All these compounds were evaluated for their enzyme inhibitory activities against two cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). From the studies, we identified compounds 4a, 4h, 5a, 5d, and 5e as selective AChE inhibitors, with IC50 values ranging from 0.023 to 0.037 µM. Furthermore, docking studies of these compounds were performed at the active sites of their target enzymes. The molecular docking study showed that 5e possessed an ideal docking pose with interactions inside AChE.

Design and synthesis of novel chalcone derivatives and evaluation of their inhibitory activities against acetylcholinesterase.

According to the cholinergic hypothesis, an increase in the acetylcholine level in Alzheimer's disease patients relatively slows down the symptoms of the disease. The most commonly used drug, donepezil, is a cholinesterase inhibitor. In this study, 12 new chalcones (2a-l) were designed and synthesized. In biological activity studies, the acetylcholinesterase (AChE) and butyrylcholinesterase inhibitory potentials of all compounds were evaluated using the in vitro Ellman method. The biological evaluation showed that compounds 2d, 2f, 2j, and 2l displayed significant activity against AChE. The compounds 2d, 2f, 2j, and 2l displayed IC50 values of 0.042, 0.024, 0.053, and 0.033 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also displayed significant inhibition of AChE. The inhibitory activities of these compounds for ß-amyloid plaque aggregation were investigated. The enzyme kinetic study was performed to observe the effect of the most active compound 2f on the substrate-enzyme relationship, and a mixed-type inhibition of AchE was determined. Further, docking simulation also revealed that these compounds (2d, 2f, 2j, and 2l) interacted with the enzyme active site in a similar manner to donepezil. The most active derivative, compound 2f, interacted with the amino acids Trp286, Phe295, Tyr341, Trp86, and Glu202.

Design, synthesis, biological activity, molecular docking, and molecular dynamics of novel benzimidazole derivatives as potential AChE/MAO-B dual inhibitors.

To develop new acetylcholinesterase (AChE)-monoamine oxidase-B (MAO-B) dual inhibitors against Alzheimer's disease, the benzimidazole ring, which has a propargyl side chain with previously proven selective MAO-B inhibitory activity, was used as the main structure. Moreover, like donepezil, it was thought that the enzyme AChE would provide π-π interactions with the peripheral anionic side in this structure. Piperazine derivatives were chosen for the cationic active site. The synthesis of the compounds was carried out in five steps. The structures of the compounds were determined using 1 H-NMR (nuclear magnetic resonance), 13 C-NMR, and high-resolution mass spectrometry spectroscopic methods. First, the in vitro AChE, butyrylcholinesterase (BChE), MAO-A, and MAO-B inhibitory potentials of the obtained compounds were investigated. As a result of activity tests, compounds 5b, 5e, 5g, and 5h showed inhibitory activity against AChE; compounds 5e and 5g showed inhibitory activity against MAO-B. None of the compounds showed inhibitory activity against BChE or MAO-A. Compounds 5e and 5g showed dual inhibition. Among these compounds, compound 5g had inhibition potential similar to that of donepezil and selegiline. For compound 5g, further kinetic studies and Aß-plaque inhibitory potentials were investigated using in vitro methods. Molecular docking studies were performed using both AChE and hMAO-B crystals to elucidate the compound's interactions with the enzyme active site. The binding modes of the compound on AChE were fully elucidated by molecular dynamics studies.

Design, synthesis, biological evaluation, and docking studies of some novel chalcones as selective COX-2 inhibitors.

A new series of chalcones (1-9) possessing an SO2 CH3 COX-2 pharmacophore at the para position of the C-1 phenyl ring was synthesized via the Claisen-Schmidt condensation reaction and examined for their inhibition potential against cyclooxygenase (COX) enzymes. Their structures were elucidated by infrared, 1 H NMR (nuclear magnetic resonance), 13 C NMR, and high-resolution mass spectroscopic methods. Enzyme inhibition studies revealed that most of the compounds showed a moderate-to-strong inhibitory activity (IC50 = 0.18-0.34 µM) against the COX-2 enzyme as compared with celecoxib (IC50 = 0.12 µM), ibuprofen (IC50 = 5.33 µM), and nimesulide (IC50 = 1.68 µM). Among these compounds, 1-[4-(methylsulfonyl)phenyl]-3-(2,3-dichlorophenyl)prop-2-en-1-one (5), 1-[4-(methylsulfonyl)phenyl]-3-(2,4-dichlorophenyl)prop-2-en-1-one (6), and 1-[4-(methylsulfonyl)phenyl]-3-(2-chloro-6-fluorophenyl)prop-2-en-1-one (8) became prominent with IC50 values of 0.21, 0.19, and 0.18 µM, respectively. According to molecular docking studies of the most effective compounds, it was found that the compounds interact with amino acids that are important in COX-2 selectivity, such as Arg499 and Phe504.

Synthesis and docking study of benzimidazole-triazolothiadiazine hybrids as aromatase inhibitors.

Aromatase is involved in the biosynthesis of estrogen and thus is a critical target for breast cancer. In this study, to identify new aromatase enzyme inhibitors, seven 3-[4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenyl]-6-(substituted phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives were synthesized. First, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the inhibitory activity of the synthesized compounds on the MCF-7 cell line. The aromatase inhibitory activity was determined for the active compounds 5b, 5c, 5e, and 5g on the MCF-7 cell line. Compound 5g showed significant aromatase inhibitory activity (IC50 = 0.037 ± 0.001 µM). Interestingly, this compound, which bears a difluoro substituent at positions 2 and 4 of the phenyl ring, displayed the most potent aromatase inhibitory activity without significant cytotoxicity to a normal healthy cell line (NIH3T3). Furthermore, the interactions between the best active compounds and the active site of the enzyme were analyzed through a docking study. The results of this study determined that benzimidazole-triazolothiadiazine derivatives are promising compounds that should be further developed as a novel class of aromatase inhibitors.

Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors.

In an effort to develop potent monoamine oxidase (MAO) inhibitors, new pyrrole derivatives were obtained via the selective reduction of the CC bonds of 1-(1-methyl-1H-pyrrol-2-yl)-3-[5-(aryl)furan-2-yl]prop-2-en-1-ones through palladium catalyzed hydrogenation in ethanol. The synthesized compounds were screened for their inhibitory effects on MAO-A and MAO-B by an in vitro fluorometric method. The selectivity index (SI) value was given as the ratio of IC50 (MAO-A)/IC50 (MAO-B) for each compound. 3-(5-(4-Chlorophenyl)furan-2-yl)-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (6) was identified as the most selective MAO-A inhibitor in this series, with an IC50 value of 0.162 µM and a SI value of 0.002. Kinetic studies were also carried out to assess the nature of MAO-A inhibition by compound 6. According to Lineweaver-Burk plots, compound 6 was found to be a competitive MAO-A inhibitor and the Ki value of compound 6 was determined as 0.1221 µM. Docking studies were performed for compound 6 and clorgyline using the human MAO-A crystal structure (PDB ID: 2Z5Y). The docking results showed that compound 6 presented similar interactions as clorgyline in the active center cavity of the enzyme. Molinspiration software was used to determine the physicochemical parameters of all compounds for an evaluation of their compliance to Lipinski's rule of five. Compound 6 did not violate Lipinski's rule, making it a potential orally bioavailable therapeutic agent.