Structure-based inhibition of acetylcholinesterase and butyrylcholinesterase with 2-Aryl-6-carboxamide benzoxazole derivatives: synthesis, enzymatic assay, and in silico studies.

An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values ​​of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.

Investigation of inhibitory effect of sulfated chitosan oligomer on human heparanase enzyme: in silico and in vitro studies.

Deaths from cancer are widespread worldwide and the numbers continue to increase day by day. During the disease progression of cancer in cells, many of its metabolic activities change. Increased heparanase enzyme release is just one example. Following heparanase enzyme activity, many molecules interact with the remodeling of glycosaminoglycan structures, which triggers the release of different enzymes, cytokines, and growth factors, including fibroblast growth factors (FGF1 and FGF2), vascular endothelial growth factor (VEGF), hepatocyte growth factor, transforming growth factor ß and platelet-derived growth factor. These are the most important factors in metastasis due to the formation of new vascular structures caused by those elements. To reduce tumor growth and metastasis, various drugs have been designed by modifying chitosan and its derivatives. In this study, we used chitosan oligomer (A), sulfated chitosan oligomer (ShCsO) (B), heparin (C), phosphate monomer (D1) of PI-88 and sulfate monomer (D2) of PI-88 as heparanase inhibitors. We modified the chitosan oligomer with chlorosulfonic acid to synthesize ShCsO to investigate its inhibitory effects on human serum heparanase. Also examined were molecular docking; molecular dynamics (MD); adsorption, distribution, metabolism, elimination and toxicity (ADMET); and target prediction. ShCsO decreased enzyme activity at a concentration of 0.0001 mg/mL. The docking scores of A, B and C from in silico studies were -6.254, -6.936 and -6.980 kcal/mol, respectively, and the scores for the two different PI-88 monomers were -5.741 and -5.824 kcal/mol. These results show that ShCsO may be a potential drug candidate for treating cancer.Communicated by Ramaswamy H. Sarma.

Exploring enzyme inhibition profiles of novel halogenated chalcone derivatives on some metabolic enzymes: Synthesis, characterization and molecular modeling studies.

Enzyme inhibition is a very active area of research in drug design and development. Chalcone derivatives have a broad enzyme inhibitory activity and function as potential molecules in the development of new drugs. In this study, the synthesized novel halogenated chalcones with bromobenzyl and methoxyphenyl moieties were evaluated toward the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and human erythrocyte carbonic anhydrase I (hCA I), and II (hCA II) isoenzymes. They showed highly potent inhibition ability toward AChE with Ki values of 1.83 ± 0.21-11.19 ± 0.96 nM and BChE with Ki values of 3.35 ± 0.91-26.70 ± 4.26 nM; hCA I with Ki values of 29.41 ± 3.14-57.63 ± 4.95 nM, and hCA II with Ki values of 24.00 ± 5.39-54.74 ± 1.65 nM. Among the tested enzyme inhibitions, compounds 14 and 13 were the most active compounds against AChE and BChE. Docking studies were performed to the most active compounds against AChE, BChE, hCA I and hCA II to propose a binding mode in the active site and molecular dynamics simulations were studied to check the molecular interactions and the stability of the ligands in the active site. The results may contribute to the development of new drugs particularly to treat some global disorders including Alzheimer's disease (AD), glaucoma, and diabetes.

Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies.

Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.

Azoles containing naphthalene with activity against Gram-positive bacteria: in vitro studies and in silico predictions for flavohemoglobin inhibition.

Azoles are first-line drugs used in fungal infections. Topical antifungals, such as miconazole and econazole, are known to be active against Gram-positive bacteria, which was reported to result from bacterial flavohemoglobin (flavoHb) inhibition. Dual antibacterial/antifungal action is believed to have benefits for antimicrobial chemotherapy. In this study, we tested antibacterial effects of an in-house library of naphthalene-bearing azoles, some of which were reported as potent antifungals, in an attempt to find dual-acting hits. Several potent derivatives were obtained against the Gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. 9 was active at a minimum inhibitor concentration (MIC) less than 1 µg/ml against E. faecalis and S. aureus, and 10 against S. aureus. 16 was also potent against E. faecalis and S. aureus (MIC = 1 and 2 µg/ml, respectively). Six more were active against S. aureus with MIC ≤ 4 µg/ml. In vitro cytotoxicity studies showed that the active compounds were safe for healthy cells within their MIC ranges. According to the calculated descriptors, the library was found within the drug-like chemical space and free of pan-assay interference compounds (PAINS). Molecular docking studies suggested that the compounds might be bacterial flavohemoglobin (flavoHb) inhibitors and the azole and naphthalene rings were important pharmacophores, which was further supported by pharmacophore modeling study. As a result, the current study presents several non-toxic azole derivatives with antibacterial effects. In addition to their previously reported antifungal properties, they could set a promising starting point for the future design of dual acting antimicrobials. Communicated by Ramaswamy H. Sarma.

New chalcone derivatives as effective against SARS-CoV-2 agent.

AIMS: Flavonoids and related compounds, such as quercetin-based antiviral drug Gene-Eden-VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The alkylated chalcones isolated from Angelica keiskei inhibit SARS-CoV proteases. In this study, we aimed to compare the anti-SARS CoV-2 activities of both newly synthesized chalcone derivatives and these two drugs. METHODS: Determination of the potent antiviral activity of newly synthesized chalcone derivatives against SARS-CoV-2 by calculating the RT-PCR cycling threshold (Ct ) values. RESULTS: Antiviral activities of the compounds varied because of being dose dependent. Compound 6, 7, 9, and 16 were highly effective against SARS-CoV-2 at the concentration of 1.60 µg/mL. Structure-based virtual screening was carried out against the most important druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase, to identify putative inhibitors that could facilitate the development of potential anti-coronavirus disease-2019 drug candidates. CONCLUSIONS: Computational analyses identified eight compounds inhibiting each target, with binding affinity scores ranging from -4.370 to -2.748 kcal/mol along with their toxicological, ADME, and drug-like properties.