Novel series of triazole containing coumarin and isatin based hybrid molecules as acetylcholinesterase inhibitors

Novel series of coumarin-triazole and isatin-triazole hybrids were rationally designed, synthesized and biologically evaluated to check their inhibitory potential against acetylcholinesterase enzyme by using in vitro Ellman's method. Most of the hybrid compounds showed significant inhibition against the enzyme. Biological assay revealed that compound B-1 (among 4-hydroxycoumarin-triazole series) and compound AS-8 (from isatin-triazole series) possessed potent inhibitory activity against the AChE with the IC50 values of 110 +/- 1.11 nM and 155 +/- 1.65 nM, respectively. These active compounds (B-1 and AS-8 ) exhibited mixed mode of enzyme's inhibition which was confirmed through enzyme kinetic studies. Molecular docking studies were performed to understand the binding modes of these potent compounds within the active pocket of AChE enzyme by using Discovery studio. Furthermore, to predict the stability of the most prominent compound B-1 within the catalytic cavity of AChE, molecular dynamic simulations were performed for 5 ns and was found that ligand and protein complex is stable within their dynamic system. Therefore, these hybrids could be taken as effective lead candidates for further designing, development and optimization of new acetylcholinesterase inhibitors. (C) 2021 Published by Elsevier B.V.

Automated summary

Novel coumarin-triazole and isatin-triazole hybrids were designed, synthesized, and evaluated for their inhibitory potential against acetylcholinesterase enzyme using Ellman's method. The compounds B-1 and AS-8 showed potent inhibitory activity with IC50 values of 110 +/- 1.11 nM and 155 +/- 1.65 nM, respectively, and exhibited a mixed mode of enzyme's inhibition. Molecular docking and dynamic simulations confirmed the stable binding of compound B-1 within the active pocket of AChE, suggesting it as a potential lead candidate for further development of acetylcholinesterase inhibitors.