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

• Design and synthesis of Coumarin-triazole and Isatin-triazole hybrids. • Biological evaluation of synthesized hybrids against AChE by using Ellman's method. • Kinetic studies of potent compounds revealed the type of inhibition. • Determine the molecular properties of the potent compounds. • Binding modes of potent compounds within the active site of AChE enzyme using molecular modelling studies. • The stability studies of potent compound within the active pocket of the enzyme by using molecular dynamic simulations with Desmond software. 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 IC 50 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. [Display omitted] [ABSTRACT FROM AUTHOR]