Computational drug design, synthesis, acetylcholinesterase inhibition and kinetic evaluation of novel benzothiazole-thiadiazole/oxadiazole derivatives

Aims Developing novel benzothiazole–thiadiazole & oxadiazole hybrids as acetylcholinesterase (AChE) inhibitors.Material and methods Benzothiazole-thiadiazole (10a-n) and benzothiazole-oxadiazole (11a-p) hybrids were synthesized and evaluated for AChE inhibition. The drug-likeness, molecular docking, molecular dynamics simulations, and cytotoxicity were also performed.Results Compounds 10b, 10d and 10j emerged as potent inhibitors, displaying IC50 0.05 µM, 0.12 µM and 0.14 µM, respectively. The IC50 of compounds 11c, 11f and 11n are 0.13 µM, 0.11 µM, and 0.09 µM, respectively, which are comparable to donepezil (IC50 0.03 µM). Further enzyme kinetic assays revealed a competitive inhibition mechanism. Drug-likeness, molecular docking and molecular dynamic simulation and cytotoxicity assays confirm the efficacy and safety profile.Conclusions Benzothiazole-thiadiazole & oxadiazole scaffolds are promising leads for the developing AChE inhibitors.