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

Abstract

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.