Discovery of thiazolo [5,4-c] isoquinoline based compounds as acetylcholinesterase inhibitors through computational target prediction, molecular docking and bioassay

A computer-aided drug design (CADD) approach was developed for a focused chemical library comprising a series of sixteen thiazolo[5,4-c]isoquinoline derivatives. Little is known about this group of heteroaromatic compounds, both from the point of view of their synthesis and their biological properties. First, our CADD approach included target prediction by Mondrian conformal prediction with the ChEMBL database. The acetylcholinesterase (AChE) was identified as having a high probability of thiazolo[5,4-c]isoquinolines being active against it. Secondly, the molecular docking predictions revealed four promising thiazoloisoquinolines (2, 7, 13 and 14) according to their prominent ligand-protein energy scores and relevant binding affinities with the AChE pocket residues. The subsequent in vitro evaluation of promising hits and related ones revealed a set of novel AChE inhibitors. Therefore, the findings reported herein may provide a new strategy for discovering novel AChE inhibitors.