Isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols for inhibition of acetylcholinesterase

A series of novel isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols (IT2Ts) 1a–1g were designed as acetylcholinesterase (AChE) inhibitors capable of interacting with both the catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme simultaneously. The target IT2Ts were prepared through a short synthesis in moderate yield. The most potent inhibitors of this series 1b and 1c (IC₅₀ = 18.2 and 27.5 μM, respectively) outperformed rivastigmine and were comparable to galantamine, both clinically used AChE inhibitors. Furthermore, 1b displayed non-competitive inhibition patterns in kinetic studies, whereas molecular modeling predicted a simultaneous interaction with both the CAS and PAS. In silico methods predicted several promising drug-like characteristics of 1b. Taken together, these results indicate 1b warrants further investigation as a multitarget-directed ligand for AChE inhibition. [Figure not available: see fulltext.]