Development of novel N-(6-methanesulfonyl-benzothiazol-2-yl)-3-(4-substituted-piperazin-1-yl)-propionamides with cholinesterase inhibition, anti-beta-amyloid aggregation, neuroprotection and cognition enhancing properties for the therapy of Alzheimer's disease

A novel series of benzothiazole-piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). The synthesized hybrid molecules illustrated modest to strong inhibition of acetylcholinesterase (AChE) and A beta(1-42) aggregation. Compound 12 emerged as the most potent hybrid molecule exhibiting balanced functions with effective, uncompetitive and selective inhibition against AChE (IC50 = 2.31 mu M), good copper chelation, A beta(1-42) aggregation inhibition (53.30%) and disaggregation activities. Confocal laser scanning microscopy and TEM analysis also validate the A beta fibril inhibition ability of this compound. Furthermore, this compound has also shown low toxicity and is capable of impeding loss of cell viability elicited by H2O2 neurotoxicity in SHSY-5Y cells. Notably, compound 12 significantly improved cognition and spatial memory against scopolamine-induced memory deficit in a mouse model. Hence, our results corroborate the multifunctional nature of novel hybrid molecule 12 against AD and it may be a suitable lead for further development as an effective therapeutic agent for therapy in the future.