Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Background: Alzheimer's disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports.

Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1)-quinolinone and dithiocarbamate.

Methods: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo.

Results: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC=0.28 µM to eeAChE; IC=0.34 µM to hAChE; IC=2.81 µM to hMAO-B; IC=0.91 µM to hMAO-A). In addition, showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of was lower than 12.5 µM. More importantly, lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.).

Conclusion: This work indicated that compound with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study.