Multifunctional 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease

Publication date: Available online 21 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Rui Xu, Ganyuan Xiao, Yan Li, Hongyan Liu, Qing Song, Xiaoyu Zhang, Ziyi Yang, Yunxiaozhu Zheng, Zhenghuai Tan, Yong Deng
A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50 = 0.29 ± 0.01 μM and 0.46 ± 0.02 μM, respectively), MAO-A (IC50 = 8.2 ± 0.08 μM and 7.9 ± 0.07 μM, respectively) and MAO-B (IC50 = 20.1 ± 0.16 μM and 43.8 ± 2.0% at 10 μM, respectively) inhibitory activities, moderate self-induced Aβ1-42 aggregation inhibitory potency (35.4 ± 0.42% and 48.0 ± 1.53% at 25 μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.

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