Phthalimide‐(N‐alkylbenzylamine) cysteamide hybrids as multifunctional agents against Alzheimer’s disease: Design, synthesis, and biological evaluation

• Published in: Chemical biology & drug design 2021-10, Vol.98 (4), p.493-500
• Main Authors: Zhang, Heng, Song, Qing, Yu, Guangjun, Cao, Zhongcheng, Qiang, Xiaoming, Liu, Xiuxiu, Deng, Yong
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; acetylcholinesterase inhibition; Alzheimer Disease - drug therapy; Alzheimer's disease; Animals; antioxidant; Antioxidants - chemical synthesis; Antioxidants - pharmacology; anti‐Aβ aggregation; Benzylamines - chemistry; Blood-Brain Barrier - metabolism; Cholinesterase Inhibitors - chemical synthesis; Cysteamine - chemistry; Drug Design; Humans; Molecular Docking Simulation; multi‐target agents; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; neuroprotective effect; PC12 Cells; Phthalimides - chemistry; phthalimide‐(N‐alkylbenzylamine)cysteamide hybrids; Protein Binding; Rats; Structure-Activity Relationship
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13905

The complex pathogenesis of Alzheimer's disease (AD) calls for multi‐target approach for disease treatment. Herein, based on the MTDLs strategy, a series of phthalimide‐(N‐alkylbenzylamine) cysteamide hybrids were designed, synthesized, and investigated in vitro for the purpose. Most of the target compounds were found to be potential multi‐target agents. In vitro results showed that compound 9e was the representative compound in this series, endowed with high EeAChE and HuAChE inhibitory potency (IC50 = 1.55 µm and 2.23 µm, respectively), good inhibitory activity against self‐induced Aβ1‐42 aggregation (36.08% at 25 µm), and moderate antioxidant capacity (ORAC‐FL value was 0.68 Trolox equivalents). Molecular docking studies rationalized the binding mode of 9e in both PAS and CAS of AChE. Moreover, 9e displayed excellent ability to against H2O2‐induced PC12 cell injury and penetrate BBB. Overall, these results highlighted that compound 9e was an effective and promising multi‐target agent for further anti‐AD drug development. A series of phthalimide‐(N‐alkylbenzylamine) cysteamide hybrids were designed, synthesized, and in vitro evaluated as potential multifunctional agents for Alzheimer's disease treatment. Among them, compound 9e demonstrated moderate inhibition towards AChE and good activity against self‐induced Aβ1‐42 aggregation. Moreover, 9e also displayed antioxidant, neuroprotective potency, and BBB permeability.