Structural Elucidation and Total Synthesis for the Pair of Unprecedented Polypyridines with Anti-AChE and HIV‑1 Protease Activities from Alangium chinense

• Published in: Journal of organic chemistry Vol. 87; no. 23; pp. 16047 - 16053
• Main Authors: Hu, Xin-Yue, Zhu, Shi-Jie, Meng, Xiu-Hua, Yu, Hao-Fei, Liu, Xia, Zhang, Li-Yan, Wei, Ying, Lei, Chuan-Wen, Wei, Xin, Zhou, Ying
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.12.2022; Amer Chemical Soc
• Subjects: Acetylcholinesterase - metabolism; Alangiaceae - metabolism; Chemistry; Chemistry, Organic; HIV Protease Inhibitors; HIV-1; Molecular Docking Simulation; Physical Sciences; Pyridines - pharmacology; Science & Technology; ALKYLATION
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.2c02180

Unlike reported pyridine hybrids, 2S (1a) and 2R-alanginenmine A (1b) from Alangium chinense featuring an unprecedented piperidine-bridged polypyridine skeleton represented a pair of alkaloid subtypes with a unique multiple pyridine scaffold. Enlightened by the rare structural characteristics and possible biosynthetic pathway, (±)-alanginenmine A (1) have been achieved in ideal yield by gram-class total synthesis with four steps. In addition, both compounds 1a and 1b exhibited anti-acetylcholinesterase (AChE) and HIV-1 protease activities in the biological activity evaluation. Further, molecular docking was investigated for the mechanism of action between the isolated compounds and HIV-1 protease. The stronger Coulomb interactions and van der Waals interaction, as well as the hydrogen bond interactions of 1a, might be the main cause for its better anti-HIV-1 protease activity than 1b. This work provided a comprehensive research including natural product discovery, bioactivity evaluation, and total synthesis for the new type of leading anti-HIV-1 protease.