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.