Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents

• Main Authors: Lee, Fong-Kai, Chan, Nathaniel Jia-Yoong, Krishnan, Premanand, Salam, Dayang Sharyati Datu Abdul, Chee, Xavier Wezen, Muhamad, Azira, Low, Yun Yee, Ting, Kang-Nee, Lim, Kuan-Hon
• Format: Article
• Published: American Chemical Society 2024
• Subjects: QD Chemistry; RM Therapeutics. Pharmacology; RS Pharmacy and materia medica
• Online Access: http://eprints.um.edu.my/45483/; https://doi.org/10.1021/acs.jnatprod.3c00707

Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (E-max) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.