Total Synthesis and Antimicrobial Evaluation of Bisoflavolin D: A Novel Biflavonoid from Streptomyces sp.

Bisoflavolin D (1) is a structurally unique biflavonoid originally isolated from Streptomyces sp. strain HDN154127 and exhibits potent antibacterial activity. However, its extremely low natural abundance has limited further biological investigation. Herein, we report the first total synthesis of bisoflavolin D (1). The key steps of our synthesis include three Suzuki–Miyaura cross-coupling reactions to construct the isoflavone monomers and establish the C-3‴–C-8 linkage of the biflavonoid scaffold. Preliminary antimicrobial testing revealed moderate antibacterial activity against Gram-positive pathogens, with a notable synergistic effect observed between bisoflavolin D (1) and norfloxacin (FICI = 0.28) against methicillin-resistant Staphylococcus aureus, as well as with amikacin against Escherichia coli (FICI < 0.16). This work provides a foundation for further exploration of bisoflavolin D (1) and its potential as an antimicrobial agent.