Synthesis and discovery of (I-3,II-3)-biacacetin as a novel non-zinc binding inhibitor of MMP-2 and MMP-9

Eleven biflavones (7a–b and 9a–i) were synthesised by a simple and efficient protocol and screened for MMP-2 and MMP-9 inhibitory activities. Amongst them, a natural product-like analog, (I-3,II-3)-biacacetin (9h) was found to be the most potent inhibitor. Molecular docking studies suggest that unlike most of the known inhibitors, 9h inhibits MMP-2 and MMP-9 through non-zinc binding interactions.