First synthesis and in vitro biological assessment of isosideroxylin, 6, 8-dimethylgenistein and their analogues as nitric oxide production inhibition agents

A modular and efficient synthesis of the biologically significant C-methylisoflavones isosideroxylin (1), 6,8-dimethylgenistein (2) and their analogues (3-8) is established for the first time. The synthesis is realized in 7-8 steps in overall yields of 16%-24% from commercially inexpensive phloroglucinol and features a high yielding Vilsmeier-Haack reaction, Friedel-Crafts acylation, Gammill's protocol and Suzuki coupling as the pivotal transformations. Next, these compounds evaluated for their inhibitory potency on the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW-264.7 cells as an indicator of anti-inflammatory activity. The results showed that all the compounds decreased NO production in a dose-dependent manner without marked cytotoxicity and IC₅₀ values are found in the range of 10.17-33.88 μmol/L. Of note, compounds 3 followed by 1, 7 and 8 show comparable inhibitory activity with positive control (N-monomethyl-_L-arginine, L-NMMA).