Design, synthesis and evaluation of chalcones as H1N1 Neuraminidase inhibitors

A series of chalcone derivatives (1a-2i) were designed based on isoliquiritigenin (the most active natural chalcone non-competitive neuraminidase (NA) inhibitor). Molecular modeling studies revealed that isoliquiritigenin and its designed analogs occupied 430-loop cavity of NA and interacted favorably with catalytic site residues. The favorable derivatives were synthesized and evaluated for cytotoxicity and for inhibition of cytopathic effect by H1N1 virus. The inhibitory effect was further quantified by heamagglutinition (HA) assay, H1N1-NA inhibition, and kinetics of inhibition. The HA assay showed compound 1e has the lowest EC50 of 1.71 nM. In contrast, the H1N1-NA inhibition assay showed compound 1f has the best activity with the IC50 of 3.58 mu M. Enzyme kinetic study suggested that the inhibition mechanism of compounds 1f and 2f was non-competitive.