In quest of small-molecules as potent non-competitive inhibitors against influenza

A series of scaffolds namely aurones, 3-indolinones, 4-quinolones and cinnamic acid-piperazine hybrids, was designed, synthesized and investigated in vitro against influenza A/H1N1pdm09 virus. Designed molecules adopted different binding mode i.e., in 430-cavity of neuraminidase, unlike sialic acid and oseltamivir in molecular docking studies. All molecules reduced the viral titer and exhibited non-cytotoxicity along with cryoprotective property towards MDCK cells. Molecules (Z)-2-(3 '-Chloro-benzylidene)-1,2-dihydro-indol-3-one (2f), (Z)-2-(4 '-Chloro-benzylidene)-1,2-dihydro-indol-3-one (2g) and 2-(2 '-Methoxy-phenyl)-1H-quinolin-4-one (3a) were the most interesting molecules identified in this research, endowed with robust potencies showing lownanomolar EC50 values of 4.0 nM, 6.7 nM and 4.9 nM, respectively, compared to reference competitive and non-competitive inhibitors: oseltamivir (EC50 = 12.7 nM) and quercetin (EC50 = 0.56 mu M), respectively. Besides, 2f, 2g and 3a exhibited good neuraminidase inhibitory activity in sub-micromolar range (IC50 = 0.52 mu M, 3.5 mu M, 1.3 mu M respectively). Moreover, these molecules were determined as non-competitive inhibitors similar to reference non-competitive inhibitor quercetin unlike reference competitive inhibitor oseltamivir in kinetics studies.

Automated summary

A series of scaffolds were designed and synthesized as potential anti-influenza agents, with some molecules demonstrating high antiviral activity and neuraminidase inhibitory activity, as well as cell-protective properties.