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

• Published in: Bioorganic chemistry 2021-09, Vol.114, p.105139-105139, Article 105139
• Main Authors: Malbari, Khushboo, Saha, Priyanka, Chawla-Sarkar, Mamta, Dutta, Shanta, Rai, Swita, Joshi, Mamata, Kanyalkar, Meena
• Format: Article
• Language: English
• Subjects: 430-cavity; Influenza; Neuraminidase; Non-competitive inhibition; Pandemic H1N1
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105139

[Display omitted] •Twenty-seven molecules comprised four scaffolds were designed and synthesized.•All molecules docked in 430-cavity unlike oseltamivir in pdmH1N1-NA enzyme.•All molecules reduce H1N1 viral titre with and showed cryo-protective property.•2f, 2g and 3a exhibited low nanomolar inhibition than oseltamivir for pdmH1N1.•Molecules are non-competitive inhibitors of H1N1 neuraminidase unlike oseltamivir.•Evaluated molecules may be useful as potential anti-influenza agents. 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 cryo-protective 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 low-nanomolar 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 µM), respectively. Besides, 2f, 2g and 3a exhibited good neuraminidase inhibitory activity in sub-micromolar range (IC50 = 0.52 µM, 3.5 µM, 1.3 µM 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.