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

Abstract

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.

• Authors: Khushboo Malbari, Priyanka Saha, Mamta Chawla-Sarkar, Shanta Dutta, Swita Rai, Mamata Joshi, Meena Kanyalkar
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 114 Pg. 105139 (09 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34243071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Small Molecule Libraries

Topics

• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Influenza A Virus, H1N1 Subtype (drug effects)
• Microbial Sensitivity Tests
• Molecular Docking Simulation
• Molecular Structure
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship