Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents

Tiwari, Ashutosh Prasad and Shenoy, Gautham G and Vandana, KE and Bhat, Varadaraj G (2020) Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents. Molecular Diversity, 24 (4). pp. 1265-1279.

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Abstract

Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3- ydroxy4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M.tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development

Item Type: Article
Uncontrolled Keywords: Antitubercular; Correlation study; Diphenylether; InhA; Molecular docking; TB
Subjects: Medicine > KMC Manipal > Microbiology
Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Depositing User: KMC Library
Date Deposited: 01 Jun 2021 10:30
Last Modified: 01 Jun 2021 10:30
URI: http://eprints.manipal.edu/id/eprint/156588

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