Design, synthesis, evaluation, and molecular dynamic simulation of triclosan mimic diphenyl ether derivatives as antitubercular and antibacterial agents

Khade, Amol B and Vandana, KE and Verma, Ruchi and Shenoy, Gautham G (2020) Design, synthesis, evaluation, and molecular dynamic simulation of triclosan mimic diphenyl ether derivatives as antitubercular and antibacterial agents. Structural Chemistry, 31. pp. 983-998. ISSN 1040-0400

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Abstract

In the present work, we have explored triclosan mimic diphenyl ether derivatives as inhibitors of Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) using a structure-based drug design approach. The virtual library of diphenyl ethers was designed and compounds with acceptable absorption, distribution, metabolism, excretion, and toxicity properties were docked. The compounds with higher dock score (5a-g) than triclosan were synthesized, characterized, and evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. Among the synthesized compounds, compounds 5f and 5c appeared to be the most promising with minimum inhibitory concentration of 18 μM and 36 μM respectively. The molecular dynamics simulation study of the most active compound 5f and triclosan was performed, which correlates with its activity in comparison with triclosan. All the compounds were further evaluated for cytotoxicity studies against Vero, and HepG2 were found to be safe. Furthermore, compound 5f was evaluated for in vitro cytotoxicity against mouse macrophage cell lines (RAW 264.7), and the study indicated its safety in eukaryotes at 50-μM concentration. In addition, compounds 5a-g were also creened for their in vitro antibacterial activity against two gram-positive and two gram-negative bacteria by esazurin-based microtiter dilution assay method. Among the synthesized compounds, 5f and 5b appeared to be promising, against various grampositive and gram-negative microorganisms, indicating its broad-spectrum potential. Keywords Diphenyl ethers . Antitubercular agents . InhA . Triclosan . Molecular dynamics

Item Type: Article
Uncontrolled Keywords: Diphenyl ethers ; Antitubercular agents; InhA ; Triclosan ; Molecular dynamics simulation
Subjects: Medicine > KMC Manipal > Microbiology
Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Depositing User: KMC Library
Date Deposited: 27 Jan 2021 12:02
Last Modified: 27 Jan 2021 12:02
URI: http://eprints.manipal.edu/id/eprint/156258

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