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Anti-Infective Agents

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ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

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Research Article

Antitubercular Potential of Novel Isoxazole Encompassed 1, 2, 4- Triazoles: Design, Synthesis, Molecular Docking Study and Evaluation of Antitubercular Activity

Author(s): Neenu Ganesh, Arun Kumar S, Manisha Singh, Venkaraddi Mangannavar Chandrashekar and Gurubasavaraj Veeranna Pujar*

Volume 19, Issue 2, 2021

Published on: 11 July, 2020

Page: [147 - 161] Pages: 15

DOI: 10.2174/2211352518999200711163714

Price: $65

Abstract

Background: Decaprenylphosphoryl-β-D-ribose epimerase (DprE1), a flavoprotein enzyme engaged in the biosynthesis of decaprenylphosphoryl-β-D-arabinofuranose (DPA), is the only contributor of arabinose residues which is fundamental for the mycobacterium cell wall constituents. DprE1 is an interesting target for antitubercular agent and has been exploring to develop potential chemical entities as antitubercular agents.

Objective: The objective of the study is the development of novel antitubercular agents targeting Mtb Decaprenylphosphoryl-β-D-ribose epimerase (DprE1).

Methods: A series of isoxazole encompassed 1, 2, 4-triazoles were designed based on the antitubercular potential of triazoles and structural features of DprE1 inhibitors. Designed 1, 2, 4- triazoles were synthesized and characterized by spectral studies. The in vitro anti-TB activity of the compounds was screened against Mycobacterium tuberculosis H37Rv strain by Microplate Almar Blue Assay and in vitro cytotoxicity against normal cell lines by MTT assay. Molecular docking study was carried out on DprE1 enzyme to understand designed compounds interactions with amino acid residues at the active site.

Results: Antitubercular activity data revealed that eight compounds (6d, 6e,7d, 7e, 10d, 10e, 11d and 11e) have shown promising antitubercular activity with minimum inhibitory concentration at 1.6μg/mL. Cytotoxicity data of anti-TB active compounds demonstrate good safety profile on normal cell lines.

Conclusion: Eight compounds have shown promising antitubercular activity with good safety profile on normal cell lines. Molecular docking study revealed that the synthesized compounds have shown non-covalent interactions with amino acid residues of DprE1 enzyme.

Keywords: Isoxazole, 1, 2, 4-triazole, Mtb H37Rv strain, MTT assay, DprE1 enzyme, antitubercular activity.

Graphical Abstract

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