2-Aryl benzazole derived new class of anti-tubercular compounds: Endowed to eradicate mycobacterium tuberculosis in replicating and non-replicating forms

Anand Babu Velappan; Dhrubajyoti Datta; Rui Ma; Shiwani Rana; Kalyan Sundar Ghosh; Natarajan Hari; Scott G Franzblau; Joy Debnath

doi:10.1016/j.bioorg.2020.104170

2-Aryl benzazole derived new class of anti-tubercular compounds: Endowed to eradicate mycobacterium tuberculosis in replicating and non-replicating forms

Bioorg Chem. 2020 Oct:103:104170. doi: 10.1016/j.bioorg.2020.104170. Epub 2020 Aug 27.

Authors

Anand Babu Velappan¹, Dhrubajyoti Datta², Rui Ma³, Shiwani Rana⁴, Kalyan Sundar Ghosh⁴, Natarajan Hari⁵, Scott G Franzblau³, Joy Debnath⁶

Affiliations

¹ Department of Chemistry, SCBT, SASTRA Deemed to be University, Tamilnadu 613401, India.
² Department of Chemistry, Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India.
³ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
⁴ Department of Chemistry, National Institute of Technology Hamirpur, Himachal Pradesh 177005, India.
⁵ NMR Laboratory, SCBT, SASTRA Deemed to be University, Tamilnadu 613401, India.
⁶ Department of Chemistry, SCBT, SASTRA Deemed to be University, Tamilnadu 613401, India. Electronic address: joydebnath@scbt.sastra.edu.

PMID: 32890990
DOI: 10.1016/j.bioorg.2020.104170

Abstract

The high mortality rate and the increasing prevalence of Mtb resistance are the major concerns for the Tuberculosis (TB) treatment in this century. To counteract the prevalence of Mtb resistance, we have synthesized 2-aryl benzazole based dual targeted molecules. Compound 9m and 9n were found to be equally active against replicating and non-replicating form of Mtb (MIC_(MABA) 1.98 and 1.66 μg/ml; MIC_(LORA) 2.06 and 1.59 μg/ml respectively). They arrested the cell division (replicating Mtb) by inhibiting the GTPase activity of FtsZ with IC₅₀ values 45 and 64 μM respectively. They were also capable of kill Mtb in non-replicating form by inhibiting the biosynthesis of menaquinone which was substantiated by the MenG inhibition (IC₅₀ = 11.62 and 7.49 μM respectively) followed by the Vit-K2 rescue study and ATP production assay.

Keywords: Benzazole; FtsZ enzyme; MenG enzyme; Tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / pharmacology
Antitubercular Agents / therapeutic use*
Humans
Mycobacterium tuberculosis / drug effects*

Substances

Antitubercular Agents