Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase

Bioorganic & Medicinal Chemistry
Olga I GudzeraMichail A Tukalo

Abstract

Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50=10.01μM and IC90=13.53μM.

References

Apr 1, 1985·Antimicrobial Agents and Chemotherapy·R SutherlandA R White
Sep 6, 2005·Science·John S ReaderPaul Schimmel

❮ Previous
Next ❯

Citations

Oct 27, 2016·Methods : a Companion to Methods in Enzymology·Eric A First, Charles J Richardson
Jul 15, 2020·Proceedings of the National Academy of Sciences of the United States of America·Sergey V MelnikovDieter Söll
Nov 28, 2018·Expert Opinion on Drug Discovery·Alexey Aleksandrov, Hannu Myllykallio
Sep 19, 2019·Pharmaceuticals·Giulia Oliveira TimoMauricio Homem-de-Mello
Nov 7, 2019·Journal of Computer-aided Molecular Design·Galyna P VolynetsMichail A Tukalo
Mar 14, 2019·Current Opinion in Pulmonary Medicine·Simon F K LeeMarc Lipman
Nov 30, 2019·Cell Death & Disease·Anzheng NieDongsheng Yu
Jul 15, 2020·Future Microbiology·Galyna P VolynetsSergiy M Yarmoluk
Dec 5, 2020·Future Medicinal Chemistry·Komal G SanguHaridas B Rode
Jan 21, 2021·Antimicrobial Agents and Chemotherapy·Diletta MazzantiniEmilia Ghelardi
May 17, 2021·Chemical Biology & Drug Design·Umar NdagiNdumiso N Mhlongo
Sep 20, 2021·Drug Discovery Today·Liu YangTingjun Hou

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Related Papers

Bioorganic & Medicinal Chemistry Letters
Qingyi MengQizheng Yao
Applied and Environmental Microbiology
Tomas BuryskaZbynek Prokop
Journal of Enzyme Inhibition and Medicinal Chemistry
Mohamed Ashraf AliRamakant Gaur
© 2021 Meta ULC. All rights reserved