Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F25%3A50022487" target="_blank" >RIV/62690094:18470/25:50022487 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/25:10504927

Result on the web

<a href="https://acta.pharmaceutica.farmaceut.org/wp-content/uploads/2025/06/18525.pdf" target="_blank" >https://acta.pharmaceutica.farmaceut.org/wp-content/uploads/2025/06/18525.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2478/acph-2025-0016" target="_blank" >10.2478/acph-2025-0016</a>

Result language

angličtina

Original language name

Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors

Original language description

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading global health challenge, exacerbated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. One promising therapeutic target is the enzyme enoyl-acyl carrier protein reductase (InhA), which plays a vital role in the biosynthesis of mycolic acids, essential components of the bacterial cell wall. Direct inhibition of InhA offers a potential strategy for overcoming resistance mechanisms, particularly in cases where the activation of conventional drugs like isoniazid is compromised. This study investigates two novel series of InhA inhibitors based on thiadiazole and tetrahydropyran lead compounds, originally identified through high-throughput screening by GSK. Analogues were synthesised using the copper-catalysed azide-alkyne cycloaddition (CuAAC) click reaction, and their inhibitory activity was tested against InhA. Among the tested compounds, only one exhibited modest inhibitory activity, with an IC50 of 11 mu mol L-1, while others were inactive. Interestingly, during the synthetic efforts, a novel reaction was discovered between aryl methyl ketones and ethynylmagnesium bromide, yielding 1,3-diols, as confirmed by X-ray diffraction analysis. These findings underscore the challenges of optimising InhA inhibitors and highlight the potential of synthetic innovations in exploring new synthetic pathways.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Acta Pharmaceutica

ISSN

1330-0075

e-ISSN

1846-9558

Volume of the periodical

75

Issue of the periodical within the volume

2

Country of publishing house

PL - POLAND

Number of pages

34

Pages from-to

185-218

UT code for WoS article

001522094000008

EID of the result in the Scopus database

2-s2.0-105010547489