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

Hrast, Martina (author), Gradišek, Nina (author), Frlan, Rok (author), Sosič, Izidor (author), Bolje, Aljoša (author), Kljun, Jakob (author), Juhás, Martin (author), Gobec, Stanislav (author), Pajk, Stane (author)

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 IC$_{50}$ of 11 µmol 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.

• Language: English
• Keywords: tuberculosis, InhA, direct inhibitors, click reaction, 1, 3-diol synthesis
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 185-218
• Numbering: Vol. 75, iss. 2
• PID: 20.500.12556/RUL-169978
• UDC: 616-002.5
• ISSN on article: 1846-9558
• DOI: 10.2478/acph-2025-0016
• COBISS.SI-ID: 240648963
• Publication date in RUL: 30.06.2025

Record is a part of a journal

• Title: Acta pharmaceutica
• Shortened title: Acta pharm.
• Publisher: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: tuberkuloza, InhA, direktni inhibitorji, klik reakcija, sinteza 1, 3-diola