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

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

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.

• Jezik: Angleški jezik
• Ključne besede: tuberculosis, InhA, direct inhibitors, click reaction, 1, 3-diol synthesis
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: Str. 185-218
• Številčenje: Vol. 75, iss. 2
• PID: 20.500.12556/RUL-169978
• UDK: 616-002.5
• ISSN pri članku: 1846-9558
• DOI: 10.2478/acph-2025-0016
• COBISS.SI-ID: 240648963
• Datum objave v RUL: 30.06.2025

Gradivo je del revije

• Naslov: Acta pharmaceutica
• Skrajšan naslov: Acta pharm.
• Založnik: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: tuberkuloza, InhA, direktni inhibitorji, klik reakcija, sinteza 1, 3-diola