20.500.12556/RUL-169978 Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors 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. tuberculosis InhA direct inhibitors click reaction 1 3-diol synthesis tuberkuloza InhA direktni inhibitorji klik reakcija sinteza 1 3-diola true false true Angleški jezik Slovenski jezik Članek v reviji 2025-06-30 11:13:40 2025-06-30 11:13:46 2025-07-01 03:55:47 0000-00-00 00:00:00 2025 0 0 Str. 185-218 iss. 2 Vol. 75 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-002.5 1846-9558 10.2478/acph-2025-0016 240648963 18525.pdf 18525.pdf 1 132C426AE3327102089F6AEA96402175 f1cf3682adb1645085f02f7c1bb5496d7c024a6c45ac2c2cec8b1993a6337fed 3af56d73-5591-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211863 https://acta.pharmaceutica.farmaceut.org/wp-content/uploads/2025/06/18525.pdf 1 a5d93354-5590-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211862 Fakulteta za farmacijo Fakulteta za kemijo in kemijsko tehnologijo 0 0 0