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), whic...
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| Language: | English |
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2025-06-01
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| Series: | Acta Pharmaceutica |
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| Online Access: | https://doi.org/10.2478/acph-2025-0016 |
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| author | Rambaher Martina Hrast Gradišek Nina Frlan Rok Sosič Izidor Bolje Aljoša Kljun Jakob Juhás Martin Gobec Stanislav Pajk Stane |
| author_facet | Rambaher Martina Hrast Gradišek Nina Frlan Rok Sosič Izidor Bolje Aljoša Kljun Jakob Juhás Martin Gobec Stanislav Pajk Stane |
| author_sort | Rambaher Martina Hrast |
| collection | DOAJ |
| 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 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. |
| format | Article |
| id | doaj-art-8c0ca840976345e8a00b537a35ffa438 |
| institution | OA Journals |
| issn | 1846-9558 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Sciendo |
| record_format | Article |
| series | Acta Pharmaceutica |
| spelling | doaj-art-8c0ca840976345e8a00b537a35ffa4382025-08-20T02:37:13ZengSciendoActa Pharmaceutica1846-95582025-06-0175218521810.2478/acph-2025-0016Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitorsRambaher Martina Hrast0Gradišek Nina1Frlan Rok2Sosič Izidor3Bolje Aljoša4Kljun Jakob5Juhás Martin6Gobec Stanislav7Pajk Stane81University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia2University of Ljubljana, Faculty of Chemistry and Chemical Technology, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, Slovenia1University of Ljubljana, Faculty of Pharmacy, 1000Ljubljana, SloveniaTuberculosis (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 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.https://doi.org/10.2478/acph-2025-0016tuberculosisinhadirect inhibitorsclick reaction1,3-diol synthesis |
| spellingShingle | Rambaher Martina Hrast Gradišek Nina Frlan Rok Sosič Izidor Bolje Aljoša Kljun Jakob Juhás Martin Gobec Stanislav Pajk Stane Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors Acta Pharmaceutica tuberculosis inha direct inhibitors click reaction 1,3-diol synthesis |
| title | Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors |
| title_full | Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors |
| title_fullStr | Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors |
| title_full_unstemmed | Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors |
| title_short | Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors |
| title_sort | development and evaluation of novel inha inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors |
| topic | tuberculosis inha direct inhibitors click reaction 1,3-diol synthesis |
| url | https://doi.org/10.2478/acph-2025-0016 |
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