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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\n                    <jats:italic>IC<\/jats:italic>\n                    <jats:sub>50<\/jats:sub>\n                    of 11 \u00b5mol L\u20131, 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.\n                  <\/jats:p>","DOI":"10.2478\/acph-2025-0016","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T12:58:44Z","timestamp":1751547524000},"page":"185-218","source":"Crossref","is-referenced-by-count":3,"title":["Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors"],"prefix":"10.2478","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0488-2445","authenticated-orcid":false,"given":"Martina Hrast","family":"Rambaher","sequence":"first","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9557-0229","authenticated-orcid":false,"given":"Nina","family":"Gradi\u0161ek","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-5537","authenticated-orcid":false,"given":"Rok","family":"Frlan","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3370-4587","authenticated-orcid":false,"given":"Izidor","family":"Sosi\u010d","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1620-5361","authenticated-orcid":false,"given":"Aljo\u0161a","family":"Bolje","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1986-4840","authenticated-orcid":false,"given":"Jakob","family":"Kljun","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Chemistry and Chemical Technology , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-9082","authenticated-orcid":false,"given":"Martin","family":"Juh\u00e1s","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"},{"name":"Charles University , Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9 , Hradec Kr\u00e1lov\u00e9 Czech Republic"},{"name":"University of Hradec Kr\u00e1lov\u00e9 , Faculty of Science , Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-3083","authenticated-orcid":false,"given":"Stanislav","family":"Gobec","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9496-5879","authenticated-orcid":false,"given":"Stane","family":"Pajk","sequence":"additional","affiliation":[{"name":"University of Ljubljana , Faculty of Pharmacy , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"2026070314051886206_j_acph-2025-0016_ref_001","unstructured":"https:\/\/www.who.int\/health-topics\/tuberculosis#tab=tab_1; last access date May 19, 2025."},{"key":"2026070314051886206_j_acph-2025-0016_ref_002","doi-asserted-by":"crossref","unstructured":"Y. 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