Martina Hrast Rambaher, Nina Gradišek, Rok Frlan, Izidor Sosič, Aljoša Bolje, Jakob Kljun, Martin Juhás, Stanislav Gobec, Stane Pajk
{"title":"Development and evaluation of novel InhA inhibitors inspired by thiadiazole and tetrahydropyran series of inhibitors.","authors":"Martina Hrast Rambaher, Nina Gradišek, Rok Frlan, Izidor Sosič, Aljoša Bolje, Jakob Kljun, Martin Juhás, Stanislav Gobec, Stane Pajk","doi":"10.2478/acph-2025-0016","DOIUrl":null,"url":null,"abstract":"<p><p>Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i>, 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 <i>IC</i> <sub>50</sub> 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.</p>","PeriodicalId":7034,"journal":{"name":"Acta Pharmaceutica","volume":"75 2","pages":"185-218"},"PeriodicalIF":2.1000,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Pharmaceutica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2478/acph-2025-0016","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/1 0:00:00","PubModel":"Print","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
AP is an international, multidisciplinary journal devoted to pharmaceutical and allied sciences and contains articles predominantly on core biomedical and health subjects. The aim of AP is to increase the impact of pharmaceutical research in academia, industry and laboratories. With strong emphasis on quality and originality, AP publishes reports from the discovery of a drug up to clinical practice. Topics covered are: analytics, biochemistry, biopharmaceutics, biotechnology, cell biology, cell cultures, clinical pharmacy, drug design, drug delivery, drug disposition, drug stability, gene technology, medicine (including diagnostics and therapy), medicinal chemistry, metabolism, molecular modeling, pharmacology (clinical and animal), peptide and protein chemistry, pharmacognosy, pharmacoepidemiology, pharmacoeconomics, pharmacodynamics and pharmacokinetics, protein design, radiopharmaceuticals, and toxicology.