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

IF 2.1 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Acta Pharmaceutica Pub Date : 2025-07-03 Print Date: 2025-06-01 DOI:10.2478/acph-2025-0016
Martina Hrast Rambaher, Nina Gradišek, Rok Frlan, Izidor Sosič, Aljoša Bolje, Jakob Kljun, Martin Juhás, Stanislav Gobec, Stane Pajk
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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 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.

以噻二唑和四氢吡喃系列抑制剂为灵感的新型InhA抑制剂的开发和评价。
由结核分枝杆菌引起的结核病仍然是全球主要的卫生挑战,多药耐药(MDR)和广泛耐药(XDR)菌株的出现加剧了这一挑战。一个有希望的治疗靶点是烯酰酰基载体蛋白还原酶(InhA),它在细菌细胞壁必需成分霉菌酸的生物合成中起着至关重要的作用。直接抑制InhA为克服耐药机制提供了一种潜在的策略,特别是在异烟肼等传统药物的激活受到损害的情况下。本研究研究了两个基于噻二唑和四氢吡喃先导化合物的新型InhA抑制剂系列,最初是通过GSK高通量筛选确定的。采用铜催化叠氮化物-炔环加成反应(CuAAC)合成了类似物,并测定了其对InhA的抑制活性。在所测试的化合物中,只有一种表现出适度的抑制活性,ic50为11µmol L-1,而其他化合物则无活性。有趣的是,在合成过程中,发现了芳基甲基酮和乙基溴化镁之间的新反应,生成1,3-二醇,经x射线衍射分析证实。这些发现强调了优化InhA抑制剂的挑战,并强调了探索新的合成途径的合成创新的潜力。
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来源期刊
Acta Pharmaceutica
Acta Pharmaceutica PHARMACOLOGY & PHARMACY-
CiteScore
5.20
自引率
3.60%
发文量
20
审稿时长
>12 weeks
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.
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