Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France.
Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia.
Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0001121. doi: 10.1128/AAC.00011-21.
Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report here the design, synthesis, and antimycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis, with MICs in the range of 0.195 to 0.39 μg/ml, and exerted a more potent bactericidal effect than the standard antitubercular drug isoniazid (INH). Importantly, these compounds were found to be well tolerated at high doses (>200 μg/ml) on Vero kidney cells, leading to high selectivity indices. Two of the most promising hybrids were evaluated for activity in THP-1 macrophages infected with M. tuberculosis, among which compound 11e was found to be slightly more effective than INH. Overexpression of InhA along with cross-resistance determination of the most potent compounds, selection of resistant mutants, and biochemical analysis, allowed us to decipher their mode of action. These compounds effectively inhibited mycolic acid biosynthesis and required KatG to exert their biological effects. Collectively, this suggests that the synthesized isatin-INH hybrids are promising antitubercular molecules for further evaluation in preclinical settings.
结核病仍然是全球传染病死亡的主要原因，因此需要开发新的药物来对抗这种疾病。我们在这里报告了靛红-单/双异烟肼杂合体的设计、合成和抗分枝杆菌活性。大多数化合物对结核分枝杆菌表现出很高的活性，MIC 值在 0.195 到 0.39μg/ml 之间，比标准抗结核药物异烟肼（INH）具有更强的杀菌作用。重要的是，这些化合物在 Vero 肾细胞上以高剂量（>200μg/ml）时被发现具有良好的耐受性，导致高选择性指数。对两种最有前途的杂化物进行了在感染结核分枝杆菌的 THP-1 巨噬细胞中的活性评估，其中化合物 11e 被发现比 INH 略有效。过表达 InhA 以及最有效化合物的交叉耐药性测定、耐药突变体的选择和生化分析，使我们能够揭示它们的作用机制。这些化合物有效地抑制了分枝菌酸的生物合成，并且需要 KatG 来发挥它们的生物学效应。总的来说，这表明合成的靛红-INH 杂合体是有前途的抗结核分子，可在临床前环境中进一步评估。
