Alcaraz Matthéo, Sharma Bharvi, Roquet-Banères Françoise, Conde Cyril, Cochard Thierry, Biet Franck, Kumar Vipan, Kremer Laurent
Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France.
Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, Punjab, India.
Eur J Med Chem. 2022 Sep 5;239:114531. doi: 10.1016/j.ejmech.2022.114531. Epub 2022 Jun 17.
Isoniazid is a cornerstone of modern tuberculosis (TB) therapy and targets the enoyl ACP reductase InhA, a key enzyme in mycolic acid biosynthesis. InhA is still a promising target for the development of new anti-TB drugs. Herein, we report the design, synthesis, and anti-tubercular activity of new isoniazid hybrids. Among these, 1H-1,2,3 triazole-tethered quinoline-isoniazid conjugates 16a to 16g exhibited high activity against Mycobacterium tuberculosis with minimal inhibitory concentrations in the 0.25-0.50 μg/mL range and were bactericidal in vitro. Importantly, these compounds were well tolerated at high doses on mammalian cells, leading to high selectivity indices. The hybrids were dependent on functional KatG production to inhibit mycolic acid biosynthesis. Moreover, overexpression of InhA in M. tuberculosis resulted in high resistance levels to 16a-16g and reduced mycolic acid biosynthesis inhibition, similar to isoniazid. Overall, these findings suggest that the synthesized quinoline-isoniazid hybrids are promising anti-tubercular molecules, which require further pre-clinical evaluation.
异烟肼是现代结核病治疗的基石，其作用靶点是烯酰基载体蛋白还原酶InhA，这是分枝菌酸生物合成中的一种关键酶。InhA仍然是开发新型抗结核药物的一个有前景的靶点。在此，我们报告新型异烟肼杂合物的设计、合成及抗结核活性。其中，1H-1,2,3-三唑连接的喹啉-异烟肼共轭物16a至16g对结核分枝杆菌表现出高活性，最低抑菌浓度在0.25 - 0.50μg/mL范围内，且在体外具有杀菌作用。重要的是，这些化合物在高剂量下对哺乳动物细胞耐受性良好，导致高选择性指数。这些杂合物依赖功能性KatG的产生来抑制分枝菌酸的生物合成。此外，结核分枝杆菌中InhA的过表达导致对16a - 16g的高耐药水平，并降低了分枝菌酸生物合成的抑制作用，这与异烟肼类似。总体而言，这些发现表明合成的喹啉-异烟肼杂合物是有前景的抗结核分子，需要进一步的临床前评估。
