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 (TB) 治疗的基石，靶向烯酰 ACP 还原酶 InhA，它是霉菌酸生物合成中的关键酶。InhA 仍然是开发新的抗结核药物的有希望的目标。在此，我们报告了新型异烟肼杂合体的设计、合成和抗结核活性。其中，1 H -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，最低抑制浓度在 0.25–0.50 μg/mL 范围内，并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具有良好的耐受性，从而导致高选择性指数。杂种依赖于功能性KatG生产来抑制霉菌酸的生物合成。此外，与异烟肼类似，InhA 在结核分枝杆菌中的过表达导致对16a - 16g的高抗性水平并降低分枝杆菌酸生物合成抑制。总体而言，这些发现表明合成的喹啉-异烟肼杂化物是有前途的抗结核分子，需要进一步的临床前评估。