Batran Rasha Z, Sabt Ahmed, Dziadek Jarosław, Kassem Asmaa F
Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre Dokki Cairo 12622 Egypt
Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences Lodz Poland.
RSC Adv. 2024 Jul 9;14(30):21763-21777. doi: 10.1039/d4ra02746a. eCollection 2024 Jul 5.
In this study, we designed and synthesized a series of coumarin derivatives as antitubercular agents targeting the enoyl acyl carrier protein reductase (InhA) enzyme. Among the synthesized compounds, the tetrazole derivative 4c showed the most potent antitubercular effect with a minimum inhibitory concentration value (MIC) of 15 μg mL against H37Rv and could also inhibit the growth of the mutant strain (Δ). Compound 4c was able to penetrate -infected human macrophages and suppress the intracellular growth of tubercle bacilli. Moreover, the target derivative 4c showed a potent inhibitory effect against InhA enzyme with an IC value of 0.565 μM, which was superior to the reference InhA inhibitor triclosan. Molecular docking of compound 4c within the InhA active site revealed the importance of the 4-phenylcoumarin ring system and tetrazole moiety for activity. Finally, the physicochemical properties and pharmacokinetic parameters of 4c were investigated.
在本研究中，我们设计并合成了一系列香豆素衍生物作为靶向烯酰基载体蛋白还原酶（InhA）的抗结核药物。在合成的化合物中，四唑衍生物4c表现出最有效的抗结核作用，对H37Rv的最低抑菌浓度值（MIC）为15μg/mL，并且还能抑制突变菌株（Δ）的生长。化合物4c能够穿透受感染的人类巨噬细胞并抑制结核杆菌的细胞内生长。此外，目标衍生物4c对InhA酶表现出强效抑制作用，IC值为0.565μM，优于参考InhA抑制剂三氯生。化合物4c在InhA活性位点内的分子对接揭示了4-苯基香豆素环系统和四唑部分对活性的重要性。最后，研究了4c的物理化学性质和药代动力学参数。
