Sabt Ahmed, Abdulla Maha-Hamadien, Ebaid Manal S, Pawełczyk Jakub, Abd El Salam Hayam A, Son Ninh The, Ha Nguyen Xuan, Vaali Mohammed Mansoor-Ali, Traiki Thamer, Elsawi Ahmed E, Dziadek Bozena, Dziadek Jaroslaw, Eldehna Wagdy M
Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center, Dokki, Egypt.
Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Front Chem. 2024 Aug 7;12:1424017. doi: 10.3389/fchem.2024.1424017. eCollection 2024.
The spread of drug-resistant tuberculosis strains has become a significant economic burden globally. To tackle this challenge, there is a need to develop new drugs that target specific mycobacterial enzymes. Among these enzymes, InhA, which is crucial for the survival of , is a key target for drug development. Herein, 24 compounds were synthesized by merging 4-carboxyquinoline with triazole motifs. These molecules were then tested for their effectiveness against different strains of tuberculosis, including , , and . Additionally, their ability to inhibit the InhA enzyme was also evaluated. Several molecules showed potential as inhibitors of . Compound displayed the highest efficacy with a MIC value of 12.5 μg/mL. Compounds , , and exhibited inhibitory effects on InhA. Notably, showed significant activity compared to the reference drug Isoniazid. Molecular docking analysis revealed interactions between these molecules and their target enzyme. Additionally, the molecular dynamic simulations confirmed the stability of the complexes formed by quinoline-triazole conjugate with the InhA. Finally, underwent analysis to predict its ADME characteristics. These findings provide promising insights for developing novel small compounds that are safe and effective for the global fight against tuberculosis.
耐药结核菌株的传播已成为全球一项重大的经济负担。为应对这一挑战，需要开发针对特定分枝杆菌酶的新药。在这些酶中，对生存至关重要的InhA是药物开发的关键靶点。在此，通过将4-羧基喹啉与三唑基序合并合成了24种化合物。然后测试了这些分子对不同结核菌株的有效性，包括、和。此外，还评估了它们抑制InhA酶的能力。几种分子显示出作为抑制剂的潜力。化合物的最低抑菌浓度（MIC）值为12.5μg/mL，显示出最高的疗效。化合物、和对InhA表现出抑制作用。值得注意的是，与参考药物异烟肼相比，显示出显著的活性。分子对接分析揭示了这些分子与其靶酶之间的相互作用。此外分子动力学模拟证实了喹啉-三唑共轭物与InhA形成的复合物的稳定性。最后，对进行了分析以预测其吸收、分布、代谢和排泄（ADME）特性。这些发现为开发对全球抗击结核病安全有效的新型小分子化合物提供了有前景的见解。
