Devaraji Mahalakshmi, Thanikachalam Punniyakoti V
Department of Pharmaceutical Chemistry, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences, Chennai, IND.
Cureus. 2024 Sep 18;16(9):e69679. doi: 10.7759/cureus.69679. eCollection 2024 Sep.
Objective The study's goal was to come up with and make a new group of 1,3,4-oxadiazole derivatives (3a-3e) and test how well they could kill (Mtb) H37Rv strain. Additionally, molecular docking and pharmacokinetic properties were analyzed using computational software to identify potential inhibitors, followed by in vitro antimycobacterial assays. Methods A group of 1,3,4-oxadiazoles was prepared by reacting acyl hydrazides with alanine, an N-protected α-amino acid, and a small amount of POCl. This was carried out under microwave treatment. The structural characterization of the newly synthesized compounds was performed using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. The in vitro antimycobacterial activity of the 1,3,4-oxadiazole derivatives (3a-3e) was assessed using the microplate Alamar Blue assay against the Mtb H37Rv strain. The synthesized compounds were subjected to molecular docking investigations in order to gain insights into their interaction mechanisms with the mycobacterial enzyme InhA (enoyl-acyl carrier protein reductase). Computational analysis of pharmacokinetic properties was performed to predict the oral bioavailability and drug-likeness of the compounds. Results All synthesized compounds inhibited the growth of Mtbat concentrations of 50 and 100 μg/mL. At a concentration of 50 μg/mL, compounds 3c and 3d exhibited the most prominent antimycobacterial action. Molecular docking results revealed that compound 3d exhibited the highest binding energy interaction with the InhA enzyme (-9.1 kcal/mol). Pharmacokinetic predictions indicated that all compounds possess favorable drug-like properties suitable for oral administration. Conclusion This study successfully synthesized a novel series of oxadiazole derivatives (3a-3e) using a microwave-assisted method with high yields. The synthesized compounds demonstrated significant antimycobacterial activity, particularly compounds 3c and 3d. Molecular docking and pharmacokinetic analyses further confirmed the potential of these compounds as promising leads for the development of anti-tubercular agents.
目的 本研究的目标是设计并合成一组新的1,3,4-恶二唑衍生物（3a - 3e），并测试它们对结核分枝杆菌（Mtb）H37Rv菌株的杀灭效果。此外，使用计算软件分析分子对接和药代动力学性质，以鉴定潜在抑制剂，随后进行体外抗分枝杆菌测定。方法 通过酰肼与丙氨酸（一种N - 保护的α - 氨基酸）以及少量POCl₃反应制备一组1,3,4 - 恶二唑。此反应在微波处理下进行。使用红外（IR）光谱、核磁共振（NMR）光谱和质谱对新合成的化合物进行结构表征。使用微孔板Alamar Blue测定法评估1,3,4 - 恶二唑衍生物（3a - 3e）对Mtb H37Rv菌株的体外抗分枝杆菌活性。对合成的化合物进行分子对接研究，以深入了解它们与分枝杆菌酶InhA（烯酰 - 酰基载体蛋白还原酶）的相互作用机制。进行药代动力学性质的计算分析，以预测化合物的口服生物利用度和类药性质。结果 所有合成化合物在50和100μg/mL浓度下均抑制Mtb的生长。在50μg/mL浓度下，化合物3c和3d表现出最显著的抗分枝杆菌作用。分子对接结果表明，化合物3d与InhA酶表现出最高的结合能相互作用（-9.1 kcal/mol）。药代动力学预测表明，所有化合物都具有适合口服给药的良好类药性质。结论本研究使用微波辅助方法成功高收率地合成了一系列新型恶二唑衍生物（3a - 3e）。合成的化合物表现出显著的抗分枝杆菌活性，特别是化合物3c和3d。分子对接和药代动力学分析进一步证实了这些化合物作为抗结核药物开发潜在先导物的潜力。
