Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 355516, Egypt.
Department of Medical Microbiology, Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.
Bioorg Chem. 2022 Jul;124:105809. doi: 10.1016/j.bioorg.2022.105809. Epub 2022 Apr 14.
Substituted aldehydes, ethyl 2-(2-amino-thiazol-4-yl)acetate), and 2-mercaptoacetic acid, in a three-component one-pot green synthetic approach afforded 2-arylthiazolidin-4-one- thiazole hybrids(T1-T13). Compounds showed good anti-tubercular activity towards sensitive M. tuberculosis strain. Compound T8 was as potent as isoniazide (INH) with MIC = 0.12 μg/ml. Compounds T2 and T13 showed potent activity with MIC = 0.48 μg/ml. Other compounds showed moderate to good anti-tubercular activity towards MDR M. tuberculosis strain with MIC range 1.95-125 μg/ml. Compounds T2, T8, T9, and T13 showed anti-tubercular activity towards XDR M. tuberculosis strain with MIC range 7.81-125 μg/ml. Compounds T2 and T8 were capable of inhibiting M. tuberculosis InhA enzyme in-vitro with IC = 1.3 ± 0.61 µM and 1.06 ± 0.97 µM, respectively. Molecular docking simulation showed that T2 and T8 were also capable of interacting at the catalytic site of InhA enzyme in a similar mode to the native ligand through binding with NAD and Tyr158. The 3D- QSAR study highlighted the relevance of substitution of phenyl group at position-2 of thiazolidin-4-one where bulky electronegative substitution at position-4 of the phenyl ring favored the activity against M. tuberculosis H37R. Additionally, compounds showed good antibacterial activity against bronchitis causing bacteria M. pneumoniae, S. pneumonia, K. pneumonia, and B. pertussis compared to Azithromycin. In-silico studies of ADMET descriptors and drug-likeness were conducted for all synthesized compounds. Compounds showed good oral bioavailability, good gastrointestinal absorption and showed no signs of adverse effects to the liver or CNS. Compounds showed no potential carcinogenicity as well.
在一个三步一锅的绿色合成方法中，用取代的醛、乙基 2-(2-氨基-噻唑-4-基)乙酸酯和 2-巯基乙酸合成了 2-芳基噻唑烷-4-酮-噻唑杂合体 (T1-T13)。这些化合物对敏感结核分枝杆菌表现出良好的抗结核活性。化合物 T8 的活性与异烟肼 (INH) 相当，MIC = 0.12μg/ml。化合物 T2 和 T13 的活性较强，MIC = 0.48μg/ml。其他化合物对 MDR 结核分枝杆菌的抗结核活性也较强，MIC 范围为 1.95-125μg/ml。化合物 T2、T8、T9 和 T13 对 XDR 结核分枝杆菌的抗结核活性也较强，MIC 范围为 7.81-125μg/ml。化合物 T2 和 T8 能够在体外抑制结核分枝杆菌 InhA 酶，IC = 1.3±0.61μM 和 1.06±0.97μM。分子对接模拟表明，T2 和 T8 也能够以与天然配体相似的方式与 NAD 和 Tyr158 结合，在 InhA 酶的催化部位相互作用。3D-QSAR 研究强调了噻唑烷-4-酮 2 位取代苯基的重要性，其中苯环 4 位的大体积吸电子取代有利于对结核分枝杆菌 H37R 的活性。此外，与阿奇霉素相比，这些化合物对引起支气管炎的细菌 M. pneumoniae、S. pneumonia、K. pneumonia 和 B. pertussis 也表现出良好的抗菌活性。对所有合成化合物进行了 ADMET 描述符和药物相似性的计算机模拟研究。这些化合物具有良好的口服生物利用度、良好的胃肠道吸收性，且对肝脏或中枢神经系统没有不良影响。这些化合物也没有表现出潜在的致癌性。
