Angelova Violina T, Pencheva Tania, Vassilev Nikolay, K-Yovkova Elena, Mihaylova Rositsa, Petrov Boris, Valcheva Violeta
Department of Chemistry, Faculty of Pharmacy, Medical University, 1431 Sofia, Bulgaria.
Department of QSAR and Molecular Modeling, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
Antibiotics (Basel). 2022 Apr 22;11(5):562. doi: 10.3390/antibiotics11050562.
Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives - and sulfonyl hydrazones - were synthesized. They were characterized by H-NMR, C NMR, and HRMS. strain H37Rv was used to assess their antimycobacterial activity. All compounds demonstrated significant minimum inhibitory concentrations (MIC) from 0.07 to 0.32 µM, comparable to those of isoniazid. The cytotoxicity was evaluated using the standard MTT-dye reduction test against human embryonic kidney cells HEK-293T and mouse fibroblast cell line CCL-1. 4-Hydroxy-3-methoxyphenyl substituted 1,2,3-thiadiazole-based hydrazone derivative demonstrated the highest antimycobacterial activity (MIC = 0.0730 µM) and minimal associated cytotoxicity against two normal cell lines (selectivity index SI = 3516, HEK-293, and SI = 2979, CCL-1). The next in order were sulfonyl hydrazones and with MIC 0.0763 and 0.0716 µM, respectively, which demonstrated comparable minimal cytotoxicity. All compounds were subjected to ADME/Tox computational predictions, which showed that all compounds corresponded to Lipinski's Ro5, and none were at risk of toxicity. The suitable scores of molecular docking performed on two crystallographic structures of enoyl-ACP reductase (InhA) provide promising insight into possible interaction with the InhA receptor. The 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives and sulfonyl hydrazones proved to be new classes of lead compounds having the potential of novel candidate antituberculosis drugs.
合成了15种基于4-甲基-1,2,3-噻二唑的腙衍生物和磺酰腙。通过核磁共振氢谱（H-NMR）、碳谱（C NMR）和高分辨质谱（HRMS）对它们进行了表征。使用H37Rv菌株评估它们的抗分枝杆菌活性。所有化合物的最低抑菌浓度（MIC）在0.07至0.32μM之间，与异烟肼相当。使用标准的MTT染料还原试验评估对人胚肾细胞HEK-293T和小鼠成纤维细胞系CCL-1的细胞毒性。基于4-羟基-3-甲氧基苯基取代的1,2,3-噻二唑的腙衍生物表现出最高的抗分枝杆菌活性（MIC = 0.0730μM），并且对两种正常细胞系的相关细胞毒性最小（选择性指数SI = 3516，针对HEK-293；SI = 2979，针对CCL-1）。其次是磺酰腙，其MIC分别为0.0763和0.0716μM，表现出相当的最小细胞毒性。所有化合物都进行了药物代谢动力学/药物毒性（ADME/Tox）计算预测，结果表明所有化合物均符合Lipinski的五规则（Ro5），没有毒性风险。对烯酰-酰基载体蛋白还原酶（InhA）的两种晶体结构进行分子对接得到的合适分数，为与InhA受体的可能相互作用提供了有前景的见解。基于4-甲基-1,2,3-噻二唑的腙衍生物和磺酰腙被证明是具有新型抗结核药物候选潜力的新型先导化合物类别。
