Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for in vitro growth inhibition activity against M. tuberculosis H37Rv, M. kansasii, M. avium and M. smegmatis by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for in vitro cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro-N-[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited M. tuberculosis, M. kansasii, and M. avium with MIC = 0.78 μg mL⁻¹ (2.3 μM) and a selectivity index related to HepG2 cells of SI > 20. Structure–activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.

中文翻译：

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吡嗪酰胺与 4-苯基噻唑-2-胺支架结合的杂化分子的设计、合成和抗分枝杆菌活性†

设计了基于一线抗结核吡嗪酰胺 (PZA) 和以前确定的 4-芳基噻唑-2-胺抗分枝杆菌支架组合的混合化合物。通过 Microplate Alamar Blue Assay 在中性 pH条件下，制备、表征和测试了 18 种化合物对结核分枝杆菌H37Rv、堪萨斯分枝杆菌、鸟分枝杆菌和耻垢分枝杆菌的体外生长抑制活性。在人肝细胞癌细胞系 (HepG2)中测试了活性化合物的体外细胞毒性。活性最强的 6-氯-N- [4-(4-氟苯基)噻唑-2-基]吡嗪-2-甲酰胺 (9b) 也具有最广谱的活性和抑制结核分枝杆菌、堪萨斯分枝杆菌和鸟分枝杆菌，MIC = 0.78 μg mL ^-1 (2.3 μM)，与 SI > 20 的 HepG2 细胞相关的选择性指数。讨论了系列内的结构-活性关系。基于其与已知抑制剂的结构相似性和分子对接研究的结果，我们建议分枝杆菌 β-酮酰基-（酰基-载体-蛋白）合酶 III (FabH) 作为潜在靶标。