Multidrug-resistant tuberculosis (MDR-TB) poses a significant threat to mankind and as such earned its place on the WHO list of priority pathogens. New antimycobacterials with a mechanism of action different to currently used agents are highly required. This study presents the design, synthesis, and biological evaluation of 3-acylaminopyrazine-2-carboxamides derived from a previously reported inhibitor of human prolyl-tRNA synthetase. Compounds were evaluated in vitro against various strains of mycobacteria, pathogenic bacteria, and fungi of clinical significance. In general, high activity against mycobacteria was noted, while the antibacterial and antifungal activity was minimal. The most active compounds were 4’-substituted 3-(benzamido)pyrazine-2-carboxamides, exerting MIC (Minimum Inhibitory Concentration) from 1.95 to 31.25 µg/mL. Detailed structure–activity relationships were established and rationalized in silico with regard to mycobacterial ProRS as a probable target. The active compounds preserved their activity even against multidrug-resistant strains of Mycobacterium tuberculosis. At the same time, they were non-cytotoxic against HepG2 human hepatocellular carcinoma cells. This project is the first step in the successful repurposing of inhibitors of human ProRS to inhibitors of mycobacterial ProRS with antimycobacterial activity.

中文翻译：

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3-氨基吡嗪-2-甲酰胺的腺苷模拟衍生物：具有抗分枝杆菌活性的脯氨酰-tRNA 合成酶抑制剂

耐多药结核病 (MDR-TB) 对人类构成重大威胁，因此在 WHO 优先病原体清单上占有一席之地。非常需要作用机制不同于目前使用的药物的新型抗分枝杆菌药物。本研究介绍了 3-acylaminopyrazine-2-carboxamides 的设计、合成和生物学评价，这些化合物源自先前报道的人脯氨酰-tRNA 合成酶抑制剂。化合物在体外对各种具有临床意义的分枝杆菌、致病菌和真菌菌株进行了评估。一般而言，注意到对分枝杆菌的高活性，而抗菌和抗真菌活性最小。活性最强的化合物是 4'-取代的 3-(苯甲酰氨基)吡嗪-2-甲酰胺，其 MIC（最低抑制浓度）为 1.95 至 31.25 µg/mL。将分枝杆菌 ProRS 作为可能的靶标，在计算机中建立并合理化了详细的结构-活性关系。活性化合物即使对多药耐药菌株也能保持活性结核分枝杆菌。同时，它们对 HepG2 人肝细胞癌细胞无细胞毒性。该项目是成功地将人 ProRS 抑制剂重新用于具有抗分枝杆菌活性的分枝杆菌 ProRS 抑制剂的第一步。