Inhibitors of Decaprenylphosphoryl‐β‐D‐ribose 2′‐epimerase (DprE1) are being thoroughly explored as potential pharmacological entities for the development of new anti‐tubercular therapeutics. In this context, benzothiazole‐bearingcompounds have emerged as potential non‐covalent DprE1 inhibitors active against mycobacterium tuberculosis. In view of the promising anti‐tubercular activity of benzothiazole based non‐covalent DprE1 inhibitor TCA1; a series of thirty small peptide conjugates of benzothiazole‐2‐carboxylic acid has been synthesized and evaluated for their anti‐tubercular activity against the M.tb H37Ra strain by broth microdilution assay. Among the compounds tested, compounds methyl (6‐methoxybenzo[d]thiazole‐2 carbonyl)tryptophylalaninate and methyl (6‐methylbenzo[d]thiazole‐2‐carbonyl)tryptophylalaninate demonstrated potential anti‐tubercular activity with minimum inhibitory concentration (MIC) values of 4 and 8 μg/mL, respectively. These compounds were further identified to be mycobactericidal and are completely killing the microbes at 8‐16 μg/mL concentrations. Furthermore, the cytotoxicity study of most potent compound methyl (6‐methoxybenzo[d]thiazole‐2 carbonyl)tryptophylalaninate illustrated no significant toxicity to the human cell line HepG2. Moreover, synthesised compounds were subject to molecular docking, ADME studies and MM‐GBSA calculations. In silico studies suggest that these compounds show strong interactions with key amino acids in the binding pocket of DprE1 (PDBID: 4KW5) with the most active conjugates residing well (with docking scores of −08.49 and −7.902 kcal/mol).

中文翻译：

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靶向 DprE1 的苯并噻唑-2-羧酸小肽缀合物抗结核病

十异戊二烯基磷酰基-β-D-核糖 2'-差向异构酶 (DprE1) 抑制剂正在被彻底探索，作为开发新抗结核疗法的潜在药理学实体。在这种背景下，含苯并噻唑的化合物已成为潜在的非共价 DprE1 抑制剂，可有效对抗结核分枝杆菌。鉴于基于苯并噻唑的非共价 DprE1 抑制剂 TCA1 具有良好的抗结核活性；合成了一系列 30 种苯并噻唑-2-羧酸小肽缀合物，并评估了它们的抗结核活性结核分枝杆菌通过微量肉汤稀释法测定H37Ra菌株。在测试的化合物中，化合物(6-甲氧基苯并[d]噻唑-2羰基)色氨酸甲酯和(6-甲基苯并[d]噻唑-2-羰基)色氨酸甲酯表现出潜在的抗结核活性，最低抑菌浓度 (MIC) 值分别为 4 和 8 μg/mL。这些化合物被进一步鉴定为具有杀分枝杆菌作用，在 8-16 μg/mL 浓度下可完全杀死微生物。此外，最有效的化合物的细胞毒性研究(6-甲氧基苯并[d]噻唑-2羰基)色氨酸甲酯表明对人类细胞系 HepG2 没有显着毒性。此外，合成的化合物还进行了分子对接、ADME 研究和 MM-GBSA 计算。计算机模拟研究表明，这些化合物与 DprE1 结合袋中的关键氨基酸（PDBID：4KW5）表现出强烈的相互作用，并且最活跃的缀合物驻留得很好（对接分数为 -08.49 和 -7.902 kcal/mol）。