Because tuberculosis is still a major health threat worldwide, identification of new drug targets is urgently needed. In this study, we considered type B ribose-5-phosphate isomerase from as a potential target, and addressed known problems of previous inhibitors in terms of their sensitivity to hydrolysis catalyzed by phosphatase enzymes, which impaired their potential use as drugs. To this end, we synthesized six novel phosphomimetic compounds designed to be hydrolytically stable analogs of the substrate ribose 5-phosphate and the best known inhibitor 5-phospho--ribonate. The phosphate function was replaced by phosphonomethyl, sulfate, sulfonomethyl, or malonate groups. Inhibition was evaluated on type A and type B ribose-5-phosphate isomerases, and stability towards hydrolysis using alkaline phosphatase and veal serum was assessed. One of the phosphomimetic analogs, 5--5-phosphonomethyl--ribonate, emerged as the first strong and specific inhibitor of the enzyme that is resistant to hydrolysis.

中文翻译：

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结核分枝杆菌 B 型核糖 5-磷酸异构酶磷酸模拟抑制剂的合成及动力学评价

由于结核病仍然是全世界的主要健康威胁，因此迫切需要确定新的药物靶点。在这项研究中，我们将 B 型核糖 5-磷酸异构酶视为潜在靶标，并解决了先前抑制剂对磷酸酶催化水解的敏感性的已知问题，这损害了它们作为药物的潜在用途。为此，我们合成了六种新型拟磷化合物，其设计为底物核糖 5-磷酸和最著名的抑制剂 5-磷酸-核糖酸酯的水解稳定类似物。磷酸官能团被膦酰甲基、硫酸酯、磺酰甲基或丙二酸基团取代。评估了对 A 型和 B 型核糖 5-磷酸异构酶的抑制作用，并评估了使用碱性磷酸酶和小牛血清进行水解的稳定性。一种磷酸模拟类似物，5--5-膦酰甲基-核糖酸酯，是第一个强效且特异性的抗水解酶抑制剂。