Synthesis and kinetic evaluation of phosphomimetic inhibitors targeting type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis

• Published in: Bioorganic & medicinal chemistry letters Vol. 102; p. 129666
• Main Authors: Courtiol-Legourd, Stéphanie, Mariano, Sandrine, Foret, Johanna, Roos, Annette K., Mowbray, Sherry L., Salmon, Laurent
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2024; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Enzyme inhibitors; Isomerase; Life Sciences & Biomedicine; Monosaccharides; Pharmacology & Pharmacy; Phosphate; Physical Sciences; Ribose; Science & Technology; Tuberculosis; Enzyme inhibitors; Tuberculosis; Ribose; Isomerase; Phosphate; Monosaccharides; ACID; ANALOGS; INFORMATION; ESCHERICHIA-COLI; COMPETITIVE INHIBITORS; REVEAL; SYNTHASE; DERIVATIVES; phosphate; ribose; monosaccharides; enzyme inhibitors; tuberculosis; isomerase
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129666

[Display omitted] •Synthesis of six phosphomimetic inhibitors of ribose-5-phosphate isomerases.•Phosphate is replaced by phosphonomethyl, sulfonomethyl, sulfate, or malonate groups.•All phosphomimetic analogs except sulfate are hydrolytically stable.•First strong and specific inhibitor of M. tuberculosis RpiB resistant to hydrolysis identified. 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 Mycobacterium tuberculosis 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-d-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-deoxy-5-phosphonomethyl-d-ribonate, emerged as the first strong and specific inhibitor of the M. tuberculosis enzyme that is resistant to hydrolysis.