Synthesis of 5-deoxy-5-phospho-d-ribonohydroxamic acid: a new competitive and selective inhibitor of type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis

5-Deoxy-5-phospho-d-ribonohydroxamic acid, a mimic of the 1,2-cis-enediolate high-energy intermediate species of the allose-6-phosphate isomerase reaction, was obtained by a six-step synthesis from d-erythronolactone. In contrast to the known competitive ribose-5-phosphate isomerase (Rpi) inhibitors 4-deoxy-4-phospho-d-erythronohydroxamic acid, 4-deoxy-4-phospho-d-erythronate, and 4-deoxy-4-phosphonomethyl-d-erythronate, the new hydroxamic acid selectively inhibits Mycobacterium tuberculosis RpiB (Ki = 0.40 mM, Km/Ki = 4.5) versus Spinacia oleracea RpiA, and hence appears as a promising lead for the design of potent species-specific inhibitors of the bacterial enzyme.

Graphical abstractThe first selective competitive inhibitor of Mycobacterium tuberculosis RpiB versus Spinacia oleracea RpiA, a mimic of the 1,2-cis-enediolate high-energy intermediate species of the allose-6-phosphate isomerase reaction, was obtained by a six-step synthesis from d-erythronolactone.Download full-size image