Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis.

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5'-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and ADME profiles.