A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest sing le infectious cause of mortality worldwide, killing roughly two million peo ple annually(1). Estimates indicate that one-third of the world population is infected with latent M. tuberculosis(2). The synergy between tuberculosi s and the AIDS epidemic(3-5), and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary publ ic health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a serie s of compounds containing a nitroimidazopyran nucleus that possess antitube rcular activity. After activation by a mechanism dependent on M. tuberculos is F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazo pyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity a gainst multidrug-resistant M. tuberculosis and promising oral activity in a nimal infection models. We conclude that nitroimidazopyrans offer the pract ical qualities of a small molecule with the potential for the treatment of tuberculosis.