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

C. Kendall Stover (), Paul Warrener, Donald R. VanDevanter, David R. Sherman, Taraq M. Arain, Michael H. Langhorne, Scott W. Anderson, J. Andrew Towell, Ying Yuan, David N. McMurray, Barry N. Kreiswirth, Clifton E. Barry and William R. Baker
Additional contact information
C. Kendall Stover: PathoGenesis Corporation
Paul Warrener: PathoGenesis Corporation
Donald R. VanDevanter: PathoGenesis Corporation
David R. Sherman: School of Public Health and Community Medicine, University of Washington
Taraq M. Arain: PathoGenesis Corporation
Michael H. Langhorne: PathoGenesis Corporation
Scott W. Anderson: PathoGenesis Corporation
J. Andrew Towell: PathoGenesis Corporation
Ying Yuan: PathoGenesis Corporation
David N. McMurray: Texas A&M University Health Science Center, Room 463 Reynolds Medical Building College Station
Barry N. Kreiswirth: Tuberculosis Center, Public Health Research Institute
Clifton E. Barry: Tuberculosis Research Section, Laboratory of Host Defenses, NIAID, NIH, Twinbrook 2, Room 239
William R. Baker: PathoGenesis Corporation

Nature, 2000, vol. 405, issue 6789, 962-966

Abstract: Abstract Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually1. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis2. The synergy between tuberculosis and the AIDS epidemic3,4,5, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrug-resistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.

Date: 2000
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DOI: 10.1038/35016103

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