A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.
Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis. The synergy between tuberculosis and the AIDS epidemic, 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 multidrugresistant 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.
Stover
C K
CK
PathoGenesis Corporation, Seattle, Washington 98119, USA. kstover@pathogenesis.com
Warrener
P
P
VanDevanter
D R
DR
Sherman
D R
DR
Arain
T M
TM
Langhorne
M H
MH
Anderson
S W
SW
Towell
J A
JA
Yuan
Y
Y
McMurray
D N
DN
Kreiswirth
B N
BN
Barry
C E
CE
Baker
W R
WR
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000096:biosynthesis; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple; D006168:Guinea Pigs; D008055:Lipids / Q000096:biosynthesis; D008795:Metronidazole / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D009593:Nitroimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010080:Oxazoles / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008055:Lipids; D009593:Nitroimidazoles; D010080:Oxazoles; C410767:pretomanid; C080161:2-ethyl-5-nitro-2,3-dihydro(2-1b)imidazo-oxazole; D008795:Metronidazole