Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis.
Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC(50)) against Vero cells of 25 μg/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.
Center for Infectious Disease and Biodefense Research, Bioscience Division, SRI International, Menlo Park, CA 94025-3493, USA.
Sidharth
S
Chopra
Gary A
GA
Koolpe
Arlyn A
AA
Tambo-Ong
Karen N
KN
Matsuyama
Kenneth J
KJ
Ryan
Tran B
TB
Tran
Rupa S
RS
Doppalapudi
Edward S
ES
Riccio
Lalitha V
LV
Iyer
Carol E
CE
Green
Baojie
B
Wan
Scott G
SG
Franzblau
Peter B
PB
Madrid
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D055808:Drug Discovery; D005260:Female; D007536:Isomerism; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009581:Nitrofurans / Q000737:chemistry / Q000494:pharmacology; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D000077704:Tirapazamine; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
D000995:Antitubercular Agents; D009581:Nitrofurans; D009593:Nitroimidazoles; D010087:Oxides; D011810:Quinoxalines; D014227:Triazines; D000077704:Tirapazamine