2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZ.
Compounds originally designed as putative tubulin inhibitors were tested as antitubercular agents for inhibition of the Mycobacterium tuberculosis analogue of tubulin, FtsZ. Initial screening of 200 2-alkoxycarbonylpyridines found several that inhibited M. tuberculosis growth. Two compounds, SRI-3072 and SRI-7614, inhibited FtsZ polymerization and were equipotent against susceptible and single-drug-resistant strains of M. tuberculosis. In addition, SRI-3072 reduced the growth of M. tuberculosis in mouse bone marrow macrophages. Our results suggest that these types of compound might be developed into antitubercular drugs effective against the current multidrug-resistant strains of M. tuberculosis.
White
E Lucile
EL
Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA. white@sri.org
Suling
William J
WJ
Ross
Larry J
LJ
Seitz
Lainne E
LE
Reynolds
Robert C
RC
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001426:Bacterial Proteins / Q000187:drug effects* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000382:microbiology; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014709:Vero Cells
D000995:Antitubercular Agents; D001381:Azepines; D001426:Bacterial Proteins; D002219:Carbamates; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D011621:Pteridines; C418468:SRI 7614; C471411:ethyl (8-((4-(diethylamino)-1-methylbutyl)amino)-2,3-diphenylpyrido(2,3-b)pyrazin-6-yl)carbamate; D020558:GTP Phosphohydrolases