Quantitative structure-activity relationships for the in vitro antimycobacterial activity of pyrazinoic acid esters.
Substituted pyrazinoic acid esters have previously been reported to have in vitro activity against Mycobacterium avium and Mycobacterium kansasii as well as Mycobacterium tuberculosis. Modification of both the pyrazine nucleus and the ester functionality was successful in expanding the antimycobacterial activity associated with pyrazinamide to include M. avium and M. kansasii, organisms usually not susceptible to pyrazinamide. In an attempt to understand the relationship between the activity of the esters with the needed biostability, a quantitative structure-activity relationship has been developed. This derived relationship is consistent with the observation that tert-butyl 5-chloropyrazinoate (13) and 2'-(2'-methyldecyl) 5-chloropyrazinoate (25), compounds which are both 100-fold more active than pyrazinamide against M. tuberculosis and possess a serum stability 900-1000 times greater than the lead compounds in the series.
Bergmann
K E
KE
Department of Chemistry, University at Albany, New York 12222, USA.
Cynamon
M H
MH
Welch
J T
JT
D017088:AIDS-Related Opportunistic Infections / Q000382:microbiology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters; D006801:Humans; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects* / Q000302:isolation & purification; D009164:Mycobacterium Infections / Q000382:microbiology; D009162:Mycobacterium avium / Q000187:drug effects / Q000302:isolation & purification; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000302:isolation & purification; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000382:microbiology
D000900:Anti-Bacterial Agents; D004952:Esters; D011718:Pyrazinamide; C005296:pyrazinoic acid