QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE IN-VITRO ANTIMYCOBACTERIAL ACTIVITY OF PYRAZINOIC ACID-ESTERS

Substituted pyrazinoic acid esters have previously been reported to ha ve in vitro activity against Mycobacterium avium and Mycobacterium kan sasii as well as Mycobacterium tuberculosis. Modification of both the pyrazine nucleus and the ester functionality was successful in expandi ng the antimycobacterial activity associated with pyrazinamide to incl ude M. avium and M. kansasii, organisms usually not susceptible to pyr azinamide. In an attempt to understand the relationship between the ac tivity of the esters with the needed biostability, a quantitative stru cture-activity relationship has been developed, This derived relations hip is consistent with the observation that tert-butyl 5-chloropyrazin oate (13) and 2'-(2'-methyldecyl) 5-chloropyrazinoate (25), compounds which are both 100-fold more active than pyrazinamide against M. tuber culosis and possess a serum stability 900-1000 times greater than the lead compounds in the series.