Bergmann K E, Cynamon M H, Welch J T
Department of Chemistry, University at Albany, New York 12222, USA.
J Med Chem. 1996 Aug 16;39(17):3394-400. doi: 10.1021/jm950538t.
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.
取代的吡嗪酸酯先前已被报道具有体外抗鸟分枝杆菌、堪萨斯分枝杆菌以及结核分枝杆菌的活性。吡嗪核和酯官能团的修饰成功地扩大了与吡嗪酰胺相关的抗分枝杆菌活性，使其包括鸟分枝杆菌和堪萨斯分枝杆菌，这些生物体通常对吡嗪酰胺不敏感。为了理解酯的活性与所需生物稳定性之间的关系，已建立了定量构效关系。这种推导关系与以下观察结果一致：5-氯吡嗪酸叔丁酯（13）和2'-（2'-甲基癸基）5-氯吡嗪酸酯（25），这两种化合物对结核分枝杆菌的活性均比吡嗪酰胺高100倍，并且血清稳定性比该系列中的先导化合物高900 - 1000倍。
