Studies on the 2,4-Diamino-6-Substituted Quinazolines

Publisher Website
Google Scholar
Abstract
Previous studies showed: 1) that the activities of the 2,4-diamino-6-substituted quinazolines, WR-158,122 and WR-159,412, against Plasmodium falciparum and Plasmodium vivax infections in owl monkeys, were seriously impaired when infecting strains were pyrimethamine-resistant; and 2) that primary treatment failure with either agent led frequently to emergence of parasites resistant to these derivatives. Taking advantage of the potencies of WR-158,122 and WR-159,412 as dihydroflic acid reductase inhibitors, the current studies were aimed at determining whether the above liabilities could be reduced to manageable levels or eliminated by concomitant administration of a ρ-aminobenzoic acid inhibitor such as sulfadiazine. Application of these combinations prevented emergence of parasites resistant to WR-158,122 or WR-159,412, but did not abolish the differences in effectiveness of either compound against infections with pyrimethamine-susceptible and pyrimethamine-resistant strains; however, activities against infections with either susceptible or resistant strains were enhanced markedly. With WR-158,122, this enhancement ranged from greater than 7-fold to 75-fold; with WR-159,412, it ranged from greater than 5-fold to 13-fold. Maximal increases in activity were attained with a remarkably small dose of sulfadiazine, 5.0 mg per kg of body weight daily. With this augmentation of activity, acceptably small doses of WR-158,122 regularly cured infections with even the most highly pyrimethamine-resistant strain.