In VitroandIn VivoAntimalarial Efficacies of Optimized Tetracyclines

Abstract

ABSTRACTWith increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potentin vitroactivity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of culturedPlasmodium falciparumwith a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence ofin vitrophototoxicity. In a murinePlasmodium bergheimodel, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.