title: In vitro and in vivo antimalarial efficacies of optimized tetracyclines.
abstract: With 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 potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50 at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 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.
authors: Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA. mdraper@paratekpharm.com
authors: Michael P
authors: MP
authors: Draper
authors: Beena
authors: B
authors: Bhatia
authors: Haregewein
authors: H
authors: Assefa
authors: Laura
authors: L
authors: Honeyman
authors: Lynne K
authors: LK
authors: Garrity-Ryan
authors: Atul K
authors: AK
authors: Verma
authors: Jiri
authors: J
authors: Gut
authors: Kelley
authors: K
authors: Larson
authors: Janice
authors: J
authors: Donatelli
authors: Ann
authors: A
authors: Macone
authors: Kevin
authors: K
authors: Klausner
authors: Raina G
authors: RG
authors: Leahy
authors: Aleksandrs
authors: A
authors: Odinecs
authors: Kwasi
authors: K
authors: Ohemeng
authors: Philip J
authors: PJ
authors: Rosenthal
authors: Mark L
authors: ML
authors: Nelson
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D013754:Tetracyclines / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D013754:Tetracyclines
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