title: Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice.
abstract: Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.
authors.affiliation: Department of Chemistry and Global Health and Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gujjar
authors.forename: Alka
authors.initials: A
authors.lastname: Marwaha
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Sharon
authors.initials: S
authors.lastname: Creason
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baldwin
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Susan
authors.initials: S
authors.lastname: Charman
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C540178:(5-methyl(1,2,4)triazolo(1,5-a)pyrimidin-7-yl)(4-trifluoromethylphenyl)amine; D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D011743:Pyrimidines; D013844:Thiazoles; D014230:Triazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors