title: Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.
abstract: Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kokkonda
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Coteron
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Marco
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: de Las Heras
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.affiliation: Syngene International Ltd. , Bangalore 560 099, India.
authors.forename: Krishne
authors.initials: K
authors.lastname: Manjalanagara
authors.affiliation: Syngene International Ltd. , Bangalore 560 099, India.
authors.forename: Kakali Rani
authors.initials: KR
authors.lastname: Rudra
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Werner
authors.initials: W
authors.lastname: Kaminsky
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez-Martínez
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Jimenez-Diaz
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: Santiago Ferrer
authors.initials: SF
authors.lastname: Bazaga
authors.affiliation: GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Dave
authors.initials: D
authors.lastname: Matthews
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors