title: Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice.
abstract: Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.
authors.affiliation: Department of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gujjar
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Sharon
authors.initials: S
authors.lastname: Creason
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: Jeremy
authors.initials: J
authors.lastname: Burrows
authors.forename: David M
authors.initials: DM
authors.lastname: Floyd
authors.forename: David
authors.initials: D
authors.lastname: Matthews
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010962:Plasmodium berghei / Q000187:drug effects* / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors