title: Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase.
abstract: Plasmodium falciparum causes approximately 1 million deaths annually. However, increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-a]pyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC(50) = 0.077 μM) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.
authors.affiliation: Department of Chemistry and Global Health, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Marwaha
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Creason
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kokkonda
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; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018716:Molecular Mimicry; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000201:enzymology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D044925:Oxidoreductases Acting on CH-CH Group Donors