Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against plasmodium falciparum dihydroorotate dehydrogenase

Alka Marwaha, John White, Farah El-mazouni, Sharon A. Creason, Sreekanth Kokkonda, Frederick S. Buckner, Susan A. Charman, Margaret A. Phillips, Pradipsinh K. Rathod

Research output: Contribution to journalArticle

43 Scopus citations

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 IC50 = 0.077 μM) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.

Original languageEnglish (US)
Pages (from-to)7425-7436
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number17
DOIs
StatePublished - Sep 13 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against plasmodium falciparum dihydroorotate dehydrogenase'. Together they form a unique fingerprint.

  • Cite this