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

38 Citations (Scopus)

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

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Plasmodium falciparum
Parasites
Plasmodium berghei
Inhibitory Concentration 50
Drug Therapy
Growth
dihydroorotate dehydrogenase

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against plasmodium falciparum dihydroorotate dehydrogenase. / Marwaha, Alka; White, John; El-mazouni, Farah; Creason, Sharon A.; Kokkonda, Sreekanth; Buckner, Frederick S.; Charman, Susan A.; Phillips, Margaret A.; Rathod, Pradipsinh K.

In: Journal of Medicinal Chemistry, Vol. 55, No. 17, 13.09.2012, p. 7425-7436.

Research output: Contribution to journalArticle

Marwaha, Alka ; White, John ; El-mazouni, Farah ; Creason, Sharon A. ; Kokkonda, Sreekanth ; Buckner, Frederick S. ; Charman, Susan A. ; Phillips, Margaret A. ; Rathod, Pradipsinh K. / Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against plasmodium falciparum dihydroorotate dehydrogenase. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 17. pp. 7425-7436.
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