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Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase.
Title | Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Marwaha, A, White, J, El Mazouni, F, Creason, SA, Kokkonda, S, Buckner, FS, Charman, SA, Phillips, MA, Rathod, PK |
Journal | J Med Chem |
Volume | 55 |
Issue | 17 |
Pagination | 7425-36 |
Date Published | 2012 Sep 13 |
ISSN | 1520-4804 |
Keywords | Animals, Enzyme Inhibitors, Mice, Molecular Mimicry, Oxidoreductases Acting on CH-CH Group Donors, Plasmodium berghei, Plasmodium falciparum, Pyrimidines, Structure-Activity Relationship |
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. |
DOI | 10.1021/jm300351w |
Alternate Journal | J. Med. Chem. |
PubMed ID | 22877245 |