ArticleJournal of medicinal chemistry2012
Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase.
Article in Journal of medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 69 citations in OpenAlex.
- The AI-driven Drug Design (AIDD) platform: an interactive multi-parameter optimization system integrating molecular evolution with physiologically based pharmacokinetic simulations.Journal of computer-aided molecular design · 2024Article
- Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistantProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Synthesis of tetrazolo[1,5-a]pyrimidine-6-carbonitriles using HMTA-BAIL@MIL-101(Cr) as a superior heterogeneous catalyst.Scientific reports · 2021Article
- The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions.Acta crystallographica. Section F, Structural biology communications · 2015Article
- Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method.PloS one · 2015Article
- Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.Journal of medicinal chemistry · 2014Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
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.
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