Bioisosteric Transformations and Permutations in the Triazolopyrimidine Scaffold To Identify the Minimum Pharmacophore Required for Inhibitory Activity against Plasmodium falciparum Dihydroorot
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- 作者：Alka Marwaha ; John White ; Farah El_Mazouni ; Sharon A Creason ; Sreekanth Kokkonda ; Frederick S. Buckner ; Susan A. Charman ; Margaret A. Phillips ; Pradipsinh K. Rathod
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：55
- 期：17
- 页码：7425-7436
- 全文大小：477K
- 年卷期：v.55,no.17(September 13, 2012)
- ISSN：1520-4804
文摘
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 渭M) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.