Highly Efficient Ligands for Dihydrofolate Reductase from Cryptosporidium hominis and Toxoplasma gondii Inspired by Structural Analysis

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• 作者：Phillip M. Pelphrey ; Veljko M. Popov ; Tammy M. Joska ; Jennifer M. Beierlein ; Erin S. D. Bolstad ; Yale A. Fillingham ; Dennis L. Wright ; Amy C. Anderson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：March 8, 2007
• 年：2007
• 卷：50
• 期：5
• 页码：940 - 950
• 全文大小：318K
• 年卷期：v.50,no.5(March 8, 2007)
• ISSN：1520-4804

文摘

The search for effective therapeutics for cryptosporidiosis and toxoplasmosis has led to the discovery ofnovel inhibitors of dihydrofolate reductase (DHFR) that possess high ligand efficiency: compounds withhigh potency and low molecular weight. Detailed analysis of the crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis and a homology model of DHFR from Toxoplasmagondii inspired the synthesis of a new series of compounds with a propargyl-based linker between a substituted2,4-diaminopyrimidine and a trimethoxyphenyl ring. An enantiomerically pure compound in this series exhibitsIC₅₀ values of 38 and 1 nM against C. hominis and T. gondii DHFR, respectively. Improvements of 368-fold or 5714-fold (C. hominis and T. gondii) relative to trimethoprim were generated by synthesizing just14 new analogues and by adding only a total of 52 Da to the mass of the parent compound, creating anefficient ligand as an excellent candidate for further study.