期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 45, 期 11, 页码 5140-5149出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2010.08.026
关键词
Malaria; Purine nucleoside phosphorylase; Uridine phosphorylase; Transition state inhibitor; Drug discovery
资金
- Plan Nacional [SAF2007-62596]
- RICET FIS Network [RD06/0021]
- Junta de Andalucia [CVI-199]
- European Union [LSHP-CT-2005-018834]
Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) has a central role in purine salvage and inhibitors of the enzyme have been shown to have antiplasmodial activity. The enzyme preferentially uses inosine as substrate (K-m = 51 mu M, k(cat)/K-m = 7.4 x 10(4) M-1 s(-1)), but can also use uridine, albeit less efficiently (K-m = 85 mu M, k(cat)/K-m = 306 M-1 s(-1)). In an effort to identify new PfPNP inhibitors, two series of compounds were prepared. Series 1 was based on known human uridine phosphorylase inhibitors whilst series 2 was uracil equivalents of purine-based PNP transition state inhibitors. These two series of compounds were assayed for inhibition of both PfPNP activity and growth of P. falciparum. The transition state analogues were found to be moderate inhibitors of PfPNP (most potent compound, K-i = 6 mu M). (C) 2010 Elsevier Masson SAS. All rights reserved.
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