期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 7, 页码 3117-3130出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501987h
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资金
- ETH Research Council
- Thailand Research Fund [RTA5680001]
- Mahidol University
- Synchrotron Light Research Institute Public Organization [2-2549/LS01, 2551/08]
- Cluster Program and Management Office, National Science and Technology Development Agency, Thailand [CPMO-P-00-20029, CPMO-DD/P-10-11274, CPMO-P-13-00835]
Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 angstrom resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.
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