期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 22, 页码 9900-9913出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3011004
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资金
- MCINN [CSD2010-00065, CTQ2009-14288-C04-01]
A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted. derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.
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