Phthalazine Derivatives Containing Imidazole Rings Behave as Fe-SOD Inhibitors and Show Remarkable Anti-T. cruzi Activity in Immunodeficient-Mouse Mode of Infection

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• 作者：Manuel S谩nchez-Moreno ; Fernando G贸mez-Contreras ; Pilar Navarro ; Clotilde Mar铆n ; Francisco Olmo ; Mar铆a J. R. Yunta ; Ana Mar铆a Sanz ; Mar铆a Jos茅 Rosales ; Carmen Cano ; Lucrecia Campayo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9900-9913
• 全文大小：558K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

A series of new phthalazine derivatives 1鈥?b>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鈥?b>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鈥?b>4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.