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Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection
Authors
Lucrecia Campayo
Carmen Cano
+8 more
Fernando Gómez-Contreras
Clotilde Marín
Pilar Navarro
F. Olmo
María José Rosales
A. M. Sanz
Manuel Sánchez-Moreno
María J. R. Yunta
Publication date
29 August 2023
Publisher
American Chemical Society
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Cite
Abstract
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. © 2012 American Chemical Society.The authors thank the MCINN Projects: Consolider Ingenio CSD2010-00065 and CTQ2009-14288-C04-01 for financial support
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Last time updated on 29/09/2023