Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents

Eur J Med Chem. 2012 Aug:54:512-21. doi: 10.1016/j.ejmech.2012.05.041.

Samir A Carvalho ¹, Larisse O Feitosa, Márcio Soares, Thadeu E M M Costa, Maria G Henriques, Kelly Salomão, Solange L de Castro, Marcel Kaiser, Reto Brun, James L Wardell, Solange M S V Wardell, Gustavo H G Trossini, Adriano D Andricopulo, Edson F da Silva, Carlos A M Fraga

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Affiliation

1 Instituto de Tecnologia em Fármacos - Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Brazil.

PMID: 22727447 DOI: 10.1016/j.ejmech.2012.05.041

Abstract

We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action.

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