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.
Subject(s)
Cinnamates/chemistry , Drug Design , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cell Line , Cell Survival/drug effects , Chemistry Techniques, Synthetic , Cysteine Endopeptidases , Hydrazones/chemistry , Hydrazones/toxicity , Inhibitory Concentration 50 , Mice , Protozoan Proteins/antagonists & inhibitors , Trypanocidal Agents/chemistry , Trypanocidal Agents/toxicity , Trypanosoma cruzi/enzymologyABSTRACT
In the title mol-ecule, C(9)H(8)N(4)O(2)S, the dihedral angle between the thia-diazole and benzene rings is 73.92â (8)° and the thia-diazole group S atom is orientated towards the benzene ring, the central S-C-C-C torsion angle being 45.44â (18)°. In the crystal, supra-molecular tapes mediated by N-Hâ¯N hydrogen bonds and comprising alternating eight-membered {â¯HNCN}(2) and 10-membered {â¯HNHâ¯NN}(2) synthons are formed along [010]. The tapes are consolidated into a three-dimensional network by a combination of C-Hâ¯O, C-Hâ¯S and C-Hâ¯π inter-actions.
