Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents.
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.
Instituto de Tecnologia em Fármacos - Farmanguinhos, Fundação Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Brazil.
Samir A
SA
Carvalho
Larisse O
LO
Feitosa
Márcio
M
Soares
Thadeu E M M
TE
Costa
Maria G
MG
Henriques
Kelly
K
Salomão
Solange L
SL
de Castro
Marcel
M
Kaiser
Reto
R
Brun
James L
JL
Wardell
Solange M S V
SM
Wardell
Gustavo H G
GH
Trossini
Adriano D
AD
Andricopulo
Edson F
EF
da Silva
Carlos A M
CA
Fraga
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002934:Cinnamates / Q000737:chemistry*; D003546:Cysteine Endopeptidases; D015195:Drug Design; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D051379:Mice; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D002934:Cinnamates; D006835:Hydrazones; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C029010:cinnamic acid; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi