3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile): A new highly active compound against epimastigote and trypomastigote form of Trypanosoma cruzi.
We have synthesized the Morita-Baylis-Hillman adduct (MBHA) 3-hydroxy-2-methylene-3-(4-nitrophenyl)-propanenitrile (3) in quantitative yield and evaluated on Trypanosoma cruzi epimastigote and bloodstream trypomastigote forms. Compound 3 strongly inhibited epimastigote growth, with IC(50)/72hof 28.5 microM and also caused intense trypomastigotes lysis, with an IC(50)/24h of 25.5 microM. Ultrastructural analysis showed significant morphological changes on both parasite forms treated with 3, including increase of cell volume and rounding of cell body as well as intense intracellular disorganization. Morphological changes indicative of apoptosis, autophagy or necrosis were observed in most affected cells. Docking calculations of 1, 2 and 3 pointed out the possibility of T. cruzi Farnesyl Pyrophosphate Synthase (TcFPPS) enzyme inhibition in 3 mechanism of action.
Sandes
Jana M
JM
Departamento de Microbiologia, Centro de Pesquisas Aggeu Magalhães, FIOCRUZ, Recife, PE, Brazil.
Borges
Andrezza R
AR
Junior
Cláudio G L
CG
Silva
Fábio P L
FP
Carvalho
Gabriel A U
GA
Rocha
Gerd B
GB
Vasconcellos
Mário L A A
ML
Figueiredo
Regina C B Q
RC
D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D001592:Benzyl Alcohols / Q000138:chemical synthesis* / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009570:Nitriles; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
C510493:3-hydroxy-2-methylene-3-(4-nitrophenyl)propanenitrile; D001592:Benzyl Alcohols; D009570:Nitriles; D014344:Trypanocidal Agents; D000181:Acrylonitrile