RESUMO
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.
Assuntos
Acrilonitrila/análogos & derivados , Álcoois Benzílicos/síntese química , Álcoois Benzílicos/farmacologia , Doença de Chagas/tratamento farmacológico , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Acrilonitrila/síntese química , Acrilonitrila/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Nitrilas , Trypanosoma cruzi/crescimento & desenvolvimentoRESUMO
Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0°C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC50 values of 6.88µgmL⻹ and 11.06µgmL⻹ respectively on L. amazonensis; 9.58µgmL⻹ and 14.34µgmL⻹ respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds.