RESUMO
Leishmaniasis' treatment is based mostly on pentavalent antimonials or amphotericin B long-term administration, expensive drugs associated with severe side effects. Considering these aforementioned, the search for alternative effective and safe leishmaniasis treatments is a necessity. This work evaluated a neolignan, licarin A anti-leishmanial activity chemically synthesized by our study group. It was observed that licarin A effectively inhibited Leishmania (Leishmania) major promastigotes (IC50 of 9.59 ± 0.94 µg/mL) growth, by inducing in these parasites genomic DNA fragmentation in a typical death pattern by apoptosis. Additionally, the neolignan proved to be even more active against intracellular amastigotes of the parasite (EC50 of 4.71 ± 0.29 µg/mL), and significantly more effective than meglumine antimoniate (EC50 of 216.2 ± 76.7 µg/mL) used as reference drug. The antiamastigote activity is associated with an immunomodulatory activity, since treatment with licarin A of the infected macrophages induced a decrease in the interleukin (IL)-6 and IL-10 production. This study demonstrates for the first time the antileishmanial activity of licarin A and suggests that the compound may be a promising in the development of a new leishmanicidal agent.
Assuntos
Antiprotozoários/farmacologia , Fatores Imunológicos/farmacologia , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Lignanas/farmacologia , Anfotericina B/farmacologia , Animais , Antiprotozoários/toxicidade , Apoptose , Citocinas/metabolismo , Fragmentação do DNA , Feminino , Fatores Imunológicos/toxicidade , Concentração Inibidora 50 , Leishmania major/genética , Lignanas/toxicidade , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/parasitologia , Meglumina/farmacologia , Meglumina/toxicidade , Antimoniato de Meglumina , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Compostos Organometálicos/farmacologia , Compostos Organometálicos/toxicidadeRESUMO
The chalcone-like series 1a-1g was efficiently synthesized from Morita-Baylis-Hillman reaction (52-74% yields). Compounds 1a-1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita-Baylis-Hillman adducts 2a-2g. The 1a-1g compounds were much more actives than precursor series 2a-2g, for example, IC(50)=7.65 µM on Leishmania amazonensis and 10.14 µM on Leishmania chagasi (compound 1c) when compared to IC(50)=50.08 µM on L. amazonensis and 82.29 µM on L. chagasi (compound 2c). The IC(50) values of compound 3 (228.49 µM on L. amazonensis and 261.45 µM on L. chagasi) and acryloyl salicylate 4 (108.50 µM on L. amazonensis and 118.83 µM on L. chagasi) were determined here, by the first time, on Leishmania.
