ABSTRACT
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.
Subject(s)
Antiprotozoal Agents/pharmacology , Immunologic Factors/pharmacology , Leishmania major/drug effects , Leishmaniasis, Cutaneous/drug therapy , Lignans/pharmacology , Amphotericin B/pharmacology , Animals , Antiprotozoal Agents/toxicity , Apoptosis , Cytokines/metabolism , DNA Fragmentation , Female , Immunologic Factors/toxicity , Inhibitory Concentration 50 , Leishmania major/genetics , Lignans/toxicity , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/parasitology , Meglumine/pharmacology , Meglumine/toxicity , Meglumine Antimoniate , Mice , Mice, Inbred BALB C , Nitric Oxide/metabolism , Organometallic Compounds/pharmacology , Organometallic Compounds/toxicityABSTRACT
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.
