ATIVIDADE LEISHMANICIDA DE DERIVADOS AMINOQUINOLINICOS E EFEITO IMUNOMODULATÓRIO EM MACRÓFAGOS PERITONEAIS INFECTADOS COM LEISHMANIA AMAZONENSIS E L. MAJOR

AUTOR(ES)
DATA DE PUBLICAÇÃO

2010

RESUMO

The leishmaniasis are parasitic-infection diseases that affect 12 million people in 88 countries, it remains a serious public health problem worldwide, including in Brazil. This disease is caused by different Leishmania species, which invade and multiply within macrophages in vertebrate host. No vaccine exists yet and chemotherapy has been based mainly in pentavalent antimonials, amphotericinB e pentamidina. However, these drugs have limited use due to their toxicities, long term treatment and high costs. Therefore, there is an urgent need for development of new drugs for leishmaniasis. The aim of this study was to evaluate the leishmanicidal activity in twelve aminoquinolines derivatives, but specifically, 4-amino-7-chloro-quinoline, those present diamine with amine-free, mono-alkyne or di-alkyne groups. In a previous analysis the compounds were tested in promastigote forms of L. amazonensis, L. major, L. chagasi and L. braziliensis and the leishmanicidal activities was established by MTT method. Our results showed varied sensibility of the Leishmania species to the tested compounds. Derivatives with amine-free groups demonstrated better leishmanicidal activity than the others compounds and the compound 3(4-amine-7-cloro-N-butilamine)quinoline showed the best IC50 (=0,16 μM for L. chagasi) displaying an IC50 better than anfothericin B (1,90 μM para L. chagasi) Interestingly, it was observed structure-activity relationships (SAR) mainly in promastigotes of L. chagasi, being important the presence of amine-free group and number of carbon atoms. The majority of compounds didnt showed citotoxicity for the mammalian cells, except compounds containing amine-free groups. The compound 5 (4-amine-7- chloro-quinoline-N-prop-2-ynil)quinoline was chosen for antileishmanial evaluation in an intramacrophage amastigotes model and the leishmanicidal activity was achieved from the count of parasites after coloration by Giemsa. The treatment with this compound from infected macrophages with L. major e L. amazonensis didnt show leishmancidal activity for the first specie of this parasite. In L. amazonensis, the treatment showed a significant activity against intracellular forms, reducing the number of amastigotes/macrophage, the infected cells and the parasite burden above 90% after 72 hours. The antiamastigote effect was dose and time response. No alteration in nitric oxide levels by infected macrophages as for L. amazonensis as well for L. major was observed after treatment with the compound 5. However, this aminoquinoline significantly enhanced and inhibit the TNF-α production in infected cells with the respective Leishmania species. Together, these results suggest strongly that leishmanicidal acitivity from compound 5 can be directly in parasites or through the immune modulatory mechanism. This study indicate that aminoquinolines have promising leishmanicidal properties being a good candidates for further research to develop of new anti-protozoan drugs

ASSUNTO(S)

ciencias biologicas leishmania quimioterapia drogas aminoquinolinas óxido nítrico tnf-α leishmania chemotherapy drug aminoquinoline nitric oxide tnf-α

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