Investigação leishmanicida de protótipos de origem natural e sintéticos

• Ano de defesa: 2016
• Autor(a) principal: Araújo, Morgana Vital de
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Alagoas; Brasil; Programa de Pós-Graduação em RENOBIO – Rede Nordeste de Biotecnologia; UFAL
• Palavras-chave em Português: Leishmaniose; Leishmania; Naftoquinona; Solanum paladosum; Retusin; Flavonoides; Atividade leishmanicida; Leishmaniasis; Naphthoquinone; leishmanicidal activity; CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA
• Link de acesso: http://www.repositorio.ufal.br/handle/riufal/1467

Leishmaniasis is among the most neglected diseases in the world. Currently, the drugs available for its treatment are limited and highly toxic, so the search for more effective and safer medicines is necessary. Thus, this paper aims to investigate the leishmanicidal activity of new natural, and synthetic. Two series of new 1,4-naphthoquinone derivatives were synthesized. The series of bis-2-hydroxy-1,4-naphthoquinone substituents exhibited significant activity against Leishmania amazonensis and Leishmania braziliensis promastigotes, six compounds showed good activity without toxic effects against the host cell. Moreover, compound 3a, which was selected to an in vivo infection assay with Leishmania amazonensis, reduced the size of the infected ear, but did not reduce parasite burden of the ear and draining lymph node. Furthermore, treatment with 3a induced no change in spleen weight or changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and urea levels. The series of 2-N,N'-dialkylamino-1,4-naphthoquinone substituents showed activity against promastigotes of L. chagasi and L. amazonensis, especially 1d, 1h and 1i, which exhibited L. amazonensis promastigote growth inhibition over 50%, and 1d, 1e, 1f, 1h, 1k and 1n derivatives which inhibited the growth of L.chagasi promastigotes over 70%. In the assay against the amastigote intracellular forms, 1a, 1b, 1c, 1d, 1h, 1i, 1k and 1m derivatives presented significant activity. The flavonoids SP1, SP2, and SP3 and S. palodosum crude extract inhibited the growth of promastigotes and amastigotes of L. amazonensis and L. chagasi. Moreover, SP4 inhibited the growth of promastigotes L. amazonensis. In regard an intracellular forms growth inhibition, SP1, SP3, and crude extract were active significantly. Furthermore, in the in vivo assay of infection with L. amazonensis, the compounds SP1 and SP3 reduced the parasitic burden on the infected ear, but did not reduce parasite burden on draining lymph node. On Leishmania cell cycle analysis, it was observed that SP1 and SP3 induced modifications on S and G2/M phases of cell cycle. In addition, SP3 induced death by apoptosis, and changed autophagy intensity, suggesting anti-proliferative activity at the concentration of 100 μM. The compound 3,7,3',4'-tetra-O-methylquercetin (retusin) inhibited the growth of promastigotes and amastigotes of L. amazonensis and L. chagasi. In the infection assay using hamsters infected with L. chagasi, retusin decreased the parasite burden in the spleen of infected animals. However, in the in vivo assay of infection using Balb/c mice infected with L. amazonensis, retusin did not reduce the parasitic load in the ear and draining lymph node. Moreover, retusin induced morphological alterations in L. chagasi promastigotes observed by scanning electron microscopy. In addition, retusin induced death by apoptosis at the concentration of 100 μM, which is probably not dependent on caspases; besides retusin inhibited Leishmania topoisomerases. The results indicate that the 1,4-naphthoquinone derivatives and flavonoid compounds derived from S. paladosum are active against Leishmania, mainly 1a, 1b, 1c, and 1m, which were active against Leishmania in the in vitro assays, without induce damage in host cells; and SP1, SP3, and rutesin, which were active in vivo by intraperitoneal route, suggesting they can be useful lead compounds candidates for antileishmanial drugs.