Planning, synthesis and biological evaluation of potentially antimalarial quinolones

A emergência e a disseminação de cepas resistentes aos fármacos antimaláricos disponíveis na quimioterapia têm conduzido à busca por novos agentes potencialmente ativos. Neste sentido, derivados 4-hidroxiquinolínicos e 4-cloroquinolínicos foram sintetizados e submetidos à avaliação biológica frente à cepa AJ de Plasmodium chabaudi e à avaliação toxicológica frente a macrófagos peritoneais de camundongos BALB/c. O planejamento sintético consistiu na preparação de β-cetoésteres-α-alquenilados através de reação de acetoacetato de etila e brometo de alila ou brometo de cinamila. Posteriormente, β-enaminoésteres-α-alquenilados foram obtidos através de reações de -β-cetoésteres-α-alquenilados com amina aromática (anilina). Os derivados 2-metil-3-alil- ou 2-metil-3-cinamil-4-hidroxiquinolínicos foram obtidos através de termociclização de Conrad-Limpach, utilizando-se difeniléter como solvente reacional. Por fim, a cloração dos agentes hidroxilados com oxicloreto de fósforo rendeu 2-metil-3-alil- ou 2-metil-3-cinamil-4-cloroquinolinas. Dos quatro derivados quinolínicos avaliados, 2-metil-3-[(2E)-3-fenilprop-2-enil]quinolin-4-ol (11) mostrou-se 1,13 vezes mais efetivo que sulfato de cloroquina contra as formas intraeritrocíticas do parasita, 1,69 vezes menos tóxico para os macrófagos peritoneais em relação ao fármaco padrão e valor de índice de seletividade igual a 280, enquanto sulfato de cloro quina apresentou valor de 146,84.The emergence and spread of resistance to antimalarial drugs have highlighted the need for the discovery and development of novel antimalarial molecules. To achieve this goal, 4-hydroxyquinoline and 4-chloroquinoline derivatives were prepared. Their biological activity was tested against the AJ Plasmodium chabaudi strain and their toxicity was evaluated toward BALB/c mouse peritoneal macrophages. The synthetic design was started by reacting ethyl-acetoacetate with allyl bromide or cinamyl bromide to obtain -α-alkenyl-β-ketoesters. The -α-alkenyl-β-enaminoesters were prepared by condensation of -α-alkenyl-β-ketoesters with aromatic amine (aniline). The derivatives 2-methyl-3-allyl- or 2-methyl-3-cinamyl-4-hydroxyquinolines were obtained by Conrad-Limpach ciclization in reacional solvent diphenyl ether. The 2-methyl-3-allyl- or 2-methyl-3-cinamyl-4-chloroquinoline derivatives had been prepared by chloration of hydroxyl group with phosphorous oxycloride. Among the quinoline compounds evaluated, 2-methyl-3-[(2E)-3-phenylpro-2-enyl]quinolin-4-ol (11) has shown more active than chloroquine sulphate (1, 13-fold) against the parasite intraerytrocytic stage. The compound 11 has presented less toxic than this drug (l,69-fold) to peritoneal macrophages. The selectivity index value has been 280, while the value to chloroquine sulphate has been 146,84