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Mémoire de Maîtrise
DOI
https://doi.org/10.11606/D.9.2004.tde-26022015-173101
Document
Auteur
Nom complet
Ana Cláudia Melo Pompeu da Silva
Adresse Mail
Unité de l'USP
Domain de Connaissance
Date de Soutenance
Editeur
São Paulo, 2004
Directeur
Jury
Brandt, Carlos Alberto (Président)
Cardoso, André Gustavo Tempone
Silveira, Maria Amelia Barata da
Titre en portugais
Planejamento, síntese e avaliação biológica de derivados quinolínicos potencialmente antimaláricos
Mots-clés en portugais
Antimaláricos (Avaliação)
Antimaláricos (Planejamento)
Antimaláricos (Síntese)
Malária (Quimioterapia)
Mecanismo de ação
Planejamento de fármacos
Quinolínico
Resumé en portugais
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.
Titre en anglais
Planning, synthesis and biological evaluation of potentially antimalarial quinolones
Mots-clés en anglais
Antimalarials (Evaluation)
Antimalarials (Planning)
Antimalarials (Synthesis)
Drugs planning
Malaria (chemotherapy)
Mechanism of action
Quinoline
Resumé en anglais
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.
 
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Date de Publication
2015-02-26
 
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