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1.
Bioorg Med Chem ; 11(16): 3407-12, 2003 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-12878135

RESUMO

Boc-aminoethylindoloquinone 8, a key intermediate for the building of pentacyclic quinoneimines, analogues of kuanoniamine A, was synthesized by alkylation of 4,7-dimethoxyindole 3 with 1,2-dibromoethane followed by transformation into azide, reduction of the latter with trimethylphosphine in the presence of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile and oxydative demethylation of the Boc-amine 6 with silver(II) oxide. Quinone 8 was then treated in situ with the thiazole o-quinodimethane 10 to afford a regioisomeric mixture of the tetracyclic quinones 11. Treatment of the mixture with trifluoroacetic acid and molecular sieves 4-A provided the corresponding quinoneimines 12. Separation of the regioisomers was performed by preparative thin-layer chromatography on silica gel. The structural assignment was made by 2D 1H-13C HMBC correlations performed on the less polar regioisomer 12b. In vitro anti-leishmanial assays showed that the tested compounds possess a good potency towards two Leishmania sp. as well as against a virulent strain of Toxoplasma gondii and without any cytotoxicity against THP-1 cells.


Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Alcaloides/química , Alcaloides/toxicidade , Animais , Antiprotozoários/química , Antiprotozoários/toxicidade , Linhagem Celular , Humanos , Concentração Inibidora 50 , Leishmania/efeitos dos fármacos , Estrutura Molecular , Toxoplasma/efeitos dos fármacos
2.
Bioorg Med Chem ; 11(10): 2175-82, 2003 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12713827

RESUMO

The synthesis of tetracyclic quinones 10a,b, 14a,b, 19a,b and 20a,b is described. The preparations involve regioselective Diels-Alder reactions via trapping the thiazole o-quinodimethane 9 with several benzofuranquinones and benzothiophenequinones. The structure of the regioisomers was assigned through 2D NMR 1H-13C HMBC experiments performed on 10a and 14a. Compounds 10a,b, 14a as well as phenol 1 and the starting quinones 2, 5, 7 and 15 are evaluated against Leishmania sp., Toxoplasma gondii and THP-1 cells. Almost all the tested compounds exhibit significant antiprotozoal activities with lower cytotoxicities than the reference compounds. Among them, quinones 2 and 14a possess the best activities towards L. donovani and T. gondii with the lowest toxicities.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Naftoquinonas/síntese química , Toxoplasma/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Furanos/química , Humanos , Estrutura Molecular , Células Mieloides/efeitos dos fármacos , Células Mieloides/parasitologia , Naftoquinonas/farmacologia , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazóis/química , Tiofenos/química
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