RESUMEN
A series of twelve analogs carrying fluoro, chloro, bromo and iodo halogens on the ortho, meta and para positions of a benzoyloxytropane skeleton were synthesized by a simple acylation of 8-methyl-8-aza-bicyclo[3.2.1]octan- 3α-ol by halogenobenzoyl chlorides. The compounds were evaluated in vitro against Plasmodium falciparum (P. f.), Trypanosoma brucei brucei (T. b. b.), Trypanosoma cruzi (T. c.) and Leishmania infantum (L. i.). This study shows that the presence of a halogenated atom and its position on the aromatic ring are important for in vitro activity. Compounds 4 (IC50 = 3.6 µM), 8 (IC50 = 6.7 µM), 5 (IC50 = 8.1 µM) and 7 (IC50 = 9.5 µM) were found the most active against P. f., whereas compounds 12 (IC50 = 5.1 µM), 11 (IC50 = 5.6 µM) and 9 (IC50 = 5.8 µM) exhibited the most pronounced activity against T. b. b. This series of compounds can be considered as non-toxic to the human cell line MRC-5.
Asunto(s)
Antimaláricos/síntesis química , Antiprotozoarios/síntesis química , Tropanos/síntesis química , Tripanocidas/síntesis química , Acilación , Animales , Antimaláricos/química , Antimaláricos/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Células Cultivadas , Cricetinae , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Fibroblastos/efectos de los fármacos , Fibroblastos/parasitología , Halogenación , Humanos , Concentración 50 Inhibidora , Leishmania infantum/efectos de los fármacos , Leishmania infantum/crecimiento & desarrollo , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/parasitología , Ratones , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Relación Estructura-Actividad , Tropanos/química , Tropanos/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/crecimiento & desarrollo , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/crecimiento & desarrolloRESUMEN
Schizanthus grahamii is an endemic Chilean plant that is known to contain tropane alkaloids. Five new alkaloids, grahamines A-E (1-5), were isolated and characterized by extensive spectroscopic analysis. Their structures were determined to be 2-{[(3α-hydroxytropo-6ß-yl)oxy]carbonyl}-2-methyl-3-{[((6ß-angeloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylic acid (1), 2-{[(3α-hydroxytropo-6ß-yl)oxy]carbonyl}-2-methyl-3-{[((6ß-tigloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylic acid (2), 1-methyl-2-{[(3α-hydroxytropo-6ß-yl)oxy]carbonyl}-4-{[((6ß-angeloyloxy)-3α-yl)oxy]carbonyl}-3-phenylcyclobutanecarboxylic acid (3), 1,2-bis{[(3α-hydroxytropo-6ß-yl)oxy]carbonyl}-2-methyl-3-{[((6ß-angeloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylate (4), and 1-{[(3α-mesaconyloxytropo-6ß-yl)oxy]carbonyl}-2-{[(3α-hydroxytropo-6ß-yl)oxy]carbonyl}-2-methyl-3-{[((6ß-angeloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylate (5).