RESUMEN
A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10H-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hemoglobin hydrolysis, however, their effect as inhibitors of beta-hematin formation was marginal, except for compound 3-amino-7-chloro-9-(3'-chlorophenyl)-1,9dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2g. The most active compound to emerge from the in vitro and in vivo murine studies was 2b, suggesting an antimalarial activity via inhibition of hemoglobin hydrolysis, however, not as efficient as chloroquine.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Plasmodium berghei/efectos de los fármacos , Tiazinas/síntesis química , Tiazinas/farmacología , Animales , Antimaláricos/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Espectrofotometría Infrarroja , Tiazinas/químicaRESUMEN
An improved procedure for the synthesis of 3-amino-9-arylsubstituted-thieno[3,2-b]benzothiazine S,S-dioxide 2-decarboxylated is reported. Thieno-[3,2-b]benzothiazine S,S-dioxide derivatives were investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their efficacy in rodent Plasmodium berghei. Compounds 5j-o were the most promising as inhibitors of hemoglobin hydrolysis, however, the compounds are not as efficient as chloroquine. A structure-activity relationship (SAR) study was carried out in this series. Our results allow us to determine the minimal structural requirements to produce the biological response.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Benceno/química , Óxidos/química , Tiazinas/síntesis química , Tiazinas/farmacología , Animales , Antimaláricos/química , Cristalografía por Rayos X , Globinas/metabolismo , Hemoproteínas/biosíntesis , Ratones , Modelos Moleculares , Estructura Molecular , Plasmodium berghei/efectos de los fármacos , Electricidad Estática , Relación Estructura-Actividad , Tiazinas/químicaRESUMEN
Three isoxazoline tetracycles were obtained enantiomerically pure by intramolecular 1,3-dipolar cycloaddition. The characterization of the new compounds was performed by high-resolution 1H and 13C NMR spectroscopy. The relative configuration of the new chiral centers was determined by NOESY experiments and confirmed by single-crystal X-ray structural analysis.