RESUMO
Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmodium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl group at R(2) significantly affecting activity. A subsequent series addressed high LogD values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R(1)/R(2). A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF(3), however antiplasmodial activity decreased without any improvement in clearance. The C6-CF(3) group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4.
Assuntos
Antimaláricos/síntese química , Pirimidinas/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Modification of the structure of trypanosomal AdoMetDC inhibitor 1 (MDL73811) resulted in the identification of a new inhibitor 7a, which features a methyl substituent at the 8-position. Compound 7a exhibits improved potencies against both the trypanosomal AdoMetDC enzyme and parasites, and better blood brain barrier penetration than 1.
