Synthesis and antimalarial activity of pyrazolo and pyrimido benzothiazine dioxide derivatives

A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2′-methylpheyl)-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 β-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. © 2008.