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 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.
Laboratorio de Síntesis Orgánica, Universidad Central de Venezuela, Aptdo. 47206, Los Chaguaramos, 1041-A Caracas, Venezuela.
Arthur
A
Barazarte
Gricela
G
Lobo
Neira
N
Gamboa
Juan R
JR
Rodrigues
Mario V
MV
Capparelli
Angel
A
Alvarez-Larena
Simón E
SE
López
Jaime E
JE
Charris
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010962:Plasmodium berghei / Q000187:drug effects*; D013055:Spectrophotometry, Infrared; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D013843:Thiazines