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.
Barazarte
Arthur
A
Laboratorio de Síntesis Orgánica, Universidad Central de Venezuela, Aptdo. 47206, Los Chaguaramos, 1041-A Caracas, Venezuela.
Lobo
Gricela
G
Gamboa
Neira
N
Rodrigues
Juan R
JR
Capparelli
Mario V
MV
Alvarez-Larena
Angel
A
López
Simón E
SE
Charris
Jaime E
JE
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