Synthesis and antimalarial activity of pyrazolo and pyrimido benzothiazine dioxide derivatives

被引:42
作者
Barazarte, Arthur [1 ]
Lobo, Gricela [1 ]
Gamboa, Neira [2 ]
Rodrigues, Juan R. [2 ]
Capparelli, Mario V. [3 ]
Alvarez-Larena, Angel [4 ]
Lopez, Simon E. [5 ]
Charris, Jaime E. [1 ]
机构
[1] Cent Univ Venezuela, Lab Sintesis Organ, Caracas 1041A, Venezuela
[2] Cent Univ Venezuela, Fac Farm, Unidad Bioquim, Caracas 1041A, Venezuela
[3] Cent Univ Venezuela, Fac Farm, Escuela Quim, Caracas 1041A, Venezuela
[4] Univ Autonoma Barcelona, Serv Difracc Rayos X, E-08193 Barcelona, Spain
[5] Univ Simon Bolivar, Dept Quim, Caracas, Venezuela
关键词
Benzothiazines; Pyrazol; Pyrimidine; Plasmodium berghei; beta-Hematin; Hemoglobin; QUINOLINE ANTIMALARIALS; HEMATIN; ETHYL;
D O I
10.1016/j.ejmech.2008.08.005
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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'-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 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. (C) 2008 Published by Elsevier Masson SAS.
引用
收藏
页码:1303 / 1310
页数:8
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