抗疟药物1,2,4-三氧杂环己烷青蒿素内酯环开环类似物的构效关系

Structure-activity relationships of lactone ring-opened analogs of the antimalarial 1,2,4-trioxane artemisinin.

作者信息

Posner G H, McGarvey D J, Oh C H, Kumar N, Meshnick S R, Asawamahasadka W

机构信息

Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland 21218.

出版信息

J Med Chem. 1995 Feb 17;38(4):607-12. doi: 10.1021/jm00004a006.

DOI:10.1021/jm00004a006

PMID:7861408

Abstract

1,2,4-Trioxane benzylic ethers 8a-e were prepared as simplified, tricyclic versions of the clinically used tetracyclic antimalarial drug artemisinin (1). Five additional artemisinin analogs (9-11) were prepared. Neither water solubility (analogs 8e and 11b) nor chelating ability (analogs 9 and 10), however, produced trioxanes of especially high in vitro antimalarial activity. Trioxane fluorobenzyl ether 8b is the most active in this series (more active than artemisinin) against Plasmodium falciparum parasites in vitro, with substantial activity also in mice infected with Plasmodium berghei parasites and with 10 times higher activity than artemisinin (1) in killing immature P. falciparum gametocytes.

摘要

1,2,4-三氧杂环己烷苄基醚8a - e被制备为临床使用的四环抗疟药物青蒿素（1）的简化三环类似物。另外还制备了五种青蒿素类似物（9 - 11）。然而，无论是水溶性（类似物8e和11b）还是螯合能力（类似物9和10），都没有产生具有特别高体外抗疟活性的三氧杂环己烷。三氧杂环己烷氟苄基醚8b是该系列中对恶性疟原虫体外活性最高的（比青蒿素更具活性），对感染伯氏疟原虫的小鼠也有显著活性，并且在杀死未成熟恶性疟原虫配子体方面的活性比青蒿素（1）高10倍。