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Reactions of artemisinin and arteether with acid: implications for stability and mode of antimalarial action.

Abstract：

:The currently accepted mechanism of trioxane antimalarial action involves generation of free radicals within or near susceptible sites probably arising from the production of distonic radical anions. An alternative mechanistic proposal involving the ionic scission of the peroxide group and consequent generation of a carbocation at C-4 has been suggested to account for antimalarial activity. We have investigated this latter mechanism using DFT (B3LYP/6-31+G* level) and established the preferred Lewis acid protonation sites (artemisinin O5a>O4a approximately O3a>O2a>O1a; arteether O4a>or=O3a>O5b>O2a>O1a; Figure 3) and the consequent decomposition pathways and hydrolysis sites. In neither molecule is protonation likely to occur on the peroxide bond O1-O2 and therefore lead to scission. Therefore, the alternative radical pathway remains the likeliest explanation for antimalarial action.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Drew MG,Metcalfe J,Dascombe MJ,Ismail FM

doi

10.1021/jm060673d

subject

Has Abstract

pub_date

2006-10-05 00:00:00

pages

6065-73

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

杂志文章

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