Arylpropanolamines Incorporating an Antioxidant Function as Neuroprotective Agents

Abstract

A series of arylpropanolamines containing dipyrrolidinylpyrimidines as an antioxidant function have been synthesized and evaluated as dual function neuroprotective agents. Their in vitro efficacy as sodium channel blocking agents and antioxidants has been evaluated and compared with those of the ethanolamine derivative (1), which has been shown to be neuroprotective in a rat model of stroke. The ability of the present compounds to displace ³H-BTX toxin from sodium-ion channels in a rat brain membrane fraction was shown to be largely independent of the substituents on the aryl ring, which suggests that this activity may be mainly associated with the aminopyrimidine moiety. Structure–activity relationships for antioxidant efficacy were less clear, but the unsymmetrical pyrimidines were consistently more active than their symmetrical isomers. A brief theoretical investigation of this observation is reported.