DESIGN, SYNTHESIS, AND IN-VITRO EVALUATION OF CYCLIC NITRONES AS FREE-RADICAL TRAPS FOR THE TREATMENT OF STROKE

Analogs of the cyclic nitrone free radical trap 1 (3,3-dimethyl-3,4-di hydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) were prepared in which (1) the fused phenyl ring was replaced with a naphthalene ring, an electron rich heterocycle, or a dimethylph enol, (2) the nitrone-containing ring comprised five, six, or seven at oms, and (3) the gem-dimethyl group was replaced with spirocyclic grou ps. The most active antioxidant, which bears a dimethylphenol fused to a 7-membered ring nitrone (compound 6h), inhibited lipid peroxidation in vitro with an IC50 of 22 mu M, a 75-fold improvement over that of 1. The previously observed correlation between lipophilicity and activ ity vs lipid peroxidation in vitro has been further substantiated and refined by this study. Moreover, certain classes of compounds (namely, dimethylphenols 6g,h and furan 6j) have now been found which are cons iderably more active in vitro than expected on the basis of their log K'(w) values.