Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones

A new series of imidazolyl nitrones spin traps has been synthesized and eva luated pharmacologically. The salient structural feature of these molecules is the presence of an imidazole moiety substituted by aromatic or heteroar omatic cycles. This connectivity imparts to the nitrone superior neuroprote ctive properties in vivo and in parallel reduced side effects and toxicity. Thus compound 6a (a 2-phenylimidazolyl nitrone) administered intraperitone ally protects (80%) mice from lethality induced by an intracerebroventricul ar administration of tert-butyl hydroperoxide (t-BHP) an oxidant capable of inducing neurodegenerative processes. Administration of the archetypal nit rone phenyl-tert-butyl nitrone (PBN) at an equimolar dose also affords some protection (60%) in this test. However, this activity is accompanied by hy pothermia, whereas no such effect is apparent for 6a. Moreover, previously prepared nonsubstituted or alkyl-substituted imidazolyl nitrones were shown to be extremely toxic to rats in contrast to the compounds prepared in thi s study. The observed activities in vivo correlate well with the calculated partition coefficients (ClogP) and HOMO energy level.