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Lipophilicity, radical stabilization and molecular weight appear to form an uneasy triangle, in which a slightly faulty selection may readily abolish neuroprotective activity.

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a b s t r a c tTocopherol is believed to be the most potent naturally occurring chain-breaking antioxidant. Hence, its refined phenolic head group chromanol may represent an optimum evolutionary solution to the problem of free-radical chain reactions in the lipid bilayer. To test the universal validity of this assumption beyond phenolic head groups, we have synthesized aromatic amine analogues of vitamin E and trolox with otherwise closely matching physicochemical properties: NH-toc and NH-trox. We have found that NH-toc and NH-trox were significantly more potent free radical scavengers, lipid peroxidation inhibitors and cytoprotective agents than their phenolic templates, tocopherol and trolox. In a chemical sense, thus, the chromanol head group does not constitute a global optimum for the design of chain-breaking antioxidants.