A series of 19 derivatives of 2,7-diazaphenothiazine was synthesized and evaluated for their antioxidant activity bearing in mind the structural similarity with "classical" phenothiazines several of which are considered powerful antioxidants. Among the new derivatives that inhibited in vitro Fe(2+)/ascorbate-induced lipid peroxidation of rat liver microsomal membranes, several exhibited significant antioxidant activity with IC(50 )values in the range of 64-125 microM. Although N-substitution led to a variable degree of antioxidant activity, the latter appears to correlate with the lipophilicity (expressed as clogP values) of the substituted derivatives. Reduced lipophilicity may also explain the relatively lower protection offered by these derivatives against lipid peroxidation when compared to their "classical" phenothiazine counterparts. Thus, modification of the phenothiazine structure by a substitution of two benzene rings with pyridine rings to form this new type of azaphenothiazines does not enhance antioxidant activity, although it retains it.