The position of imidazopyridine and metabolic activation are pivotal factors in the antimutagenic activity of novel imidazo[1,2-a]pyridine derivatives.

The antimutagenic activity of eight novel imidazo[1,2-a]pyridine derivatives (I-VIII) against sodium azide (NaN3) and benzo[a]pyrene (B[a]P) was evaluated using the Salmonella reverse mutation assay. At non-toxic concentrations (12.5-50 µM), imidazopyridines I, II, III, and V with a terminal imidazopyridine group were mutagenic, while derivatives VII and VIII with a central imidazopyridine group were not mutagenic. Compounds IV, VII, and VIII exerted a moderate antimutagenic activity against NaN3 under pre-exposure conditions, and a strong activity (>40%) against B[a]P in the presence of S9 under both pre- and co-exposure conditions and mostly independent on the dose. Imidazopyridines possibly inhibited the microsomal-dependent activation of B[a]P. The demethylated derivative VII was the most active antimutagen. All imidazopyridines had a low to moderate antioxidant activity. The antibacterial activity of imidazopyridines was sporadic and moderate probably due to the failure of bacteria to convert imidazopyridines into active metabolites. The position of imidazopyridine was a pivotal factor in the mutagenic/antimutagenic activity. The strong antimutagenic compounds were dicationic planar compounds with a centered imidazo[1,2-a]pyridine spacer. With LD50 of 60 mg/kg in mice for both derivatives VII and VIII, it is safe to investigate the anticancer activity of these derivatives in animal models.