Antimalarial Pyrido[1,2-a]benzimidazole Derivatives with Mannich Base Side Chains: Synthesis, Pharmacological Evaluation and Reactive Metabolite Trapping Studies.

A novel series of pyrido[1,2-a]benzimidazoles bearing Mannich base side chain and their metabolites were synthesised and evaluated for antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4x50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent antiplasmodium activity against chloroquine-sensitive and multidrug resistant P. falciparum strains. Rapid metabolism was observed for all the analogues with < 40% of parent compound remaining after 30 minutes of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-hydroxyl, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodial activity, which was significantly lowered.