Synthesis of 2,3-diaminopyridine-derived 4-azabenzimidazoles and (benzylimino)pyridine analogues as potential anti-plasmodial agents

Azabenzimidazoles are frequently found in small-molecule drugs due to their broad-spectrum biological activity. Newer drugs are continually needed to replace existing drugs which encounter microorganism drug resistance. The reaction of 2,3-diaminopyridine precursors with variously substituted benzaldehydes has provided convenient and efficient access to a series of 4-azabenzimidazole derivatives and, regioselectively, to a series of 2-amino-5-bromo-3-(benzylimino)pyridine derivatives, while sodium cyanoborohydride reduction of the latter has afforded the corresponding 2-amino-5-bromo-3-(benzylimino)pyridine analogues. Bioassays of these and other compounds have been undertaken to explore their cytotoxicity and their activity against the parasitic protozoans, Plasmodium falciparum and Trypanosoma brucei. A number of the compounds show promising selective activity against T. brucei with IC50 values as low as 1.3 ??????M while two of them exhibit encouraging activity against both T. brucei and P. falciparum.