10.1016/j.bmc.2007.10.042
The research focuses on the synthesis and evaluation of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines for their antiprotozoal activity and DNA binding affinity. The key dinitrile intermediates 4a–d were synthesized by reacting phenacyl bromide 1 with appropriate 2-amino-5-bromopyridines to yield 3a–d, followed by Suzuki coupling with 4-cyanophenylboronic acid. The bis-amidoximes 5a–d were then converted to the bis-O-acetoxyamidoximes and further catalytically hydrogenated to yield the acetate salts of 2,6-bis[4-(amidinophenyl)]-imidazo[1,2-a]pyridines 7a–d and the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine 8. The N-methoxyamidines 6a–d were prepared as potential prodrugs. These compounds exhibited strong DNA binding affinity and were very active in vitro against Trypanosoma brucei rhodesiense (T. b. r.), with IC50 values between 7 and 38 nM, but less effective against Plasmodium falciparum (P. f.), with IC50 values between 23 and 92 nM. In the T. b. r. STIB900 mouse model, compounds 7c and 7d showed slightly higher activity than furamidine, while only one prodrug 6b exhibited moderate activity. The research highlights the potential of these compounds as antiprotozoal agents and demonstrates the importance of the choice of linker and solvent in the synthesis and activity of these compounds.
