Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2- a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2- a]pyridines

Abstract

The key dinitrile intermediates 4a– d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a– d. Suzuki coupling of 3a– d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2- a]pyridine derivatives 4a– d. The bis-amidoximes 5a– d, obtained from 4a– d by the action of hydroxylamine, were converted to the bis- O-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts of 2,6-bis[4-(amidinophenyl)]-imidazo[1,2- a]pyridines 7a– d. In contrast, catalytic hydrogenation of the bis- O-acetoxyamidoxime of 5a in glacial acetic acid gave the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2- a]pyridine 8. O-Methylation of the amidoximes 5a– d gave the N-methoxyamidines 6a– d. The diamidines showed strong DNA binding affinity, were very active in vitro against T. b. r. exhibiting IC 50 values between 7 and 38 nM, but were less effective against P. f. with IC 50 values between 23 and 92 nM. Two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T. b. r. STIB900 mouse model. Only one prodrug 6b showed moderate activity in the same mouse model.