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

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 or 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]pyridine8. 0-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 IC50 values between 7 and 38 nM, but were less effective against P. f with IC50 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. (c) 2007 Elsevier Ltd. All rights reserved.