Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[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 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 38nM, but were less effective against P. f. with IC(50) values between 23 and 92nM. 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.
Ismail
Mohamed A
MA
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA.
Arafa
Reem K
RK
Wenzler
Tanja
T
Brun
Reto
R
Tanious
Farial A
FA
Wilson
W David
WD
Boykin
David W
DW
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
D000962:Antimalarials; D000981:Antiprotozoal Agents; D011355:Prodrugs; D011725:Pyridines