An exploration of the structure-activity relationships of 4-aminoquinolines: novel antimalarials with activity in-vivo.
The structure-activity relationships of bisquinolines, a potentially important group of novel antimalarial drugs, were studied. The high-temperature (180-250 degrees C) synthesis of 4-aminoquinolines, including bisquinolines, by nucleophilic displacement was both fast and efficient Several bisquinolines including (+/-)-trans-N1,N2-bis(7-trifluoroquinolin-4-yl)cyclohexane-1, 2-diamine and 1R,2R-(-)-, 1S,2S-(+)-, (+/-)-trans- and cis-N1, N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine exhibited potent activity against Plasmodium berghei in mice; (+/-)-trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1, 2-diamine was orally active. Our results indicate that these compounds conform to a putative receptor for quinoline antimalarials. In addition, a 7-haloquinoline linked by a heterocyclic bridge, at the 4-position, to another heterocycle (such as an acridine at the 9-position) maximally occupies the active site of our postulated target.
Division of Chemical Sciences, School of Natural Sciences, University of Hertfordshire, Hatfield, UK.
F M
FM
Ismail
M J
MJ
Dascombe
P
P
Carr
S E
SE
North
D000634:Aminoquinolines / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000627:therapeutic use*; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D010962:Plasmodium berghei; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D000962:Antimalarials