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°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.