An Exploration of the Structure-activity Relationships of 4−Aminoquinolines: Novel Antimalarials with Activity In-vivo

Abstract

Abstract 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−trifluoroquin-olin-4−yl)cyclohexane-1,2−diamine and 1R,2R-(-)-, 1S,2S-(+)-, (±)-trans- and cis-N1,N2-bis(7−chloroquin-olin-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.