title: Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria.
abstract: On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 (+/-)-trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamin e was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity--80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha 68198-6025.
authors.forename: J L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: W Y
authors.initials: WY
authors.lastname: Ellis
authors.forename: A L
authors.initials: AL
authors.lastname: Ager
authors.forename: S L
authors.initials: SL
authors.lastname: Andersen
authors.forename: L
authors.initials: L
authors.lastname: Gerena
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002738:Chloroquine / Q000627:therapeutic use; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D008288:Malaria / Q000188:drug therapy*; D008968:Molecular Conformation; D015394:Molecular Structure; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D003514:Cyclohexylamines; D011804:Quinolines; C074925:WR 268668; D002738:Chloroquine