title: Synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds.
abstract: We have previously shown that a "reversed chloroquine (RCQ)" molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum ( Burgess , S. J. ; Selzer , A. ; Kelly , J. X. ; Smilkstein , M. J. ; Riscoe , M. K. ; Peyton , D. H. J. Med. Chem. 2006 , 49 , 5623 . Andrews , S. ; Burgess , S. J. ; Skaalrud , D. ; Kelly , J. X. ; Peyton , D. H. J. Med. Chem. 2010 , 53 , 916 ). Here, we present an investigation into the structure-activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite's digestive vacuole in a manner similar to that of chloroquine.
authors.affiliation: Department of Chemistry, Portland State University, PO Box 751, Portland, Oregon 97207-0751, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burgess
authors.forename: Jane X
authors.initials: JX
authors.lastname: Kelly
authors.forename: Shawheen
authors.initials: S
authors.lastname: Shomloo
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Katherine
authors.initials: K
authors.lastname: Liebmann
authors.forename: David H
authors.initials: DH
authors.lastname: Peyton
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004351:Drug Resistance; D006418:Heme / Q000737:chemistry; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C552341:7-chloro-N-(3-(4-(dipyridin-2-ylmethylamino)piperidin-1-yl)propyl)quinolin-4-amine; D000962:Antimalarials; D006420:Hemeproteins; D011725:Pyridines; C020753:hemozoin; D006418:Heme; D002738:Chloroquine