title: Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.
abstract: A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.
authors.affiliation: Medical Research Service, R&D 33, Portland Veterans Affairs Medical Center, Portland, OR 97239, USA. kellyja@ohsu.edu
authors.forename: Jane X
authors.initials: JX
authors.lastname: Kelly
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smilkstein
authors.forename: Roland A
authors.initials: RA
authors.lastname: Cooper
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Lane
authors.forename: Robert A
authors.initials: RA
authors.lastname: Johnson
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
authors.forename: Rozalia A
authors.initials: RA
authors.lastname: Dodean
authors.forename: David J
authors.initials: DJ
authors.lastname: Hinrichs
authors.forename: Rolf
authors.initials: R
authors.lastname: Winter
authors.forename: Michael
authors.initials: M
authors.lastname: Riscoe
mesh_terms: D054831:Acridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D054831:Acridones; D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins