title: Evaluation and lead optimization of anti-malarial acridones.
abstract: With 2-methoxy-6-chloroacridone as a lead compound, we synthesized and tested acridone derivatives to develop a better understanding of the anti-malarial structure-activity relationships. Over 30 acridone derivatives were synthesized. The most potent compounds contained extended alkyl chains terminated by trifluoromethyl groups and located at the 3-position of the tricyclic system. Acridones optimized in the length of the side chain and the nature of the terminal fluorinated moiety exhibited in vitro anti-malarial IC(50) values in the low nanomolar and picomolar range and were without cytotoxic effects on the proliferation and differentiation of human bone marrow progenitors or mitogen-activated murine lymphocytes at concentrations up to 100,000-fold higher. Based on a structural similarity to known anti-malarial agents it is proposed that the haloalkoxyacridones exert their anti-malarial effects through inhibition of the Plasmodium cytochrome bc(1) complex. Haloalkoxyacridones represent an extraordinarily potent novel class of chemical compounds with the potential for development as therapeutic agents to treat or prevent malaria in humans.
authors.affiliation: Medical Research Service, RD-33, VA Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, USA.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Winter
authors.forename: Jane X
authors.initials: JX
authors.lastname: Kelly
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smilkstein
authors.forename: Rozalia
authors.initials: R
authors.lastname: Dodean
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.forename: R Keaney
authors.initials: RK
authors.lastname: Rathbun
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Levin
authors.forename: David
authors.initials: D
authors.lastname: Hinrichs
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D054831:Acridones; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000469:parasitology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D054831:Acridones; D000962:Antimalarials; C041300:acridone