title: Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine.
abstract: On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.forename: Deborah
authors.initials: D
authors.lastname: Stanford
authors.forename: Gemma
authors.initials: G
authors.lastname: Nixon
authors.forename: Eghbaleh
authors.initials: E
authors.lastname: Asadollahy
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: James L
authors.initials: JL
authors.lastname: Maggs
authors.forename: Phil
authors.initials: P
authors.lastname: Roberts
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stocks
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Biagini
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Bray
authors.forename: Jill
authors.initials: J
authors.lastname: Davies
authors.forename: Neil
authors.initials: N
authors.lastname: Berry
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hall
authors.forename: Karen
authors.initials: K
authors.lastname: Rimmer
authors.forename: Peter A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: Stephen
authors.initials: S
authors.lastname: Hindley
authors.forename: Ramesh B
authors.initials: RB
authors.lastname: Bambal
authors.forename: Charles B
authors.initials: CB
authors.lastname: Davis
authors.forename: Martin
authors.initials: M
authors.lastname: Bates
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Gresham
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brigandi
authors.forename: Federico M
authors.initials: FM
authors.lastname: Gomez-de-Las-Heras
authors.forename: Domingo V
authors.initials: DV
authors.lastname: Gargallo
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Hollie
authors.initials: H
authors.lastname: Lander
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival; D002738:Chloroquine / Q000494:pharmacology; D004285:Dogs; D004351:Drug Resistance; D005260:Female; D000882:Haplorhini; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: C540175:(3-(tert-butylaminomethyl)-4-fluorophenyl)(7-chloroquinolin-4-yl)amine; D000634:Aminoquinolines; D000962:Antimalarials; C540176:N-tert-butylisoquine; D000655:Amodiaquine; D002738:Chloroquine