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.
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.
O'Neill
Paul M
PM
Department of Chemistry, University of Liverpool, Liverpool, UK.
Shone
Alison E
AE
Stanford
Deborah
D
Nixon
Gemma
G
Asadollahy
Eghbaleh
E
Park
B Kevin
BK
Maggs
James L
JL
Roberts
Phil
P
Stocks
Paul A
PA
Biagini
Giancarlo
G
Bray
Patrick G
PG
Davies
Jill
J
Berry
Neil
N
Hall
Charlotte
C
Rimmer
Karen
K
Winstanley
Peter A
PA
Hindley
Stephen
S
Bambal
Ramesh B
RB
Davis
Charles B
CB
Bates
Martin
M
Gresham
Stephanie L
SL
Brigandi
Richard A
RA
Gomez-de-Las-Heras
Federico M
FM
Gargallo
Domingo V
DV
Parapini
Silvia
S
Vivas
Livia
L
Lander
Hollie
H
Taramelli
Donatella
D
Ward
Stephen A
SA
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
C540175:(3-(tert-butylaminomethyl)-4-fluorophenyl)(7-chloroquinolin-4-yl)amine; D000634:Aminoquinolines; D000962:Antimalarials; C540176:N-tert-butylisoquine; D000655:Amodiaquine; D002738:Chloroquine