Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials.
Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC(50) = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED(50) activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.
O'Neill
Paul M
PM
Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK. saward@liv.ac.uk
Mukhtar
Amira
A
Stocks
Paul A
PA
Randle
Laura E
LE
Hindley
Stephen
S
Ward
Stephen A
SA
Storr
Richard C
RC
Bickley
Jamie F
JF
O'Neil
Ian A
IA
Maggs
James L
JL
Hughes
Ruth H
RH
Winstanley
Peter A
PA
Bray
Patrick G
PG
Park
B Kevin
BK
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000655:Amodiaquine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
C479683:5-(7-chloroquinolin-4-ylamino)-2-diethylaminomethylphenol; D000634:Aminoquinolines; D000962:Antimalarials; D000655:Amodiaquine