Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.
A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Department of Pharmaceutical Chemistry, University of Nairobi, Nairobi, Kenya.
Dennis S B
DS
Ongarora
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Natasha
N
Strydom
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Kathryn
K
Wicht
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
Mathew
M
Njoroge
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
Lubbe
L
Wiesner
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Timothy J
TJ
Egan
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland; University of Basel, Socinstrasse 57, 4002 Basel, Switzerland.
Sergio
S
Wittlin
AstraZeneca R&D, Mölndal, Sweden.
Ulrik
U
Jurva
African Institute of Biomedical Science and Technology, Zimbabwe.
Collen M
CM
Masimirembwa
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.
Kelly
K
Chibale
D000634:Aminoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001555:Benzene Derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D000962:Antimalarials; D001555:Benzene Derivatives; C001920:4-aminoquinoline
4-Aminoquinolines; Amodiaquine; Antimalarial activity; Antiplasmodial activity; Benzoxazole; Bioactivation; Malaria; Quinone imine; Reactive metabolite; Structure–activity relationship; β-Haematin