Characterisation of artemisinin-chloroquinoline hybrids for potential metabolic liabilities.
1. Chemotherapy remains the effective way of controlling malaria infections. Many of the treatments have been rendered ineffective as a result of drug resistance by plasmodia species as well as toxicity. Molecular hybridisation is one of the techniques used in the synthesis of new-generation antimalarial techniques. In this paper, we explore some potential metabolic challenges associated with this technique. 2. In vitro metabolic clearance and metabolite identification were performed in cryopreserved hepatocytes. Reaction phenotyping and inhibition studies were conducted in human liver microsomes and recombinant cytochrome P450s (CYPs) 3. Metabolism in hepatocytes was not extensive with less than 25% of the hybrids being metabolised by contributing CYP enzymes. The hybrids were, however, potent inhibitors of CYPs 2C9 2C19 and 3A4. 4. Our data indicated that artemisinin-chloroquinoline hybrid both gained and lost favourable properties from the individual pharmacophoric units from which they were built. This highlights the challenges associated with the molecular hybridisation technique and a need to optimise the chemistry in an effort to maintain good properties while addressing new liabilities that arise.
a Department of ADMET/PK & BAC , African Institute of Biomedical Science and Technology , Harare , Zimbabwe .|b Department of Chemistry, Drug Discovery and Development Research Unit , South African Medical Research Council, University of Cape Town , Cape Town , South Africa .
Roslyn
R
Thelingwani
c AstraZeneca , Molndal , Sweden , and.
Carina
C
Leandersson
c AstraZeneca , Molndal , Sweden , and.
Britta
B
Bonn
d Department of Clinical Pharmacology , University of Cape Town , Cape Town , South Africa.
Peter
P
Smith
b Department of Chemistry, Drug Discovery and Development Research Unit , South African Medical Research Council, University of Cape Town , Cape Town , South Africa .
Kelly
K
Chibale
a Department of ADMET/PK & BAC , African Institute of Biomedical Science and Technology , Harare , Zimbabwe .|d Department of Clinical Pharmacology , University of Cape Town , Cape Town , South Africa.
Collen
C
Masimirembwa
D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002739:Chloroquinolinols / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004351:Drug Resistance; D022781:Hepatocytes / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008962:Models, Theoretical; D017711:Nonlinear Dynamics
D000962:Antimalarials; D037621:Artemisinins; D002739:Chloroquinolinols; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; C031327:artemisinin
Antimalarial; biotransformation; clearance; cytochrome P450; inhibition