Characterisation of artemisinin–chloroquinoline hybrids for potential metabolic liabilities

Abstract

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.

• Antimalarial
• biotransformation
• clearance
• cytochrome P450
• inhibition

Declaration of interest

The authors declare no conflict of interest. The authors would like to acknowledge funding from the European Union (AntiMal Project), International Programme in the Chemical Sciences (IPICS, Sweden), University of Cape Town, South African Medical Research Council, South African Research Chairs Initiative (SARChI), South African Malaria Initiative (SAMI) of the Department of Science and Technology (DST) administered through the South African the National Research Foundation (NRF), and AstraZeneca (Sweden).