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.

Characterization of antimalarial activity of artemisinin-based hybrid drugs

“…Moreover, artesunate showed a low clearance rate. In the literature, artesunate is categorized as a drug of low to intermediate hepatic clearance [49, 50]. Among the compounds, artesunate showed the lowest clearance (Cl int of 11.6 µL/min/mg of protein) and hybrid 2 the highest (Cl int between 186.88 and 422.86 µL/min/mg of protein).…”

Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

“…Thelingwani et al (83) addressed the various metabolic challenges that arise in covalently linking two active pharmacophores by characterizing artemisinin-chloroquinoline hybrids (47) and concluded that though the technique combines the desirable properties, certain unfavorable properties are also carried along in the process and need to be accounted for. The experiment investigating metabolic stability and metabolite identification showed that the hybrids were not extensively metabolized, with the major amount of the parent compound remaining unchanged after 1 h of incubation in hepatocytes.…”