Physicochemical and drug metabolism characterization of a series of 4-aminoquinoline-3-hydroxypyridin-4-one hybrid molecules with antimalarial activity

Abstract

Background and objective: Drug resistance by Plasmodium falciparum remains a challenge in malaria chemotherapy. This paper will focus on physicochemical and drug metabolism characterization of a series of 4-aminoquinoline-3-hydroxypyridin-4-one hybrid shown to have antimalarial activity against chloroquine-resistant P. falciparum. The aim is to identify potential liabilities that could arise from covalently linking two pharmacophoric units of different drug classes into one functional drug.

Methods: Metabolism and biotransformation of hybrids were investigated using cryopreserved human hepatocytes. Generic incubation conditions with respect to substrate concentration, cell concentration and incubation time were used. Evaluation of the hybrids for metabolism-based drug–drug interaction (DDI) risk was done with recombinant CYPs. A generic UPLC-MSMS bioanalytical method was used for quantitation and metabolite identification. Prediction of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the hybrid compounds was done using various software.

Results: The analogs generally had good physicochemical profiles. Metabolism was mainly via the linker chain and was predicted to be intermediate to fast in cryopreserved human hepatocytes. However, analogs had potential to cause DDIs as they were potent inhibitors of CYP3A4 and CYP2D6.

Conclusions: Although the efficacy of the compounds is promising, they carry a potentially limiting liability of CYP inhibition and rapid metabolic clearance.

Keywords::

• biotransformation
• CYP inhibition
• hybrid analogs
• metabolic clearance