title: Physicochemical and drug metabolism characterization of a series of 4-aminoquinoline-3-hydroxypyridin-4-one hybrid molecules with antimalarial activity.
abstract: 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.
authors.affiliation: African Institute of Biomedical Science and Technology, Department of ADMET/PK and BAC , Dominion House, 211 Herbert Chitepo Street, Harare , Zimbabwe +263 4 710563 ; roslyn.thelingwani@aibst.com.
authors.forename: Roslyn
authors.initials: R
authors.lastname: Thelingwani
authors.forename: Britta
authors.initials: B
authors.lastname: Bonn
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.forename: Collen
authors.initials: C
authors.lastname: Masimirembwa
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015925:Cryopreservation; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D011725:Pyridines; C014047:hydroxypyridines; D002738:Chloroquine
keywords: CYP inhibition; biotransformation; hybrid analogs; metabolic clearance