Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach

Curcuminoids are the main bioactive components of well-known Asian spice and traditional medicine turmeric. have poor chemical stability bioavailability; in vivo they rapidly metabolized to a set bioreduced derivatives and/or glucuronide sulfate conjugates. The reduced curcuminoid metabolites were also reported exert various bioactivities vitro vivo. In this work, we aimed perform comparative evaluation curcuminoids their hydrogenated from medicinal chemistry point view, by determining key pharmacokinetic parameters evaluating antioxidant potential relation such properties.Reduced prepared curcumin demethoxycurcumin through continuous-flow hydrogenation. As selected parameters, kinetic solubility, stability, metabolic human liver microsomes, parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal blood-brain barrier determined. Experimentally determined logP for hydrocurcumins octanol-water toluene-water systems provided valuable data on tendency intramolecular hydrogen bonding these compounds. Drug likeness compounds further evaluated silico calculations. Antioxidant properties diphenyl-2-picrylhydrazyl (DPPH) radical scavenging oxygen absorbance capacity (ORAC) assays comparatively determination ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility as compared corresponding parent compound. Hexahydrocurcumin was found best candidate drug development based complex pharmacokinetical comparison high LLE values its properties. Development tetrahydrocurcumin tetrahydro-demethoxycurcumin would be limited very therefore an effort rely formulations bypassing first-pass metabolism.