Synthesis, analysis and determination of partition coefficients of N-arylhydroxypyridinone derivatives as iron chelators

Abstract

Iron overload is a serious clinical condition which can be largely prevented by the use of iron-specific chelating agents. In this study, the synthesis and determination of partition coefficients (Kpart) of a range of N-alkyl hydroxypyridinones, as orally active iron chelators, are described. Synthesis of N-aryl hydroxypyridinones was achieved via a single step synthetic pathway. In this method, maltol (2-methyl-3-hydroxypyra-4-one) was reacted with an excess of suitable aryl primary amines under reflux condition in dilute hydrochloric acid at pH about 5. The progress of reactions was monitored by TLC. The reaction mixture was adjusted to pH 7 using sodium hydroxide and the product was collected by filtration. Purification was achieved by re-crystallization from hot methanol. In this work, 1-phenyl-2-methyl-3-hydroxypyridin-4-one, 1- (3-chlorophenyl) -2-methyl-3-hydroxypyridin-4-one, 1- (3-hydro-xyphenyl) -2-methyl-3-hydroxypyridin-4-one, 1- (3-carboxyphenyl) -2-methyl-3-hydroxy-pyridin-4-one and 1-(4-carboxyphenyl)-2-methyl-3-hydroxypyridin-4-one were synthesized. Identification and structural elucidation of compounds were achieved by 1HNMR, IR, elemental analysis, mass spectra and through physical constants. Kpart values of the compounds were also determined in an aqueous/octanol system using an automated continuous flow method (a filter probe method).