Physicochemical and Biological Evaluation of <i>gem</i>‐Difluorinated Saturated Oxygen Heterocycles as Bioisosteres for Drug Discovery

Edition

Chemistry – A European Journal

Abstract

<jats:title>Abstract</jats:title><jats:p>A comprehensive study on the physicochemical properties of <jats:italic>gem</jats:italic>‐fluorinated <jats:italic>O</jats:italic>‐heterocyclic substituents is reported. Systematic additive effects of introducing <jats:italic>O</jats:italic>‐ and <jats:italic>gem</jats:italic>‐CF<jats:sub>2</jats:sub> group introduction on acidic properties (p<jats:italic>K</jats:italic><jats:sub>a</jats:sub>) of the corresponding carboxylic acids/protonated primary amines were demonstrated. The impact of the O/CF<jats:sub>2</jats:sub> moieties on lipophilicity (Log<jats:italic>P</jats:italic>) was found to be complex; significant mutual influence of the corresponding polar moieties governed the compound's overall properties in this case. Biological evaluation of MAPK kinase inhibitors incorporating the title substituents demonstrated their utility as promising fragments for bioisosteric replacements in drug discovery campaigns.</jats:p>

Authors

Kostiantyn P. Melnykov; Liashuk O.; Serhii Holovach; Valeriia Shatnia; Artur Horbenko; Dmytro Lesyk; Varvara Melnyk; Daniil Skrypnik; Anna Beshtynarska; Petro Borysko; Oleksandr Viniichuk; Grygorenko O.