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. 2024 Dec 23;30(72):e202403277.
doi: 10.1002/chem.202403277. Epub 2024 Oct 31.

3,3-Difluorooxetane-A Versatile Functional Group for Bioisosteric Replacements in Drug Discovery

Oleksandr S Liashuk  1   2 , Anastasiya Fedinchyk  1   2 , Kostiantyn P Melnykov  1   2 , Maksym Herasymchuk  1   2 , Diana Alieksieieva  3 , Dmytro Lesyk  2   3 , Yuliia P Bas  2 , Tetiana Ye Keda  2 , Andriy V Yatsymyrskiy  2 , Yuliia Holota  3 , Petro Borysko  3 , Volodymyr S Yarmolchuk  1   2 , Oleksandr O Grygorenko  1   2
Affiliations

3,3-Difluorooxetane-A Versatile Functional Group for Bioisosteric Replacements in Drug Discovery

Oleksandr S Liashuk et al. Chemistry. .

Abstract

Functional group (FG) is one of the cornerstone concepts in organic chemistry and related areas. The wide spread of bioisosterism ideas in medicinal chemistry and beyond caused a striking rise in demand for novel FGs with a defined impact on the developed compound properties. In this work, the evaluation of the 3,3-difluorooxetane unit (3,3-diFox) as a functional group for bioisosteric replacements is disclosed. A comprehensive experimental study (including multigram building block synthesis, quantification of steric and electronic properties, measurements of pKa, LogP, chemical stability, and biological evaluation of the 3,3-diFox-derived bioisostere of a drug candidate) revealed a prominent behavior of the 3,3-diFox fragment as a versatile substituent for early drug discovery programs.

Keywords: Bioisosteres; Building blocks; Fluorine; Functional groups; Oxetane.

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