Physicochemical and Biological Evaluation of <i>gem</i> ‐Difluorinated Saturated Oxygen Heterocycles as Bioisosteres for Drug Discovery
A comprehensive study on the physicochemical properties of gem-fluorinated O-heterocyclic substituents is reported. Systematic additive effects of introducing O- and gem-CF<sub>2</sub> group introduction on acidic properties (pK<sub>a</sub>) of the corresponding carboxylic acids/protonated primary amines were demonstrated. The impact of the O/CF<sub>2</sub> moieties on lipophilicity (LogP) 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.
Authors
- Serhii Holovach (ORCID: https://orcid.org/0009-0004-2214-1880)
- Oleksandr S. Liashuk (ORCID: https://orcid.org/0000-0002-2677-435X)
- Oleksandr O. Grygorenko (ORCID: https://orcid.org/0000-0002-6036-5859)
- Artur Horbenko (ORCID: https://orcid.org/0000-0002-7579-543X)
- Kostiantyn P. Melnykov (ORCID: https://orcid.org/0009-0003-6522-681X)
- Varvara Melnyk
- Petro Borysko (ORCID: https://orcid.org/0000-0002-5840-5233)
- Dmytro Lesyk (ORCID: https://orcid.org/0009-0001-3391-5165)
- Oleksandr Viniichuk (ORCID: https://orcid.org/0009-0004-4120-3856)
- Valeriia Shatnia
- Daniil Skrypnik
- Anna Beshtynarska
Institutions
- National Academy of Sciences of Ukraine (UA)
- Taras Shevchenko National University of Kyiv (UA)
- National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute” (UA)
- Institute of General and Inorganic Chemistry (BG)
- Institute of Organic Chemistry (UA)
- Enamine (Ukraine) (UA)
Publication Details
- Journal
- Chemistry - A European Journal
- Published
- 2024-12-11
- DOI
- https://doi.org/10.1002/chem.202404390
- Citations
- 5
- Primary Topic
- Fluorine in Organic Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 1.04
Funders
- Enamine