Physicochemical and Biological Evaluation of gem-Difluorinated Saturated Oxygen Heterocycles as Bioisosteres for Drug Discovery.

Autor: Melnykov KP; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine., Liashuk OS; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine., Holovach S; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 5, Kyїv, 02660, Ukraine., Shatnia V; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; National Technical University of Ukraine 'Igor Sikorsky Kyiv Polytechnic Institute', Beresteiskyi Avenue 37, Kyїv, 03056, Ukraine., Horbenko A; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; V. I. Vernadsky Institute of General and Inorganic Chemistry, National Academy of Sciences of Ukraine, Akademik Palladin Street 32/34, Kyїv, 03142, Ukraine., Lesyk D; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine.; Bienta/Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine., Melnyk V; Bienta/Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine., Skrypnik D; Bienta/Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine., Beshtynarska A; Bienta/Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine., Borysko P; Bienta/Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine., Viniichuk O; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine., Grygorenko OO; Enamine Ltd., Winston Churchill Street 78, 02094, Kyїv, Ukraine.; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Dec 11, pp. e202404390. Date of Electronic Publication: 2024 Dec 11.
DOI: 10.1002/chem.202404390
Abstrakt: A comprehensive study on the physicochemical properties of gem-fluorinated O-heterocyclic substituents is reported. Systematic additive effects of introducing O- and gem-CF 2 group introduction on acidic properties (pK a ) of the corresponding carboxylic acids/protonated primary amines were demonstrated. The impact of the O/CF 2 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.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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