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Effect of gem-Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes |
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| Authors: | Sergey Holovach Dr Kostiantyn P Melnykov Artem Skreminskiy Maksym Herasymchuk Olha Tavlui Danylo Aloshyn Dr Petro Borysko Prof Dr Alexander B Rozhenko Prof Dr Sergey V Ryabukhin Prof Dr Dmitriy M Volochnyuk Prof Dr Oleksandr O Grygorenko |
| Institution: | 1. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv, 02660 Ukraine;2. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601 Ukraine;3. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine;4. Bienta / Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine;5. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv, 02660 Ukraine Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601 Ukraine |
| Abstract: | Physico-chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes and compared to those of non-fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem-difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes. |
| Keywords: | fluorine cycloalkanes lipophilicity acidity and basicity metabolic stability |