Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept

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• 作者：Yossi Zafrani ; Dina Yeffet ; Gali Sod-Moriah ; Anat Berliner ; Dafna Amir ; Daniele Marciano ; Eytan Gershonov ; Sigal Saphier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：60
• 期：2
• 页码：797-804
• 全文大小：418K
• ISSN：1520-4804

文摘

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085–0.126) were determined using Abraham’s solute ¹H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water–octanol) values (log P(XCF₂H) – log P(XCH₃)) spanned from −0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.