CF 2 H, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH 3 ?

• Published in: Journal of medicinal chemistry Vol. 62; no. 11; pp. 5628 - 5637
• Main Authors: Zafrani, Yossi, Sod-Moriah, Gali, Yeffet, Dina, Berliner, Anat, Amir, Dafna, Marciano, Daniele, Elias, Shlomi, Katalan, Shahaf, Ashkenazi, Nissan, Madmon, Moran, Gershonov, Eytan, Saphier, Sigal
• Format: Journal Article
• Language: English
• Published: United States 13.06.2019
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00604

The effects of the CF H moiety on H-bond (HB) acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers, or electron-withdrawing groups, are discussed. It was found that the CF H group acts as a HB donor with a strong dependence on the attached functional group ( A = 0.035-0.165). Regarding lipophilicity, the CF H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH , respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH /CF H exchange at the α position. Interestingly, this exchange significantly affects not only the polarity and the volume of the solutes but also their HB-accepting ability, the main factors influencing log  P . Accordingly, this study may be helpful in the rational design of drugs containing this moiety.