TY - JOUR
T1 - CF2H, a Functional Group-Dependent Hydrogen-Bond Donor
T2 - Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH3?
AU - Zafrani, Yossi
AU - Sod-Moriah, Gali
AU - Yeffet, Dina
AU - Berliner, Anat
AU - Amir, Dafna
AU - Marciano, Daniele
AU - Elias, Shlomi
AU - Katalan, Shahaf
AU - Ashkenazi, Nissan
AU - Madmon, Moran
AU - Gershonov, Eytan
AU - Saphier, Sigal
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/13
Y1 - 2019/6/13
N2 - The effects of the CF2H 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 CF2H group acts as a HB donor with a strong dependence on the attached functional group (A = 0.035-0.165). Regarding lipophilicity, the CF2H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH3, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH3/CF2H 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 Poct. Accordingly, this study may be helpful in the rational design of drugs containing this moiety.
AB - The effects of the CF2H 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 CF2H group acts as a HB donor with a strong dependence on the attached functional group (A = 0.035-0.165). Regarding lipophilicity, the CF2H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH3, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH3/CF2H 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 Poct. Accordingly, this study may be helpful in the rational design of drugs containing this moiety.
UR - http://www.scopus.com/inward/record.url?scp=85066468080&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b00604
DO - 10.1021/acs.jmedchem.9b00604
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C2 - 31091098
AN - SCOPUS:85066468080
SN - 0022-2623
VL - 62
SP - 5628
EP - 5637
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -