Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic log P values...

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Published inJournal of medicinal chemistry Vol. 63; no. 3; pp. 1002 - 1031
Main Authors Jeffries, Benjamin, Wang, Zhong, Felstead, Hannah R, Le Questel, Jean-Yves, Scott, James S, Chiarparin, Elisabetta, Graton, Jérôme, Linclau, Bruno
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.02.2020
Amer Chemical Soc
Subjects
1-Butanol / chemistry Halogenation Hydrocarbons, Fluorinated / chemistry Hydrophobic and Hydrophilic Interactions Molecular Conformation Pentanols / chemistry
Biochemistry, Molecular Biology
Chemistry, Medicinal
Life Sciences
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
KETONES
TRIFLUOROMETHYL
ENANTIOSELECTIVE SYNTHESIS
POLARITY
CONSTRUCTION
REACTIVITY
CHEMISTRY
ALDOL REACTIONS
CONVENIENT
ALPHA-FLUORINATION
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Summary:Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic log P values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity-reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as “motif extensions” and “motif rearrangements”, including with concomitant extension of the carbon chain, as well as one- and two-fluorine ‘deletions’ within perfluoroalkyl groups. Quantum chemical log P calculations (SMD-MN15) based on solvent-dependent three-dimensional (3D) conformational analysis gave excellent correlations with experimental values, superior to Clog P predictions based on 2D structural motifs. The availability of a systematic collection of data based on a small number of parent molecules illustrates the relative lipophilicity modulations of aliphatic fluorination motifs.
Bibliography:UKRI
ObjectType-Article-1
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01172