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A systematic investigation of lipophilicity modulation by aliphatic fluorination motifs

A systematic investigation of lipophilicity modulation by aliphatic fluorination motifs
A 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 logP 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 logP calculations (SMD-MN15) based on solvent-dependent 3D conformational analysis gave excellent correlations with experimental values, superior to ClogP 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.
0022-2623
1002-1031
Jeffries, Benjamin Francis Joseph
5dd25e94-d698-4270-9c65-800495794388
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Felstead, Hannah, Rebecca
724886d1-059f-42b0-a44e-127e2115c376
Le Questel, Jean-Yves
38aea4ae-64a3-43b7-8049-ea2f351459f2
Scott, James
38da9dc5-ce87-4dc9-96c9-14af6592c2fb
Chiarparin, Elisabetta
5051f89a-b801-4746-8f20-457fdcbed396
Graton, Jérôme
12432694-552e-4a40-9935-9ff7c77fbf07
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Jeffries, Benjamin Francis Joseph
5dd25e94-d698-4270-9c65-800495794388
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Felstead, Hannah, Rebecca
724886d1-059f-42b0-a44e-127e2115c376
Le Questel, Jean-Yves
38aea4ae-64a3-43b7-8049-ea2f351459f2
Scott, James
38da9dc5-ce87-4dc9-96c9-14af6592c2fb
Chiarparin, Elisabetta
5051f89a-b801-4746-8f20-457fdcbed396
Graton, Jérôme
12432694-552e-4a40-9935-9ff7c77fbf07
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Jeffries, Benjamin Francis Joseph, Wang, Zhong, Felstead, Hannah, Rebecca, Le Questel, Jean-Yves, Scott, James, Chiarparin, Elisabetta, Graton, Jérôme and Linclau, Bruno (2020) A systematic investigation of lipophilicity modulation by aliphatic fluorination motifs. Journal of Medicinal Chemistry, 63 (3), 1002-1031. (doi:10.1021/acs.jmedchem.9b01172).

Record type: Article

Abstract

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 logP 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 logP calculations (SMD-MN15) based on solvent-dependent 3D conformational analysis gave excellent correlations with experimental values, superior to ClogP 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.

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motif scanning manuscript v26_revised2acc - Accepted Manuscript
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More information

Accepted/In Press date: 2 January 2020
e-pub ahead of print date: 2 January 2020
Published date: 13 February 2020

Identifiers

Local EPrints ID: 436869
URI: http://eprints.soton.ac.uk/id/eprint/436869
ISSN: 0022-2623
PURE UUID: 629d82aa-9632-4cf0-88db-c0586c82e191
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

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Date deposited: 13 Jan 2020 17:30
Last modified: 18 Feb 2021 16:55

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