N‑Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist’s Toolbox

Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-trifluoromethyl amines and azo...

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Published inJournal of medicinal chemistry Vol. 63; no. 21; pp. 13076 - 13089
Main Authors Schiesser, Stefan, Chepliaka, Hanna, Kollback, Johanna, Quennesson, Thibaut, Czechtizky, Werngard, Cox, Rhona J
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 12.11.2020
Amer Chemical Soc
Subjects
Amines - chemical synthesis
Amines - chemistry
Amines - pharmacokinetics
Azoles - chemical synthesis
Azoles - chemistry
Azoles - pharmacokinetics
Biochemistry and Molecular Biology
Biokemi och molekylärbiologi
Caco-2 Cells
Chemistry, Medicinal
Drug Design
Drug Stability
Fluorine - chemistry
Glutathione - chemistry
Half-Life
Humans
Hydrogen-Ion Concentration
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
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Summary:Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that N-trifluoromethyl amines are prone to hydrolysis, whereas N-trifluoromethyl azoles have excellent aqueous stability. Compared to their N-methyl analogues, N-trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N-trifluoromethyl azoles can serve as bioisosteres of N-iso-propyl and N-tert-butyl azoles. Consequently, we suggest that N-trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01457