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Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, -trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of -trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that -trifluoromethyl amines are prone to hydrolysis, whereas -trifluoromethyl azoles have excellent aqueous stability. Compared to their -methyl analogues, -trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, -trifluoromethyl azoles can serve as bioisosteres of --propyl and --butyl azoles. Consequently, we suggest that -trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.
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| http://dx.doi.org/10.1021/acs.jmedchem.0c01457 | DOI Listing |
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