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.
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