Details

Autor(en) / Beteiligte

• Schiesser, Stefan
• Chepliaka, Hanna
• Kollback, Johanna
• Quennesson, Thibaut
• Czechtizky, Werngard
• Cox, Rhona J

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2020-11, Vol.63 (21), p.13076-13089

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.