Kinetics of racemization of enantiopure N-imidazole derivatives, aromatase inhibitors: studies in organic, aqueous, and biomimetic media

The configurational stability of N-imidazole derivatives, aromatase inhibitors, was investigated under organic, aqueous, and biomimetic media, by studying the effect of organic solvent, pH, and temperature. Validated chiral HPLC or CD-EKC methods allowed us to quantify the presence of both enantiomers. The rate constants, half-lives, and apparent free energy barriers of the racemization phenomenon were determined using a mathematical model of this first-order reaction.The presence of triethylamine (2000 equiv) at high temperature (70 °C) induces the fastest racemization with a t1/2 rac less than 7 h. This result can be related to the lability of benzylic proton in these strongly basic conditions. Biomimetic media (the presence of bovine serum albumin in a pH 7.4 buffer at 37.4 °C) do not seem to preserve the initial configuration of each enantiomer.