111456-84-9Relevant academic research and scientific papers
Estrogen Synthetase Inhibitors. 2. Comparison of the in Vitro Aromatase Inhibitory Activity for a Variety of Nitrogen Heterocycles Substituted with Diarylmethane or Diarylmethanol Groups
Jones, C. David,Winter, Mark A.,Hirsch, Kenneth S.,Stamm, Nancy,Taylor, Harold M.,et al.
, p. 416 - 429 (2007/10/02)
The preparation and in vitro aromatase inhibitory activity of a wide variety of heterocyclic (4,4'-dichlorodiphenyl)methanes and -methanols are described.The choice of the two diaryl-bearing moieties as a vehicle for the evaluation of the heterocycles was made by the comparison of series of imidazole and pyridine-derived compunds with similar pyrimidine compounds reported previously.A structural model for the most active compounds is also presented.The activity of a related series of compounds which contain two heterocyclic moieties was found to be consistent with the model.Many of the compounds evaluated, including representatives of the pyridine, imidazole, pyrimidine, pyrazole, triazole, thiazole, and isothiazole classes, exhibit EC50 potencies for aromatase inhibition at low nanomolar levels.These compunds are at least as potent as other nonsteroidal aromatase inhibitors reported previously.
Hydration of acylimidazoles: tetrahedral intermediates in acylimidazole hydrolysis and nucleophilic attack by imidazole on esters. The question of concerted mechanisms for acyl transfers
Guthrie, J. Peter,Pike, David C.
, p. 1951 - 1970 (2007/10/02)
Heats of hydrolysis have been measured for three acylimidazole acetals.From these results free energies of formation in aqueous solution have been calculated for the acetals and the corresponding tetrahedral intermediates.Having free energies of formation for the tetrahedral intermediates allows a detailed analysis of the energetics of both the unobservable nucleophilic reaction of imidazole with ethyl acetate and also the observable reaction of imidazole with p-nitropehnyl acetate. pKa values of 1-(3-aminopropyl)-imidazole and 1-(2-aminoethyl)-imidazole have been determined to allow calculation of the ?* value for the imidazolyl substituent .The dependence of imidazole pKa values on the electron-withdrawing properties of the 1-substituent was also determined.There is a linear free energy relation between the free energy change for replacement of OH in a carbonyl hydrate by imidazolyl and the sum of the ?* values for the other substituents.The implications of these results for the question of concerted versus stepwise mechanism for the reaction of imidazole with aryl acetates have been examined.An equilibrium constant has been calculated for the addition of imidazole to p-nitrophenyl acetate.A simple extension of Marcus theory allows the free energy surface for a three-dimensional reaction coordinate diagram to be calculated using the energy levels of the tetrahedral intermediate determined in this work, the energy level of the acylium ion derived from literature data, and intrinsic barriers for the edge reactions.It is shown, that the reaction of imidazole with p-nitrophenyl acetate probably follows a concerted path.General conclusions from this theory of concerted reaction are discussed.
