Structure-hydrolyzability relationships in a series of piperidinyl and tropinyl esters with antimuscarinic activity

Abstract

The hydrolysis of a series of antimuscarinic tropinyl and N- methylpiperidinyl esters was investigated in 70% dimethyl sulfoxide (DMSO) (0.1 M NaOH) at 25 °C. The hydrolysis followed pseudo-first order kinetics and the piperidinyl esters were hydrolyzed more rapidly than their tropinyl counterparts. Variation in the acyl (R-CO) moiety of the esters generally affected the hydrolysis of piperidinyl and tropinyl esters in a similar manner, but the orientation of the acyl moiety (axial or equatorial) did not influence the hydrolysis rate. The influence of hydrophobic, electronic and steric factors on the hydrolysis was investigated by using appropriate parameters to represent the hydrophobicity (log k(w)), size (molecular volume MV) and electronic character (Taft's polar substituent constant σ* and 13C chemical shift difference Aδ of R) of the esters. These were correlated to the rate constants of hydrolysis (pK1) by a series of regression equations. It was found that the hydrophobic character of the esters could account for 64% of the observed variation in pK1. However, a combination of σ* and molecular volume improved the correlation significantly, with r=0.94. The regression equation showed that an increase in the electron-withdrawing character of the acyl group R and a decrease in molecular volume of the ester favored hydrolysis.