A THEORETICAL INVESTIGATION OF SOME NOVEL PILOCARPINE PRODRUGS

A new class of pilocarpine double prodrugs of the bispilocarpic acid d iester type has been investigated. Molecular orbital and molecular mec hanics calculations have been done to obtain information about the con formational preferences and general physicochemical properties. Geomet ries of the structures were obtained with the force field implemented in the CHEM-X program and using the semiempirical quantum chemical pro gram AMPAC and the AM1 method. A correlation between the van der Waals volume, van der Waals area, and log P of the bispilocarpic acid diest er structures is observed. The structures of these biscompounds are co mpared with the structures of the corresponding monopilocarpic acid di esters. Electrostatic and electronic properties of the compounds will be discussed in the context of the interaction between the prodrugs an d the hydrolyzing esterase enzymes. (C) 1994 John Wiley & Sons, Inc.