A THEORETICAL APPROACH TO DRUG DESIGN .1. RELATIVE SOLVATION THERMODYNAMICS FOR THE ANTIBACTERIAL COMPOUND TRIMETHOPRIM AND ETHYL DERIVATIVES SUBSTITUTED AT THE 3', 4', AND 5' POSITIONS

Free energy simulation methods are used to compute the relative solvation thermodynamics of the antibacterial drug trimethoprim [2, 4-diamino-5-(3', 4',5'-trimethoxybenzyl)pyrimidine] and a family of congeners derived from methoxy → ethyl substitution on the benzyl ring. The aqueous solubility is found to decrease as more hydrophobic character is introduced into the parent molecule. Nearly additive effects on the solvation free energy are observed for the mono- and disubstituted derivatives, with exception of the 3',5'-diethyl derivative. This compound shows an increased aqueous solubility (over that of the other diethyl compound), which is linked to anomalous entropic effects of the p-methoxy group. The triethyl-substituted molecule exhibits a similar solvation free energy to that of the 3', 4'-diethyl compound, which appears as additive contributions from the 3',5'-diethyl and 4'-monoethyl derivatives. © 1990, American Chemical Society. All rights reserved.