Computer-Aided Molecular Modeling and Structure—Activity Analyses of New Antifungal Tertiary Amines

Abstract

Various computational procedures such as the Hansch-Fujita method and the ACACS molecular graphics system have been used in agrochemical design research in our laboratory for many years. The ACACS system was applied to the structure-activity analyses of antifungal amine compounds. We designed two series of azasterol mimics on the basis of the structure of fecosterol, the substrate of the Δ 8 -->Δ 7 -isomerization step in the ergosterol biosynthetic pathway of fungi. As expected, two types of new tertiary amines, which we synthesized, showed a high antifungal activity against various plant -pathogenic fungi. One of the series inhibited well the Δ 8 -->Δ 7 -isomerase as expected, while the other blocked strongly the Δ 14 -reduction step, but scarcely the Δ 8 -->Δ 7 -isomerization. The structure -activity relationships were reasonably rationalized by conformational analyses using the MNDO-PM3 molecular orbital method in the MOPAC program package incorporated in the ACACS system.Various computational procedures are used in designing new agrochemicals and medicines these days. In our laboratory, the classical Hansch-Fujita QSAR (Quantitative Structure-Activity Relationship) method (7) has been used in agrochemical design research for many years. We have also been using a number of other procedures such as theoretical physicochemical calculations and molecular modeling. Various computer programs and databases have been organized so that they are interactive with each other.In this chapter, after a brief introduction to computational systems used in the Sumitomo Chemical, an example of the application to structure-activity analyses of new antifungal tertiary amines is described.