CONFORMATIONAL-ANALYSIS OF THE FUNGICIDE FENPROPIMORPH BY MOLECULAR MECHANICS CALCULATIONS AND NMR-SPECTROSCOPY

Fenpropimorph is an inhibitor of DELTA8 --> DELTA7-isomerase and DELTA14-reductase in fungi and cycloeucalenol-obtusifoliol-isomerase and DELTA8 --> DELTA7-isomerase in higher plants. A detailed conformational analysis of the most potent enantiomer (S)-fenpropimorph is described. The conformational analysis is based on three different methods: molecular mechanics calculations, NMR spectroscopy and X-ray crystallography. In solution several conformations coexist. The molecular mechanics calculations using MM2(85) show a folded conformation of the unprotonated form of fenpropimorph to be stabilized by at least 3 kcal mol-1 relative to the next lowest energy conformer, suggesting only one conformation of fenpropimorph to be present. A corresponding stabilization of the protonated form (5.4 kcal mol-1) is obtained. However, this stabilization is found partly to be due to attractive steric interactions and may be a phenomenon occurring only in vacuum. In the solid state, fenpropimorph exists in an L-shaped conformation resembling one of the low-energy conformers obtained with MM2(85). Based on comparison with the natural substrate, a totally extended conformation of fenpropimorph is suggested to be the biologically: active conformation for interaction with the DELTA8 --> DELTA7-isomerase in fungi.