Conformational analysis of the fungicide fenpropimorph by molecular mechanics calculations and NMR spectroscopy

Abstract

Fenpropimorph is an inhibitor of A8 + A7-isomerase and AlCreductase in fungi and cycloeucalenol-obtusifoliol-isomerase and A8 + A7-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. N M R 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-I 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-') 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 A8 + A7-isomerase in fungi.

The biosynthesis of steroids and triterpenoids

“…1073 The CYP51A1 gene from Saccharomyces cerevisiae has been expressed in tobacco 1074 and the CYP51 gene encoding eburicol 14 -demethylase from Penicillium italicum has also been cloned. 1075 The morpholine fungicide fenpropimorph has been confirmed to inhibit at least three enzymes in the ergosterol pathway, including 14 -reductase, [1076][1077][1078] the enzyme which removes the 14 double bond created by 14-demethylation; the piperidine fungicide piperalin is a relatively poor inhibitor of this enzyme. 1079 A25822 B, a 15-azasteroid natural product which is thought to inhibit 14 -reductase by mimicking the putative C-14 cation generated during the course of the reduction (morpholine inhibitors are also believed to act in this manner), has now been obtained by chemical synthesis 1080 and a synthesis of an A25822 B side-chain analogue has been reported.…”

“…1076,1077,1079,1082,[1100][1101][1102] Molecular modelling studies of fenpropimorph have indicated that the totally extended conformation is probably responsible for inhibitory activity of 8 < 7 SI. 1078 Novel morpholine inhibitors continue to be developed 1063,1103 and other inhibitors also designed to mimic the putative cation intermediate have been described. 1082,1104 7-Aminocholesterol 1083 and the immunosuppresant SR 31747 1105 both inhibit this enzyme.…”

The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro

“…CA in explicit solvent may be used to predict the single pesticide stability prior to AChE binding. Herein, CAs were tentatively carried out by using five different force fields (FFs): MM3, AMBER94, MMFF, MMFFs, and OPLSAA [ 35 ]. Either for crystallized pesticides or pesticides with unknown experimental structures, the procedure was divided into the following steps: (1) conformational analysis; (2) determination of energy of the global minimum ( E glob_min ), and (3) the LB superposition of structures to define the alignment accuracy.…”

“…Bearing in mind that different ACh conformations can trigger different receptors (nicotinics and muscarinics, respectively), conformational analysis (CA, ligand-based (LB) approach) could be considered as a computational tool to predict pesticides behaviour before their interaction with AChE [ 34 ]. Due to the lack of crystal structures of any pesticides co-crystallized with AChE, CA can be used to gather pesticide conformations that are, upon the interaction with AChE, going to be transformed into the bioactive ones [ 35 ].…”

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

“…The substructure 1H\ 3H\ 4H\ and 5H' is enclosed with dotted lines. the carbocationic intermediate in the A 8 ->A 7 -isomerase reaction(44). The initial geometries were fully optimized by the MO calculation to obtain the minimumenergy conformation for each cationic intermediate.…”