New trifluoromethyl ketones as potent inhibitors of esterases: 19F NMR spectroscopy of transition state analog complexes and structure-activity relationships.
A variety of trifluoromethyl ketones (TFMKs) have been studied as inhibitors of the antennal esterases of the Egyptian armyworm Spodoptera littoralis. The chemicals behaved as tight slow-binding inhibitors, the beta-thio derivatives being the most potent ones, particularly 3-octylthio-1,1,1-trifluoropropan-2-one (OTFP) with an IC50 of 0.08 microM. Other TFMKs, containing a propenyl group at the non-polar end of the molecule as in the natural pheromone structure (compounds 4, 8 and 9), were also notably active. Correlation studies of inhibition with lipophilicity (log P) indicated that the optimum log P values for activity of the beta-thio compounds are in the range of 3.03-5.11, while a higher lipophilicity (range 5.37-5.89) was required among the devoid of sulfur ketones. 19F NMR studies, carried out with OTFP, showed that the inhibitor binds the enzyme in a reversible manner, forming an adduct (probably a hemiacetal) of tetrahedral geometry with the active site of the enzyme. To our knowledge, this is the first time that such a study on a natural esterase extract has been undertaken.