RATIONAL DESIGN AND SYNTHESIS OF POLARIZED KETONES AS INHIBITORS OF JUVENILE-HORMONE ESTERASE - IMPORTANCE OF JUVENILE-HORMONE MIMICRY

A series of β,β-disubstituted α,β-unsaturated and β-substituted α-acetylenic trifluoromethyl ketones were prepared and assayed as inhibitors of juvenile hormone (JH) esterase and α-naphthyl acetate esterase from the cabbage looper, Trichoplusia ni, and of electric eel acetylcholinesterase (AChE). The most potent inhibitor from each series had a molar refractivity similar to that of the natural JH esterase substrate. The unsaturated fluoro ketones were less active than the analogous and structurally similar α-alkylthio-substituted trifluoropropanones, suggesting that mimicry of the α,β-unsaturation of JH was not a critical feature in inhibition. The structurally dissimilar acetylenic compounds were more potent inhibitors than the unsaturated fluoro ketones but had even greater activity toward AChE. Studies with several α- and α'-substituted derivatives of 3-(octylthio)-l,l,l-trifluoropropan- 2-one (OTFP) demonstrated the importance of mimicry of the C-3 methyl substituent of JH in inhibition and α'-Me-OTFP emerged as the most potent inhibitor of JH esterase available. The role of the S atom in OTFP inhibition of JH esterase is discussed. © 1990, American Chemical Society. All rights reserved.