Juvenile hormone esterase Inhibitors

Our target has been an insect enzyme of developmental and reproductional importance, juvenile hormone esterase (4-12). The development of those extremely potent inhibitors served several aims in addition to providing "traditional inhibitors that can... 

In Vitro Inhibitors of Insect Juvenile Hormone Esterase... 

Trifluoromethyl ketones (TFKs) have been found to inhibit various hydrolytic enzymes (1-6 ). Series of aliphatic and aromatic trifluoromethyl ketone sulfides (7-10 ) proved to be exceptionally powerful inhibitors of insect juvenile hormone esterase (JHE), an enzyme of key importance in insect metamorphosis. The trifluoroketone moiety is believed to behave as a transition state mimic (11,12) of juvenile hormones (JHs), substrates of the enzyme. The /3 sulfur atom is anticipated to mimic the a-/3 double bond present in all natural JH substrates. In earlier structure-activity relationship (SAR) studies (7,11) clear correlation was found among the molar I50 values of these compounds against JHE and the calculated molar refractivlty of the inhibitors. 

Esterases of the Juvenile Hormone of Insects Many works have been dedicated to the inhibition of esterases of the juvenile hormone of insects. The purpose of these works is to control insect populations by ehminating their metamorphosis. Among the numerous trifluoromethyl ketones that have been synthesized, thioalkyl derivatives of trifluoroacetone have been shown to be the most active ones. Curiously, the corresponding alcohols are also excellent inhibitors. Trifluoromethyl ketones can also inhibit other insect esterases antenna esterases and esterases that are involved in the release of pheromones (Figure 7.33). The inhibition of these latter ones can also be interesting for insect control purposes. 

Fluoroketone analogues are also inhibitors of esterases. For example, the difluoro-ketone analogue 36 of sn-glycerol phospholipids is a potent competitive inhibitor of phospholipase A27 while the trifluoromethyl ketone 37 analogue of an insect juvenile hormone 38 is a potent and selective inhibitor of juvenile hormone esterase78. 

Hammock and co-workers (Hammock et ai, 1982 Abdel-Aal, 1984 Prestwich et ai, 1984) prepared several 3-alkylthio-l,l,l-trifluoro-2-propanones with juvenile hormone-like side chains. These compounds were designed as possible transition-state analogue inhibitors of JH esterases. The most active analogue (78) showed a dose-dependent delay in pupation and a selective inhibition of JH esterase of the cabbage looper, Trichopltisia ni. 

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