Heterocyclic derivatives of 3-substituted-1,1,1-trifluoro-2-propanones as inhibitors of esterolytic enzymes

András Székács, Premjit P. Halarnkar, Marilyn M. Olmstead, Kathleen A. Prag, Bruce D. Hammock

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

A series of (alkylthio)trifluoropropanones containing a heterocyclic moiety was synthesized. The compounds were tested for in vitro inhibition of four hydrolytic enzymes including insect juvenile hormone esterase (JHE), eel acetylcholinesterase (AChE), yeast lipase (LP), and bovine α-chymotrypsin. The I50 values ranged from 10-3 to 10-7 M. 3-(2-Pyridylthio)-1,1,1-trifluoro-2-propanone was found to be the most potent inhibitor as compared to the other tested heterocyclic analogues with an I50 value of 98 nM against JHE from the fifth-instar larvae of Trichoplusia ni. Results from X-ray crystallography showed that the compound exists in a tetrahedral gem-diol form stabilized by an intramolecular hydrogen bond in the solid state. X-ray crystallography of a less potent inhibitor, 3-(4-pyridylthio)-1,1,1-trifluoro-2-propanone, showed that it also exists in the hydrated form, but it lacks an intramolecular hydrogen bond. These results provide indirect support that trifluoromethyl ketones are transition-state mimic inhibitors of esterases, and the bearing of the results on the transition-state mimic theory is discussed. The I50 values against AChE were in the micromolar range. Compounds containing a imidazolyl, triazolyl, and pyrimidyl moiety showed the highest inhibition of this enzyme. Differential selectivity of inhibition was associated with the bond distances between the nitrogen and the carbonyl group as in the natural substrate, when measured in the molecules in their minimal energy conformations. Inhibition of LP was moderate to weak, when compared to JHE and AChE. None of the tested compounds showed significant inhibition of α-chymotrypsin. In vivo toxicity assays with the fruit fly, Drosophila melanogaster, indicate considerable variation among the compounds, with differential toxicity toward different life stages of the insect, but all were significantly less toxic than malathion.

Original languageEnglish
Pages (from-to)325-332
Number of pages8
JournalChemical Research in Toxicology
Volume3
Issue number4
Publication statusPublished - 1990

Fingerprint

Enzyme Inhibitors
Acetylcholinesterase
Acetone
X ray crystallography
X Ray Crystallography
Chymotrypsin
Derivatives
Lipase
Toxicity
Hydrogen
Hydrogen bonds
Bearings (structural)
Insect Hormones
Gems
Malathion
Eels
Poisons
Esterases
Enzymes
Fruits

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Heterocyclic derivatives of 3-substituted-1,1,1-trifluoro-2-propanones as inhibitors of esterolytic enzymes. / Székács, András; Halarnkar, Premjit P.; Olmstead, Marilyn M.; Prag, Kathleen A.; Hammock, Bruce D.

In: Chemical Research in Toxicology, Vol. 3, No. 4, 1990, p. 325-332.

Research output: Contribution to journalArticle

Székács, András ; Halarnkar, Premjit P. ; Olmstead, Marilyn M. ; Prag, Kathleen A. ; Hammock, Bruce D. / Heterocyclic derivatives of 3-substituted-1,1,1-trifluoro-2-propanones as inhibitors of esterolytic enzymes. In: Chemical Research in Toxicology. 1990 ; Vol. 3, No. 4. pp. 325-332.
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