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

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

doi:10.1021/tx00016a009

Cited by 14 publications

(8 citation statements)

References 33 publications

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“…Despite the remarkable (i.e. picomolar) potencies that can be achieved [61], with few exceptions [62] this class of compounds has received little attention as insecticides. Difluoromethyl and fluoromethyl ketones are relatively unexplored as anticholinesterases, [63] but have been used as serine protease inhibitors[64–66].…”

Section: Development Of Species-selective and Resistance-breaking mentioning

confidence: 99%

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Carlier

Bloomquist

Totrov

et al. 2017

CMC

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Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets only employ pyrethroids, insecticides that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess low mammalian toxicity. In this review, we will describe efforts to develop highly species-specific and resistance-breaking inhibitors of An. gambiae acetylcholinesterase (AgAChE). These efforts have been greatly aided by advances in knowledge of the structure of the enzyme, and two major inhibitor design strategies have been explored. Since AgAChE possesses an unpaired Cys residue not present in mammalian AChE, a logical strategy to achieve selective inhibition involves design of compounds that could ligate that Cys. A second strategy involves the design of new molecules to target the catalytic serine of the enzyme. Here the challenge is not only to achieve high inhibition selectivity vs human AChE, but also to demonstrate toxicity to An. gambiae that carry the G119S resistance mutation of AgAChE. The advances made and challenges remaining will be presented. This review is part of the special issue “Insecticide Mode of Action: From Insect to Mammalian Toxicity.

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Section: Development Of Species-selective and Resistance-breaking mentioning

confidence: 99%

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Carlier

Bloomquist

Totrov

et al. 2017

CMC

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“…These hit compounds were analysed in more detail: two compounds proved to be aryltrifluoromethylketones, which are not truly non-covalent inhibitors. This type of compound can form reversible covalent hemiketal bonds to the active site serine of serine esterases (Brodbeck et al, 1979;Székács et al, 1990;Nair et al, 1994), and the derivatives that we identified (71, 72), while potent inhibitors, proved not to be selective for the L. cuprina enzyme. Therefore, the two hit aryltrifluoromethylketones were considered poor starting points for further optimization.…”

Section: Discussionmentioning

confidence: 91%

“…This compound class comprised substances with high selectivity, such as (73) and (76), but also some with poor selectivity, such as (80) and (81), which have similar inhibitor potency on the blowfly and the human enzyme. Two compounds belonged to the class of trifluoromethylarylketones (71, 72), that have been described as reversible covalent inhibitors of serine esterases (Brodbeck et al, 1979;Székács et al, 1990;Nair et al, 1994). While these compounds were highly potent on LcAChE, with IC 50 s of 37 nM and 57 nM, respectively, their selectivity factors versus human AChE were low (Table 5).…”

Section: Identification Of Lcache Inhibitors By High Throughput Screementioning

confidence: 99%

The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening

Ilg¹,

Cramer²,

Lutz³

et al. 2011

Insect Biochemistry and Molecular Biology

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“…20,33 In addition, the potential role of the putative intramolecular hydrogen bond needs to be addressed in greater detail. To date, most studies have attempted to infer the presence and/or role of the bond in inhibitor potency via ab initio calculations 29,30 or crystallography 29,51 . Unfortunately, neither of these approaches represents an appropriate study of the potential interactions within a biological system and as such, these studies can only provide suggestive conclusions.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, two sulfurcontaining heterocyclic compounds gave mixed results with 3-(2-pyridylthio)-1,1,1-trifluoro-2-propanone showing intramolecular hydrogen bonding and 3-(4-pyridylthio)-1,1,1-trifluoro-2-propanone showing only intermolecular. 51 However, the intramolecular hydrogen bond in 3-(2-pyridylthio)-1,1,1-trifluoro-2-propanone was with the nitrogen in the pyridyl ring and not with the sulfur. One possible explanation is that there are potentially multiple crystal morphologies associated with these compounds.…”

Section: Intramolecular Hydrogen Bonding Studiesmentioning

confidence: 99%

Influence of sulfur oxidation state and steric bulk upon trifluoromethyl ketone (TFK) binding kinetics to carboxylesterases and fatty acid amide hydrolase (FAAH)

Wheelock

Nishi

Ying

et al. 2008

Bioorganic & Medicinal Chemistry

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Carboxylesterases metabolize numerous exogenous and endogenous ester-containing compounds including the chemotherapeutic agent CPT-11, anti-influenza viral agent oseltamivir and many agrochemicals. Trifluoromethyl ketone (TFK)-containing compounds with a sulfur atom beta to the ketone moiety are some of the most potent carboxylesterase and amidase inhibitors identified to date. This study examined the effects of alkyl chain length (i.e., steric effects) and sulfur oxidation state upon TFK inhibitor potency (IC 50 ) and binding kinetics (k i ). The selective carboxylesterase inhibitor benzil was used as a non-TFK containing control. These effects were examined using two commercial esterases (porcine and rabbit liver esterase) and two human recombinant esterases (hCE-1 and hCE-2) as well as human recombinant fatty acid amide hydrolase (FAAH). In addition, the inhibition mechanism was examined using a combination of 1 H NMR, X-ray crystallography and ab initio calculations. Overall, the data show that while sulfur oxidation state profoundly affects both inhibitor potency and binding kinetics, the steric effects dominate and override the contributions of sulfur oxidation. In addition, the data suggest that inclusion of a sulfur atom beta to the ketone contributes an increase (~5-fold) in inhibitor potency due to effects upon ketone hydration and/or intramolecular hydrogen bond formation. These results provide further information on the nature of the TFK binding interaction and will be useful in increasing our understanding of this basic biochemical process.

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

Cited by 14 publications

References 33 publications

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening

Influence of sulfur oxidation state and steric bulk upon trifluoromethyl ketone (TFK) binding kinetics to carboxylesterases and fatty acid amide hydrolase (FAAH)

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