Novel 1,3,4-oxadiazol-2(3H)-ones as potential pest control agents

Huang, Jamin; Bushey, Dean F.

doi:10.1021/jf00075a022

Cited by 5 publications

(4 citation statements)

References 2 publications

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“…Oxadiazolone is one of the most interesting classes, and 5-methoxy-3-(4phenoxyphenyl)-3H- [1,3,4]oxadiazol-2-one (compound 7600, the structure of which is shown in Figure 1) was selected since it was found to be the most potent members of this class. Oxadiazolones with aliphatic moieties on N3 have been reported (29) to be acetylcholinesterase (AchE) inhibitors as well as potent insecticides. The aim of this study was to investigate the selective inhibition exerted on three members of the HSL family (HSL, EST2, and AFEST) by compound 7600.…”

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confidence: 99%

Use of an Inhibitor To Identify Members of the Hormone-Sensitive Lipase Family

et al. 2006

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Hormone-sensitive lipase (HSL) contributes importantly to the mobilization of fatty acids from the triacylglycerols stored in adipocytes, which provide the main source of energy in mammals. On the basis of amino acid sequence alignments and three-dimensional structures, this enzyme was previously found to be a suitable template for defining a family of serine carboxylester hydrolases. In this study, the HSL family members are characterized rather on the basis of their inhibition by 5-methoxy-3-(4-phenoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (compound 7600). This compound inhibits mammalian HSL as well as other HSL family members, such as EST2 from the thermophilic eubacterium Alicyclobacillus acidocaldarius and AFEST from the hyperthermophilic archaeon Archaeoglobus fulgidus. Various carboxylester hydrolases that are not members of the HSL family were found not to be inhibited by compound 7600 under the same experimental conditions. These include nonlipolytic hydrolases such as Torpedo californica acetylcholinesterase and pig liver esterase, as well as lipolytic hydrolases such as human pancreatic lipase, dog gastric lipase, Thermomyces lanuginosus lipase, and Bacillus subtilis LipA. When vinyl esters were used as substrates, the residual activity of HSL, AFEST, and EST2 decreased with an increase in compound 7600 concentration in the incubation mixture. The inhibitor concentration at which the enzyme activity decreased to 50% after incubation for 5 min was 70, 20, and 15 nM with HSL, AFEST, and EST2, respectively. Treating EST2 and AFEST with the inhibitor resulted in an increase in the molecular mass, as established by performing matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis. This increase in the molecular mass, which corresponds approximately to the molecular mass of the inhibitor, indicates that a covalent enzyme-inhibitor complex has been formed. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry analysis of a trypsin digest of AFEST treated with the inhibitor or not treated showed the occurrence of an increase in the molecular masses of the "GESAGG"-containing peptide, which is compatible with the formation of a covalent complex with the inhibitor.

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confidence: 99%

Use of an Inhibitor To Identify Members of the Hormone-Sensitive Lipase Family

et al. 2006

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“…For both the carbamoyl-triazoles and compound 7 an analogous acylated HSL−serine intermediate is formed despite that different tetrahedral complexes are formed as the two types of compounds contain different leaving groups. Since the reactive groups of 5 and 6 are an isoxazole-5-one, the intermediate formed for this class of compounds is believed to be a ring open form as also suggested by Huang …”

Section: Resultsmentioning

confidence: 72%

“…Since the reactive groups of 5 and 6 are an isoxazole-5-one, the intermediate formed for this class of compounds is believed to be a ring open form as also suggested by Huang. 34 Preliminary studies of the reactivation rate of HSL for 4b and 4g, performed in accordance with the chromatographic method described by Perola et al, 35 indicate that the reactivation half-life (t 1/2 ) is in the order of hours. This is in line with data for carbamate inhibitors of AChE.…”

Section: Resultsmentioning

confidence: 95%

“…On the basis of the chemical structure, it is expected that all the HSL inhibitors 4b , 4g , 5 , 6, and 7 are pseudosubstrates or pseudoirreversible inhibitors . It is believed that the inhibitors are capable of acylating the active site serine in a time-dependent manner as described for carbamates such as physostigmine and postulated for oxadiazol-2-ones (both AChE inhibitors). We postulate that the carbamoyl-triazole reacts with the HSL active site serine as described in Figures and .…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Structure−Activity Relationship for a Novel Class of Potent and Selective Carbamoyl-Triazole Based Inhibitors of Hormone Sensitive Lipase

et al. 2003

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The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.

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