Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL)

Mayer, Nicole; Schweiger, Martina; Melcher, Michaela-Christina; Fledelius, Christian; Zechner, Rudolf; Zimmermann, R.; Breinbauer, Rolf

doi:10.1016/j.bmc.2015.02.051

Cited by 18 publications

(13 citation statements)

References 22 publications

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“…Hydrazide-hydrazones are known as antitumor [30][31][32] and antimicrobial agents [33][34][35], as well as enzyme inhibitors [31,[36][37][38][39][40][41]. Hydrazones are less recognized as inhibitors of metallo-enzymes and only the rare examples can be found in the literature so far [38,[40][41][42][43].…”

Section: Syntheses and Characterizationsmentioning

confidence: 99%

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

et al. 2020

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A series of hydrazide-hydrazones 1–3, the imine derivatives of hydrazides and aldehydes bearing benzene rings, were screened as inhibitors of laccase from Trametes versicolor. Laccase is a copper-containing enzyme which inhibition might prevent or reduce the activity of the plant pathogens that produce it in various biochemical processes. The kinetic and molecular modeling studies were performed and for selected compounds, the docking results were discussed. Seven 4-hydroxybenzhydrazide (4-HBAH) derivatives exhibited micromolar activity Ki = 24–674 µM with the predicted and desirable competitive type of inhibition. The structure–activity relationship (SAR) analysis revealed that a slim salicylic aldehyde framework had a pivotal role in stabilization of the molecules near the substrate docking site. Furthermore, the presence of phenyl and bulky tert-butyl substituents in position 3 in salicylic aldehyde fragment favored strong interaction with the substrate-binding pocket in laccase. Both 3- and 4-HBAH derivatives containing larger 3-tert-butyl-5-methyl- or 3,5-di-tert-butyl-2-hydroxy-benzylidene unit, did not bind to the active site of laccase and, interestingly, acted as non-competitive (Ki = 32.0 µM) or uncompetitive (Ki = 17.9 µM) inhibitors, respectively. From the easily available laccase inhibitors only sodium azide, harmful to environment and non-specific, was over 6 times more active than the above compounds.

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Section: Syntheses and Characterizationsmentioning

confidence: 99%

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

et al. 2020

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“…The emphasis was also placed on avoiding the potential loss of any active scaffolds identified by the competing computational groups, rather than on the early elimination of less desirable chemical series. Substituting hydrazones with their non-reactive isosteres during hit-to-lead optimization is a feasible medicinal chemistry endeavor as is illustrated by some research publications 36 – 38 . We will discuss these hydrazone-containing compounds in more details in the following section.…”

Section: Screening Of Compoundsmentioning

confidence: 99%

An iterative compound screening contest method for identifying target protein inhibitors using the tyrosine-protein kinase Yes

Chiba

Ishida

Ikeda³

et al. 2017

Sci Rep

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We propose a new iterative screening contest method to identify target protein inhibitors. After conducting a compound screening contest in 2014, we report results acquired from a contest held in 2015 in this study. Our aims were to identify target enzyme inhibitors and to benchmark a variety of computer-aided drug discovery methods under identical experimental conditions. In both contests, we employed the tyrosine-protein kinase Yes as an example target protein. Participating groups virtually screened possible inhibitors from a library containing 2.4 million compounds. Compounds were ranked based on functional scores obtained using their respective methods, and the top 181 compounds from each group were selected. Our results from the 2015 contest show an improved hit rate when compared to results from the 2014 contest. In addition, we have successfully identified a statistically-warranted method for identifying target inhibitors. Quantitative analysis of the most successful method gave additional insights into important characteristics of the method used.

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“…Optical density was read, and conc. of reducing sugar was calculated which is used to determine the activity of amylase [11,12].…”

Section: Type Of Inhibition Analysismentioning

confidence: 99%

“…Therefore it is crucial to control the lipase and α-amylse enzymes to reduce the obesity and diabetes in our body [11]. Various heterocyclic compounds were used as a drug to inhibit these enzymes.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of α-Amylase and Lipase Inhibitory Activities of Synthetic Coumarin Derivatives

Mangalpady¹,

Anil²,

N³

2019

Preprint

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This research work involved synthesis of nine Coumarin-hydrazone derivatives and study of their enzyme inhibition activity. The purpose of the study was to investigate the α-amylase and lipase inhibition activity of the synthesized coumarin derivatives. The experiment was performed by taking 5, 10, 50,100 μg/mL of each of the compounds and Acarbose and Orlistat was taken as a positive control. The studies showed that compound 5d (120.6 μM), 5e (111.5 μM) and 5h (124.0 μM) was showing better inhibition activity against α-amylase enzyme, in comparison with the standard (IC50=81.70 μM). The lipase enzyme inhibition revealed that the compounds, 5c (142.3 μM), 5d (82.3 μM) and 5i (93.6 μM) showed better inhibition compared to the standard (IC50=236.4±2.83 μM). The enzyme kinetics study also revealed good results and it has been discussed in the results section.

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Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL)

Abstract: Graphical abstract

Cited by 18 publications

References 22 publications

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

An iterative compound screening contest method for identifying target protein inhibitors using the tyrosine-protein kinase Yes

Synthesis and Evaluation of α-Amylase and Lipase Inhibitory Activities of Synthetic Coumarin Derivatives

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