Discovery and evaluation of novel benzazepinone derivatives as glycogen phosphorylase inhibitors with potent activity

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzazepinone derivatives were discovered as GP inhibitors with potent activity. Among these derivatives, compound 5d showed significant potential against rabbit muscle GPa (IC50 = 0.25 ± 0.05 μM) and cellular efficacy. The in vivo study revealed that 5d significantly inhibited increases in fasting blood glucose level in two kinds of hyperglycemic mice models. The possible binding mode of compound 5d was explored based on molecular docking simulations. These results indicated that derivatives with benzazepinone were potential chemical entities against hyperglycemia.

Download Full-text

Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2020.127117 ◽

2020 ◽

Vol 30 (14) ◽

pp. 127117

Author(s):

Guang-xin Miao ◽

You-de Wang ◽

Zhi-wei Yan ◽

Li-ying Zhang

Keyword(s):

Glycogen Phosphorylase ◽

Pharmacological Evaluation ◽

Glycogen Phosphorylase Inhibitors

Download Full-text

In silicoidentification of putativeTrypanosoma cruzienolase inhibitors

10.1101/685206 ◽

2019 ◽

Author(s):

Edward A. Valera-Vera ◽

Melisa Sayé ◽

Chantal Reigada ◽

Mariana R. Miranda ◽

Claudio A. Pereira

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Virtual Screening ◽

Active Site ◽

Screening Strategy ◽

Glycolytic Enzyme ◽

Docking Simulations ◽

Enzyme Active Site ◽

Key Enzyme

AbstractEnolase is a glycolytic enzyme that catalyzes the interconversion between 2-phosphoglycerate and phosphoenolpyruvate. In trypanosomatids enolase was proposed as a key enzyme afterin silicoandin vivoanalysis and it was validated as a protein essential for the survival of the parasite. Therefore, enolase constitutes an interesting enzyme target for the identification of drugs against Chagas disease. In this work, a combined virtual screening strategy was implemented, employing similarity virtual screening, molecular docking and molecular dynamics. First, two known enolase inhibitors and the enzyme substrates were used as queries for the similarity screening on the Sweetlead database using five different algorithms. Compounds retrieved in the top 10 of at least three search algorithms were selected for further analysis, resulting in six compounds of medical use (etidronate, pamidronate, fosfomycin, acetohydroximate, triclofos, and aminohydroxybutyrate). Molecular docking simulations predicted acetohydroxamate and triclofos would not bind to the active site of the enzyme, and a re-scoring of the obtained poses signaled fosfomycin and aminohydroxybutyrate as bad enzyme binders. Docking poses obtained for etidronate, pamidronate, and PEP, were used for molecular dynamics calculations to describe their mode of binding. From the obtained results, we propose etidronate as a possibleTcENO inhibitor, and describe desirable and undesirable molecular motifs to be taken into account in the repurposing or design of drugs aiming this enzyme active site.

Download Full-text

Antiviral Potential of Spondias mombin L. Leaves Extract Against Herpes Simplex Virus Type-1 Replication Using In Vitro and In Silico Approaches

Planta Medica ◽

10.1055/a-1135-9066 ◽

2020 ◽

Vol 86 (07) ◽

pp. 505-515 ◽

Cited By ~ 1

Author(s):

Emerson M. da S. Siqueira ◽

Tábata L. C. Lima ◽

Laurita Boff ◽

Sarah G. M. Lima ◽

Estela M. G. Lourenço ◽

...

Keyword(s):

In Silico ◽

Therapeutic Potential ◽

Binding Mode ◽

Surface Glycoprotein ◽

Viral Attachment ◽

Docking Simulations ◽

Simplex Virus ◽

Hsv 1

Abstract Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.

Download Full-text

Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2008.12.085 ◽

2009 ◽

Vol 19 (4) ◽

pp. 1177-1182 ◽

Cited By ~ 13

Author(s):

Stephen A. Thomson ◽

Pierette Banker ◽

D. Mark Bickett ◽

Joyce A. Boucheron ◽

H. Luke Carter ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycogen Phosphorylase ◽

In Vivo Efficacy ◽

X Ray ◽

Glycogen Phosphorylase Inhibitors

Download Full-text

Mechanochemical Synthesis and reactivity of 1,2,3-Triazole Carbohydrate Derivatives as Glycogen Phosphorylase Inhibitors

Current Organic Synthesis ◽

10.2174/1570179417666201217142634 ◽

2020 ◽

Vol 17 ◽

Author(s):

Naoufel Ben Hamadi

Keyword(s):

Organic Chemistry ◽

Glycogen Phosphorylase ◽

Biological Activities ◽

Water Soluble ◽

Dipolar Cycloaddition ◽

Rabbit Muscle ◽

Cycloaddition Reactions ◽

Triazole Derivatives ◽

Glycogen Phosphorylase Inhibitors ◽

Vibration Milling

Aims: In this aim, we have developed this work to recommend an original route for the preparation of triazole derivatives. Background: Carbohydrates containing 1,2,3-triazole derivatives have various biological activities. Due to their advantageous and biological property, they are eye-catching synthetic targets in the arsenal of organic chemistry. Thus, finding green and efficient methods, as well as using ball millig procedure for the synthesis of these heterocycles is of interest to organic chemistry researchers. Objective: The objective of this study was to synthesize carbohydrate-derived triazoles under high-speed vibration milling conditions and investigate their properties. Materials and Method: A mixture of glycoside azide derivatives (1 mmol) and prop-2-yn-1-ol (1.5 mmol) in the presence of copper (I) was vigorously shaken under vibration milling conditions at 650 rpm with three balls for 15 min. The deprotection of the resulting triazole derivatives was effected by treatment with 4M hydrochloric acid in methanol under reflux. Results and Discussion: A short and convenient route to synthesize carbohydrate-derived triazoles, based in a ball-mill via 1,3-dipolar cycloaddition reactions to prop-2-yn-1-ol was developed. Cleavage of the isopropylidene protecting group provided water-soluble triazoles, evaluated as glycogen phosphorylase inhibitors. 1-[6-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)- 2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethane-1,2-diol was the best inhibitor of rabbit muscle glycogen phosphorylase b (IC50 = 60 μM). Conclusion: In summary, we developed new, short and convenient routes to glucose-derived 1,2,3-triazole based on 1,3- dipolar cycloaddition reactions flowed by ball milling. Use of isopropylidene protective groups gave access to the analogous deprotected water-soluble motifs, analogous to known inhibitors of glycogen phosphorylase.

Download Full-text

The effect of glucose on the potency of two distinct glycogen phosphorylase inhibitors

Biochemical Journal ◽

10.1042/bj20020153 ◽

2002 ◽

Vol 367 (2) ◽

pp. 443-450 ◽

Cited By ~ 26

Author(s):

Birgitte ANDERSEN ◽

Niels WESTERGAARD

Keyword(s):

Synergistic Effect ◽

Glycogen Phosphorylase ◽

Rat Hepatocytes ◽

Rabbit Muscle ◽

Ic50 Value ◽

Cultured Rat Hepatocytes ◽

Effect Of Glucose ◽

Glycogen Phosphorylase Inhibitors ◽

Glucose Analogue

Two distinct glycogen phosphorylase inhibitors, 5-chloro-1H-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl]amide (CP-320,626) and 1,4-dideoxy-1,4-d-arabinitol (DAB), were characterized in vitro with respect to the influence of glucose on their potencies. CP-320,626 has previously been shown to bind to a newly characterized indole site, whereas DAB seems to act as a glucose analogue, but with slightly different properties from those of glucose. When analysed in pig liver glycogen phosphorylase a (GPa) activity assays, the two inhibitors showed very different properties. When GPa activity was measured in the physiological direction (glycogenolysis), DAB was the most potent inhibitor with an IC50 value of 740±9nM compared with the IC50 value for CP-320-626 of 2.39±0.37μM. There was no effect of glucose on the inhibitory properties of DAB, whereas a glucose analogue N-acetyl-β-d-glucopyranosylamine (1-GlcNAc) antagonized the effect of DAB. Likewise, there was no synergistic effect of CP-320,626 and glucose, whereas CP-320,626 and 1-GlcNAc inhibited GPa in synergy. Moreover, the synergistic effect of glucose and CP-320,626 was GPa-isoform-specific, since CP-320,626 and glucose inhibited rabbit muscle GPa in synergy when the GPa activity was measured towards glycogenolysis. When GPa activity was measured towards glycogen synthesis, CP-320,626 showed a synergistic effect with glucose, whereas the effect of DAB was slightly antagonized by glucose in this assay direction. Caffeine was included in the investigation as a control GP inhibitor, and both glucose and 1-GlcNAc potentiated the effect of caffeine independent of the assay direction. In primary cultured rat hepatocytes 1-GlcNAc and CP-320,626 inhibited basal and glucagon-induced glycogenolysis in synergy, whereas the ability of DAB to inhibit basal or glucagon-induced glycogenolysis was unaltered by 1-GlcNAc. Glucose had no effect on either CP-320,626 or DAB inhibition of glycogenolysis in cultured rat hepatocytes. In conclusion, the present study shows that the two GP inhibitors are kinetically very distinct and neither of the inhibitors demonstrates a physiologically relevant glucose dependence in vitro.

Download Full-text

Design, Synthesis, Antihyperglycemic Studies, and Docking Simulations of Benzimidazole-Thiazolidinedione Hybrids

Journal of Chemistry ◽

10.1155/2019/1650145 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Abraham Gutierréz-Hernández ◽

Yelzyn Galván-Ciprés ◽

Elix Alberto Domínguez-Mendoza ◽

Yoshajandith Aguirre-Vidal ◽

Samuel Estrada-Soto ◽

...

Keyword(s):

Mrna Expression ◽

In Silico ◽

Knoevenagel Condensation ◽

Binding Mode ◽

Spectral Studies ◽

Design Synthesis ◽

Docking Simulations ◽

Step Procedure

A simple and cheap three-step procedure for the synthesis of three (5Z)-5-[3(4)-(1H-benzimidazol-2-ylmethoxy)benzylidene]-1,3-thiazolidine-2,4-diones has been described via a SN2 reaction of generally recognized as safe hydroxybenzaldehydes and 2-(chloromethyl)-1H-benzimidazole, followed by a Knoevenagel condensation with thiazolidine-2,4-dione in moderated yields. All the newly synthesized compounds were characterized using analytical and spectral studies. In vitro treatment on adipocytes with compounds increased the mRNA expression of two proteins recognized as strategic targets in diabetes: PPARγ and GLUT-4. In silico studies were conducted in order to explain the interaction binding mode of the synthesized compounds on PPARγ. In vivo studies confirmed that compounds 1–3 have robust antihyperglycemic action linked to insulin sensitization mechanisms. The present study provides three compounds with a promising antidiabetic action.

Download Full-text

Fish muscle glycogen phosphorylase

Canadian Journal of Biochemistry ◽

10.1139/o68-064 ◽

1968 ◽

Vol 46 (5) ◽

pp. 423-432 ◽

Cited By ~ 25

Author(s):

M. Yamamoto

Keyword(s):

Skeletal Muscle ◽

Glycogen Phosphorylase ◽

Active Form ◽

Maximal Activity ◽

Fish Muscle ◽

Salmo Gairdneri ◽

Rabbit Muscle ◽

Muscle Phosphorylase

Glycogen phosphorylase b was purified 70- to 90-fold from skeletal muscle of rainbow trout (Salmo gairdneri). The purified enzyme exhibited maximal activity near pH 6.8 at 37°. Of several 5′-nucleotides tested, only 5′-AMP caused stimulation of phosphorylase b. The Km value for glucose-1-phosphate was 10–15 mM, and for 5′-AMP, 0.2–0.4 mM. Glucose (25 mM) and ATP (5 mM) were both inhibitory, but glucose-6-phosphate (5 mM) had no effect. Inactive trout muscle phosphorylase was converted to the active form in vivo by subjecting a fish to physical exercise. The conversion of fish muscle phosphorylase b to a was also catalyzed in vitro with purified rabbit muscle phosphorylase b kinase in the presence of ATP and Mg++. Evidence is presented to indicate the presence of phosphorylase b kinase and phosphorylase phosphatase in trout skeletal muscle.

Download Full-text

Hypoglycemic Effects in Alloxan-Induced Diabetic Rats of the Phenolic Extract Enriching Ellagic Acid, Kaempferol and Their Derivatives from Mongolian Oak Cups

10.20944/preprints201804.0087.v1 ◽

2018 ◽

Author(s):

Peipei Yin ◽

Yu Wang ◽

Lingguang Yang ◽

Jinling Sui ◽

Yujun Liu

Keyword(s):

Blood Glucose ◽

Blood Glucose Level ◽

Ellagic Acid ◽

Fasting Blood Glucose ◽

Diabetic Rats ◽

Protein Glycation ◽

Fasting Blood Glucose Level ◽

Mongolian Oak ◽

Alpha Glucosidase

Our previous in vitro reports showed that crude extract prepared with 50% ethanol (ethanol crude extract, ECE) from Mongolian oak cups possessed excellent antioxidant capacities as well as inhibitory activities against α-glucosidase, α-amylase and protein glycation caused by its enrichment in phenolics, including mainly ellagic acid, kaempferol and their derivatives. Nevertheless, few in vivo studies on antidiabetic activities of these phenolics were conducted. The present study investigated hypoglycemic effects with normal and diabetic rats being administrated orally without or with ECE at 200 and 800 mg/kg for 15 days. In normal rats, no significant differences were exhibited after ECE administration in body weight, fasting blood glucose level, levels of chelesterol, triglyceride, LDL and AST in serum, organ indexes, and levels of GSH and MDA in organs. In diabetic rats, the fasting blood glucose level, indexes of heart and liver, and levels of chelesterol and triglyceride in serum and MDA in heart tissue were significantly decreased. Moreover, HDL levels in serum and SOD activities in the four organs of diabetic rats were significantly improved after ECE administration at 800 mg/kg. Thus, in addition to inhibiting α-glucosidase, α-amylase and protein glycation reported previously, oak cups might contain novel dietary phytonutrients in preventing abnormal changes in blood glucose and lipid profile and attenuating oxidant stress in vivo. The results also implied that it is ellagic acid, kaempferol and their derivatives enriched in ECE that might play vital roles in managing type 1 as well as type 2 diabetes.

Download Full-text