scholarly journals STRUCTURE BASED DRUG DESIGNING, SCORING, AND SYNTHESIS OF SOME SUBSTITUTED SULPHONYLUREAS/GUANIDINE -BASED DERIVATIVES AS HYPOGLYCEMIC AGENTS

2017 ◽  
Vol 9 (12) ◽  
pp. 226 ◽  
Author(s):  
Ishan Panchal ◽  
Dhrubo Jyoti Sen ◽  
Archana Navle ◽  
Umang Shah
Keyword(s):  
Analytical Data ◽  
Binding Pocket ◽  
Docking Studies ◽  
Diabetic Rats ◽  
Hypoglycemic Activity ◽  
Hypoglycemic Agents ◽  
Reference Drug ◽  
Glide Docking ◽  
Docking Program

Objective: The present work deals with the designing, scoring, synthesis and, characterization of 1-(4-(2-(4-Substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B),1-(4-(2-(4-substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substituted-benzoyl)guanidine(5C-5E) and, 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) based derivatives as hypoglycemic agents.Methods: Docking calculations were performed to predict the binding affinity between the AKR1C1 complexes and sulphonylureas compounds using the Glide docking program. Docking studies on LigPrep treated ligands were carried out to predict the binding pocket of protein 4YVP using the docking program. The QikProp program was used to predict the ADME/T properties of the analogues. All these newly synthesized compounds were screened for their in vivo hypoglycemic activity by most relevant animal models like alloxan-induced diabetic rats by measuring blood plasma concentration compared with reference drug glibenclamide.Results: Novel compounds 1-(4-(2-(4-Substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B), 1-(4-(2-(4-substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl) guanidine (5C-5E), and 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) were synthesised and characterized using spectral and analytical data. The results of molecular docking and in vivo hypoglycemic activity, all compounds have shown considerable activity with respect to glibenclimide, but compounds 5D (52.49±7.73) and 5E(48.18±4.22)are equipotent with respect to activity as compared to standard glibenclamide(55.97±3.19).Conclusion: Compounds 5D and 5E have exhibited good hypoglycemic activity,hence both the derivatives will consider as a lead molecule and further some modification in their structures to get a more potent anti-diabetic agent.

scholarly journals Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Prasanna A. Datar ◽  
Sonali R. Jadhav
Keyword(s):  
Amino Acid ◽  
Docking Studies ◽  
Diabetic Rats ◽  
Hypoglycemic Activity ◽  
Amino Acid Residues ◽  
Docking Score ◽  
Design And Synthesis ◽  
Hypoglycaemic Agents ◽  
Standard Compound

Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series.

Structural and Therapeutic Insights from the Species Specificity and in Vivo Antithrombotic Activity of a Novel αIIb-Specific αIIbβ3 Antagonist

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 256-256
Author(s):  
Robert Blue ◽  
M. Anna Kowalska ◽  
Marta Murcia ◽  
Christin A. Janczak ◽  
Marketa Jirouskova ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Binding Pocket ◽  
Docking Studies ◽  
Flow Probe ◽  
Thrombotic Occlusion ◽  
Kaplan Meier ◽  
Flow Through ◽  
Combined Data ◽  
Rat Platelets

Abstract The search for novel inhibitors of the platelet αIIbβ3 receptor continues with the dual goals of better defining structure-function relationships and developing second generation oral agents. We previously reported on a novel small compound (Compound 1; RUC-1) identified by high throughput screening that inhibits human αIIbβ3. RUC-1 did not inhibit αVβ3, suggesting that it interacts with αIIb, and molecular docking studies supported this speculation. RUC-1 also induced less extensive changes in αIIbβ3 conformation than existing small molecule inhibitors, which may be therapeutically desirable. We have now studied RUC-1’s effects on murine and rat platelets, which are less sensitive than human to inhibition by RGD peptides due to differences in the αIIb sequences contributing to the binding pocket. We found that RUC-1 (100 μM) was much less potent in inhibiting platelet aggregation of murine and rat platelets than human platelets or the platelets of a mouse expressing a hybrid receptor composed of human αIIb and murine β3 (hαIIb/mβ3) (mouse, 6±6%, n=4; rat, 0±15%, n=3; human, 97±2% n=3; hαIIb/mβ3 99±1%, n=4). RUC-1 also inhibited fibrinogen binding to murine platelets expressing the hybrid hαIIb/mβ3 receptor (94± 2%, n=4), but not a hybrid receptor composed of murine αIIb and human β3 (mαIIb/hβ3; 0%, n=4). Molecular docking studies of RUC-1 were consistent with the functional data with RUC-1 binding entirely within the β-propeller. αIIb In vivo studies of RUC-1 administered intraperitoneally (IP) at a dose of 26.5 mg/kg demonstrated antithrombotic effects in the FeCl3 carotid artery model in mice expressing hαIIb/mβ3 (Figure 1A), but did not protect WT mice from thrombotic occlusion at the same dose (Figure 1B). Collectively, these data support RUC-1’s specificity for αIIb, provide new insights into the αIIb ligand-binding pocket, and establish RUC-1’s anti-thrombotic effects in vivo. In addition, the hαIIb/mβ3 mice provide a convenient model for testing low molecular weight αIIbβ3 antagonist drugs such as RUC-1 for toxicity and therapeutic potential. Figure 1. RUC-1 protects hαIIb/mβ3 mice, but not WT mice from FeCl3-induced carotid artery thrombotic occlusion. A. Mice expressing hαIIb/mβ3 receptor were injected IP with vehicle control (n=4), an inactive congener of RUC-1 (RUC-1-piperidine; n=4; 26.5 mg/kg), or RUC-1 (n=7; 26.5 mg/kg) 25 min before carotid artery injury with 20% FeCl3 for 3 min. Blood flow through the carotid artery was monitored for 30 min with a Doppler flow probe. Kaplan-Meier analysis was calculated from the time the FeCl3 was applied to the artery until complete occlusion. The control curve contains the combined data from the mice treated with vehicle and RUC-1-piperidine. B. WT mice (n=4) were given RUC-1 (26.5 mg/kg) and their data are compared to those reported in panel A for mice expressing hαIIb/mβ3. Figure 1. RUC-1 protects hαIIb/mβ3 mice, but not WT mice from FeCl3-induced carotid artery thrombotic occlusion. A. Mice expressing hαIIb/mβ3 receptor were injected IP with vehicle control (n=4), an inactive congener of RUC-1 (RUC-1-piperidine; n=4; 26.5 mg/kg), or RUC-1 (n=7; 26.5 mg/kg) 25 min before carotid artery injury with 20% FeCl3 for 3 min. Blood flow through the carotid artery was monitored for 30 min with a Doppler flow probe. Kaplan-Meier analysis was calculated from the time the FeCl3 was applied to the artery until complete occlusion. The control curve contains the combined data from the mice treated with vehicle and RUC-1-piperidine. B. WT mice (n=4) were given RUC-1 (26.5 mg/kg) and their data are compared to those reported in panel A for mice expressing hαIIb/mβ3.

Hypoglycemic activity of 6-bromoembelin and vilangin in high-fat diet fed-streptozotocin-induced type 2 diabetic rats and molecular docking studies

Life Sciences ◽  
2016 ◽  
Vol 153 ◽  
pp. 100-117 ◽  
Author(s):  
Antony Stalin ◽  
Santiagu Stephen Irudayaraj ◽  
Gopalsamy Rajiv Gandhi ◽  
Kedike Balakrishna ◽  
Savarimuthu Ignacimuthu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Fat Diet ◽  
Docking Studies ◽  
Diabetic Rats ◽  
Hypoglycemic Activity ◽  
High Fat ◽  
Molecular Docking Studies ◽  
Type 2 Diabetic

Assessing the affinity of oxazolidinedione/hydantoin derivatives for the human 5HT1A/2A receptor through homology modeling and docking studies

2021 ◽  
Vol 23 (09) ◽  
pp. 46-66
Author(s):  
Meenakshi Dhanawat ◽  
◽  
Sumeet Gupta ◽  
Rina Das ◽  
Dinesh Kumar Mehta ◽  
...  
Keyword(s):  
Binding Site ◽  
Adrenergic Receptor ◽  
Homology Model ◽  
Docking Studies ◽  
Binding Affinities ◽  
Docking Algorithm ◽  
Glide Docking ◽  
Β2 Adrenergic Receptor ◽  
Hydantoin Derivatives

A flexible docking of a series of heteroaryl compounds to the binding site of a model of human 5-HT1A/2A receptor was exercised using GLIDE docking methods. The resultant docking scores were used to correlate the in vivo affinity data. The GLIDE docking algorithm when used with a homology model of 5HT1A/2A was based on β2- adrenergic receptor template. The influence of structure and hydrophobic properties of aryl moiety on binding affinities was discussed and a model for ligand binding in the hydrophobic part of the binding site was proposed.

scholarly journals Biological Evaluation ofPupalia lappaceafor Antidiabetic, Antiadipogenic, and Hypolipidemic Activity BothIn VitroandIn Vivo

Scientifica ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Vivek Kumar ◽  
Parag Jain ◽  
Kalpana Rathore ◽  
Zabeer Ahmed
Keyword(s):  
Cell Line ◽  
Reference Group ◽  
Lipid Level ◽  
Biological Evaluation ◽  
Diabetic Rats ◽  
Hypolipidemic Activity ◽  
Albino Rats ◽  
Reference Drug

Objective. The present study assesses the effect ofPupalia lappacea(L.) Juss. (Amaranthaceae) (PL) leaves ethanolic extract on adipocytes, blood glucose level, and lipid level in streptozotocin (STZ) induced diabetic rats.Materials and Methods. Male Albino rats were rendered diabetic by a single moderately sized dose of STZ (45 mg/kg, intraperitoneally) at once before starting the treatment. Animals were divided into five groups: normoglycemic control, diabetic control, reference group (glibenclamide, 5.0 mg/kg), AS001 (250 mg/kg extract), and AS002 (500 mg/kg extract) each containing six animals forin vivostudy. Antidiabetic and hypolipidemic activity of extract were determined byin vivomethod on STZ induced diabetic rats. Antiadipogenic activity was determined byin vitromethod on 3T3-L1 cell line in comparison to simvastatin as reference drug.Result. The extract showed significant fall in fasting serum glucose (FSG), that is, 234.68 and 211.61 mg/dL, in STZ induced diabetic animals for dose groups AS001 and AS002, respectively. ThePLextract also exhibited noteworthy antiadipogenic activity on 3T3-L1 cell line. The value of inhibitory concentration (IC50) ofPLextract to reduce adipocyte cells was found to be 662.14 μg/mL.Conclusion. ThePLextract exhibited significant antiadipogenic, antidiabetic, and hypolipidemic activities.

In Silico Design, Synthesis and Evaluation of Novel Series of Benzothiazole- Based Pyrazolidinediones as Potent Hypoglycemic Agents

2020 ◽  
Vol 16 (6) ◽  
pp. 812-825 ◽  
Author(s):  
Michelyne Haroun
Keyword(s):  
Hydrophobic Interactions ◽  
Docking Study ◽  
Hypoglycemic Agents ◽  
Peroxisome Proliferator ◽  
Antidiabetic Agents ◽  
Peroxisome Proliferator Activated Receptor ◽  
Design Synthesis ◽  
Reference Drug ◽  
Design And Synthesis

Background: The discovery of novel ligand binding domain (LBD) of peroxisome proliferator- activated receptor γ (PPARγ) has recently attracted attention to few research groups in order to develop more potent and safer antidiabetic agents. Objective: This study is focused on docking-based design and synthesis of novel compounds combining benzothiazole and pyrazolidinedione scaffold as potential antidiabetic agents. Methods: Several benzothiazole-pyrazolidinedione hybrids were synthesized and tested for their in vivo anti-hyperglycemic activity. Interactions profile of title compounds against PPARγ was examined through molecular modelling approach. Results: All tested compounds exhibited anti-hyperglycemic activity similar or superior to the reference drug Rosiglitazone. Introducing chlorine atom and alkyl group at position-6 and -5 respectively on benzothiazole core resulted in enhancing the anti-hyperglycemic effect. Docking study revealed that such groups demonstrated favorable hydrophobic interactions with novel LBD Ω- pocket of PPARγ protein. Conclusion: Among the tested compounds, N-(6-chloro-5-methylbenzo[d]thiazol-2-yl-4-(4((3,5- dioxopyrazolidin-4-ylidene)methyl)phenoxy)butanamide 5b was found to be the most potent compound and provided valuable insights to further develop novel hybrids as anti-hyperglycemic agents.

scholarly journals Synthesis, Hypoglycemic Effect, Antimicrobial and Molecular Docking Studies of Organotin(IV) Complexes Derived from N-Phthalimido β-Amino Acid Derivatives

2021 ◽  
Author(s):  
Muhammad Ahmed ◽  
Nagina Riaz ◽  
Muhammad Kashif ◽  
Muhammad Ashfaq ◽  
Muhammad Arshad ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Docking Studies ◽  
Hypoglycemic Agents ◽  
Amino Acid Derivatives ◽  
Propanoic Acid ◽  
Ionization Mass ◽  
Amino Acid Residues ◽  
Diabetic Rabbits

N-Phthalimido β-amino acid derivatives, 3-phthalimido-3(2-hydroxyphenyl) propanoic acid (P2HPA) and 3-phthalimido-3(2-nitrophenyl) propanoic acid (P2NPA) with new series of diand triorganotin(IV) complexes (1-12) have been designed and synthesized. All the ligands and organotin(IV) complexes were characterized by elemental analysis, Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (1H, 13C, 119Sn) spectroscopy and electron ionization mass spectrometry (EI-MS). Synthesized ligands and complexes were screened to determine the antibacterial activity and results showed that the triorganotin(IV) complexes have better activity compared to diorganotin(IV) complexes and ligands. In addition, molecular docking analysis of ligands on the catalytic pocket of sortase A (PDB ID 1T2W) showed that the ligands can bind the active amino acid residues in the pocket. The antioxidant activity was also performed by the DPPH (1,1-diphenyl-2-picrylhydrazyl radical) method and complexes showed better results than ligands. The compounds were also tested in vivo to determine the hypoglycemic activities on different groups of alloxan induced diabetic rabbits. The complexes (1-6) were found better hypoglycemic agents as they stabilized the glucose level to about 175-105 mg dL-1 as compared to ligand P2HPA.

scholarly journals Exploration of Hypoglycemic Activity of Saccharomyces pastorianus Extract and Evaluation of the Molecular Mechanisms

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4232
Author(s):  
Chien-Hui Wu ◽  
Chung-Hsiung Huang ◽  
Ming-Chuan Chung ◽  
Shun-Hsien Chang ◽  
Guo-Jane Tsai
Keyword(s):  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Diabetic Rats ◽  
Hypoglycemic Activity ◽  
Limited Information ◽  
Saccharomyces Pastorianus ◽  
Glucose Transporter Glut4

Although the hypoglycemic potential of brewer’s yeast extract has been reported, there is limited information pertaining to the hypoglycemic ingredients of Saccharomyces pastorianus extract and their mechanisms of action available. This study aimed to investigate the in vivo and in vitro hypoglycemic effect of S. pastorianus extract and to elucidate its molecular mechanisms. S. pastorianus extract was mainly composed of proteins followed by carbohydrates. In diabetic rats, oral administration of S. pastorianus extract significantly reduced the levels of plasma glucose and enhanced the activity of hepatic glucose-6-phosphatase dehydrogenase. Treatment with S. pastorianus extract increased the localization of type 4 glucose transporter (GLUT4), PTP, and insulin receptor at 3T3-L1 cell membranes and raised the levels of P38 MAPK, PI3K, and AKT in the cytosol. In agreement with these results, pretreatment of 3T3-L1 cells with inhibitors of PTP, PI3K, Akt/PKB, and p38 MAPK inhibited glucose uptake induced by application of S. pastorianus extract. Most importantly, a 54 kDa protein with hypoglycemic activity was identified and suggested as the major ingredient contributing to the hypoglycemic activity of S. pastorianus extract. In summary, these results clearly confirm the hypoglycemic activity of S. pastorianus extract and provide critical insights into the underlying molecular mechanisms.

scholarly journals Enhancement of Berberine Hypoglycemic Activity by Oligomeric Proanthocyanidins

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3318 ◽  
Author(s):  
Haoyue Zhang ◽  
Xueping Wang ◽  
Ting Wang ◽  
Kaixian Chen ◽  
Heyao Wang ◽  
...  
Keyword(s):  
Underlying Mechanism ◽  
Hypoglycemic Activity ◽  
Hypoglycemic Agents ◽  
Intestinal Cells ◽  
Sprague Dawley ◽  
Oral Hypoglycemic Agents ◽  
Oligomeric Proanthocyanidins ◽  
Average Maximum

This study investigated the possible enhancement of berberine’s (BB) hypoglycemic activity by oligomeric proanthocyanidins (OPCs) and its underlying mechanism. The hypoglycemic activity of the studied compounds was evaluated in diabetic db/db mice. The cellular uptake and efflux of BB with or without OPCs were investigated using Caco-2 intestinal cells. A pharmacokinetic study of BB and OPCs was performed in Sprague Dawley (SD) mice by oral administration of the study compounds. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was employed to determine the cellular efflux, retention, and the serum concentrations of the compounds. The results revealed that OPCs considerably potentiated the hypoglycemic efficacy of BB in diabetic db/db mice. In the in vitro experiments, OPCs significantly inhibited the efflux and increased the uptake of the P-glycoprotein (P-gp) substrate rhodamine-123 (R123) and BB in Caco-2 intestinal cells. Moreover, OPCs substantially reduced the expression of P-gp in Caco-2 cells. The inhibition of BB efflux by OPCs was translated into the improved pharmacokinetics in vivo. When co-administered, OPCs obviously increased the average maximum concentration of BB in mice. In summary, this study demonstrated that combination of BB with OPCs could significantly improve the pharmacokinetics and hypoglycemic efficacy of BB, which is valuable for future exploration of the combination of BB and OPCs as oral hypoglycemic agents.

scholarly journals Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel αIIb-specific αIIbβ3 antagonist

Blood ◽  
2009 ◽  
Vol 114 (1) ◽  
pp. 195-201 ◽  
Author(s):  
Robert Blue ◽  
M. Anna Kowalska ◽  
Jessica Hirsch ◽  
Marta Murcia ◽  
Christin A. Janczak ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Throughput Screening ◽  
Binding Pocket ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Rgd Peptides ◽  
Molecular Docking Studies ◽  
Antithrombotic Effects ◽  
Rat Platelets

Abstract We previously reported on a novel compound (Compound 1; RUC-1) identified by high-throughput screening that inhibits human αIIbβ3. RUC-1 did not inhibit αVβ3, suggesting that it interacts with αIIb, and flexible ligand/rigid protein molecular docking studies supported this speculation. We have now studied RUC-1's effects on murine and rat platelets, which are less sensitive than human to inhibition by Arg-Gly-Asp (RGD) peptides due to differences in the αIIb sequences contributing to the binding pocket. We found that RUC-1 was much less potent in inhibiting aggregation of murine and rat platelets. Moreover, RUC-1 potently inhibited fibrinogen binding to murine platelets expressing a hybrid αIIbβ3 receptor composed of human αIIb and murine β3, but not a hybrid receptor composed of murine αIIb and human β3. Molecular docking studies of RUC-1 were consistent with the functional data. In vivo studies of RUC-1 administered intraperitoneally at a dose of 26.5 mg/kg demonstrated antithrombotic effects in both ferric chloride carotid artery and laser-induced microvascular injury models in mice with hybrid hαIIb/mβ3 receptors. Collectively, these data support RUC-1's specificity for αIIb, provide new insights into the αIIb binding pocket, and establish RUC-1's antithrombotic effects in vivo.

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