Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents

Jan, Muhammad; Ahmad, Sajjad; Hussain, Fida; Ahmad, Ashfaq; Mahmood, Fawad; Rashid, Umer; Abid, Obaid‐ur‐Rahman; Ullah, Farhat; Ayaz, Muhammad; Sadiq, Abdul

doi:10.1016/j.ejmech.2019.111863

Cited by 95 publications

(67 citation statements)

References 49 publications

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“…Palmitic acid has also been proven to be an excellent candidate in type-2 diabetes mellitus (Chae et al, 2010). Correspondingly, the pyrolidone derivative has been proven to possess strong α-glucosidase inhibitory and anti-inflammatory properties (Trapero and Llebaria, 2012;Jan et al, 2020). Moreover, several antioxidant compounds identified in the GC-MS spectrum have been reported to scavenge the free radicals effectively.…”

Section: Discussionmentioning

confidence: 99%

Treating Hyperglycemia From Eryngium caeruleum M. Bieb: In-vitro α-Glucosidase, Antioxidant, in-vivo Antidiabetic and Molecular Docking-Based Approaches

et al. 2020

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Natural-based drugs are believed to be safe, effective and economical. Based on the medicinal importance of the genus Eryngium and unexplored nature of Eryngium caeruleum, we have evaluated its antidiabetic and antioxidant potentials. Both in-vitro and in-vivo assays have been carried out for antidiabetic assays. The antioxidant activity was determined by using different free radicals [i.e., 1,1-diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS), and hydrogen peroxide (H2O2)]. Moreover, different phytoconstituents were identified in the most active solvent fraction by GC-MS analysis. Furthermore, comparative fingerprints of methanolic extract and chloroform fraction were also analyzed via High Performance Liquid Chromatography coupled with Diode Array Detector (HPLC-DAD). The crude methanolic extract of E. caeruleum (Ec.Cr) and its sub-fractions [i.e., n-hexane (Ec.Hex), chloroform (Ec.Chf), ethyl acetate (Ec.EtAc), and aqueous (Ec.Aq) were employed in this study]. In the α-glucosidase inhibition assay, a concentration-dependent inhibitory response was observed against the enzyme. The most active sample was Ec.Chf which revealed an IC50 of 437 μg/ml in comparison to the standard acarbose (IC50 25 μg/ml). The rest of the samples showed moderate inhibition of α-glucosidase. In antioxidant assays, Ec.Chf and Ec.Cr exhibited a considerable scavenging effect against all the free radicals. The IC50 values recorded for Ec.Chf were 112, 109, and 150 μg/ml against DPPH, ABTS, and H2O2 respectively. Based on the in-vitro potential of Ec.Chf, this was subjected to the in-vivo model experiment. The Ec.Chf lowered the blood glucose level up to 10.3 mmol/L at 500 μg/Kg. The Ec.Chf was also subjected to GC-MS analysis. The GC-MS analysis confirmed the presence of 60 compounds. The identified phytoconstituents consist of some essential compounds previously reported with antidiabetic and antioxidant studies, which include thymol, tocopherol, phytol, nerolidol, (I)-neophytadiene, linolenic acid, and falcarinol. Similarly, the HPLC-DAD chromatograms of Ec.Cr and Ec.Chf exhibited a variety of peaks, which further demonstrates the possibility of important phytochemicals. In a nutshell, we can conclude that Eryngium caeruleum is a potential source of bioactive compounds which may be beneficial for the management of ailments like diabetes and free radicals mediated disorders. Molecular docking was performed to explore the possible role of all the identified bioactive compounds in the chloroform fraction of Eryngium caeruleum into active sites of the homology model of α-glucosidase.

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Section: Discussionmentioning

confidence: 99%

Treating Hyperglycemia From Eryngium caeruleum M. Bieb: In-vitro α-Glucosidase, Antioxidant, in-vivo Antidiabetic and Molecular Docking-Based Approaches

et al. 2020

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“…Mice were randomly distributed into different experimental groups as (n = 6). The Committee of animal ethics of the University of Malakand KPK accepted the protocols in strict compliance with internationally accepted principles for laboratory animal use and care after conforming to ARRIVE guidelines for the experimental animal studies through letter No; DREC/122 for Control and Supervision of Experiments on Animals standard [48]. After the experimental procedures, the animals were euthanized properly as per the standard procedures using the guideline of the American Veterinary Medical Association (AVMA) for the euthanasia of the animals.…”

Section: Experimental Animalsmentioning

confidence: 99%

WITHDRAWN: Identification, Molecular Profiling, Docking Studies and determination of In-vivo Anti-Inflammatory Potential of Teucrium Stocksianum Bioss Fixed Oil (FO)

Shah

Zafar

et al. 2021

Preprint

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Background: Considering the positive and valuable upshots of the naturally occurring ingredients as the complementary treatment for many ailments, this study investigates the Teucrium Stocksianum Bioss Fixed Oil (FO) for the treatment of inflammation.Methods: Different plants of the Teucrium genera have been employed occasionally for the management of different disorders. Teucrium stocksianum (Lamiaceae) is traditionally use as antipyretic along with remedy of inflammation, diabetes and tumors. It also occupies the capacity to purify the blood. The aim of this study is to determine the chemical constituents and anti-inflammatory potentials of Teucrium stocksianum fixed oil (FO). Qualitative and quantitative analysis of fixed oil were performed via GC-MS (Gas Chromatography coupled with Mass Spectrometer). Preliminary inflammation antagonistic activity was calculated in mice using the carrageenan-induced paw edema model while the mechanism behind this inflammatory antagonistic effect was determined by employing various inflammogens including arachidonic acid, prostaglandins E2 and leukotriene via paw edema model.Results: The acute toxicity of fixed oil was determined at 3, 6 and 10 ml/kg body weight of the mouse. The GC-MS analysis documented 21 various unsaturated and saturated fatty acids elements. The methyl esters of octadecadienoic and linoleic acids were found predominantly at 22.60% and 23.84% respectively. In preliminary screening, FO demonstrated substantial anti-inflammatory capacity (67.87%, **P ˂ 0.01) in carrageenan induced paw edema model at 3 ml/kg body weight. The activity reached a peak value at the 3rd hour and continued persistent until the 5th hour of sample administration. FO displayed dose-dependent inhibition against all inflammogens at 3 ml/kg at 3rd h of the FO administration. These have shown marvelous protection i.e. 64.92%, 68.75%and 58.3% against arachidonic acid, prostaglandin E2 and leukotriene accordingly, at 3 ml/kg. The arachidonic acid antagonist (Caffeic acid) demonstrated 69.43% activity at 100 mg/kg after 3rd h of its administration while in the acute toxicity test, FO has shown no grass lethality at 10 ml/kg dose.Conclusion: According to our findings, the FO of T. stocksianum exhibits inflammation antagonistic potential through both lipoxygenase (LOX) and cyclooxygenase (COX) enzyme inhibition strategies that intensely sustenance the traditional practice of T. stocksianum in the management of multiple pathological inflammatory situations. The computed binding energies of the molecules exposed have synergistic potential to avert inflammation.

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“…25 Succinimides or 2.5-dioxopyrrolidines, a well-known class of drugs, possess a variety of biological potentials. 26,27 The basic structure can be derivatized by various aryl and/or alkyl groups on nitrogen or carbon positions. 28,29 Formerly, succinimides had been synthesized through various methods.…”

Section: Introductionmentioning

confidence: 99%

<p>Comparative Cholinesterase, α-Glucosidase Inhibitory, Antioxidant, Molecular Docking, and Kinetic Studies on Potent Succinimide Derivatives</p>

Ahmad

Ullah

Sadiq

et al. 2020

DDDT

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Introduction: The current study was designed to synthesize derivatives of succinimide and compare their biological potency in anticholinesterase, alpha-glucosidase inhibition, and antioxidant assays. Methods: In this research, two succinimide derivatives including (S)-1-(2,5-dioxo-1-phenylpyrrolidin-3-yl) cyclohexanecarbaldehyde (Compound 1) and (R)-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylpropanal (Compound 2) were synthesized using Michael addition. Both the compounds, ie, 1 and 2 were evaluated for in-vitro acetylcholinesterase (AChE), butyrylctcholinesterase (BChE), antioxidant, and α-glucosidase inhibitory potentials. Furthermore, molecular docking was performed using Molecular Operating Environment (MOE) to explore the binding mode of both the compounds against different enzymes. Lineweaver-Burk plots of enzyme inhibitions representing the reciprocal of initial enzyme velocity versus the reciprocal of substrate concentration in the presence of synthesized compounds and standard drugs were constructed using Michaelis-Menten kinetics. Results: In AChE inhibitory assay, compounds 1 and 2 exhibited IC 50 of 343.45 and 422.98 µM, respectively, against AChE enzyme. Similarly, both the compounds showed IC 50 of 276.86 and 357.91 µM, respectively, against BChE enzyme. Compounds 1 and 2 displayed IC 50 of 157.71 and 471.79 µM against α-glucosidase enzyme, respectively. In a similar pattern, compound 1 exhibited to be more potent as compared to compound 2 in all the three antioxidant assays. Compound 1 exhibited IC 50 values of 297.98, 332.94, and 825.92 µM against DPPH, ABTS, and H 2 O 2 free radicals, respectively. Molecular docking showed a triple fold in the AChE and BChE activity for compound 1 compared with compound 2. The compound 1 revealed good interaction against both the AChE and BChE enzymes which revealed the high potency of this compound compared to compound 2. Conclusion: Both succinimide derivatives exhibited considerable inhibitory activities against cholinesterases and α-glucosidase enzymes. Of these two, compound 1 revealed to be more potent against all the in-vitro targets which was supported by molecular docking with the lowest binding energies. Moreover, compound 1 also proved to have antiradical properties.

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Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents

Cited by 95 publications

References 49 publications

Treating Hyperglycemia From Eryngium caeruleum M. Bieb: In-vitro α-Glucosidase, Antioxidant, in-vivo Antidiabetic and Molecular Docking-Based Approaches

Treating Hyperglycemia From Eryngium caeruleum M. Bieb: In-vitro α-Glucosidase, Antioxidant, in-vivo Antidiabetic and Molecular Docking-Based Approaches

WITHDRAWN: Identification, Molecular Profiling, Docking Studies and determination of In-vivo Anti-Inflammatory Potential of Teucrium Stocksianum Bioss Fixed Oil (FO)

<p>Comparative Cholinesterase, α-Glucosidase Inhibitory, Antioxidant, Molecular Docking, and Kinetic Studies on Potent Succinimide Derivatives</p>

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