Tailoring the substitution pattern of Pyrrolidine-2,5-dione for discovery of new structural template for dual COX/LOX inhibition

Sadiq, Abdul; Mahnashi, Mater H.; Alyami, Bandar A.; Alqahtani, Yahya S.; Alqarni, Ali O.; Rashid, Umer

doi:10.1016/j.bioorg.2021.104969

Cited by 43 publications

(56 citation statements)

References 48 publications

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“…Thiazolidinedione is one of the most common classes of clinically practiced drugs for diabetes. Similarly, the succinimide is a known class of drugs for neuropharmacology and inflammation [ 44 ]. Various derivatives of succinimide-type compounds can be synthesized with different methods [ 51 – 54 ].…”

Section: Resultsmentioning

confidence: 99%

“…The experiments were repeated three times. The percent inhibitions with its subsequent IC 50 values were calculated as per the standard reported formula and were compared with the standard diclofenac [ 44 ].…”

Section: Methodsmentioning

confidence: 99%

“…The experiments were performed three times. The percent 5-LOX inhibitions and the IC 50 values were calculated as per the standard formula [ 44 ].…”

Section: Methodsmentioning

confidence: 99%

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Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules

Mahnashi

Alyami

Alqahtani

et al. 2022

Oxidative Medicine and Cellular Longevity

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Prostrate knotweed also called Polygonum aviculare is an important edible plant. The polygonum is majorly known for the phenolics and antioxidants. The antioxidants combat the excessive free radicals within the body. The excessive free radicals are implicated in various other diseases like diabetes, Alzheimer’s, and inflammation. This study was aimed at exploring the antioxidant bioactives and their derivatizations to produce new molecules with advanced pharmacological features. We have isolated six compounds (1–6) from Polygonum aviculare. Furthermore, rational-based chemical derivatives for compound 5 have been formed for the management of diabetes, Alzheimer’s, and inflammation. In preliminary antioxidant studies, all the isolated compounds (1–6) showed potential results against DPPH and ABTS free radicals. Based on the IC50 and chemical nature of the compounds, compound 5 was subjected to derivatization. Keeping the phenolic part of compound 5 unaffected, hydroxy succinimide (5A) and thiazolidinedione (5B) were synthesized. The compound 5A was found to be a potent inhibitor of AChE, BChE, COX-1, COX-2, 5-LOX, and DPPH giving IC50 values of 10.60, 15.10, 13.91, 1.08, 0.71, and 1.05 μM, respectively. The COX-2 selectivity of compound 5A was found at 12.9. The compound 5B was found to be a potent multitarget antidiabetic agent giving IC50 values of 15.34, 21.83, 53.28, and 1.94 μM against α-glucosidase, α-amylase, protein tyrosine phosphatase 1B, and DPPH. Docking studies were performed to manipulate the binding interactions. The docking pose of all the tested compounds was found to have increased binding affinity against all tested targets that supported the in vitro results. Our results showed that Polygonum aviculare is a rich source of antioxidant compounds. The two new derivatives have enhanced pharmacological features to treat diabetes, inflammation, and Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules

Mahnashi

Alyami

Alqahtani

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…5I38 was obtained from the Protein Data Bank. Preparation of downloaded enzymes for binding site determination, 3-D protonation, and energy minimization was conducted as per previously reported methods [ 22 , 23 ]. Structures of the compounds were built using the builder option in the MOE software.…”

Section: Methodsmentioning

confidence: 99%

Antioxidant and Cytotoxic Activity of a New Ferruginan A from Olea ferruginea: In Vitro and In Silico Studies

Shah

Mujawah

Ullah

et al. 2022

Oxidative Medicine and Cellular Longevity

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Studies of the ethyl acetate extract bark extract of Olea ferruginea led to the isolation of one new compound Ferruginan A (1) in addition to two known compounds, Ferruginan (2) and cycloolivil (3). Structures of the isolated compounds were confirmed by mass spectrometry (MS) and NMR spectral data. The ethyl acetate fraction and compounds (1–3) were evaluated against breast cancer cell line (MCF-7) and as antioxidants using the free radical scavenging assay. Results revealed that compound 2 exhibits significant antioxidant activity with an I C 50 value of 21.74 μg/mL. In addition, the ethyl acetate fraction showed good cytotoxic activity (79.31% inhibition at 250 μg/mL), whereas compounds 1–3 exerted mild cytotoxic activity ( I C 50 = 8.03 – 12.01 μ g / mL ) as compared to the standard ( I C 50 = 4.41 μ g / mL ) against MCF-7. Docking studies suggested that antioxidant activity is due to the chelation of compounds with copper present in the active site of tyrosinase. These results suggest that the extract exhibits considerable antioxidant activity, and the isolated compounds exert moderate anticancer activity.

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“…Recent literature survey revealed that various classes of drugs like sulfonylureas, biguanides, thiazolidinediones, and dipeptidyl peptidase-4 (dpp-4) inhibitors are used for the management of diabetes but most of these are associated with obnoxious effects [ 17 ]. Therefore we need to develop new therapeutic moieties having better efficacy and safety profiles [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antioxidant, and Antidiabetic Activities of Ketone Derivatives of Succinimide

Waheed

Shah

Hussain

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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The prevalence of diabetes mellitus is persistently increasing globally creating a serious public health affliction. Diabetes mellitus is categorized into two major types designated as type I and Type II. Type I diabetes mellitus is characterized by complete lack of secretion of insulin, while Type II diabetes mellitus is the resistance of peripheral tissues to the action of insulin and inadequate compensatory secretion of insulin. Chronic hyperglycemia associated with diabetes causes failure of cardiovascular system, nervous system, kidneys, and eyes. At present, different types of drugs are used for the management of diabetes, but each of them is associated with more or less serious side effects. Therefore, we need to develop new therapeutic agents that have better efficacy and safety profile. In this study, three ketone derivatives of succinimides were synthesized based on Michael addition and characterized using NMR. All the synthesized compounds were checked for their in vitro α-amylase and α-glucosidase inhibitory activities. Further the synthesized compounds were also explored for their antioxidant activities, i.e, DPPH and ABTS assays. Based on the in vitro results, the synthesized compounds were further evaluated for in vivo antidiabetic activity. The synthesized compounds were (2-oxocyclohexyl)-1-phenylpyrrolidine-2,5-dione (BW1), benzyl-3-(2-oxocyclohexyl) pyrrolidine-2,5-dione (BW2), and (4-bromophenyl)-3-(2-oxocyclohexyl) pyrrolidine-2,5-dione (BW3). BW1 showed the highest inhibitory activity for DPPH causing 83.03 ± 0.48 at 500 μg/ml with IC50 value of 10.84 μg/ml and highest inhibitory activity for ABTS causing 78.35 ± 0.23 at 500 μg/ml with IC50 value of 9.40 μg/ml against ascorbic acid used as standard. BW1 also exhibited the highest activity against α-amylase and α-glucosidase inhibition causing 81.60 ± 0.00 at concentrations of 500 μg/ml with IC50 value of 13.90 μg/ml and 89.08 ± 1.04 at concentrations of 500 μg/ml with IC50 value of 10.49 μg/ml, respectively, against the standard drug acarbose.

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Tailoring the substitution pattern of Pyrrolidine-2,5-dione for discovery of new structural template for dual COX/LOX inhibition

Cited by 43 publications

References 48 publications

Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules

Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules

Antioxidant and Cytotoxic Activity of a New Ferruginan A from Olea ferruginea: In Vitro and In Silico Studies

Synthesis, Antioxidant, and Antidiabetic Activities of Ketone Derivatives of Succinimide

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