Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches

Mahnashi, Mater H.; Alam, Waqas; Abdulwahab, Alqahtani; Alzahrani, Mohammed Jamaan; Alshaibari, Khaled S.; Umar, Rashid; Sadiq, Abdul; Jan, Muhammad

doi:10.3390/molecules28041589

Cited by 4 publications

(1 citation statement)

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“…Different plants and microorganisms produce α-glucosidase and α-amylase inhibitors for the regulation of such enzyme activities [25]. Synthetic compounds are also being developed in parallel in order to create α-glucosidase and α-amylase inhibitors [26,27]. Inhibitors of α-amylase enzymes reduce the conversion of starch into glucose usually after eating a meal, which results in a decrease in the level of glucose in the blood.…”

Section: Introductionmentioning

confidence: 99%

Antidiabetic, Antihyperlipidemic, and Antioxidant Evaluation of Phytosteroids from Notholirion thomsonianum (Royle) Stapf

Huneif,

Fahad,

Abdulwahab

et al. 2023

Plants

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Diabetes mellitus (DM) is a metabolic complication and can pose a serious challenge to human health. DM is the main cause of many life-threatening diseases. Researchers of natural products have been continuously engaged in treating vital diseases in an economical and efficient way. In this research, we extensively used phytosteroids from Notholirion thomsonianum (Royle) Stapf for the treatment of DM. The structures of phytosteroids NtSt01 and NtSt02 were confirmed with gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) analyses. Through in vitro studies including α-glucosidase, α-amylase, and DPPH assays, compound NtSt01 was found to be comparatively potent. An elevated dose of compound NtSt01 was also found to be safe in an experimental study on rats. With a dose of 1.0 mg/kg of NtSt01, the effect on blood glucose levels in rats was observed to be 519 ± 3.98, 413 ± 1.87, 325 ± 1.62, 219 ± 2.87, and 116 ± 1.33 mg/dL on the 1st, 7th, 14th, 21st, and 28th, days, respectively. The in vivo results were compared with those of glibenclamide, which reduced the blood glucose level to 107 ± 2.33 mg/dL on the 28th day. On the 28th day of NtSt01 administration, the average weights of the rats and vital organs (liver, kidney, pancreas, and heart) remained healthy, with a slight increase. The biochemical parameters of the blood, i.e., serum creatinine, blood urea, serum bilirubin, SGPT (or ALT), and serum alkaline phosphatase, of rats treated with NtSt01 remained in the normal ranges. Similarly, the serum cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels also remained within the standard ranges. It is obvious from our overall results that the phytosteroids (specifically NtSt01) had an efficient therapeutic effect on the blood glucose level, protection of vital organs, and blood biochemistry.

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Section: Introductionmentioning

confidence: 99%

Antidiabetic, Antihyperlipidemic, and Antioxidant Evaluation of Phytosteroids from Notholirion thomsonianum (Royle) Stapf

Huneif,

Fahad,

Abdulwahab

et al. 2023

Plants

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Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches

Talib,

Shah,

Jan

et al. 2023

Green Processing and Synthesis

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Diabetes mellitus (DM) is one of the most challenging diseases among all the other diseases in the recent era, and it is a life-threatening disorder. The best enzymes to target for treating DM are α-glucosidase and α-amylase. For this purpose, we explored numerous succinimides with ketone functionalities. First, we explored these compounds for their in vitro analysis. Compounds 1 and 4 exhibited excellent inhibition of both enzymes in in vitro studies. These compounds displayed excellent activity with IC50 values of 3.69 and 1.526 µg·mL−1 against the α-glucosidase enzyme. In the α-amylase inhibitory assay, compound 1 has shown excellent potential with an IC50 value of 1.07 µg·mL−1 and compound 4 with an IC50 value of 0.115 µg·mL−1. Based on the in vitro analysis, the potent compounds were further subjected to their in vivo analysis. Before the in vivo analysis, the toxicity profile was checked, and it was confirmed that the compounds were safe at 1,500 µg·kg−1. Then, these compounds were subjected for their in vivo anti-diabetic potential in a mouse model of diabetes. Various concentrations of compounds 1 and 4 were explored by in vivo analysis using glibenclamide as a standard drug. The blood glucose level of the tested and control groups was measured at 0 to 15 days accordingly. Similarly, we also explored compounds 1 and 4 for the oral glucose tolerance test at 0–120 min using glibenclamide as the standard drug. Hence, the succinimide having ketone moiety displayed excellent potential against diabetes.

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Synthesis and Anti-Inflammatory and Analgesic Potentials of Ethyl 2-(2,5-Dioxo-1-Phenylpyrrolidin-3-yl)-2-Methylpropanoate

Sadiq,

Khan,

Zafar

et al. 2024

Pharmaceuticals

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Background/Objectives: Inflammation and analgesia are two prominent symptoms and often lead to chronic medical conditions. To control inflammation and analgesia, many marketed drugs are in practice but the majority of them have severe side effects. Methods: This study involved the synthesis of a pivalate-based Michael product and evaluated it for in vitro COX-1, COX-2, and 5-LOX inhibitory potentials using specific assays. Molecular docking studies were also assessed. Based on the in vitro results, the compound was also subjected to in vivo anti-inflammatory and antinociceptive studies. Results: The pivalate-based Michael product (MAK01) was synthesized by an organocatalytic asymmetric Michael addition of ethyl isobutyrate to N-phenylmaleimide with an isolated yield of 96%. The structure of the compound was confirmed through 1H and 13C NMR analyses. The observed IC50 values for COX-1, COX-2, and 5-LOX were 314, 130, and 105 μg/mL, respectively. The molecular docking studies on the synthesized compound showed binding interactions with the minimized pockets of the respective enzymes. In a carrageenan model, a percent reduction in edema when administered at 10 mg/kg (a reduction of 33.3 ± 0.77% at the second hour), 20 mg/kg (a reduction of 34.7 ± 0.74% at the second hour), and 30 mg/kg (a reduction of 40.58% ± 0.84% after the fifth hour) was observed. The compound showed a significant response at concentrations of 50, 100, and 150 mg/kg with latency times of 10.32 ± 0.82, 12.16 ± 0.51, and 12.93 ± 0.45 s, respectively. Conclusion: In this study, we synthesized a pivalate-based Michael product for the first time. Moreover, based on its rationality and potency, it was found to be an effective future medicine for the management of analgesia and inflammation.

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Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches

Cited by 4 publications

References 64 publications

Antidiabetic, Antihyperlipidemic, and Antioxidant Evaluation of Phytosteroids from Notholirion thomsonianum (Royle) Stapf

Antidiabetic, Antihyperlipidemic, and Antioxidant Evaluation of Phytosteroids from Notholirion thomsonianum (Royle) Stapf

Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches

Synthesis and Anti-Inflammatory and Analgesic Potentials of Ethyl 2-(2,5-Dioxo-1-Phenylpyrrolidin-3-yl)-2-Methylpropanoate

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