Antidiabetic Potential of Novel 1,3,5-Trisubstituted-2-Thioxoimidazloidin-4-One Analogues: Insights into α-Glucosidase, α-Amylase, and Antioxidant Activities

Abstract

As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity of carbohydrate-hydrolyzing enzymes, including α-amylase and α-glucosidase, could be a potential strategy for managing the development of DM. In the presented study, a novel set of 1,3,5-trisubstituted-2-thioxoimidazolidin-4-ones was designed, synthesized, and characterized. The antidiabetic activity of the synthesized compounds was explored by assessing their inhibitory activity toward α-amylase and α-glucosidase enzymes. The results demonstrated that this class of compounds exhibits considerable inhibitory activity toward both α-amylase and α-glucosidase enzymes. Among the synthesized compounds, compound 5a demonstrated the most inhibitory activity with IC50 of 5.08 and µg/mL and 0.21 µg/mL toward α-glucosidase and α-amylase activities, respectively, as compared to the drug Acarbose (IC50 =5.76 µg/mL and 0.39 µg/mL, respectively). To gain insights into the antidiabetic potential of compound 5a, we assessed the cytotoxic and antioxidant activities. Our findings indicated that compound 5a displays considerable cytotoxicity toward WI-38 cells with an IC50 of 88.54 µg/mL, as compared to the drug Celecoxib (IC50 =93.05 µg/mL). Further, compound 5a exhibited a high scavenging activity toward 2,2-Diphenyl1-picrylhydrazyl (DPPH) free radicals (IC50 = 51.75 µg/mL) and showed a low potential to produce ROS as indicated by the monitoring of the generated H2O2 (132.4 pg/mL), as compared to Trolox (IC50 =58.09 µg/mL) and Celecoxib (171.6 pg/mL). Finally, we performed extensive molecular modeling studies to affirm the binding affinity of this class of compounds to the binding pocket of α-amylase and α-glucosidase enzymes. Collectively, our findings indicate that this class of compounds, particularly compound 5a, could be utilized as a lead structure for the development of novel compounds with potential antidiabetic and antioxidant activities.

Ameliorative Effect of Citrus Lemon Peel Extract and Resveratrol on Premature Ovarian Failure Rat Model: Role of iNOS/Caspase-3 Pathway

“…Oxidative stress damages the intraovarian environment by slowing the nuclear and cytoplasmic maturation of oocytes and encouraging apoptosis, resulting in an imbalance between the generation and elimination of ROS. Therefore, the increase of ROS in the ovaries degrades oocyte quality, causes granulosa cell (GC) death, and results in rapid corpus luteum degradation [41][42][43]. In addition, the amplification of lipid peroxidation cascades causes oxidative damage to the ovary, which significantly impacts folliculogenesis, meiosis, and ovulation, finally leading to ovarian failure [44].…”

Insight into the phytochemical profile and antimicrobial activities of Amomum subulatum and Amomum xanthioides: an in vitro and in silico study

“…Docking simulations and binding affinity were performed and calculated using AutoDock Vina ( Trott and Olson, 2010 ). The molecular interactions were further investigated by visualizing the formed chemical bonds in each ligand–receptor complex as well as the 3D surface structures showing the aromatic interactions, H-bond formation, ionizability, solvent-accessible surface (SAS), and other properties by using BIOVIA Discovery Studio ( Gaber et al., 2020 ; Samaha et al., 2020 ; El Azab et al., 2021 ; Gaber et al., 2021 ; Mohamed et al., 2021 ; Saied et al., 2021 ; Healey et al., 2022 ; Khirallah et al., 2022a ; Khirallah et al., 2022b ).…”

Unveiling the multifaceted antiproliferative efficacy of Cichorium endivia root extract by dual modulation of apoptotic and inflammatory genes, inducing cell cycle arrest, and targeting COX-2

“…The structure of selected secondary metabolites was acquired from the ChemDraw program, and energy minimization and geometry verication were assessed using the MOE program as previously reported. 53,54,[67][68][69][70] The modelling protocol was adjusted for the force eld (MMFF94x), the scoring function (London dG), and the placement (Triangle) and subsequently validated by modelling the binding mode of ibuprofen. The binding poses were then evaluated to affirm the original binding mode of ibuprofen to the target proteins, compared to the reported data.…”