Efficient Synthesis and in Silico Studies of the Benzimidazole Hybrid Scaffold with the Quinolinyloxadiazole Skeleton with Potential α-Glucosidase Inhibitory, Anticoagulant, and Antiplatelet Activities for Type-II Diabetes Mellitus Management and Treating Thrombotic Disorders

Abstract

The current study evaluates antidiabetic, anticoagulant, and antiplatelet activity of novel benzimidazole-containing quinolinyl oxadiazoles. These derivatives are synthesized and characterized using spectroscopy (FT-IR, 1H NMR, and mass spectroscopy) and single-crystal X-ray diffraction methods. The inhibitory effects of these compounds were evaluated by the α-glucosidase inhibitory assay and shows the activity in the range of IC50 = 0.66 ± 0.05 to 3.79 ± 0.46 μg/mL. In addition, molecular docking studies revealed that benzimidazole-containing quinolinyl oxadiazoles can correctly dock into the target receptor protein of the human intestinal α-glucosidase, while their bioavailability/drug-likeness was predicted to be acceptable but requires further optimization. On the other hand, compound 8a and 8d showed anticoagulant activity as they enhanced the clotting time from control 180–410 and 180–390 s, respectively, in platelet rich plasma and 230–460 and 230–545 s in platelet poor plasma. Furthermore, only 8a showed antiplatelet activity by inhibiting epinephrine-induced platelet aggregation, and the observed aggregation inhibition was found to be 93.4%. Compounds 8a–f show nontoxic properties because of the non-hydrolyzing properties in the RBC cells. In addition, 8a and 8d show anti-edema and anti-hemorrhagic properties in the experimental mice. These findings reveal that benzimidazole-containing quinolinyl oxadiazoles act as α-glucosidase inhibitors to develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic and antithrombotic agents.

Alpha glucosidase inhibition activity of phenolic fraction from Simarouba glauca: An in-vitro, in-silico and kinetic study

“…Ethanol extract and purified ‘fraction-14’ were dissolved in Milli-Q water at 10 mg/ml concentration, centrifuged at 16,873 x g for 10 min (Eppendorf, 5418) and filtered through 0.2 μm filters before the analysis. AGI assay was carried out using the previously described method with slight modifications ( Bharadwaj et al., 2018 ). Briefly, in a 96 well microplate, the 50 μL of sample at different concentrations (10, 5, 1, 0.1, 0.01, 0.05 and 0.005 μg/mL) mixed with 40 μL (0.0015 units/mL) of yeast alpha glucosidase enzyme and 10 μL of phosphate buffer (100 mM) pH 7.…”

Potential antidiabetic activity of benzimidazole derivative albendazole and lansoprazole drugs in different doses in experimental type 2 diabetic rats

“…Some benzimidazoles have been reported to have antidiabetic effects by mainly activation of AMPK and PPAR, inhibition of α-amylase and α-glucosidase enzymes and other antidiabetic mechanisms. [10,[26][27][28]. However, these effects on AMPK may vary depending on the dose, the ratio of binding to the AMPK, and activating different subunits of AMPK [5].…”

“…Furthermore, some benzimidazole molecules cause regeneration of pancreas β cell, and the regulation of adipose tissue [21,22,26,27]. It was emphasized that telmisartan and lansoprazole, benzimidazole derivatives, could be used as an antidiabetic in the treatment of T2D by activating PPAR [27].…”

Synthesis of mono and bis-substituted asymmetrical compounds, (1-(pyridin-2-yl)ethylidene)carbonohydrazide and 1-(2'-hydroxybenzylidene)-5-(1'-pyridylethylidene)carbonohydrazone: Structural characterization and antioxidant activity study

“…The reactivity as well as the biological properties of these derivatives have been investigated in the past decades for the development of drugs [5,6] or industrial applications [7,8]. They are known to possess a broad spectrum of biological activities such as antioxidant [9], analgesic [10], antiplatelet [11], antifungal [2], antimicrobial [12], anticonvulsant [13], antidepressant [14], anti-inflammatory [15], anti-tubercular [16], anti-HIV [5], anti-diabetic [10,17], and anticancer activities [3,18]. While most of the older work on carbohydrazide Schiff bases focused on their applicability in classical fields, nowadays these systems are increasingly acknowledged as supreme multitopic ligands for the targeted construction of original metal-organic architectures such as grids [19,20].…”