Design, Synthesis, Antihyperglycemic Studies, and Docking Simulations of Benzimidazole-Thiazolidinedione Hybrids

Abstract

A simple and cheap three-step procedure for the synthesis of three (5Z)-5-[3(4)-(1H-benzimidazol-2-ylmethoxy)benzylidene]-1,3-thiazolidine-2,4-diones has been described via a SN2 reaction of generally recognized as safe hydroxybenzaldehydes and 2-(chloromethyl)-1H-benzimidazole, followed by a Knoevenagel condensation with thiazolidine-2,4-dione in moderated yields. All the newly synthesized compounds were characterized using analytical and spectral studies. In vitro treatment on adipocytes with compounds increased the mRNA expression of two proteins recognized as strategic targets in diabetes: PPARγ and GLUT-4. In silico studies were conducted in order to explain the interaction binding mode of the synthesized compounds on PPARγ. In vivo studies confirmed that compounds 1–3 have robust antihyperglycemic action linked to insulin sensitization mechanisms. The present study provides three compounds with a promising antidiabetic action.

Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole- and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein

“…A mixture of ortho-phenylene diamine (1.0 g, 9.25 mmol) and chloroacetic acid (1.32 g, 13.97 mmol) in 4 N HCl (60 mL) was refluxed for 24 h. The purified product was obtained by re-crystallization from water after neutralization with 6 N NH 4 OH, yield 0.4 g (40%). The product was used in the following step without further purification [ 63 ]. M.p.…”

Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

“…We performed this assay according to a previous methodology that was used in our lab [5,37]. Briefly, the animals were fasted for 8 h, after which the groups (n = 6) were administered a 100 mg/kg dose of the different treatments, in addition to one vehicle group (10% Tween 80) and one positive control group (20 mg/kg glibenclamide).…”

A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin-Induced Rat Model of Diabetes

“…These receptors are found in diverse tissues. Through the activation of PPAR-γ, thiazolidinediones (TZDs, also known as glitazones) modify the transcription of genes that encode for factors involved in the intake of glucose (e.g., GLUT-4 [5,6]) and in the metabolism of glucose and fatty acids [4,7]. Accordingly, they promote the sensitization of tissues to insulin.…”

“…Regarding TZDs that serve as PPAR-γ agonists (Figure 1), the structure contains an acid region (a TZD ring acting as the pharmacophore), an aromatic center, and a cyclic polar/nonpolar region or hydrophobic side chain [5][6][7][8][9][10]. Due to the relatively large ligandbinding pocket (1200 Å 3 ) of the receptor [4,7], numerous chemical modifications have been proposed to construct glitazone derivatives, generating great structural diversity [5][6][7][8][9][10]. Several authors have suggested that the presence of a double bond in carbon 5 of glitazone derivatives is a favorable characteristic [5][6][7][8]11].…”

“…Due to the relatively large ligandbinding pocket (1200 Å 3 ) of the receptor [4,7], numerous chemical modifications have been proposed to construct glitazone derivatives, generating great structural diversity [5][6][7][8][9][10]. Several authors have suggested that the presence of a double bond in carbon 5 of glitazone derivatives is a favorable characteristic [5][6][7][8]11]. The resulting unsaturated tail prevents racemization and provides rigidity to the molecule [7], possibly explaining the capacity of such glitazone derivatives to increase PPAR-γ expression in vitro and in vivo (in rat models of type 2 diabetes), and thus to decrease hyperglycemia [5,6,8].…”