Synthesis, In‐Vitro Evaluation and Molecular Docking Study of N‐Substituted Thiazolidinediones as α‐Glucosidase Inhibitors

Abstract

Thiazolidinedione (TZD) drugs have been shown to improve insulin sensitivity, hyperglycemia, and lipid metabolism in people with type 2 diabetes mellitus. In this study, we have explored the alpha‐glucosidase inhibitor action of new N‐substituted 5‐benzylidene‐2,4‐thiazolidinedione derivatives. Various substituted benzothiazoles linked to the 5‐benzylidene‐2,4‐TZD with acetamide linker were synthesized and characterized by FTIR, 1H‐NMR, 13C‐NMR, and mass spectrometry. After the in‐silico screening of all the compounds, the IC50 values of 32 compounds were determined using an in vitro α‐glucosidase assay (maltase yeast extract) with acarbose as a standard drug. All compounds showed varying degrees of α‐glucosidase inhibitory action as compared to acarbose. When compared to acarbose (IC50=67.06±1.24 μM), molecules GB24, GB21, GB16, GB17 and GB25 exhibited very significant inhibitory activity, with IC50 values of 29.91±0.82, 36.52±0.49, 39.19±1.09, 41.35±1.37 μM and 60.47±1.49 respectively. Moreover, a molecular docking study of active compounds was performed to rationalize the in‐vitro results and to understand the binding interactions with the target enzyme. Based on the findings, we can predict that these compounds could be taken further for the development of new antidiabetic agents.

Dual active pyrimidine-based carbocyclic nucleoside derivatives: synthesis, and in silico and in vitro anti-diabetic and anti-microbial studies

“…When compared to acarbose (IC 50 = 67.06 ± 1.24 μM), most compounds displayed extremely considerable inhibitory activity towards α-glucosidase. 46 Flavonoids are known to play a function in hypoglycemia via blocking α-glucosidase. A study indicated that the diverse flavonoid compounds exhibited inhibitory activity and good docking score and the presence of Asp 215 was implicated in the hydrogen-bonding interaction between each flavonoid with the enzyme.…”

Recent Studies of Nitrogen and Sulfur Containing Heterocyclic Analogues as Novel Antidiabetic Agents: A Review

“…Synthesized N‐Substituted Thiazolidinediones, In‐Vitro study and Molecular Docking Study, and α‐Glucosidase Inhibitory activity of N‐Substituted Thiazolidinediones. Compound 46 has showed promising inhibitory α‐glucosidase activity with IC 50 : 29.91±0.82 μM and molecular docking study suggests the formation of three hydrogen bonds with Asp232, Ser497, and Ser505 [54] . RB C et al.…”

“…[53] Patil Ser497, and Ser505. [54] RB C et al identified rhodanine benzothiazole compounds as α-amylase and α-glucosidase inhibitors. Compound 47 showed good activity with IC 50 : 24.22 � 1.65 μM and IC 50 : 28.4 � 0.57 μM as compared to standard acarbose and We found Asp1279 and Hie1584, respectively, in hydrogen bonding interactions including hydroxyl and methoxy group substitution on the phenyl ring.…”

Innovation of 6-sulfonamide-2H-chromene derivatives as antidiabetic agents targeting α-amylase, α-glycosidase, and PPAR-γ inhibitors with in silico molecular docking simulation

“…The docking simulation was performed using Molecular Operating Environmental (MOE) 10.2009 soware 53,54 inside the active site of a-amylase (PDB: 2QV4), a-glucosidase (PDB: 3w37), and PPAR-g (PDB: 3SZ1). [55][56][57] 2.4.1. Ligand-protein complex interaction inside aamylase (PDB: 2QV4).…”

“…To determine the binding mode pattern for the most active chromene derivatives 2 and 9, the docking simulation conducted inside the active site of a-amylase (PDB: 2QV4, chain A), a-glucosidase (PDB: 3w37, chain A), and PPAR-g (PDB: 3SZ1, chain B) as described previously. [55][56][57] The 3D structure of proteins was obtained from the protein data bank (https:// www.rcsb.org/), and each protein was prepared by default protocol where the water molecules were removed, and only one chain was selected for docking purposes. The active site was protonated, then the energy was minimized using MMFF94X with a gradient of 0.05 kcal mol −1 and saved as an mdb le.…”