Synthesis of Pyrazoline‐Embedded 1,2,3‐Triazole Derivatives via 1,3‐Dipolar Cycloaddition Reactions with in vitro and in silico Studies

Abstract

A series of hybrid molecules containing pyrazolines and 1,2,3‐triazoles have been synthesized via Cu(I) mediated 1,3‐dipolar cycloaddition reactions bearing para substituted azides and dipolarophile (acetylenes) as a reactive precursors. Structure of all the synthesized derivatives were confirmed by 1HNMR, 13C NMR, LC–MS and IR spectral analysis and they are screened for α‐glucosidase and α‐amylase inhibitory and antioxidant activities by DPPH (2,2‐diphenyl‐1‐picrylhydrazyl) and ABTS (2,2‐azinobis (3‐ethylbenzothiazoline‐6‐sulfonic acid)) methods. Among the synthesized compounds, 3‐(4‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐5‐(4‐fluorophenyl)‐4,5‐dihydropyrazole‐1‐carbaldehyde (5 k) showed promising inhibition of the antidiabetic enzymes with IC50=0.81±0.20 μM for α‐glucosidase and IC50=1.00±0.05 μM for α‐amylase compared with the standard therapeutic drug acarbose which shows IC50=1.30±0.06 μM and IC50=0.75±0.08 μM for α‐glucosidase and α‐amylase. Compared to all the synthesized compounds, the bleeching ability of 3‐(4‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐5‐(4‐fluorophenyl)‐4,5‐dihydropyrazole‐1‐carbaldehyde (5 k) showed promising antioxidant activity in comparison with standard Butylated hydroxyl anisole. The molecular docking studies revealed the compound 3‐(4‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐5‐(4‐fluorophenyl)‐4,5‐dihydropyrazole‐1‐carbaldehyde having lower binding energy with the maximum efficacy.

Quinoline- and Isoindoline-Integrated Polycyclic Compounds as Antioxidant, and Antidiabetic Agents Targeting the Dual Inhibition of α-Glycosidase and α-Amylase Enzymes

“…Thus, based on the evaluation, the 7d complex showed better stability than the control complex. The study result had a similar pattern to previous studies that have performed binding free energy calculations for α-glycosidase [ 43 , 44 , 45 , 46 , 47 , 48 ] and α-amylase [ 43 , 49 ].…”

“…The results were also in accordance with a study where the phytocompounds caffeic acid, syringic acid [ 43 ], and rutin [ 46 ] from jackfruit flour were evaluated for their α-glycosidase-inhibitory activity using the same homology-built model for in silico studies, and yeast α-glycosidase for in vitro studies. For synthesized chemical compounds, a similar pattern of results was obtained in a study where pyrazoline-embedded 1,2,3-triazole derivatives were evaluated for their α-glycosidase-inhibitory activity using the same model in vitro and in silico [ 47 ]. Furthermore, another study also depicted the 1-(4-(Methoxy(phenyl)methyl)-2-methylphenoxy)butan-2-one derivative as a single crystal α-glycosidase inhibitor molecule [ 48 ].…”

“…It is another use of molecular dynamics simulations and thermodynamics to determine the amount of ligand binding to the protein. The binding free energy for each ligand–protein combination was calculated using the g_mmpbsa v1.2 software with the MmPbSaStat.py script and the GROMACS 2018.1 trajectories as the input [ 47 , 48 , 49 , 50 ]. The binding free energy is calculated using three components in the g_mmpbsa program: molecular mechanical energy, polar and apolar solvation energies, and molecular mechanical energy.…”

Inhibition of carbohydrate hydrolyzing enzymes by a potential probiotic Levilactobacillus brevis RAMULAB49 isolated from fermented Ananas comosus

“…Hydroxycitric acid was observed to remain inside the inhibitor binding site throughout the simulation period. Compared with the interaction with the acarbose complex, the hydroxycitric acid complex reached equilibrium more rapidly, thus showing higher stability (Kumar et al, 2021 ; Banu et al, 2023 ). The RMSF analysis of α-amylase depicts that the hydroxycitric acid complex and apoprotein were found to be within the range of 0.20–0.30 nm, whereas the acarbose complex ranged between 0.25 and 0.35 nm.…”

“…The ability of the isolate to inhibit α-glucosidase and α-amylase was determined as per the protocol described by Maradesha et al ( 2022a ) and Banu et al ( 2023 ) with slight modifications. In this assay, the inhibitory activity of intact cells (I), cell-free extract (E), and cell-free supernatant (S) was prepared as per the description by Kumari et al ( 2022a , b ).…”