Synthesis, enzyme inhibitory kinetics mechanism and computational study ofN-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides as novel therapeutic agents for Alzheimer’s disease

Abstract

The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (1). The synthesis was initiated by the reaction of 1 with 4-methylbenzenesulfonyl chloride (2) in aqueous sodium carbonate solution at pH 9 to yield N-(4-methoxyphenethyl)-4-methylbenzensulfonamide (3).This parent molecule 3 was subsequently treated with various alkyl/aralkyl halides, (4a–j), using N,N-dimethylformamide (DMF) as solvent and LiH as activator to produce a series of new N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides (5a–j). The structural characterization of these derivatives was carried out by spectroscopic techniques like IR, 1H-NMR, and 13C-NMR. The elemental analysis data was also coherent with spectral data of these molecules. The inhibitory effects on acetylcholinesterase and DPPH were evaluated and it was observed that N-(4-Methoxyphenethyl)-4-methyl-N-(2-propyl)benzensulfonamide (5c) showed acetylcholinesterase inhibitory activity 0.075 ± 0.001 (IC50 0.075 ± 0.001 µM) comparable to Neostigmine methylsulfate (IC50 2.038 ± 0.039 µM).The docking studies of synthesized ligands 5a–j were also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC50 values. The kinetic mechanism analyzed by Lineweaver-Burk plots demonstrated that compound (5c) inhibits the acetylcholinesterase competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (5c) is 2.5 µM. It was also found from kinetic analysis that derivative 5c irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound 5c may serve as lead structure for the design of more potent acetylcholinesterase inhibitors.

In silicoapproach on drug repurposing - Antimalarial drugs against HIV-1 protease

“…In this experiment, the grid box dimension values were attuned up to Grid center X-dimension: 100, Y-dimension: 126, Z-dimension: 126; Grid box spacing (in Ångström) X-center: 15.381, Y-center: 17.175, Z-center: 65.532 with an exhaustiveness value=8 (Abbasi et al ., 2018). All the test compounds were docked distinctly with HIV-1 protease structure (PDB ID: 6DJ1).…”

The THERAPEUTIC EFFECT OF HUANGLIAN JIEDU DECOCTION ON ALZHEIMER’S DISEASE BY REGULATING PHAGOCYTOSIS INDUCED BY Aβ IN BV-2 MICROGLIAL CELLS

“…BV-2 cell is an immortalized mouse microglia, which is widely used in the inflammatory reaction in the brain. This cell line is the most commonly used model cell for the release and swallowing of inflammatory factors [15]. Therefore, we used BV-2 cells to detect the effect of Huanglian Jiedu Decoction on its phagocytic function.…”

Structure-activity relationship and in silico study of unique bi-heterocycles: 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole-2-thiol derivatives

“…The active site of the enzyme was defined from the co-crystallized ligands from Protein Data Bank and literature data. [25][26][27][28] Furthermore, docking experiment was performed against all synthesized ligands and target protein using the Glide docking protocol. 29 The predicted binding energies (docking scores) and conformational positions of ligands within active region of protein were also defined using Glide experiment.…”

“…The present docking results showed good correlation with already published data. 35 The synthesized derivatives were computationally docked against BChE to explore their binding modes. Among them, 5g made a couple of interactions with Asn57 and Trp56 (Figs.…”