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

PeerJ

article

Muhammad Athar Abbasi¹  Mubashir Hassan¹  Aziz-ur-Rehman²  Sabahat Zahra Siddiqui²  Syed Adnan Ali Shah³  Hussain Raza¹  Sung Yum Seo¹ 

[1] College of Natural Science, Department of Biological Sciences, Kongju National University;Department of Chemistry, Government College University;Faculty of Pharmacy, Universiti Teknologi MARA;Atta-ur-Rahman Institute for Natural Products Discovery ,(AuRIns), Universiti Teknologi MARA

关键词: Sulfonamides;    Molecular docking;    Acetylcholinesterase;    Alkyl/aralkyl halides;    Spectral analysis;   

DOI  :  10.7717/peerj.4962

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

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.

【 授权许可】

CC BY