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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.
Highlights
Sulfonamides are derivatives of sulfonic acids and are the basis of several groups of drugs
We have reported some sulfonamides as acetylcholinesterase inhibitors and these molecules were having either no substituent or an ethoxy along with halogen substituents in the starting amine (Abbasi et al, 2014a; Abbasi et al, 2014b)
The first step involved the reaction of 4-methoxyphenethylamine (1) and 4-methylbenzenesulfonyl chloride (2) in aqueous alkaline medium with 4–5 h stirring at room temperature to afford parent molecule; N -(4-methoxyphenethyl)-4-methylbenzensulfonamide (3), which was isolated by acidification of the reaction mixture to pH 2–3 with concentrated HCl in good yield as off-white powder
Summary
Sulfonamides are derivatives of sulfonic acids and are the basis of several groups of drugs. The original antibacterial sulfonamides (sulfa drugs) are synthetic. A general method for the synthesis of sulfonamides involves the coupling of sulfonyl chloride with primary or secondary amine or a substituted amine. A sulfonyl group plays a very important role as a key constituent of number of biologically active molecules (Kataoka et al, 1998). Sulfonamides occupy a unique position in the drug industry and exhibit a wide spectrum of biological activities (Shaabani, Soleimani & Rezayan, 2007; Hanson et al, 1990). It has been reported that the antibacterial activity of Prontosil drug was an attribute of the presence of sulfanilamide component (Fouts, Kamm & Brodie, 1957; Neu & Gootz, 1996; Van Meter & Hubert, 2016).
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