Synthesis, characterization and biological screening of some 4-O-substituted derivatives of N-(4-hydroxyphenyl)-N-methyl-4-methylbenzenesulfonamide

Objective: The sole purpose of this study was to synthesize different 4-O-substituted derivatives of N-(4-hydroxyphenyl)-N-methyl-4 methylbenzenesulfonamide and to evaluate their enzyme inhibition activities. Methods: In the present research, a series of O-substituted derivatives of N-(4-hydroxyphenyl)-N-methyl-4-methylbenzenesulfonamide has been synthesized. The parent compound N-(4-hydroxyphenyl)-N-methyl-4-methylbenzenesulfonamide (3) was synthesized by the reaction of metol (planetol or p–methylaminophenol; 1) with tosyl chloride (toluene-4-sulfonyl chloride; 2), which further on treatment with different electrophiles (4, 1 5a-d) in the presence of sodium hydride furnished into 4-O-substituted sulfonamides (6,7a-d). These derivatives were characterized by H-NMR, IR & EI-MS and then screened against 1,1-diphenyl-2-picrylhydrazyl radical (DPPH), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX) enzymes. Results: The screening of the synthesized derivatives showed that these were active against lipoxygenase enzyme and some were remained active against acetylcholinesterase butylcholinesterase enzymes but all were stayed inactive against 1,1-Diphenyl-2-picrylhydrazyl radical. Among these compounds, N-(4-benzoyloxyphenyl)-N-methyl-4-methylbenzene sulfonamide (6) was found to be the most potent inhibitor for lipoxygenase and butylcholinesterase having IC value of 57 ± 0.97 and 89 ± 0.79 µmoles relative to quercetin and eserine a reference standards with IC value of 37.12 ± 50 50 0.07 and 0.85 ± 0.001 µmoles respectively, probably due to benzoyl group attached to 4-O position of parent molecule 3. Against AChE, N-(4hydroxyphenyl)-N-methyl-4-methylbenzenesulfonamide (3) itself was found to be the most suitable inhibitor, having IC value of 75 ± 0.83 µmoles 50 relative to eserine standard. Conclusion: In all the synthesized compounds, N-(4-benzoyloxyphenyl)-N-methyl-4-methylbenzenesulfonamide (6) was found to be the most potent inhibitor for lipoxygenase and butylcholinesterase enzymes.