Synthesis, characterization, and enzyme inhibition activities of 4-(methylthio)-N-propylaniline-phenylpiperazine and sulfonamide derivatives

Abstract

We have combined piperazine, thioether, and sulfonamide structural motifs in a mainframe for biological evaluation. The synthesis involved the alkylation of 4-aminothioanisole with chloroalkyl piperazine followed by treatment of resulting amino piperazine 3 with various aryl sulfonyl chlorides. All target compounds (3–7) were characterized by 1H, 13C, HRMS, and IR. In addition, all obtained piperazine derivatives were evaluated for their tyrosinase and pancreatic lipase enzyme inhibitory activities. The enzyme analyses showed that some of the piperazine derivatives possess effective tyrosinase inhibitions with IC50 values of 18.7 ± 1.8 for compound 6 and 24.7 ± 3.4 for compound 4, which is close to the IC50 value of kojic acid (19.2 ± 1.2 µM). On the other hand, the synthesized compounds showed low IC50 values in the range from 46.2 ± 4.9 to 86.6 ± 8.4 µM against pancreatic lipase enzyme. Compound 3 was found to be the most effective pancreatic lipase inhibitor among the synthesized compounds. The IC50 value of compound 3 (46.2 ± 4.9 µM) was determined slightly lower than the IC50 value of orlistat (49.5 ± 3.2 µM), pointing to more effective inhibition. Finally, in silico molecular docking interactions of piperazine derivatives were evaluated for their tyrosinase and pancreatic lipase enzyme inhibitory activities using Chimera molecular visualization and AutoDock Vina software.