title: Structure-based modification of 3-/4-aminoacetophenones giving a profound change of activity on tyrosinase: from potent activators to highly efficient inhibitors.
abstract: In this study, we developed 3-/4-aminoacetophenones and their structure-based 3-/4-aminophenylethylidenethiosemicarbazide derivatives, respectively, as novel tyrosinase activators and inhibitors. Notably, all the obtained thiosemicarbazones displayed more potent tyrosinase inhibitory activities than kojic acid. Especially, compound 7k was found to be the most active tyrosinase inhibitor with IC50 value of 0.291 μM. The structure-activity relationships (SARs) analysis showed that: (1) the amine group was absolutely necessarily for determining the tyrosinase activation activity; (2) the introduction of thiosemicarbazide group played a very vital role in transforming tyrosinase activators into tyrosinase inhibitors; (3) the phenylethylenethiosemicarbazide moiety was crucial for determining the tyrosinase inhibitory activity; (4) the type of acyl group had no obvious effect on the inhibitory activity; (5) the position of amide substituent on the phenyl ring influenced the tyrosinase inhibitory potency. Moreover, the inhibition mechanism and inhibition kinetics study revealed that compound 7k was reversible and non-competitive inhibitor, and compound 8h was reversible and competitive-uncompetitive mixed-II type inhibitor.
authors: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China.
authors: Ao
authors: A
authors: You
authors: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China; VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors: Jie
authors: J
authors: Zhou
authors: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China.
authors: Senchuan
authors: S
authors: Song
authors: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China.
authors: Guoxun
authors: G
authors: Zhu
authors: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China. Electronic address: yjhxhc@mail.sysu.edu.cn.
authors: Huacan
authors: H
authors: Song
authors: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China; VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: yiwei.simm@simm.ac.cn.
authors: Wei
authors: W
authors: Yi
mesh_terms: D000098:Acetophenones / Q000737:chemistry* / Q000494:pharmacology*; D000363:Agaricales / Q000201:enzymology; D015195:Drug Design; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012663:Semicarbazides / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000098:Acetophenones; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D012663:Semicarbazides; C032065:4-aminoacetophenone; C005151:thiosemicarbazide; C004475:3-aminoacetophenone; D014442:Monophenol Monooxygenase
keywords: Aminophenylethylidenethiosemicarbazide compounds; Inhibition mechanism; Inhibitory kinetics; SARs; Tyrosinase activator; Tyrosinase inhibitor