Identification of a Novel Class of Anti-Melanogenic Compounds, ( Z )-5-(Substituted benzylidene)-3-phenyl-2-thioxothiazolidin-4-one Derivatives, and Their Reactive Oxygen Species Scavenging Activities

• Published in: Antioxidants Vol. 11; no. 5; p. 948
• Main Authors: Jeong, Yeongmu, Hong, Sojeong, Jung, Hee Jin, Ullah, Sultan, Hwang, YeJi, Choi, Heejeong, Ko, Jeongin, Lee, Jieun, Chun, Pusoon, Chung, Hae Young, Moon, Hyung Ryong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11-05-2022; MDPI
• Subjects: anti-melanogenesis; Biosynthesis; Catechol; Chromatography; Cytotoxicity; docking simulation; dual mechanism; Free radicals; Kojic acid; Melanin; Melanoma; NMR; Nuclear magnetic resonance; Proteins; radical scavenging; Reactive oxygen species; ROS; Spectrum analysis; tyrosinase; United States > US; radical scavenging; kojic acid; anti-melanogenesis; dual mechanism; ROS; tyrosinase; docking simulation
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox11050948

The rate-determining role of tyrosinase makes it a critical component in the mechanism that is responsible for melanogenesis. Thirteen (
)-5-(substituted benzylidene)-3-phenyl-2-thioxothiazolidin-4-one ((
)-BPTT) analogs were designed based on the structural features of two potent tyrosinase inhibitors, viz. (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT) and (
)-2-(2,4-dihydroxybenzylidene)benzo[4,5]imidazo[2,1-
]thiazol-3(2
)-one (compound I). The trisubstituted double bond geometry of the (
)-BPTT analogs that were generated by Knoevenagel condensation was determined using vicinal
H and
C coupling constants in
C NMR spectra. Four analogs, numbers
-
and
inhibited mushroom tyrosinase 9 to 29 times more potently than kojic acid did. Kinetic study results indicated that these four analogs inhibited mushroom tyrosinase competitively and this was supported by docking simulation. Also, docking results using human tyrosinase suggested that analogs
and
might be potent human tyrosinase inhibitors. In vitro studies using B16F10 cells (a melanoma cell line) showed that analogs
,
,
, and
inhibited cellular tyrosinase and melanin production more than kojic acid did, without perceptible cytotoxicity. In particular, analog
, which possesses a catechol group, exerted an extremely potent anti-melanogenic effect. In addition, analog
showed strong scavenging activity against DPPH and ABTS radicals. Furthermore, analog
not only reduced ROS levels, which induce melanogenesis, but it also suppressed tyrosinase and MITF (microphthalamia-associated transcription factor) protein levels and the expressions of melanogenesis-related genes. These results suggest that analog
is an efficient tyrosinase inhibitor that alleviates melanogenesis by dual mechanisms of (i) the inhibition of melanogenesis-related proteins and genes and (ii) the direct inhibition of tyrosinase activity.