Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights
Many compounds containing the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, including cinnamamide derivatives, have been shown to inhibit tyrosinase potently in vitro and in vivo. Structural changes to cinnamamide derivatives were produced by adding a dithionate functional group to provide eigh...
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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/10/1918 |
| _version_ | 1797475769572655104 |
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| author | Jeongin Ko Jieun Lee Hee Jin Jung Sultan Ullah Yeongmu Jeong Sojeong Hong Min Kyung Kang Yu Jung Park YeJi Hwang Dongwan Kang Yujin Park Pusoon Chun Jin-Wook Yoo Hae Young Chung Hyung Ryong Moon |
| author_facet | Jeongin Ko Jieun Lee Hee Jin Jung Sultan Ullah Yeongmu Jeong Sojeong Hong Min Kyung Kang Yu Jung Park YeJi Hwang Dongwan Kang Yujin Park Pusoon Chun Jin-Wook Yoo Hae Young Chung Hyung Ryong Moon |
| author_sort | Jeongin Ko |
| collection | DOAJ |
| description | Many compounds containing the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, including cinnamamide derivatives, have been shown to inhibit tyrosinase potently in vitro and in vivo. Structural changes to cinnamamide derivatives were produced by adding a dithionate functional group to provide eight (<i>Z</i>)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs with high log <i>p</i> values for skin. These analogs were synthesized using a two-step reaction, and their stereochemistry was confirmed using the <sup>3</sup><i>J</i><sub>C4-Hβ</sub> values of C4 measured in proton-coupled <sup>13</sup>C mode. Analogs <b>2</b> (IC<sub>50</sub> = 5.21 ± 0.86 µM) and <b>3</b> (IC<sub>50</sub> = 1.03 ± 0.14 µM) more potently inhibited mushroom tyrosinase than kojic acid (IC<sub>50</sub> = 25.26 ± 1.10 µM). Docking results showed <b>2</b> binds strongly to the active site of tyrosinase, while <b>3</b> binds strongly to an allosteric site. Kinetic studies using <span style="font-variant: small-caps;">l</span>-tyrosine as substrate indicated <b>2</b> and <b>3</b> competitively and non-competitively inhibit tyrosinase, respectively, which was supported by our docking results. In B16F10 cells, <b>3</b> significantly and concentration-dependently reduced α–MSH plus IBMX induced increases in cellular tyrosinase activity and melanin production and the similarity between these inhibitory patterns implied that the anti-melanogenic effect of <b>3</b> might be due to its tyrosinase-inhibitory ability. In addition, <b>2</b> and <b>3</b> exhibited strong antioxidant effects; for example, they reduced ROS and ONOO<sup>–</sup> levels and exhibited radical scavenging activities, suggesting that these effects might underlie their anti-melanogenic effects. Furthermore, <b>3</b> suppressed the expressions of melanogenesis-associated proteins and genes in B16F10 cells. These results suggest (<i>Z</i>)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs offer a means of producing novel anti-melanogenesis agents. |
| first_indexed | 2024-03-09T20:49:29Z |
| format | Article |
| id | doaj.art-5137a8168c4242748a642c8b1280a248 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T20:49:29Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-5137a8168c4242748a642c8b1280a2482023-11-23T22:37:50ZengMDPI AGAntioxidants2076-39212022-09-011110191810.3390/antiox11101918Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico InsightsJeongin Ko0Jieun Lee1Hee Jin Jung2Sultan Ullah3Yeongmu Jeong4Sojeong Hong5Min Kyung Kang6Yu Jung Park7YeJi Hwang8Dongwan Kang9Yujin Park10Pusoon Chun11Jin-Wook Yoo12Hae Young Chung13Hyung Ryong Moon14Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaNew Drug Development Center, Department of Medicinal Chemistry, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, KoreaNew Drug Development Center, Department of Medicinal Chemistry, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, KoreaCollege of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae 50834, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaDepartment of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, KoreaMany compounds containing the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, including cinnamamide derivatives, have been shown to inhibit tyrosinase potently in vitro and in vivo. Structural changes to cinnamamide derivatives were produced by adding a dithionate functional group to provide eight (<i>Z</i>)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs with high log <i>p</i> values for skin. These analogs were synthesized using a two-step reaction, and their stereochemistry was confirmed using the <sup>3</sup><i>J</i><sub>C4-Hβ</sub> values of C4 measured in proton-coupled <sup>13</sup>C mode. Analogs <b>2</b> (IC<sub>50</sub> = 5.21 ± 0.86 µM) and <b>3</b> (IC<sub>50</sub> = 1.03 ± 0.14 µM) more potently inhibited mushroom tyrosinase than kojic acid (IC<sub>50</sub> = 25.26 ± 1.10 µM). Docking results showed <b>2</b> binds strongly to the active site of tyrosinase, while <b>3</b> binds strongly to an allosteric site. Kinetic studies using <span style="font-variant: small-caps;">l</span>-tyrosine as substrate indicated <b>2</b> and <b>3</b> competitively and non-competitively inhibit tyrosinase, respectively, which was supported by our docking results. In B16F10 cells, <b>3</b> significantly and concentration-dependently reduced α–MSH plus IBMX induced increases in cellular tyrosinase activity and melanin production and the similarity between these inhibitory patterns implied that the anti-melanogenic effect of <b>3</b> might be due to its tyrosinase-inhibitory ability. In addition, <b>2</b> and <b>3</b> exhibited strong antioxidant effects; for example, they reduced ROS and ONOO<sup>–</sup> levels and exhibited radical scavenging activities, suggesting that these effects might underlie their anti-melanogenic effects. Furthermore, <b>3</b> suppressed the expressions of melanogenesis-associated proteins and genes in B16F10 cells. These results suggest (<i>Z</i>)-5-(substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one analogs offer a means of producing novel anti-melanogenesis agents.https://www.mdpi.com/2076-3921/11/10/1918tyrosinasePUSC scaffoldantioxidantanti-melanogenesisdockingrhodanine |
| spellingShingle | Jeongin Ko Jieun Lee Hee Jin Jung Sultan Ullah Yeongmu Jeong Sojeong Hong Min Kyung Kang Yu Jung Park YeJi Hwang Dongwan Kang Yujin Park Pusoon Chun Jin-Wook Yoo Hae Young Chung Hyung Ryong Moon Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights Antioxidants tyrosinase PUSC scaffold antioxidant anti-melanogenesis docking rhodanine |
| title | Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights |
| title_full | Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights |
| title_fullStr | Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights |
| title_full_unstemmed | Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights |
| title_short | Design and Synthesis of (<i>Z</i>)-5-(Substituted benzylidene)-3-cyclohexyl-2-thioxothiazolidin-4-one Analogues as Anti-Tyrosinase and Antioxidant Compounds: In Vitro and In Silico Insights |
| title_sort | design and synthesis of i z i 5 substituted benzylidene 3 cyclohexyl 2 thioxothiazolidin 4 one analogues as anti tyrosinase and antioxidant compounds in vitro and in silico insights |
| topic | tyrosinase PUSC scaffold antioxidant anti-melanogenesis docking rhodanine |
| url | https://www.mdpi.com/2076-3921/11/10/1918 |
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