Novel morpholine containing cinnamoyl amides as potent tyrosinase inhibitors

• Published in: International journal of biological macromolecules 2019-08, Vol.135, p.978-985
• Main Authors: Ghafary, Shahrzad, Ranjbar, Sara, Larijani, Bagher, Amini, Mohsen, Biglar, Mahmood, Mahdavi, Mohammad, Bakhshaei, Maryam, Khoshneviszadeh, Mahsima, Sakhteman, Amirhossein, Khoshneviszadeh, Mehdi
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Chemical Phenomena; Cinnamamide; Cinnamic acid; Docking; Drug Design; Enzyme Activation; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Kinetics; Kojic acid; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Monophenol Monooxygenase - antagonists & inhibitors; Morpholines - chemistry; Morpholines - pharmacology; Phenyl-N-(2-morpholinoethyl)acrylamide; Structure-Activity Relationship; Tyrosinase
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2019.05.201

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. Hence, tyrosinase inhibitors are important in the fields of medicine, cosmetics and agriculture. In this study, novel N-(2-morpholinoethyl)cinnamamide derivatives bearing different substituents on phenyl ring were designed, synthesized and evaluated for their tyrosinase diphenolase inhibitory activity. The compounds were found to be better tyrosinase inhibitors (IC50s were in micro molar range) than cinnamic acid. (E)-3-(3-chlorophenyl)-N-(2-morpholinoethyl)acrylamide (B6) exhibited the highest inhibition with IC50 value of 15.2 ± 0.6 μM which was comparable to that of kojic acid. The inhibition kinetic analysis of B6 indicated that the compound was a mixed-type tyrosinase inhibitor. In silico ADME prediction indicated that B6 might show more skin penetration than kojic acid. Molecular docking analysis confirmed that the active inhibitors well accommodated in the mushroom tyrosinase active site and it was also revealed that B6 formed the most stable drug-receptor complex with the target protein. Therefore, cinnamamide B6 could be introduced as a potent tyrosinase inhibitor that might be a promising lead in cosmetics, medicine and food industry. [Display omitted] •Novel morpholine containing cinnamoyl amides were designed and synthesized.•B6 exhibited the highest tyrosinase inhibition comparable to kojic acid.•Kinetic analysis indicated that B6 is a mixed-type tyrosinase inhibitor.•Docking analysis confirmed that B6 well accumulated in the tyrosinase active site.•B6 could be a promising lead in cosmetics, medicine and food industry.