Design, synthesis, and biological evaluation of symmetrical azine derivatives as novel tyrosinase inhibitors

Somaye Karimian,Maryam Kabiri,Yasaman Behzadipour,Fatemeh Kazemi,Mahshid Attarroshan,Amirhossein Sakhteman,Mehdi Khoshneviszadeh,Shiva Hemmati,Maryam Gholampour,Aida Iraji

doi:10.1186/s13065-021-00780-z

Somaye Karimian, Maryam Kabiri + Show 8 more

Open Access

https://doi.org/10.1186/s13065-021-00780-z

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Abstract

A series of symmetrical azine derivatives containing different substituted benzyl moieties were designed, synthesized, and evaluated for their inhibitory activity against tyrosinase. The results showed that compounds 3e, 3f, 3h, 3i, 3j, and 3k possess effective tyrosinase inhibition with IC50 values ranging from 7.30 μM to 62.60 μM. Particularly, compounds 3f displayed around three-fold improvement in the potency (IC50 = 7.30 ± 1.15 μM) compared to that of kojic acid (IC50 = 20.24 ± 2.28 μM) as the positive control. Kinetic study of compound 3f confirmed uncompetitive inhibitory activity towards tyrosinase indicating that it can bind to enzyme–substrate complex. Next, molecular docking analysis was performed to study the interactions and binding mode of the most potent compound 3f in the tyrosinase active site. Besides, the cytotoxicity of 3f, as well as its potency to reduce the melanin content were also measured on invasive melanoma B16F10 cell line. Also, 3f exhibited above 82% cell viability in the A375 cell line at 10 µM. Consequently, compounds 3f could be introduced as a potent tyrosinase inhibitor that might be a promising candidate in the cosmetics, medicine, and food industry.

Highlights

Melanin is known as a major pigment found in the eyes, hair, and skin of animals and humans which has protective roles against the harmful effects of ultraviolet (UV) irradiation, oxidative stress, DNA damage, and malignant transformation [1, 2]
A large number of tyrosinase inhibitors have been discovered [8] such as chalcones [9], stilbenes [10,11,12,13], flavonol [14], flavone [15, 16], flavanone [17], flavanol [18], kojic acid [19,20,21,22,23], tropolone [8, 24,25,26,27], phthalimide [28], triazole [29] thiosemicarbazide [30] and quinazoline [31] derivatives (Fig. 1), only a few of them have been applied to the market due to their harmful and undesirable side effects, such as lack of safety, low efficacy and allergenic reactions [32, 33]
The most active compound 3f bearing 2,4-dihydroxy on the benzyl ring (IC50 = 7.30 ± 1.15 μM) showed 3 times better potency compared to that of kojic acid as the positive control

Summary

Introduction

Melanin is known as a major pigment found in the eyes, hair, and skin of animals and humans which has protective roles against the harmful effects of ultraviolet (UV) irradiation, oxidative stress, DNA damage, and malignant transformation [1, 2]. Tyrosinase plays a central role in the biosynthesis pathway of melanin pigment by catalyzing the hydroxylation and oxidation of monophenols to o-diphenols (monophenolase activity) and the oxidation of o-diphenols to o-quinones (diphenolase activity) [7]. A large number of tyrosinase inhibitors have been discovered [8] such as chalcones [9], stilbenes [10,11,12,13], flavonol [14], flavone [15, 16], flavanone [17], flavanol [18], kojic acid [19,20,21,22,23], tropolone [8, 24,25,26,27], phthalimide [28], triazole [29] thiosemicarbazide [30] and quinazoline [31] derivatives (Fig. 1), only a few of them have been applied to the market due to their harmful and undesirable side effects, such as lack of safety, low efficacy and allergenic reactions [32, 33]. It is necessary to search for new and potent tyrosinase inhibitors with fewer adverse effects

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Conclusion