Synthesis and biological evaluation of substituted aurone derivatives as potential tyrosinase inhibitors: in vitro, kinetic, QSAR, docking and drug-likeness studies

Abstract

Tyrosinase enzyme plays an essential role in melanin biosynthesis and enzymatic browning of fruits and vegetables. To discover potent tyrosinase inhibitors, the present studies were undertaken. In this context, synthetic aurone derivatives 26–50 were designed, synthesized, and structurally elucidated by various spectroscopic techniques including IR, UV, ¹H- & ¹³C-NMR and mass spectrometry. The target compounds 26–50 were screened for their anti-tyrosinase inhibitory potential, and thus kinetic mechanism was analyzed by Lineweaver-Burk plots. All target compounds exhibited good to excellent IC₅₀ values in the range of 7.12 ± 0.32 μM to 66.82 ± 2.44 μM. These synthesized aurone derivatives were found as potent tyrosinase inhibitors relative to the standard kojic acid (IC₅₀ = 16.69 ± 2.81 μM) and the compound 39 inhibited tyrosinase non-competitively (K_i = 11.8 μM) by forming an enzyme-inhibitor complex. The binding modes of these molecules were ascribed through molecular docking studies against tyrosinase protein (PDB ID: 2Y9X). The quantitative structure-activity relationship studies displayed a good correlation between 26–50 structures and their anti-tyrosinase activity (IC₅₀) with a correlation coefficient (R²) of 0.9926. The computational studies were coherent with experimental results and these ligands exhibited good binding values against tyrosinase and interacted with core residues of target protein. Moreover, the drug-likeness analysis also showed that some compounds have a linear correlation with Lipinski’s rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets.

Communicated by Ramaswamy H. Sarma

Keywords:

• Aurones
• tyrosinase
• kinetic study
• QSAR
• docking study
• drug-likeness study

Acknowledgments

The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University, for supporting this work by Grant Code: 22UQU4340549DSR04. The authors are also highly grateful to the Higher Education Commission of Pakistan (HEC) for providing financial assistance under Project No. NRPU-15800.

Disclosure statement

Authors declare that they have no conflict of interest.

Authors’ contributions

Najla A. Alshaye: Formal analysis, reviewing and editing; Ehsan Ullah Mughal: Conceptualization, Supervision, Funding acquisition, Investigation, Writing—review & editing; Eslam B. Elkaeed: Formal analysis, reviewing and editing; Zaman Ashraf: Performed enzyme inhibition and kinetic studies; Sana Kehili: Formal analysis, reviewing and editing; Yasir Nazir: Performed molecular docking and QSAR studies; Nafeesa Naeem: Data analysis and collection, first-draft preparation, formal analysis; Nida Abdul Majeed: Experimental work performance; Amina Sadiq: Co-supervision, manuscriptwriting

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.