Elucidating bis-pyrimidines as new and efficient mushroom tyrosinase inhibitors: synthesis, SAR, kinetics and computational studies

Abstract

In this study, a series of novel bis-pyrimidine derivatives (1P–8P) were designed, synthesized, characterized, and investigated for their in vitro inhibitory activity against mushroom tyrosinase, an enzyme critical in melanin biosynthesis and implicated in various hyperpigmentation disorders. To the best of our knowledge, the bispyrimidine scaffold has been evaluated for the first time for its tyrosinase inhibitory activity. Their inhibitory activities were assessed, revealing inhibition with IC₅₀ values in the micromolar range. Additionally, this series of compounds were found to inhibit tyrosinase activity in a mixed-type manner, with IC₅₀ values ranging from 12.36 ± 1.24 to 86.67 ± 3.08 μM. To further elucidate the binding interactions, molecular docking simulations were performed, identifying key residues in the active site responsible for binding affinity. Furthermore, molecular dynamics (MD) simulations were conducted to assess the dynamic behavior, stability, and binding affinity of the most potent inhibitor, compound 6P. Quantitative Structure–Activity Relationship (QSAR) models were developed to correlate the structural features of the bis-pyrimidines with their inhibitory activity, providing insights into the structure–activity relationships (SAR) that govern their potency. The experimental and theoretical findings demonstrated excellent agreement. These findings pave the way for the development of novel bis-pyrimidine-based therapeutic agents for treating hyperpigmentation and related conditions.