Discovery, total synthesis, and biological evaluation of tyrcinnamins as antibacterial agents and tyrosinase activators.

Microorganisms serve as critical resources for the discovery of new antibacterial drug leads. Herein, we report the screening, isolation, and identification of tyrcinnamin (1) from the endophytic Streptomyces sp. JS-B1. The total synthesis, biological evaluation, and structural-activity relationship study of tyrcinnamin and its synthetic derivatives led to the discovery of 7a, a promising lead compound with significant antibacterial activity, notable tyrosinase activation activity, and an excellent safety profile. The analysis of molecular docking of 7a with mushroom tyrosinase reveals that 7a may competitively occupy the binding site of l-DOPA on the surface of tyrosinase without interfering with the substrate binding at the active center, thereby reducing the ineffective occupancy of l-DOPA on the tyrosinase surface and improving the binding efficiency of l-DOPA at the active center. The structure of 7a represents a new chemical scaffold for the development of new antibiotics and tyrosinase activators, making valuable contributions to both drug discovery and cosmetics development.