Strebluses A and B as tyrosinase inhibitors from the stems of Streblus ilicifolius (S. Vidal) Corn.

Tyrosinase inhibitors from natural sources are promising skin-whitening agents for treating pigment disorders. The phytochemical analysis of Streblus ilicifolius stems identified two new compounds, strebluses A (cp1) and B (cp2), with strong tyrosinase inhibitory activity. Their structures were determined using NMR, mass spectrometry, and absolute configurations by circular dichroism (CD) combined with ab initio calculations. In the tyrosinase inhibitory activity test, both compounds display more potent inhibitory activity (i.e., IC50 = 6.8 and 22.9 µM, respectively) than the positive control kojic acid (44.6 µM). Moreover, the results from combined different molecular modeling and simulation are consistent with the in vitro test and thus suggest mechanistic insights into tyrosinase inhibition. Specifically, molecular docking indicates stronger binding affinities for cp1 and cp2 (-9.97 and -9.83 kcal mol-1) than kojic acid (-5.69 kcal mol-1). The pharmacophore analysis also suggests that these two compounds have a similar inhibition mechanism as kojic acid, forming interactions with essential residues at the active site of tyrosinase, such as His259, Asn260, His263, Met280, and Ser282. Finally, the molecular dynamics (MD) simulation results consistently confirm the stability, which is due to the hydrogen bonding, of the binding complex of cp1 and cp2 with tyrosinase. Despite being isolated in bench-scale quantities (4.7 mg and 6.9 mg, respectively), the remarkable potency of these compounds provides an excellent structural foundation, serving as a valuable blueprint for future synthetic or biotechnological optimization to meet industrial cosmetic and pharmaceutical demands.