Bionic Synthesis of Novel Monoterpenoid Indole Alkaloid-like Analogs with Tyrosinase Inhibition Activity Based on Loganetin

A series of novel monoterpenoid indole alkaloid (MIA)-like analogs (1–24) were synthesized by using a biomimetic synthetic strategy and combinatorial chemistry. The tyrosinase inhibitory activities and antioxidant properties of these compounds were assessed through tyrosinase inhibition assay, DPPH and ABTS free radicals scavenging assays, respectively. The results showed that most synthesized compounds (2, 4–8, 10–12, 14–17, 19) exhibited significant inhibitory activities against both monophenolase and diphenolase. In particular, compound 14, with an IC50 value of 0.18 ± 0.02 mM, displayed approximately 72-fold stronger monophenolase inhibitory activity than that of loganetin with an IC50 value of 12.76 ± 1.00 mM. Similarly, compound 17 exhibited the best diphenolase inhibitory activity (IC50, 0.30 ± 0.09 mM), which was approximately 47 times higher than that of loganetin (IC50, 14.05 ± 0.47 mM). Additionally, six compounds (3, 13–17) showed significant in vitro antioxidant activities. Compound 17 exhibited the most promising ABTS radical scavenging activity with an IC50 value of 2.90 ± 0.07 μM, while compound 15 exhibited the highest DPPH free radical scavenging capacity with an IC50 value of 17.59 ± 0.21 μM. The structure-activity relationships analysis revealed that the substituents at C-5 and C-11 in the tryptamine moiety might significantly impact antioxidant activity. Furthermore, the detailed interactions and binding modes of the most potent derivative toward tyrosinase were elucidated by a molecular docking study, which indicated that 14 and 17 might exert their inhibitory effects by binding to key amino acid residues (His 85 and His 263) at the tyrosinase active site.