Design and synthesis of 4-amino-2’,4’-dihydroxyindanone derivatives as potent inhibitors of tyrosinase and melanin biosynthesis in human melanoma cells

08 November 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Melanogenesis inhibition constitutes a privileged therapeutic solution to treat skin hyperpigmentation, a major dermatological concern associated with the overproduction of melanin by human tyrosinase (hsTYR). Despite the existence of many well-known TYR (tyrosinase) inhibitors commercialized in skin formulations, their hsTYR-inhibition efficacy remains poor since most of them were investigated over mushroom tyrosinase (abTYR), a model with low homology relative to hsTYR. Considering the need for new potent hsTYR inhibitors, we designed and synthesized a series of indanones starting from 4-hydroxy compound 1a, one of the two most active derivatives reported to date against the human enzyme, together with marketed thiamidol. We observed that analogues featuring 4-amino and 4-amido-2’,4’-dihydroxyindanone motifs showed two- to ten-fold increase in activity over human melanoma MNT-1 cell lysates, and a ten-fold improvement in a 4-days whole-cell experiment, compared to parent analogue 1a. Molecular docking investigation was performed for the most promising 4-amido derivatives and suggested a plausible interaction pattern with the second coordination sphere of hsTYR, notably through hydrogen bonding with Glu203, confirming their impact in the binding mode with hsTYR active site.



Supplementary materials

Chemical and biological characterization
1H and 13C NMR spectra of new evaluated compounds. Inhibition curves for all the reported assays: screening against mushroom tyrosinase and human tyrosinase in MNT-1 lysates; MNT-1 melanoma whole-cells assays at 4 and 14 days. Cytotoxicity curves for cell-based assays: MNT-1 melanoma whole-cells assays at 4 and 14 days.


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