Design and synthesis of 4-amino-2',4'-dihydroxyindanone derivatives as potent inhibitors of tyrosinase and melanin biosynthesis in human melanoma cells.
Eur J Med Chem
; 266: 116165, 2024 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-38262119
ABSTRACT
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Monofenol Mono-Oxigenase
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Melanoma
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
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Eur. j. med. chem
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European journal of medicinal chemistry
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
França