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Discovery of Indole–Thiourea Derivatives as Tyrosinase Inhibitors: Synthesis, Biological Evaluation, Kinetic Studies, and In Silico Analysis
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Discovery of Indole–Thiourea Derivatives as Tyrosinase Inhibitors: Synthesis, Biological Evaluation, Kinetic Studies, and In Silico Analysis
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Journal Article
Discovery of Indole–Thiourea Derivatives as Tyrosinase Inhibitors: Synthesis, Biological Evaluation, Kinetic Studies, and In Silico Analysis
2024
Overview
Tyrosinase, a key enzyme in melanin synthesis, represents a crucial therapeutic target for hyperpigmentation disorders due to excessive melanin production. This study aimed to design and evaluate a series of indole–thiourea derivatives by conjugating thiosemicarbazones with strong tyrosinase inhibitory activity to indole. Among these derivatives, compound 4b demonstrated tyrosinase inhibitory activity with an IC50 of 5.9 ± 2.47 μM, outperforming kojic acid (IC50 = 16.4 ± 3.53 μM). Kinetic studies using Lineweaver–Burk plots confirmed competitive inhibition by compound 4b. Its favorable ADMET and drug-likeness properties make compound 4b a promising therapeutic candidate with a reduced risk of toxicity. Molecular docking revealed that the compounds bind strongly to mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (TYRP1), with compound 4b showing superior binding energies of −7.0 kcal/mol (mTYR) and −6.5 kcal/mol (TYRP1), surpassing both kojic acid and tropolone. Molecular dynamics simulations demonstrated the stability of the mTYR−4b complex with low RMSD and RMSF and consistent Rg and SASA values. Persistent strong hydrogen bonds with mTYR, along with favorable Gibbs free energy and MM/PBSA calculations (−19.37 kcal/mol), further support stable protein–ligand interactions. Overall, compound 4b demonstrated strong tyrosinase inhibition and favorable pharmacokinetics, highlighting its potential for treating pigmentary disorders.
Publisher
MDPI AG
Subject
/ Carbon
/ Enzyme Inhibitors - chemical synthesis
/ Enzyme Inhibitors - chemistry
/ Enzyme Inhibitors - pharmacology
/ Enzymes
/ Humans
/ Indoles - chemical synthesis
/ Kinetics
/ Ligands
/ Melanoma
/ Molecular Docking Simulation
/ Molecular Dynamics Simulation
/ Monophenol Monooxygenase - antagonists & inhibitors
/ Monophenol Monooxygenase - chemistry
/ Monophenol Monooxygenase - metabolism
/ Proteins
/ Structure-Activity Relationship
