Pyridine‐Mediated Synthesis of Melatonin Derivatives: Assessment of Molecular Dynamics and Apoptotic Induction by Quantum‐Chemical Studies for Targeting BRAF‐V600e Melanoma

ABSTRACT

Melanoma, a highly aggressive skin cancer, requires new therapeutic strategies. The present drugs suffer from limitations such as side effects, limited efficacy, and resistance. There is a strong demand for the development of promising drug candidates to treat melanoma. In this regard, Melatonin (MEL) and two novel N ‐acyl derivatives, such as N ‐propionyl analogue (NPA) and N ‐chloroacetyl analogue (NCA) were synthesized and structurally confirmed by XRD, FT‐IR, NMR, and high‐resolution mass spectrometry. TD‐DFT calculations supported the spectral features and revealed HOMO–LUMO energy gaps of 4.78 eV (MEL), 0.176 eV (NPA), and 0.175 eV (NCA), consistent with their relative electronic hardness/softness. Docking and molecular dynamics simulations demonstrated stable binding of MEL to BRAF V600E, with conserved hinge hydrogen bonds and hydrophobic contacts and MM‐PBSA analysis indicated favorable binding energies. In vitro assays showed reproducible low micromolar activity, with MEL (IC ₅₀ = 7.1 ± 0.8 µM) inducing the strongest apoptosis and p‐ERK _1/2 suppression, while NPA (IC ₅₀ = 9.3 ± 0.5 µM) and NCA (IC ₅₀ = 10.5 ± 0.6 µM) also inhibited A375 melanoma cells, though with comparatively lower efficacy. These integrated experimental and computational findings establish MEL and its N ‐acyl derivatives as promising scaffolds for rational optimization toward more potent BRAF V600E‐targeted therapeutics.