Indole-tethered thiazoles: Synthesis, computational evaluation as BACE-1 inhibitor for Alzheimer’s disease, and photophysical studies

This study highlights the significance of thiazole-indole scaffolds in the development of potential therapeutics for Alzheimer’s disease. A new series of indole-tethered thiazole derivatives was synthesized and characterized by spectroscopic techniques. Docking revealed favorable binding poses, and MM/GBSA binding free energies (-36 to -55 kcal/mol) confirmed strong ligand-protein interactions within the BACE-1 active site. A 200 ns molecular dynamics simulation confirmed complex stability, with protein RMSD of ∼2-3 Å and ligand RMSD of ∼3-4.5 Å, supported by persistent hydrophobic and hydrogen-bond interactions with key residues, and in silico ADMET analysis suggested acceptable pharmacokinetic properties (QplogBB values between -3.0 and 1.2 and oral bioavailability >80%). DFT calculations were performed to assess the electronic stability of the molecule using the B3LYP/TZVP basis set. Further, optical properties studies were conducted using ultraviolet-visible and photoluminescence spectroscopy. UV-Vis spectra obtained in DMF displayed two sets of absorption bands near 250-300 nm and 350-400 nm, attributed to π-π* transitions. Photoluminescence measurements revealed a single emission peak centered near 440-560 nm in solution. Furthermore, density functional theory (DFT) was employed for excited-state and absorption studies to gain deeper insight into molecular structure and electronic transitions. Excited-state DFT analysis provided deeper insight into electronic transitions. Overall, these hybrids demonstrate promising stability and drug-like properties as potential BACE-1 inhibitors.