New Indole Derivatives As Multitarget anti-Alzheimer's Agents: synthesis, Biological Evaluation and Molecular Dynamics

Abstract

<b>Background:</b> Alzheimer's disease is a neurological disorder that causes brain cells to shrink and die. <b>Aim:</b> Thirteen novel 'oxathiolanyl', 'pyrazolyl' and 'pyrimidinyl' indole derivatives were designed and synthesized as anti-Alzheimer's disease treatment. <b>Method:</b> <i>In vitro</i> enzyme assay was performed against both AChE and BChE enzymes. In addition, antioxidant assay and cytotoxicity on a normal cell line were determined. Molecular docking and dynamic simulations were conducted to confirm the binding mode in both esterases' active sites. <i>In silico</i> absorption, distribution, metabolism, excretion and toxicity studies were also carried out. <b>Results & conclusion:</b> Compounds <b>5</b>, <b>7</b> and <b>11</b> exhibited superior inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with IC₅₀ values of 0.042 and 3.003 μM, 2.54 and 0.207 μM and 0.052 and 2.529 μM, respectively, compared with donepezil.