Synthesis and Evaluation of Novel S-alkyl Phthalimide- and S-benzyl-oxadiazole-quinoline Hybrids as Inhibitors of Monoamine Oxidase and Acetylcholinesterase

Abstract

New <i>S</i>-alkyl phthalimide <b>5a</b>-<b>f</b> and <i>S</i>-benzyl <b>6a</b>-<b>d</b> analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol (<b>4</b>) were prepared by reacting <b>4</b> with <i>N</i>-bromoalkylphthalimide and CF₃-substituted benzyl bromides in excellent yields. Spectroscopic techniques were employed to elucidate the structures of the synthesized molecules. The inhibition activity of newly synthesized molecules toward MAO-A, MAO-B, and AChE enzymes, was also assessed. All these compounds showed activity in the submicromolar range against all enzymes. Compounds <b>5a</b> and <b>5f</b> were found to be the most potent compounds against MAO-A (IC₅₀ = 0.91 ± 0.15 nM) and MAO-B (IC₅₀ = 0.84 ± 0.06 nM), while compound <b>5c</b> showed the most efficient acetylcholinesterase inhibition (IC₅₀ = 1.02± 0.65 μM). Docking predictions disclosed the docking poses of the synthesized molecules with all enzymes and demonstrated the outstanding potency of compounds <b>5a</b>, <b>5f</b>, and <b>5c</b> (docking scores = -11.6, -15.3, and -14.0 kcal/mol against MAO-A, MAO-B, and AChE, respectively). These newly synthesized analogs act as up-and-coming candidates for the creation of safer curative use against Alzheimer's illness.