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

New S-alkyl phthalimide 5a-f and S-benzyl 6a-d analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol (4) were prepared by reacting 4 with N-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 5a and 5f 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 5c showed the most efficient acetylcholinesterase inhibition (IC50 = 1.02 +/- 0.65 mu M). Docking predictions disclosed the docking poses of the synthesized molecules with all enzymes and demonstrated the outstanding potency of compounds 5a, 5f, and 5c (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.

Automated summary

New S-alkyl phthalimide and S-benzyl analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol were successfully synthesized. The synthesized molecules were characterized using spectroscopic techniques. The inhibition activity of these compounds against MAO-A, MAO-B, and AChE enzymes was evaluated, and they showed submicromolar activity against all enzymes. Compounds 5a, 5f, and 5c exhibited the most potent inhibition activity and promising docking scores, making them potential candidates for the treatment of Alzheimer's disease.