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

Bilal Ahmad Khan; Syeda Shamila Hamdani; Saquib Jalil; Syeda Abida Ejaz; Jamshed Iqbal; Ahmed M Shawky; Alaa M Alqahtani; Gamal A Gabr; Mahmoud A A Ibrahim; Peter A Sidhom

doi:10.3390/ph16010011

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

Pharmaceuticals (Basel). 2022 Dec 22;16(1):11. doi: 10.3390/ph16010011.

Authors

Affiliations

¹ Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad 13100, Pakistan.
² Center for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
⁴ Science and Technology Unit (STU), Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁵ Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁶ Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
⁷ Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza 12619, Egypt.
⁸ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt.
⁹ School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.
¹⁰ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.

Abstract

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 μM). 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.

Keywords: AChE; Alzheimer’s illness; molecular modeling; monoamine oxidase; oxadiazole-quinoline hybrids.

Grants and funding

This research received no external funding.