Drug Design, Development and Therapy (Jun 2021)
Prospective Application of Two New Pyridine-Based Zinc (II) Amide Carboxylate in Management of Alzheimer’s Disease: Synthesis, Characterization, Computational and in vitro Approaches
Abstract
Rehman Zafar,1,2 Humaira Naureen,3 Muhammad Zubair,4 Khadija Shahid,1 Muhammad Saeed Jan,5 Samar Akhtar,2 Hammad Ahmad,2 Wajeeha Waseem,6 Ali Haider,4 Saqib Ali,4 Muhammad Tariq,7 Abdul Sadiq8 1Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan; 2Yusra Institute of Pharmaceutical Sciences, Islamabad, 44000, Pakistan; 3Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan; 4Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan; 5Department of Pharmacy, University of Swabi, Swabi, KP, Pakistan; 6Department of Basic Medical Sciences, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan; 7Department of PCB, Rokhan University, Jalalabad, Nangrahar, Afghanistan; 8Department of Pharmacy, University of Malakand, Chakdara, KP, PakistanCorrespondence: Abdul SadiqDepartment of Pharmacy, University of Malakand, Chakdara, 18000 Dir (L), KP, PakistanTel +92-332-50 46 485Email [email protected] AliDepartment of Chemistry, Quaid-i-Azam University, Islamabad, 45320, PakistanEmail [email protected]: Alzheimer’s disease (AD) is a neurodegenerative illness described predominantly by dementia. Even though Alzheimer’s disease has been known for over a century, its origin remains a mystery, and researchers are exploring many therapy options, including the cholinesterase technique. A decreased acetylcholine ACh neurotransmitter level is believed to be among the important factors in the progression of Alzheimer’s disease.Methods: In continuation of synthesizing potential anti-Alzheimer agents and known appreciative pharmacological potential of amide-containing compounds, this study presents the synthesis of two novel amide-based transition metal zinc (II) complexes, AAZ7 and AAZ8, attached with a heterocyclic pyridine ring, which was synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), elemental analysis, 1H_NMR, and 13C_NMR. FT-IR spectroscopic records showed the development of bidentate ligand as Δν value was decreased in both complexes when compared with the free ligand. Both of the synthesized complexes were analyzed for acetylcholinesterase and butyrylcholinesterase inhibitory potential along with the antioxidizing activity.Results: Importantly, the complex of AAZ8 exhibited more potent activity giving IC50 values of 14 μg/mL and 18μg/mL as AChE and BChE cholinesterase inhibitors, respectively, when compared with standard positive control galantamine. Interestingly, AAZ8 also displayed promising antioxidant potential by showing IC50 values of 35 μg/mL for DPPH and 29 μg/mL for ABTS in comparison with positive control ascorbic acid.Conclusion: Herein, we report two new amide carboxylate zinc (II) complexes which were potentially analyzed for various biological applications like acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory potentials, and antioxidant assays. Computational docking studies also simulated results to understand the interactions. Additionally, thermodynamic parameters utilizing molecular dynamic simulation were performed to determine the ligand protein stability and flexibility that supported the results. Studies have shown that these compounds have the potential to be good anti-Alzheimer candidates for future studies due to inhibition of cholinesterase enzymes and display of free radical scavenging potential against DPPH as well as ABTS free radicals.Keywords: Zn(II) carboxylate, acetylcholinesterase, butyrylcholinesterase, elemental analysis, docking studies
