No abstract

Background: 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, 1 H_NMR, and 13 C_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 IC 50 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 IC 50 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.

No abstract

Alzheimer’s disease is the most common progressive neurodegenerative mental disorder associated with loss of memory, decline in cognitive function, and dysfunction of language. The prominent pathogenic causes of this disease involve deposition of amyloid-β plaques, acetylcholine neurotransmitter deficiency, and accumulation of neurofibrillary tangles. There are multiple pathways that have been targeted to treat this disease. The inhibition of the intracellular cyclic AMP regulator phosphodiesterase IV causes the increase in CAMP levels that play an important role in the memory formation process. Organometallic chemistry works in a different way in treating pharmacological disorders. In the field of medicinal chemistry and pharmaceuticals, zinc-based amide carboxylates have been shown to be a preferred pharmacophore. The purpose of this research work was to investigate the potential of zinc amide carboxylates in inhibition of phosphodiesterase IV for the Alzheimer’s disease management. Swiss Albino mice under controlled conditions were divided into seven groups with 10 mice each. Group I was injected with carboxymethylcellulose (CMC) at 1 mL/100 g dose, group II was injected with Streptozotocin (STZ) at 3 mg/kg dose, group III was injected with Piracetam acting as a standard drug at 200 mg/kg dosage, while groups IV–VII were injected with a zinc scaffold at the dose regimen of 10, 20, 40, and 80 mg/kg through intraperitoneal injection. All groups except group I were injected with Streptozotocin on the first day and third day of treatment at the dose of 3 mg/kg through an intracerebroventricular route to induce Alzheimer’s disease. Afterward, respective treatment was continued for all groups for 23 days. In between the treatment regimen, groups were analyzed for memory and learning improvement through various behavioral tests such as open field, elevated plus maze, Morris water maze, and passive avoidance tests. At the end of the study, different biochemical markers in the brain were estimated like neurotransmitters (dopamine, serotonin and adrenaline), oxidative stress markers (superoxide dismutase, glutathione, and catalase), acetylcholinesterase (AchE), tau proteins, and amyloid-β levels. A PCR study was also performed. Results showed that the LD 50 of the zinc scaffold is greater than 2000 mg/kg. Research indicated that the zinc scaffold has the potential to improve the memory impairment and learning behavior in Alzheimer’s disease animal models in a dose-dependent manner. At the dose of 80 mg/kg, a maximum response was observed for the zinc scaffold. Maximum reduction in the acetylcholinesterase enzyme was observed at 80 mg/kg dose, which was further strengthened and verified by the PCR study. Oxidative stress was restored by the zinc scaffold due to the significant activation of the endogenous antioxidant enzymes. This research ended up with the conclusion that the zinc-based amide carboxylate scaffold has the potential to improve behavioral disturbances and vary the biochemica...