Exploring beta amyloid cleavage enzyme‐1 inhibition and neuroprotective role of benzimidazole analogues as anti‐alzheimer agents

Abstract

Beta amyloid cleavage enzyme-1 (BACE1) is the key enzyme involved in Aβ peptide formation in Alzheimer's disease pathogenesis. We intend to target this enzyme by exploring benzimidazole analogues against BACE1 as potential anti-Alzheimer agents. Docking studies were performed to determine the hydrogen bond interactions between the designed molecules and the target protein's active site. Research indicates the relationship between oxidative stress and Aβ effect in precipitating neurodegeneration; hence, the series was also studied in vitro to ascertain its neuroprotective role by performing the lipid peroxidation assay. In silico absorption, distribution, metabolism, and excretion studies were undertaken to assess the drug-like suitability of the analogues. To judge the effect of the synthesized analogues on central nervous system (CNS), toxicity and memory model studies were conducted on mice. Thus, overall results showcase analogues 11 and 14 as the most promising ones with the dual role of BACE1 inhibition and neuroprotection, along with memory retention. K E Y W O R D SBACE1, docking, in silico ADME studies, in vitro LPO assay, memory model studies, toxicity study

Benzimidazole Derivatives as New Potential NLRP3 Inflammasome Inhibitors That Provide Neuroprotection in a Rodent Model of Neurodegeneration and Memory Impairment

“…4 Furthermore, many benzimidazoles are screened for their potential anti-inflammatory, 5 antiviral 6 antiproliferative, and anthelmintic properties. 7 Likely, these compounds exhibited potent free radical scavenging properties as demonstrated in several reports, 8,9 which can be attributed to neuroprotection in Parkinson's, 10 Alzheimer's, 11 and other memory impairment models. 12,13 In this context, the beneficial effects of benzimidazole against multiple neurodegenerative's targets have been recently reviewed.…”

“…Several studies reported benzimidazole derivatives' antioxidant and anti-inflammatory activities. 11,12,[45][46][47][48][49] GSH and GST are essential endogenous antioxidants that help to eliminate free radicals. Benzimidazole derivatives are effective ROS inhibitors via activating GSH and inhibiting LPO.…”

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

“…Recently, compounds 500–501 were reported as promising AChE and BuChE inhibitors (IC 50 = 0.14 and 0.22 μM, respectively), highly neuroprotective against hydrogen peroxide mediated toxicity, metal chelators, and free radical scavengers in the treatment of Alzheimer’s disease ( Sarıkaya et al, 2018 ). Similarly, compounds 502–503 demonstrated duel effects as anti-Alzheimer agents by beta amyloid cleavage enzyme-1 (BACE1) inhibition and neuroprotection ( Gurjar et al, 2020 ). In a 6-hydroxydopamine (6-OHDA)-induced oxidative stress in vitro model assay, compound 504 exerted neuroprotective action compared to melatonin, and reduced superoxide anion radical and hypochlorite level in a luminol-dependent chemiluminescent assay ( Anastassova et al, 2020 ).…”

Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer’s Disease along with Molecular Docking Study

“…However, it was observed that BuChE provides a backup to AChE when its activity decreases, and is active at high concentrations of AChE [ 8 ]. Another non-cholinergic role of AchE is the formation of senile plaque by the deposition of beta-amyloid (βA) [ 9 ]. In the beginning, therapeutic strategies for treating diminished cholinergic neurotransmission were mainly focused on AChE inhibitors, but studies have shown the significance of both AChE and BuChE [ 10 ].…”