Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease.

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), ß-secretase-1 (BACE-1), and inhibition of amyloid ß (Aß) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.

Indole-3 Carbinol and Diindolylmethane Mitigated ß-Amyloid-Induced Neurotoxicity and Acetylcholinesterase Enzyme Activity: In Silico, In Vitro, and Network Pharmacology Study.

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by beta-amyloid (Aß) deposition and increased acetylcholinesterase (AchE) enzyme activities. Indole 3 carbinol (I3C) and diindolylmethane (DIM) are reported to have neuroprotective activities against various neurological diseases, including ischemic stroke, Parkinson's disease, neonatal asphyxia, depression, stress, neuroinflammation, and excitotoxicity, except for AD. In the present study, we have investigated the anti-AD effects of I3C and DIM. Methods: Docking and molecular dynamic studies against AchE enzyme and network pharmacological studies were conducted for I3C and DIM. I3C and DIM's neuroprotective effects against self and AchE-induced Aß aggregation were investigated. The neuroprotective effects of I3C and DIM against Aß-induced neurotoxicity were assessed in SH-S5Y5 cells by observing cell viability and ROS. Results: Docking studies against AchE enzyme with I3C and DIM show binding efficiency of -7.0 and -10.3, respectively, and molecular dynamics studies revealed a better interaction and stability between I3C and AchE and DIM and AchE. Network pharmacological studies indicated that I3C and DIM interacted with several proteins involved in the pathophysiology of AD. Further, I3C and DIM significantly inhibited the AchE (IC50: I3C (18.98 µM) and DIM (11.84 µM)) and self-induced Aß aggregation. Both compounds enhanced the viability of SH-S5Y5 cells that are exposed to Aß and reduced ROS. Further, I3C and DIM show equipotential neuroprotection when compared to donepezil. Conclusions: Our findings indicate that both I3C and DIM show anti-AD effects by inhibiting the Aß induced neurotoxicity and AchE activities.

Discovery of multi-target directed 3-OH pyrrolidine derivatives through a semisynthetic approach from alkaloid vasicine for the treatment of Alzheimer's disease.

Vasicine is a pyrroloquinazoline alkaloid, which has been isolated from the plant Adhatoda vasica. Naturally inspired semi-synthetic transformations were prepared using vasicine as a synthetic precursor to overcome Alzheimer's disease (AD). These semi-synthetic analogs exhibited stable interactions and were well resided at AChE and BChE active sites in in-silico studies. Further, in-vitro experiments were performed to assess the cholinesterase inhibitory activity and reduction of amyloid-beta (Aß1-42) plaques potency, PAMPA assay permeability, and antioxidant activity, these findings suggested that compound VA10 can be a lead molecule among all the synthesized analogs. The compound VA10 binds towards AChE peripheral anionic site (PAS) property was established through propidium iodide displacement assay. Moreover, VA10 showed no notable cytotoxicity and exhibited neuroprotective nature on Aß1-42 treated SH-SY5Y cell line. In addition, VA10 was found to be safe in rats, which was confirmed by acute oral toxicity studies. Furthermore, in-vivo studies suggested that compound VA10 (10 mg/kg, p.o) ameliorated the memory and cognition impairment in scopolamine-induced amnesia model and Aß1-42 induced Alzheimer rat model. Ex-vivo studies of compound VA10 demonstrate improved ACh levels by inhibiting AChE activity in rat brain. Moreover, histopathological observations on rats brain sections indicate VA10 (10 mg/kg, p.o) recovered the neuronal cells at hippocampus region (DG, CA3, and CA1). These positive experimental data from in-silico, in-vitro and in-vivo studies, suggested that compound VA10 can be a lead compound for further preclinical development studies as a naturally derived alkaloid for anti-AD.

Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer's Disease.

A series of some novel compounds (SD-1-17) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Aß aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer's disease. Compounds SD-4 and SD-6 have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes in vitro. Compounds SD-4 and SD-6 have also shown anti-Aß aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood-brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound SD-6 ameliorates cognition and memory functions in scopolamine- and Aß-induced behavioral rat models of Alzheimer's disease (AD). Ex vivo biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the SD-6-treated experimental animals. The in silico molecular docking results of compounds SD-4 and SD-6 showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand-protein complex's stability, while quikprop analysis suggested drug-like properties of the compounds.