Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer’s Agents

Abstract

In continuous efforts to develop anti-Alzheimer’s agents, we rationally designed and synthesized a series of multitargeting molecules by incorporating the essential molecular features of the standard drug donepezil. Among the series, compound 4b showed multitargeting properties to act as an anti-Alzheimer’s agent, which is better tolerable in vivo than donepezil. Acetylcholinesterase (AChE) inhibition data showed that compound 4b inhibits the enzyme with a half-maximal inhibitory concentration (IC50) value of 0.78 μM and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of 4b against oxidative DNA damage. Compound 4b also showed 53.04% inhibition against Aβ1–42 aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound 4b with the enzyme AChE, which showed that the enzyme–ligand complex is stable enough to block the hydrolysis of acetylcholine in the brain. Its higher LD50 cutoff value (50 mg/kg) in comparison to donepezil (LD50: 25 mg/kg) made it safer, suggesting that it can be used in further clinical experiments. To evaluate its anti-Alzheimer property, a mice model with melamine-induced cognitive dysfunction was used, and Morris water maze and Rotarod tests were performed. A significant improvement in memory was observed after the treatment with compound 4b and donepezil. The study postulated that the introduction of important structural features of donepezil (dimethoxyindanone moiety as ring-A) embarked with terminal aromatic ether (ring-B and ring-C) made 4b a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer’s disease (AD).

Design, Synthesis, and Pharmacological Evaluation of Embelin–Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood–Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer’s Disease: Discovery of SB-1448

“…ChEs from different species, Electrophorus electricus AChE (EeAChE) and equine serum BChE (eqBChE), are frequently used for in vitro enzyme inhibition studies as suitable models for the corresponding recombinant human enzymes owing to their better stability. − Moreover, EeAChE and eqBChE share a sequence identity of 87 and 93.4% with their human counterparts. , Thus, these enzymes were employed for ChE inhibition studies. The blood–brain barrier (BBB) permeability and aqueous solubility were also determined for all synthesized compounds.…”

Aspartic Acid-Modified Phospholipids Regulate Cell Response and Rescue Memory Deficits in APP/PS1 Transgenic Mice

“…Considering the targeting and long-acting properties of drugs, the advantages of liposomes should be fully exploited, especially the enhancement of structural design and functional regulation. Taken together, these findings offer a new approach to develop drugs that inhibit Aβ aggregation and/or neurotoxicity and are expected to become a potential drug for preventing and treating AD in the future. − …”

Design, Synthesis, and Biological Activity of Donepezil: Aromatic Amine Hybrids as Anti-Alzheimerss Drugs

“…Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. Its clinical manifestations include loss of memory function, cognitive function, visual space function, and self-care ability. − The progression of AD is associated with loss of cholinergic transmission, oxidative damage, imbalance of metallics, excitotoxicity, and neuroinflammation, which can lead to a “domino” cascade of events in AD. − At this stage, the efficacy of most single drugs can only be based on delaying the course of the disease, and it is difficult to further prevent and block the course of the disease fundamentally and as a whole. Due to the complexity of AD disease, single-target drugs cannot provide an ideal therapeutic effect .…”