Novel Donepezil–Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

“…The synthesis of final compounds 11a–e , 12a–e and 13 is described in Scheme 2 . The preparation of the aminoalkyl-piperidine and -piperazine intermediates ( 9a–e and 10a–e ) involves a selective protection of the primary alkylamine group of commercial 4-(aminomethyl)piperidine or 1-(2-aminoethyl)piperazine by a neat reaction with phthalic anhydride at 150–160 °C [ 48 ]. The subsequent N -benzylation of the cyclic amine involved a reaction with the suitable commercially available substituted benzyl bromide under basic conditions [ 18 ].…”

Effects of Tea Polyphenols and Theaflavins on Three Oral Cariogenic Bacteria

“…Streptococcus mutans , Streptococcus sobrinus , and Actinomyces viscosus, used in this experiment, are the main cariogenic bacteria in the oral cavity. They can ferment various carbohydrates to produce acids, reduce plaque pH below 5, and synthesize intracellular and extracellular polysaccharides using sucrose as a substrate [ 20 , 21 ]. They also have a high affinity for bacterial biofilms, which determines their important role in the occurrence of dental caries [ 22 ].…”

Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer’s Diseases: Emerging Paradigms and Strategies

“…Donepezil is a rapidly reversible inhibitor of AChE approved for the treatment of AD, and it is the first and only AChE inhibitor approved for the treatment of severe AD. Donepezil derivatives and hybrids target various AD-related targets, such as BuChE, Aβ cascade and metal ions [ 31 , 60 , 61 , 62 , 63 , 64 , 65 ]. Ma et al generated a series of deoxyvasicinone–donepezil hybrids 21 , in which the piperidine fragment of donepezil was replaced by the piperazine moiety and studied the inhibitory activities against AChE, BACE-1 and the Aβ protein ( Figure 9 A).…”