Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

Brunetti, Leonardo; Leuci, Rosalba; Carrieri, Antonio; Catto, Marco; Occhineri, Sara; Vinci, Giuseppe; Gambacorta, Lucia; Baltrukevich, Hanna; Chaves, Sı́lvia; Laghezza, Antonio; Altomare, Cosimo; Tortorella, Paolo; Santos, M. Amélia; Loiodice, Fulvio; Piemontese, Luca

doi:10.1016/j.ejmech.2022.114358

Cited by 26 publications

(19 citation statements)

References 71 publications

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“…The crude brown solid was purified by column chromatography (n-hexane/EtOAc 7:3), affording a glassy solid, yield 37%. 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 2.21 (s, 3H, NCOCH 3 ), 2.60 (s, 3H, COCH 3 ), 7.22-7.52 (m, 5H, aromatics), 7.81 (dd, J = 8.1 Hz, 1.8 Hz, 1H, aromatic), 8.09 (d, J = 1.5 Hz, 1H, aromatic); 13 (15) [M] + , 241 (100) [26].…”

Section: Chemistrymentioning

confidence: 99%

“…= 249-251 • C. 1 H-NMR (300 MHz, CDCl 3 ), δ (ppm): 6.59-6.62, 6.68-6.78, 6.83-6.97 and 7.90-8.00 (m, 7H, aromatics), 8.25 (s, COOH). 13 (5) An intimate mixture of 4-(aminomethyl)piperidine (10 mmol, 1 eq) and phthalic anhydride (powder, 10 mmol, 1 eq) was left at 150 • C for 4 h. The resulting solid was added with a solution of HCl in absolute ethanol solution (1 N, 8 mL). After 10 min, the solvent was removed under vacuum.…”

Section: -Acetyl-10h-phenothiazine-2-carboxylic Acid (3)mentioning

confidence: 99%

“…In the present work, we designed and prepared a series of eleven derivatives (Fig 1 ) with the aim of combining for the first time five different activities in one molecule in the recent past, we decided to use both N-benzylpiperidine and N-benzylpiperazin donepezil-like moieties, using different substitutions on the aromatic ring, on the bas the results obtained in another of our recent publications [18]. These moieties were lin via the classic one-or two-methylene-amido chains [13,[17][18][19][20] to the phenothia fragment. This nucleus is known as a very effective antioxidant [21] and also as inhibitor of the tau protein aggregation in neurons, thus being the active moiety Rember ® (methylthioninium chloride), a TauRx drug that entered phase III clin evaluation in March 2010 [22], and was recently included in several hybrids contain the tacrine moiety in a preliminary study of novel anti-Alzheimer's disease agents [23 Herein, we studied a different kind of substitution, which could allow to main the antioxidant properties of the obtained hybrids.…”

Section: Introductionmentioning

confidence: 99%

“…Following this paradigm, one recent work of ours [ 13 ] involved the design, synthesis and biological evaluation of a series of donepezil-like hybrids as inhibitors of three different enzymes, namely AChE, BChE and fatty acid amide hydrolase (FAAH). In silico studies were also performed to rationalize the obtained results and compounds were also assayed for their ability to inhibit amyloid aggregation and for their ability to chelate copper(II).…”

Section: Introductionmentioning

confidence: 99%

“…In silico studies were also performed to rationalize the obtained results and compounds were also assayed for their ability to inhibit amyloid aggregation and for their ability to chelate copper(II). These compounds included a donepezil-like N -benzylpiperidine or N -benzylpiperazine moiety in their structure and resulted as promising multi-functional compounds, as well as potent cholinesterase inhibitors [ 13 ]. This work is one of the first in which a particular cluster of biological properties was highlighted.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Alzheimer’s disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aβ1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.

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Section: Chemistrymentioning

confidence: 99%

Section: -Acetyl-10h-phenothiazine-2-carboxylic Acid (3)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Recent Studies on Heterocyclic Cholinesterase Inhibitors Against Alzheimer's Disease

Tok

2024

Chemistry & Biodiversity

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Alzheimer's disease is a progressive and neurodegenerative disease characterized by impairment in emotion, language, memory and cognitive judgment. There are many factors related to Alzheimer's disease, such as amyloid beta plaques (Aβ) due to impaired metabolism of amyloid precursor protein (APP), tau hyperphosphorylation and accumulation of neurofibrillary tangles, and disruption of the cholinergic system. Disruption of the cholinergic system responsible for cognitive function and memory processes is one of the important causes of Alzheimer's disease. Therefore, cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitors that maintain choline (acetylcholine and butyrylcholine) levels in the synaptic gap play an important role in the symptomatic treatment of Alzheimer's disease. Numerous studies have been carried out against Alzheimer's disease involving acetylcholinesterase and butyrylcholinesterase inhibitors. However, there are very few drugs (tacrine, rivastigmine, galantamine and donepezil) approved as cholinesterase inhibitors. Therefore, cholinesterase inhibitors are needed against Alzheimer's disease. This review is focused on using heterocyclic rings that show remarkable cholinesterase inhibitory activity for Alzheimer's disease. In this review, chemical structures and structure‐activity relationships of recently reported cholinesterase inhibitors are emphasized. This review will give important ideas to medicinal chemists in the discovery and development of potent cholinesterase inhibitors in their future studies.

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Recent Progress in the Treatment Strategies for Alzheimer’s Disease

Kumar

Roy

2023

Neuromethods

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Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

Cited by 26 publications

References 71 publications

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

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

Recent Studies on Heterocyclic Cholinesterase Inhibitors Against Alzheimer's Disease

Recent Progress in the Treatment Strategies for Alzheimer’s Disease

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