Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease – a patent review (2016–present)

Bortolami, Martina; Rocco, Daniele; Messore, Antonella; Santo, Roberto Di; Costi, Roberta; Madia, Valentina Noemi; Scipione, Luigi; Pandolfi, Fabiana

doi:10.1080/13543776.2021.1874344

Cited by 42 publications

(23 citation statements)

References 91 publications

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“…The level of AChE in the hippocampus and cortex of AD patients is higher than that of healthy individuals; AChE can hydrolyze ACh and reduce the synaptic concentration more than expected. [29] Hence, improving the level of ACh by inhibiting AChE is a crucial method for treatment of the cognitive impairment of AD patients. [30] Thus, AChE inhibitors (AChEIs) are currently the first-line drugs approved by the FDA to treat AD (donepezil, galantamine, rivastigmine, and tacrine) (Scheme 2).…”

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Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

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et al. 2021

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New hybrid thiazolyl-pyrazoline derivatives (4a-k) were obtained through a facile and versatile synthetic procedure, and their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I and II as well as on acetylcholinesterase (AChE) were determined.All new thiazolyl-pyrazolines showed activity at nanomolar levels as hCA I, hCA II, and AChE inhibitors, with K I values in the range of 13.35-63.79, 7.01-115.80, and 17.89-48.05 were identified as highly potent inhibitors, superior to the standard drugs, acetazolamide and tacrine, respectively. Compounds 4a-k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Moreover, a comprehensive ligand-receptor interaction prediction was performed using the ADME-Tox, Glide XP, and MM-GBSA modules of the Schrödinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.

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Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

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et al. 2021

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“…As a result of these studies, the inhibitors, such as donepezil, rivastigmine, and galantamine have been discovered, and these inhibitors are still used in the treatment of AD. [49][50][51][52] However, it has been determined that these inhibitors have many side effects (nausea, vomiting, diarrhea, etc.). In addition, the disruption of liver metabolism by inhibitors other than rivastigmine has revealed the need to discover new enzyme inhibitors for the treatment of AD.…”

Section: Biochemical Studiesmentioning

confidence: 99%

Synthesis, characterization, and biological evaluation of some novel Schiff bases as potential metabolic enzyme inhibitors

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2022

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In this study, a series of novel Schiff base derivatives containing a pyrazolone ring (2a-e) were designed, successfully synthesized for the first time, and characterized by elemental analysis and some spectroscopic methods. These compounds were tested for their inhibitory activities on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and the human carbonic anhydrase isoenzymes I and II (hCA I and II). All synthesized molecules indicated significant inhibition effects with IC 50 values ranging from 14.15 to 107.62 nM against these enzymes. Compound 2d showed the most potent inhibitory activity among the tested molecules toward AChE and BChE (IC 50 = 15.07 and 14.15 nM) compared to the standard drug neostigmine. We determined that the IC 50 values of the tested molecules ranged between 16.86 and 57.96 nM for hCA I and 15.24-46.21 nM for hCA II. As a consequence, we may say that some of the Schiff base derivatives may be used as potential drug candidates in later studies.

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“…Overall, ChE inhibition is likely to maintain its critical role in the therapeutic armamentarium, as well as in the drug discovery pipeline (see [ 30 ] for a recent review). It is well accepted that cholinergic impairment is an important event in AD progression and a valuable target for symptomatic therapies that can be integrated in a polypharmacological approach to improve the overall drug profile.…”

Section: Relevant Alzheimer’s Disease Pathways and Their Potential As Drug Targetsmentioning

confidence: 99%

“…Particularly, we sought to link the cardanol skeleton, which might interact with the PAS through its aromatic end, with a fragment able to fish the CAS, to obtain dual binding AChE inhibitors (Figure 7) [81]. As a CAS key molecular feature, we selected fragments bearing a cationic head, which included a protonatable amino moiety belonging to different systems: heterocyclic amines such as pyrrolidine (25), piperidine (26), morpholine (27), thiomorpholine (28), N-substituted piperazines (29)(30)(31)(32)(33), hydroxylated pyrrolidine (34) and piperidines (35)(36)(37) and their corresponding O-acetyl (38)(39)(40)(41) and O-dimethylcarbamates (42)(43)(44)(45). Since the N-ethyl-N-(2-methoxybenzyl)amino moiety has been successfully exploited by us and others to obtain powerful dual binding AChEIs [82][83][84][85][86][87], we also synthesized hybrids 46-48 (Figure 7).…”

Section: Cnsl-derived Dual Binding Ache Inhibitorsmentioning

confidence: 99%

Cashew Nut Shell Liquid (CNSL) as a Source of Drugs for Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-AD drugs. Recently, a therapeutic strategy based on the exploitation of Brazilian biodiversity was set with the aim of discovering new disease-modifying and safe drugs for AD. In this review, we will illustrate our efforts in developing new molecules derived from Brazilian cashew nut shell liquid (CNSL), a natural oil and a byproduct of cashew nut food processing, with a high content of phenolic lipids. The rational modification of their structures has emerged as a successful medicinal chemistry approach to the development of novel anti-AD lead candidates. The biological profile of the newly developed CNSL derivatives towards validated AD targets will be discussed together with the role of these molecular targets in the context of AD pathogenesis.

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Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease – a patent review (2016–present)

Cited by 42 publications

References 91 publications

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Synthesis, characterization, and biological evaluation of some novel Schiff bases as potential metabolic enzyme inhibitors

Cashew Nut Shell Liquid (CNSL) as a Source of Drugs for Alzheimer’s Disease

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