Carbamate as a potential anti‐Alzheimer's pharmacophore: A review DOI
Yash Pal Singh, Navneet Kumar, Brijesh Singh Chauhan

et al.

Drug Development Research, Journal Year: 2023, Volume and Issue: 84(8), P. 1624 - 1651

Published: Sept. 11, 2023

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms AD pathogenesis are very complex still not fully explored. Cholinergic neuronal loss, accumulation amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, mitochondrial dysfunction major hallmarks AD. current treatment options for acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects progression. So, there an urgent need novel drug development that only addresses basic but also shows neuroprotective property. Various research groups across globe working on multifunctional agents amelioration using different core scaffolds their design, carbamate among them. Rivastigmine was first investigated management. fragment, scaffold act as potential inhibitor acetylcholinesterase. In this review, we summarize last 10 years conducted modification with substituents primarily target ChE inhibition, reduce modulate Aβ aggregation.

Language: Английский

Cholinesterase inhibitors as Alzheimer's therapeutics (Review) DOI Open Access
Kamlesh Sharma

Molecular Medicine Reports, Journal Year: 2019, Volume and Issue: unknown

Published: June 11, 2019

Alzheimer's disease (AD) is one of the most common forms dementia. AD a chronic syndrome central nervous system that causes decline in cognitive function and language ability. Cholinergic deficiency associated with AD, various cholinesterase inhibitors have been developed for treatment including naturally‑derived inhibitors, synthetic analogues hybrids. Currently, available drugs are predominantly inhibitors. However, efficacy these limited as they may cause adverse side effects not able to completely arrest progression disease. Since multifactorial disease, dual multi‑target developed. The clinical applications limitations used treat discussed present review. Additionally, this review presents current status future directions development novel reduced toxicity preserved pharmacological activity.

Language: Английский

Citations

513
Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress DOI
Zhipei Sang, Keren Wang, Jianghong Dong

et al.

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 238, P. 114464 - 114464

Published: May 20, 2022

Language: Английский

Citations

88
Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase DOI Creative Commons

Rami J. Obaid,

Nafeesa Naeem, Ehsan Ullah Mughal

et al.

RSC Advances, Journal Year: 2022, Volume and Issue: 12(31), P. 19764 - 19855

Published: Jan. 1, 2022

The present review focuses on various heterocyclic scaffolds and their role in designing developing new potential AChE BChE inhibitors to treat AD.

Language: Английский

Citations

85
Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications DOI Open Access
Nikita A. Frolov, A. N. Vereshchagin

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2937 - 2937

Published: Feb. 2, 2023

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in pharmaceutical industry. Their derivatives present more than twenty classes of pharmaceuticals, as well alkaloids. The current review summarizes recent scientific literature on intra- intermolecular reactions leading to formation various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidinones. Moreover, applications natural piperidines were covered, latest advances discovery biological evaluation potential containing moiety. This is designed help both novice researchers taking their first steps this field experienced scientists looking suitable substrates synthesis biologically active piperidines.

Language: Английский

Citations

82
Review of Pharmacotherapeutic Targets in Alzheimer’s Disease and Its Management Using Traditional Medicinal Plants DOI Open Access
Prabhash Nath Tripathi,

Ankit Lodhi,

Sachchida Nand

et al.

Degenerative Neurological and Neuromuscular Disease, Journal Year: 2024, Volume and Issue: Volume 14, P. 47 - 74

Published: May 1, 2024

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. While there currently no cure for AD, several pharmacotherapeutic targets management strategies have been explored. Additionally, traditional medicinal plants gained attention their potential role in AD management. Pharmacotherapeutic include amyloid-beta (Aβ) aggregation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, cholinergic dysfunction. Traditional plants, such as Ginkgo biloba, Huperzia serrata, Curcuma longa (turmeric), Panax ginseng, demonstrated the ability to modulate these through bioactive compounds. biloba , instance, contains flavonoids terpenoids that exhibit neuroprotective effects reducing Aβ deposition enhancing cerebral blood flow. serrata natural source of huperzine A, has acetylcholinesterase-inhibiting properties, thus improving function. enriched with curcumin, exhibits anti-inflammatory antioxidant effects, potentially mitigating neuroinflammation stress. ginseng's ginsenosides shown anti-amyloidogenic properties. The investigation complementary approach offers advantages, including lower risk adverse multi-target interactions. Furthermore, cultural knowledge utilization provide rich information development new therapies. However, further research necessary elucidate precise mechanisms action, standardize preparations, assess safety efficacy remedies. Integrating medicinal-plant-based therapies modern pharmacotherapies may hold key more comprehensive effective treatment. This review aims explore its Keywords: disease, acetylcholinesterase, amyloid beta, protein, medicine, Ayurvedic herbs, acetylcholinesterase inhibitors, disorders, cognition

Language: Английский

Citations

53
Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases DOI
Vanessa Silva Gontijo, Flávia P. Dias Viegas, Cindy Juliet Cristancho Ortiz

et al.

Current Neuropharmacology, Journal Year: 2019, Volume and Issue: 18(5), P. 348 - 407

Published: Oct. 21, 2019

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments available for any NDs, this lack of efficacy has been attributed the multitude interconnected factors involved in their pathophysiology. In last two decades, a new approach rational design drug candidates, also called multitarget-directed ligands (MTDLs) strategy, emerged used development variety hybrid compounds capable act simultaneously diverse biological targets. Based on polypharmacology concept, paradigm thought as more secure way modulating concomitantly or biochemical pathways responsible onset progress trying overcome low therapeutical effectiveness. As complement our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed cover period 2008 2019 highlight most recent advances exploitation Molecular Hybridization (MH) tool innovative multifunctional candidate prototypes treatment specially focused AD, PD, HD ALS.

Language: Английский

Citations

92
Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches DOI
Juan F. González, Andrés R. Alcántara, A. Doadrio

et al.

Expert Opinion on Drug Discovery, Journal Year: 2019, Volume and Issue: 14(9), P. 879 - 891

Published: June 5, 2019

Introduction: Alzheimer's disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes progressive loss cognitive functioning with decline rational skills. It well known AD multifactorial, so there are many different pharmacological targets can be pursued.Areas covered: The authors highlight strategic value privileged scaffolds in multi-target lead compound generation against AD, exploring concept design, special emphasis on hybrid compounds. Hence, promising building blocks for designing and synthesizing anti-AD drugs shown, while also presenting more advanced compounds.Expert opinion: available therapeutic arsenal designed under traditional paradigm 'one-drug/one target/one-disease', based inhibition brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used treat any multifactor-depending (cancer, diabetes or AD). drug quickly adopted by medicinal chemists. basic research developments reported recent years solid foundation will pave way construction future therapeutics.

Language: Английский

Citations

81
Phenoxyethyl Piperidine/Morpholine Derivatives as PAS and CAS Inhibitors of Cholinesterases: Insights for Future Drug Design DOI Creative Commons
Yaghoub Pourshojaei, Ardavan Abiri, Khalil Eskandari

et al.

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Dec. 27, 2019

Abstract Acetylcholinesterase (AChE) catalyzes the conversion of Aβ peptide to its aggregated form and peripheral anionic site (PAS) AChE is mainly involved in this phenomenon. Also catalytic active (CAS) donepezil stimulates break-down acetylcholine (ACh) depletion ACh cholinergic synapses are well established brains patients with AD. In study, a set compounds bearing phenoxyethyl amines were synthesized their inhibitory activity toward electric eel (eeAChE) equine butyrylcholinesterase (eqBuChE) evaluated. Molecular dynamics (MD) was employed record binding interactions best against human cholinesterases (hAChE hBuChE) as reference drug. vitro results revealed that compound 5c capable inhibiting eeAChE at IC 50 0.50 µM while no found for eqBuChE up 100 concentrations. Compound , also due facile synthesis, small structure high selectivity would be very interesting candidate forthcoming studies. The main interacting parts 7c (most potent inhibitors respectively) receptors which confer BuChE inhibition identified, discussed, compared donepezil’s interactions. during MD simulation it discovered first time substrates like dual CAS PAS or solely region might have suppressive impact on 4-α-helical bundles near tryptophan amphiphilic tetramerization (WAT) domain residues far away from site. proposed (Trp86 Phe295) located mid-gorge mediator conformational changes whole protein structure.

Language: Английский

Citations

80
Design, synthesis, in-silico and biological evaluation of novel chalcone derivatives as multi-function agents for the treatment of Alzheimer's disease DOI
Zhipei Sang, Keren Wang, Pengfei Zhang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 180, P. 238 - 252

Published: July 12, 2019

Language: Английский

Citations

77
Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review DOI Creative Commons
Sirasa Ruangritchankul, Prawat Chantharit, Sahaphume Srisuma

et al.

Therapeutics and Clinical Risk Management, Journal Year: 2021, Volume and Issue: Volume 17, P. 927 - 949

Published: Sept. 1, 2021

Abstract: The rising of global geriatric population has contributed to increased prevalence dementia. Dementia is a neurodegenerative disease, which characterized by progressive deterioration cognitive functions, such as judgment, language, memory, attention and visuospatial ability. not only profoundly devastating physical psychological health outcomes, but it also poses considerable healthcare expenditure burdens. Acetylcholinesterase inhibitors (AChEIs), or so-called anti-dementia medications, have been developed delay the progression neurocognitive disorders decrease needs. AChEIs widely prescribed in clinical practice for treatment Alzheimer's account 70% use results adverse drug reactions (ADRs) cardiovascular gastrointestinal effects, resulting from overstimulation peripheral cholinergic activity muscarinic receptor activation. Changes pharmacokinetics (PK), pharmacodynamics (PD) pharmacogenetics (PGx), occurrence interactions are said be major risk factors ADRs this population. To date, comprehensive reviews so far scarcely studied. Therefore, we aimed recapitulate update diverse aspects AChEIs, including mechanisms action, characteristics ADRs, preventive strategies their ADRs. collation knowledge essential facilitate efforts reduce AChEIs. Keywords: older adults, dementia, acetylcholinesterase inhibitors, reactions, drug–drug

Language: Английский

Citations

69