scholarly journals Triazolopyridopyrimidine: A New Scaffold for Dual-Target Small Molecules for Alzheimer’s Disease Therapy

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3190
Author(s):  
Lazhar Zribi ◽  
Irene Pachòn-Angona ◽  
Òscar M. Bautista-Aguilera ◽  
Daniel Diez-Iriepa ◽  
José Marco-Contelles ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Structural Diversity ◽  
Oxygen Radical ◽  
Therapeutic Success ◽  
Antioxidant Power ◽  
Disease Therapy ◽  
Ad Therapy ◽  
Dual Target

Alzheimer’s disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1′,5′:1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile(3c) with IC50 equal to 1.32 μM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy.

scholarly journals Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1519 ◽  
Author(s):  
Habtemariam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Therapeutic Approaches ◽  
Mediated Effects ◽  
Pharmacological Targets ◽  
Disease Therapy ◽  
Therapeutic Principles ◽  
Novel Drug ◽  
Ad Therapy

Despite extensive progress in understanding the pathology of Alzheimer’s disease (AD) over the last 50 years, clinical trials based on the amyloid–beta (Aβ) hypothesis have kept failing in late stage human trials. As a result, just four old drugs of limited clinical outcomes and numerous side effects are currently used for AD therapy. This article assesses the common pharmacological targets and therapeutic principles for current and future drugs. It also underlines the merits of natural products acting through a polytherapeutic approach over a monotherapy option of AD therapy. Multi-targeting approaches through general antioxidant and anti-inflammatory mechanisms coupled with specific receptor and/or enzyme-mediated effects in neuroprotection, neuroregeneration, and other rational perspectives of novel drug discovery are emphasized.

scholarly journals Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 350
Author(s):  
Ashwani Arya ◽  
Rubal Chahal ◽  
Rekha Rao ◽  
Md. Habibur Rahman ◽  
Deepak Kaushik ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activities ◽  
Structural Diversity ◽  
Time Frame ◽  
World Health ◽  
Cholinergic Transmission ◽  
Disease Therapy ◽  
Inhibitory Potential ◽  
Health Organization

Alzheimer’s disease (AD) is a gradually growing irreversible illness of the brain that almost affects every fifth person (aged > 80 years) in the world. World Health Organization (WHO) also revealed that the prevalence of this disease will enhance (upto double) significantly upto 2030. The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder. Natural inhibitors of acetylcholine (ACh) such as galanthamine and rivastigmine are used commercially in the treatmentof AD. The biomolecules such assesquiterpenes, possess a great structural diversity and are responsible for a plethora of pharmacological properties. The potential of various sesquiterpenes as anticholinesterase has been reviewed in this article. For this purpose, the various databases, mainly PubMed, Scopus, and Web of Science were investigatedwith different keywords such as “sesquiterpenes+acetylcholinesterase” and “sesquiterpenes+cholinesterase+inhibitors” in the surveyed time frame (2010–2020). A vast literature was evident in the last decade, which affirms the potential of various sesquiterpenes in the improvement of cholinergic transmission by inhibiting the AChE. After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9μM and can be considered as potential candidates for the improvement of learning and memory. Sesquiterpene is an important category of terpenoids, found to possess a large spectrum of biological activities. The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol,etc) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.

Tacrine-Natural-Product Hybrids for Alzheimer’s Disease Therapy

2020 ◽  
Vol 27 (26) ◽  
pp. 4392-4400 ◽  
Author(s):  
María Jesús Oset-Gasque ◽  
José Luis Marco-Contelles
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Complex Nature ◽  
Biological Targets ◽  
Disease Therapy ◽  
Aβ Aggregation ◽  
Recent Developments ◽  
New Compounds ◽  
Ad Therapy

Alzheimer’s disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, Aβ-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments. In this review, we will update recent developments of multitarget tacrinenatural products hybrids for AD therapy.

scholarly journals Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy

2020 ◽  
Vol 21 (11) ◽  
pp. 3913
Author(s):  
Óscar M. Bautista-Aguilera ◽  
Lhassane Ismaili ◽  
Mourad Chioua ◽  
Rudolf Andrys ◽  
Monika Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoamine Oxidase ◽  
Small Molecules ◽  
Competitive Inhibitor ◽  
Acetylcholinesterase Inhibition ◽  
Docking Analysis ◽  
Mao Inhibition ◽  
Disease Therapy ◽  
Nanomolar Range

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.

Synthesis of new Hantzsch adducts showing Ca2+ channel blockade capacity, cholinesterase inhibition and antioxidant power

2021 ◽  
Author(s):  
Irene Pachón-Angona ◽  
Maciej Maj ◽  
Artur Wnorowski ◽  
Helene Martin ◽  
Krzysztof Jóźwiak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Disease ◽  
Antioxidant Effect ◽  
Cholinesterase Inhibition ◽  
Channel Blockade ◽  
Multicomponent Synthesis ◽  
Antioxidant Power ◽  
Disease Therapy ◽  
Interesting Compound

Background: Alzheimer’s disease is a chronic neurodegenerative chronic disease with a heavy social and economic impact in our developed societies, which still lacks an efficient therapy. Method: This paper describes the Hantzsch multicomponent synthesis of twelve alkyl hexahydro-quinoline-3-carboxylates, 4a–l, along with the evaluation of their Ca2+ channel blockade capacity, cholinesterase inhibition and antioxidant power. Results: Compound 4l showed submicromolar inhibition of butyrylcholinesterase, Ca2+ channel antagonism and an antioxidant effect. Conclusion: Compound 4l is an interesting compound that deserves further investigation for Alzheimer’s disease therapy.

Small Molecules and Alzheimer’s Disease: Misfolding, Metabolism and Imaging

2015 ◽  
Vol 12 (5) ◽  
pp. 445-461 ◽  
Author(s):  
Viharkumar Patel ◽  
Xueli Zhang ◽  
Nicolas Tautiva ◽  
Akwe Nyabera ◽  
Opeyemi Owa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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