First in class pyrrolo[2,3‐d]pyrimidine derivatives fused to fluorobenzylpiperidines as dual ligands of acetylcholinesterase and histamine H3 receptor DOI Open Access

Tito Añazco,

Tobias Werner, Marı́a José Torres

et al.

Archiv der Pharmazie, Journal Year: 2025, Volume and Issue: 358(3)

Published: March 1, 2025

Alzheimer's disease (AD) is a multifactorial neurodegenerative with manifold underlying pathophysiological mechanisms. Therefore, multitarget-directed ligands potentially offer beneficial therapeutic effects compared classical therapies. Dual targeting of the histamine H3 receptor (H3R) and acetylcholinesterase (AChE) valid strategy for treatment AD. In this work, new series pyrrolo[2,3-d]pyrimidines fused to fluorobenzylpiperidine derivatives was designed, synthesized, pharmacologically evaluated. Among 16 reported here, compounds 4a (IC50 = 2.19 µM human (hAChE) Ki 1.05 H3R) 4f 4.27 hAChE 1.31 show most balanced dual behavior coupled moderate affinities at both targets. Selected showed medium inhibition butyrylcholinesterase (BuChE). Moreover, these did not any toxicity in SH-SY5Y or HEK-293 cell lines relevant concentrations. silico studies allowed proposition binding modes prediction favorable absorption, distribution, metabolism excretion properties. The cumulative results suggest as lead structures further development novel dual-targeted AD therapy.

Language: Английский

NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders DOI Creative Commons
Ayodeji O. Egunlusi, Jacques Joubert

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 639 - 639

Published: May 15, 2024

Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples Alzheimer's disease (AD) Parkinson's (PD). The global prevalence NDs is on the rise, imposing significant economic social burdens. Despite extensive research, mechanisms underlying remain incompletely understood, hampering development effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, key pathological process implicated in NDs. Targeting N-methyl-D-aspartate (NMDA) receptor, which plays central role holds therapeutic promise. However, challenges, such as blood-brain barrier penetration adverse effects, extrapyramidal have hindered success many NMDA receptor antagonists clinical trials. This review explores molecular antagonists, emphasizing their structure, function, types, future prospects treating research competitive noncompetitive quest for treatments still faces hurdles. partly because same that necessitates blockage under also responsible normal physiological function receptors. Allosteric modulation receptors presents potential alternative, with GluN2B subunit emerging attractive target due its enrichment presynaptic extrasynaptic receptors, are major contributors excitotoxic-induced cell death. low side-effect profiles, selective like ifenprodil radiprodil encountered obstacles poor bioavailability Moreover, selectivity these often relative, they been shown bind other GluN2 subunits, albeit minimally. Recent advancements developing phenanthroic naphthoic acid derivatives offer promise enhanced GluN2B, GluN2A or GluN2C/GluN2D improved pharmacodynamic properties. Additional challenges antagonist conflicting preclinical results, well complexity neurodegenerative poorly defined subtypes. Although multifunctional agents targeting multiple degenerative processes being explored, data limited. Designing antagonists/modulators polycyclic moieties multitarget properties would be addressing disorders. understanding structure coupled collaborative efforts drug design, imperative realizing antagonists/modulators.

Language: Английский

Citations

19
New insights into butyrylcholinesterase: Pharmaceutical applications, selective inhibitors and multitarget-directed ligands DOI
Tian‐Yu Sun,

Tengfei Zhen,

Chrisanta Hamis Harakandi

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 275, P. 116569 - 116569

Published: June 5, 2024

Language: Английский

Citations

16
RIPK1 inhibitors: A key to unlocking the potential of necroptosis in drug development DOI

Yinliang Bai,

Yujun Qiao,

Mingming Li

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 265, P. 116123 - 116123

Published: Jan. 3, 2024

Language: Английский

Citations

15
Pristine 2-chloroquinoline-based-thiosemicarbazones as multitarget agents against alzheimer's disease: In vitro and in silico studies of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors DOI
Saquib Jalil,

Rabia Basri,

Mubashir Aziz

et al.

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1306, P. 137841 - 137841

Published: Feb. 22, 2024

Language: Английский

Citations

9
Design, synthesis and anticholinesterase activity of coumarin-1,3,5-triazine derivatives DOI

Xiaoqing Zhang,

Liuqing Shi,

Zhao‐Yuan Zhang

et al.

Journal of Molecular Structure, Journal Year: 2025, Volume and Issue: unknown, P. 142439 - 142439

Published: April 1, 2025

Language: Английский

Citations

1
Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease DOI Creative Commons
Hongsong Chen,

Jing Mi,

Sen Li

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: Jan. 23, 2023

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated AChE/BuChE inhibition anti-inflammatory property. in vitro activities showed that compound 3f a reversible dual eeAChE/eqBuChE inhibitor with IC50 values 1.3 µM 0.81 µM, respectively. Moreover, displayed good property decreasing the production IL-6, IL-1β NO. In addition, presented significant neuroprotective effect on Aβ25-35-induced PC12 cell injury. Furthermore, stabilities artificial gastrointestinal fluids, liver microsomes plasma. could improve AlCl3-induced zebrafish AD model increasing level ACh. Therefore, promising multifunctional agent treatment AD.

Language: Английский

Citations

20
Effect and mechanism of acupuncture on Alzheimer’s disease: A review DOI Creative Commons
Liu Wu, Yuting Dong, Chengcheng Zhu

et al.

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: March 3, 2023

With the development trend of an aging society, Alzheimer’s disease (AD) has become urgent problem in field medicine worldwide. Cognitive impairment AD patients leads to a decline ability perform daily living and abnormalities behavior personality, causing abnormal psychiatric symptoms, which seriously affect life patients. Currently, mainly drug therapy is used for clinic, but large proportion will experience efficacy not working, even some drugs bring severe sleep disorders. Acupuncture, with its unique concept treatment method, been validated through number experiments proved reliability acupuncture AD. Many advances have made study neurobiological mechanisms AD, further demonstrating good advantages This review first summarizes pathogenesis then illustrates research progress includes effect on changes biochemical indicators vivo specific mechanism action exert therapeutic effect. Changes relevant similarly validate effectiveness treatment. The clinical mechanistic studies are intensified fit need social development. It believed that achieve new achievements as progresses.

Language: Английский

Citations

19
Development of the “hidden” multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease DOI
Rui Chen, Xinjuan Li, Hongsong Chen

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 251, P. 115253 - 115253

Published: March 10, 2023

Language: Английский

Citations

19
Sweroside: An iridoid glycoside of potential neuroprotective, antidiabetic, and antioxidant activities supported by molecular docking DOI
Gökhan Zengin, Mohamed A. El Raey, Walaa A. El‐Kashak

et al.

Amino Acids, Journal Year: 2023, Volume and Issue: 55(12), P. 1765 - 1774

Published: March 20, 2023

Language: Английский

Citations

19
Design of a new potent Alzheimer's disease inhibitor based on QSAR, molecular docking and molecular dynamics investigations DOI Creative Commons

Meriem Khedraoui,

Hassan Nour, Imane Yamari

et al.

Chemical Physics Impact, Journal Year: 2023, Volume and Issue: 7, P. 100361 - 100361

Published: Nov. 14, 2023

A series of 32 molecules derived from 7-prenyloxy-2,3-dihydroflavanone and 5-hydroxy-7-prenyloxy-2,3-dihydro-flavanone possessing an inhibitory activity against the Acetylcholinesterase (AChE) enzyme were studied using structure-activity (QSAR) investigations. Electronic descriptors calculated Gaussian software DFT method at B3YP/6-31G(d, p) level. In addition, constitutional, physicochemical, topological Chem3D software. The best model obtained by multiple linear regression (MLR) was subjected to external internal statistical validations. What is more, applicability domain (ad) has been defined for built Williams plot. We have designed new molecular structures similar basis giving dataset their predicted model. Then, docking used predict affinity between newly inhibitors candidates AChE protein. This study completed dynamic simulation (MDs) stability formed complexes, RMSD RMSF plots complexes analyzed.

Language: Английский

Citations

18