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Journal articles on the topic 'Multi-target directed ligands (MTDLs)'

Author: Grafiati

Published: 5 June 2025

Last updated: 2 August 2025

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1

Pachón-Angona, Irene, Paul J. Bernard, Alexey Simakov, et al. "Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca2+ Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties." Pharmaceutics 16, no. 1 (2024): 121. http://dx.doi.org/10.3390/pharmaceutics16010121.

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This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL

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Kareem, Rzgar Tawfeeq, Fahimeh Abedinifar, Evan Abdolkareem Mahmood, Abdol Ghaffar Ebadi, Fatemeh Rajabi, and Esmail Vessally. "The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020." RSC Advances 11, no. 49 (2021): 30781–97. http://dx.doi.org/10.1039/d1ra03718h.

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Singh, Manjinder, and Om Silakari. "Design, synthesis and biological evaluation of novel 2-phenyl-1-benzopyran-4-one derivatives as potential poly-functional anti-Alzheimer's agents." RSC Advances 6, no. 110 (2016): 108411–22. http://dx.doi.org/10.1039/c6ra17678j.

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Abatematteo, Francesca Serena, Mauro Niso, Marialessandra Contino, Marcello Leopoldo та Carmen Abate. "Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives". International Journal of Molecular Sciences 22, № 12 (2021): 6359. http://dx.doi.org/10.3390/ijms22126359.

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The sigma-1 (σ1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targete

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Bhatia, Rohit, Sankha S. Chakrabarti, Upinder Kaur, Gaurav Parashar, Anindita Banerjee, and Ravindra K. Rawal. "Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer’s Disease." Current Alzheimer Research 18, no. 10 (2021): 802–30. http://dx.doi.org/10.2174/1567205018666211208140551.

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Alzheimer’s disease (AZD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cognitive domains, including executive function. The progression of AZD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AZD include a decreased concentration of acetylcholine (ACh), deposition of amyloid-β (Aβ) peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the

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Mezeiova, Eva, Lukas Prchal, Martina Hrabinova, et al. "Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease." Biomedicine & Pharmacotherapy 173 (March 15, 2024): 116399. https://doi.org/10.1016/j.biopha.2024.116399.

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The search for novel drugs to address the medical needs of Alzheimer’s disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine

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Bianco, Maria da Conceição Avelino Dias, Debora Inacio Leite, Frederico Silva Castelo Branco, et al. "The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy." Molecules 27, no. 23 (2022): 8502. http://dx.doi.org/10.3390/molecules27238502.

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The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resist

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de Freitas Silva, Matheus, Kris Simone Tranches Dias, Vanessa Silva Gontijo, Cindy Juliet Cristancho Ortiz, and Claudio Viegas. "Multi-Target Directed Drugs as a Modern Approach for Drug Design Towards Alzheimer’s Disease: An Update." Current Medicinal Chemistry 25, no. 29 (2018): 3491–525. http://dx.doi.org/10.2174/0929867325666180111101843.

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Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therape

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Azam, Uzma, Muhammad Moazzam Naseer, and Christophe Rochais. "Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer's disease." European Journal of Medicinal Chemistry 286 (March 2025): 117277. https://doi.org/10.1016/j.ejmech.2025.117277.

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10

Drakontaeidi, Aliki, and Eleni Pontiki. "Multi-Target-Directed Cinnamic Acid Hybrids Targeting Alzheimer’s Disease." International Journal of Molecular Sciences 25, no. 1 (2024): 582. http://dx.doi.org/10.3390/ijms25010582.

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Progressive cognitive decline in Alzheimer’s disease (AD) is a growing challenge. Present therapies are based on acetylcholinesterase inhibition providing only temporary relief. Promising alternatives include butyrylcholinesterase (BuChE) inhibitors, multi-target ligands (MTDLs) that address the multi-factorial nature of AD, and compounds that target oxidative stress and inflammation. Cinnamate derivatives, known for their neuroprotective properties, show potential when combined with established AD agents, demonstrating improved efficacy. They are being positioned as potential AD therapeutic l

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Jankowska, Agnieszka, Anna Wesolowska, Maciej Pawlowski, and Grazyna Chlon-Rzepa. "Multi-Target-Directed Ligands Affecting Serotonergic Neurotransmission for Alzheimer’s Disease Therapy: Advances in Chemical and Biological Research." Current Medicinal Chemistry 25, no. 17 (2018): 2045–67. http://dx.doi.org/10.2174/0929867324666170529122802.

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Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and chronic inflammation that affects over 30 million people all over the world. Most of the Alzheimer's patients also suffer from psychosis, aggression, agitation, depression, anxiety, and many other behavioral and psychological symptoms of dementia. Unfortunately, the currently available anti-AD drugs provide modest symptomatic relief, and they do not reverse the neurodegeneration. Therefore, the average life expectancy after diagnosis is between six and ten years. Researc

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Corvino, Angela, Antonia Scognamiglio, Ferdinando Fiorino, et al. "Pills of Multi-Target H2S Donating Molecules for Complex Diseases." International Journal of Molecular Sciences 25, no. 13 (2024): 7014. http://dx.doi.org/10.3390/ijms25137014.

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Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs) able to modulate multiple targets of interest, including the pathways where hydrogen sulfide (H2S) is involved. By incorporating an H2S donor moiety into a native drug, researchers have been able to simultaneously target multiple therapeutic pathways, resulting in improved treatment outcomes. This review gives the reader some pills of successful multi-target H2S-donating molecules as worthwhile tools to combat the multifactorial nature of complex disorders, suc

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Ogos, Martyna, Dorota Stary, and Marek Bajda. "Recent Advances in the Search for Effective Anti-Alzheimer’s Drugs." International Journal of Molecular Sciences 26, no. 1 (2024): 157. https://doi.org/10.3390/ijms26010157.

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Alzheimer’s disease, the most common form of dementia, is characterized by the deposition of amyloid plaques and neurofibrillary tangles in the brain, leading to the loss of neurons and a decline in a person’s memory and cognitive function. As a multifactorial disease, Alzheimer’s involves multiple pathogenic mechanisms, making its treatment particularly challenging. Current drugs approved for the treatment of Alzheimer’s disease only alleviate symptoms but cannot stop the progression. Moreover, these drugs typically target a single pathogenic mechanism, leaving other contributing factors unad

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Jalili-Baleh, Leili, Elaheh Babaei, Shahin Abdpour, et al. "A review on flavonoid-based scaffolds as multi-target-directed ligands (MTDLs) for Alzheimer's disease." European Journal of Medicinal Chemistry 152 (May 2018): 570–89. http://dx.doi.org/10.1016/j.ejmech.2018.05.004.

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Mazej, Tjaša, Damijan Knez, Anže Meden, Stanislav Gobec, and Matej Sova. "4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B." Molecules 26, no. 14 (2021): 4118. http://dx.doi.org/10.3390/molecules26144118.

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The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 e

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Ghafir El Idrissi, Imane, Angela Santo, Enza Lacivita, and Marcello Leopoldo. "Multitarget-Directed Ligands Hitting Serotonin Receptors: A Medicinal Chemistry Survey." Pharmaceuticals 17, no. 9 (2024): 1238. http://dx.doi.org/10.3390/ph17091238.

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Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus a

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Alov, Petko, Hristo Stoimenov, Iglika Lessigiarska, et al. "In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development." International Journal of Molecular Sciences 23, no. 21 (2022): 13650. http://dx.doi.org/10.3390/ijms232113650.

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The conventional treatment of neurodegenerative diseases (NDDs) is based on the “one molecule—one target” paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as “multi-target-directed ligands” (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research

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Mezeiova, Eva, Katarina Chalupova, Eugenie Nepovimova та ін. "Donepezil Derivatives Targeting Amyloid-β Cascade in Alzheimer's Disease". Current Alzheimer Research 16, № 9 (2019): 772–800. http://dx.doi.org/10.2174/1567205016666190228122956.

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: Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made a

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Pravin, Narayanaperumal, and Krzysztof Jozwiak. "Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer’s Diseases: Emerging Paradigms and Strategies." International Journal of Molecular Sciences 23, no. 11 (2022): 6085. http://dx.doi.org/10.3390/ijms23116085.

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Alzheimer’s disease (AD) is multifactorial, progressive and the most predominant cause of cognitive impairment and dementia worldwide. The current “one-drug, one-target” approach provides only symptomatic relief to the condition but is unable to cure the disease completely. The conventional single-target therapeutic approach might not always induce the desired effect due to the multifactorial nature of AD. Hence, multitarget strategies have been proposed to simultaneously knock out multiple targets involved in the development of AD. Herein, we provide an overview of the various strategies, fol

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20

Żołek, Teresa, Rosa Purgatorio, Łukasz Kłopotowski, Marco Catto, and Kinga Ostrowska. "Coumarin Derivative Hybrids: Novel Dual Inhibitors Targeting Acetylcholinesterase and Monoamine Oxidases for Alzheimer’s Therapy." International Journal of Molecular Sciences 25, no. 23 (2024): 12803. http://dx.doi.org/10.3390/ijms252312803.

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Multi-target-directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies like Alzheimer’s disease (AD). The synergistic inhibition of MAO-B, MAO-A, and AChE is believed to enhance treatment efficacy. A novel coumarin-based molecule substituted with O-phenylpiperazine via three- and four-carbon linkers at the 5- and 7-positions, has been identified as an effective MTDL against AD. Employing a medicinal chemistry approach, combined with molecular docking, molecular dynamic simulation, and ΔGbind estimation, two series of derivatives emerged as

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Marotta, Giambattista, Filippo Basagni, Michela Rosini, and Anna Minarini. "Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease." Molecules 25, no. 17 (2020): 4005. http://dx.doi.org/10.3390/molecules25174005.

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Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once o

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Asghar, Saira, Nousheen Mushtaq, Ahsaan Ahmed, Laila Anwar, Rabya Munawar, and Shamim Akhtar. "Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer’s Disease: AChE, MAO-B, and COX-2 as Molecular Targets." Molecules 29, no. 2 (2024): 490. http://dx.doi.org/10.3390/molecules29020490.

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Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer’s disease (AD) treatment due to a growing understanding of AD’s complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant A

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Kondeva-Burdina, Magdalena, Kaloyan Krastev, Tania Pencheva, and Violina T. Angelova. "Indole-based hydrazide-hydrazone and sulfonylhydrazone derivatives as MAO-B inhibitors with multitarget potential for neurodegenerative diseases." Pharmacia 72 (June 17, 2025): 1–13. https://doi.org/10.3897/pharmacia.72.e155372.

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Given the complex, multifactorial nature of Parkinson’s and Alzheimer’s diseases (PD and AD), along with the limited effectiveness of single-target treatments, multi-target-directed ligands (MTDLs) present a promising alternative approach. Monoamine oxidases A and B (MAO-A, MAO-B), as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are key targets in the development of MTDLs. In our previous study, we developed melatonin–donepezil hybrids with hydrazone (3a–r) and sulfonylhydrazone (5a–l) scaffolds, which showed AChE/BChE inhibition, antioxidant activity, low neurotoxicit

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Abatematteo, Francesca Serena, Mauro Niso, Enza Lacivita та Carmen Abate. "σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach". Molecules 26, № 12 (2021): 3743. http://dx.doi.org/10.3390/molecules26123743.

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Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse grou

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Yu, Lintao, Jian Shi, Xinfeng Cheng, et al. "Development of Phthalimide-Donepezil Hybrids as Potent Multitarget- Directed Ligands for the Treatment of Alzheimer’s Disease." Letters in Drug Design & Discovery 17, no. 9 (2020): 1155–63. http://dx.doi.org/10.2174/1570180817999200420120519.

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Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD. Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/ MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode. Results: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC

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Sherifa, Elabar. "Review on Multitarget Drug Design Based on Computational Strategies for the Treatment of Alzheimer's Disease." Alq J Med App Sci 4, no. 2 (2021): 181–90. https://doi.org/10.5281/zenodo.5248318.

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The multi-target drugs have recently attracted much attention as promising tools due to their advantages in the treatment of complex diseases and health conditions linked to drug resistance issues. The pharmaceutical industry is increasingly linking cheminformatics in the search for the development of novel drugs to be used in the treatment of diseases. These computational studies have the benefit of being less expensive and optimize the study time.  Amongst the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due

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Wang, Guoxing, Jiyu Du, Jie Ma, et al. "Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer’s Disease." Pharmaceuticals 16, no. 10 (2023): 1468. http://dx.doi.org/10.3390/ph16101468.

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Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 ± 0.04 μM) and butyrylcholinesterase (BuChE, IC50 = 6.11 ± 0.15 μM). And it could also potentially prevent t

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Gontijo, Vanessa Silva, Flávia P. Dias Viegas, Cindy Juliet Cristancho Ortiz, et al. "Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases." Current Neuropharmacology 18, no. 5 (2020): 348–407. http://dx.doi.org/10.2174/1385272823666191021124443.

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Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compou

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Rullo, Mariagrazia, Gabriella La Spada, Angela Stefanachi, Eleonora Macchia, Leonardo Pisani, and Francesco Leonetti. "Playing Around the Coumarin Core in the Discovery of Multimodal Compounds Directed at Alzheimer’s-Related Targets: A Recent Literature Overview." Molecules 30, no. 4 (2025): 891. https://doi.org/10.3390/molecules30040891.

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Alzheimer’s disease (AD) causes a great socioeconomic burden because of its increasing prevalence and the lack of effective therapies. The multifactorial nature of AD prompts researchers to search for new strategies for discovering disease-modifying therapeutics. To this extent, the multitarget approach holds the potential of synergic or cooperative activities arising from compounds that are properly designed to address two or more pathogenetic mechanisms. As a privileged and nature-friendly scaffold, coumarin has successfully been enrolled as the heterocyclic core in the design of multipotent

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Pandya, Maulik K., Himanshu Nilesh Panchal, Ashok Thalkar, Rehanabanu Darvadiya, Darshit Ram, and Pooja R. Maru. "Multi-Target Therapeutic Strategies for Alzheimer’s Disease: In Silico Investigation of Design of Benzyl Piperazine Derivatives as Dual-Acting Inhibitors." Journal of Neonatal Surgery 14, no. 32S (2025): 883–95. https://doi.org/10.63682/jns.v14i32s.7482.

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Alzheimer’s disease (AD) is advanced neurodegenerative complaint driven by pathological mechanisms, including acetyl cholinesterase over activity and beta-Amyloid plaque formation. Existing therapeutic strategies predominantly focus on single targets, offering only symptomatic relief without addressing the multifactorial countryside of the ailment. In this context, the present study aims to develop benzyl Piperazine-based results as promising multi-target-directed ligands (MTDLs) for AD management. A rational design is used to synthesize series of benzyl Piperazine derivatives, followed by ext

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Bolognesi, Maria, Anna Minarini, Michela Rosini, Vincenzo Tumiatti, and Carlo Melchiorre. "From Dual Binding Site Acetylcholinesterase Inhibitors to Multi-Target-Directed Ligands (MTDLs): A Step Forward in the Treatment of Alzheimers Disease." Mini-Reviews in Medicinal Chemistry 8, no. 10 (2008): 960–67. http://dx.doi.org/10.2174/138955708785740652.

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Zhou, Qian, Xu-Nian Wu, Wei-Hao Luo, et al. "Discovery of Effective Inhibitors Against Phosphodiesterase 9, a Potential Therapeutic Target of Alzheimer’s Disease with Antioxidant Capacities." Antioxidants 14, no. 2 (2025): 123. https://doi.org/10.3390/antiox14020123.

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Alzheimer’s disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) is emerging as a promising target for AD therapy. In this study, by combining a PDE9 inhibitor C33 with the antioxidant melatonin, we designed and discovered a series of pyrazolopyrimidinone derivatives that simultaneously inhibit PDE9 and possess a

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Maramai, Samuele, Mohamed Benchekroun, Moustafa T. Gabr, and Samir Yahiaoui. "Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations." BioMed Research International 2020 (July 3, 2020): 1–27. http://dx.doi.org/10.1155/2020/5120230.

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Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at

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Simakov, Alexey, Stecy Chhor, Lhassane Ismaili, and Hélène Martin. "Nrf2 Activation and Antioxidant Properties of Chromone-Containing MTDLs for Alzheimer’s Disease Treatment." Molecules 30, no. 9 (2025): 2048. https://doi.org/10.3390/molecules30092048.

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide and imposing a significant social and economic burden. Despite extensive research, there is still no effective cure for this disease. AD is multifactorial and involves multiple etiopathogenic mechanisms, one of which is oxidative stress. Consequently, the Nrf2/ARE pathway, which regulates the expression of cellular defense genes, including those for antioxidant enzymes, is considered to be a prospective therapeutic target for AD. Meanwhile, multitarget-directed ligands (MTDLs) are a promising appr

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Bachurin, Sergey O., Elena F. Shevtsova, Galina F. Makhaeva, et al. "Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease." International Journal of Molecular Sciences 23, no. 22 (2022): 13925. http://dx.doi.org/10.3390/ijms232213925.

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The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set o

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Nachon, Florian, Eugénie Carletti, Cyril Ronco, et al. "Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase." Biochemical Journal 453, no. 3 (2013): 393–99. http://dx.doi.org/10.1042/bj20130013.

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The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesteras

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Polini, Beatrice, Lorenzo Zallocco, Francesca Gado та ін. "A Proteomic Approach Identified TFEB as a Key Player in the Protective Action of Novel CB2R Bitopic Ligand FD22a against the Deleterious Effects Induced by β-Amyloid in Glial Cells". Cells 13, № 10 (2024): 875. http://dx.doi.org/10.3390/cells13100875.

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Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration the multifaceted nature of NDDs, development of multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target the cannabinoid receptor type II (CB2R) are rapidly emerging as novel effective MTDLs against common NDDs, such as Alzheimer’s disease (AD). We recently developed the first CB2R bitopic/d

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Hu, Jinhui, Li Chen, Zhonghui Lu, et al. "Design, Synthesis and Antitumor Activity of Novel Selenium-Containing Tepotinib Derivatives as Dual Inhibitors of c-Met and TrxR." Molecules 28, no. 3 (2023): 1304. http://dx.doi.org/10.3390/molecules28031304.

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Cellular mesenchymal–epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands (MTDLs) strategy provides a logical approach to drug combinations and would adequately address the pathological complexity of cancer. In this work, we designed and synthesized a series of selenium-containing tepotinib derivatives b

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Iman, Kanzal, Muhammad Usman Mirza, Nauman Mazhar, Michiel Vanmeert, Imran Irshad, and Mohammad A. Kamal. "In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease." CNS & Neurological Disorders - Drug Targets 17, no. 1 (2018): 54–68. http://dx.doi.org/10.2174/1871527317666180115162422.

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Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic fu

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Wang, Xiao-Qin, Chu-Ping Zhao, Long-Cheng Zhong, et al. "Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-target Agents for the Treatment of Alzheimer’s Disease." Molecules 23, no. 12 (2018): 3100. http://dx.doi.org/10.3390/molecules23123100.

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Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ1–42 aggregation inhibition and antioxidant activity. The structure-a

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Alaaeddine, Rana A. "The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs)". Current Medicinal Chemistry 28, № 11 (2021): 2260–300. http://dx.doi.org/10.2174/1875533xmta54mzkc0.

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Raevsky, Oleg A., Azat Mukhametov, Veniamin Y. Grigorev, et al. "Applications of Multi-Target Computer-Aided Methodologies in Molecular Design of CNS Drugs." Current Medicinal Chemistry 25, no. 39 (2019): 5293–314. http://dx.doi.org/10.2174/0929867324666170920154111.

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The discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to the discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bioinformatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL. In this review, we analyze the current status of the development of mu

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Vishesh, Verma, Kumar Nitin, and Kumar Sumit. "Anti-Alzheimer potential of coumarin derivatives: A review." World Journal of Advanced Research and Reviews 20, no. 1 (2023): 825–35. https://doi.org/10.5281/zenodo.12239640.

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Alzheimer’s is a type of neurodegenerative diseases (NDs) found in old age people which main causes the dementia and various brain disorders. FDA approved drugs used commonly in treatment of moderate to severe Alzheimer's disease are Donepezil, Rivastigmine, Galantamine and Memantine. However, these approved drugs provide only palliative support not complete cure. So, urgency of new molecules has been becoming so important to cure this complex Disease. Coumarin or 2-H-Chromen-2-one is an oxygenated heterocyclic compound, which is isolated from plants named Dipteryx odorata Willd, (Fabace

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Blaikie, Laura, Graeme Kay, and Paul Kong Thoo Lin. "Current and emerging therapeutic targets of alzheimer's disease for the design of multi-target directed ligands." MedChemComm 10, no. 12 (2019): 2052–72. http://dx.doi.org/10.1039/c9md00337a.

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Chaves, Sílvia, Simonetta Resta, Federica Rinaldo, et al. "Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease." Molecules 25, no. 4 (2020): 985. http://dx.doi.org/10.3390/molecules25040985.

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A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluo

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Carocci, Alessia, Alexia Barbarossa, Rosalba Leuci, et al. "Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease." Antioxidants 11, no. 9 (2022): 1631. http://dx.doi.org/10.3390/antiox11091631.

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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 mo

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Lu, Xin, Si-yu He, Qi Li, et al. "Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer’s disease." Bioorganic & Medicinal Chemistry 26, no. 8 (2018): 1665–74. http://dx.doi.org/10.1016/j.bmc.2018.02.014.

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Toczek, Marek, Piotr Ryszkiewicz, Patryk Remiszewski, et al. "Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis." International Journal of Molecular Sciences 24, no. 13 (2023): 10942. http://dx.doi.org/10.3390/ijms241310942.

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The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then

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Pons, Jean, Routier, Buron, Chalon та Renard. "Toward an Innovative Treatment of Alzheimer’s Disease: Design of MTDLs Targeting Acetylcholinesterase and α-7 Nicotinic Receptors". Proceedings 22, № 1 (2019): 88. http://dx.doi.org/10.3390/proceedings2019022088.

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Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to symptomatic treatment, and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Since the therapeutic paradigm “one compound–one-target” has shown its limits in the treatment of AD, new strategies are emerging to overcome the lack of efficiency of the current pharmacotherapy in the past decade. The most promising is the multitarget-directed ligands (MTDL

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Liu, Weihua, Donghai Zhao, Zhiwen He, et al. "Synthesis, Characterization and Biological Evaluation of Benzothiazole–Isoquinoline Derivative." Molecules 27, no. 24 (2022): 9062. http://dx.doi.org/10.3390/molecules27249062.

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Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi–target–directed ligands (MTDLs), we synthesized a series of (R)–N–(benzo[d]thiazol–2–yl)–2–(1–phenyl–3,4–dihydroisoquinolin–2(1H)–yl) acetamides with substituted benzothiazoles and (S)–1–phenyl–1,2,3,4–tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory

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