Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer’s Diseases: Emerging Paradigms and Strategies

Pravin, Narayanaperumal; Jóźwiak, Krzysztof

doi:10.3390/ijms23116085

Cited by 15 publications

(6 citation statements)

References 91 publications

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“…Nonetheless, a multitude of compelling studies have reported that they can act only for limited periods and present a risk of harmful side effects. To overcome these drawbacks, researchers are eager to find and develop innovative candidates to combat this disorder. − In this line, burgeoning evidence revealed that a wide range of selenocompounds has great effectiveness in AD. − …”

Section: Selenized Small Molecule Drugsmentioning

confidence: 99%

Selenization of Small Molecule Drugs: A New Player on the Board

Morán-Serradilla,

Plano,

Sanmartín

et al. 2024

J. Med. Chem.

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There is an urgent need to develop safer and more effective modalities for the treatment of a wide range of pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Throughout the years, selenium (Se) has attracted a great deal of attention due to its important role in human health. Besides, a growing body of work has unveiled that the inclusion of Se motifs into a great number of molecules is a promising strategy for obtaining novel therapeutic agents. In the current Perspective, we have gathered the most recent literature related to the incorporation of different Se moieties into the scaffolds of a wide range of known drugs and their feasible pharmaceutical applications. In addition, we highlight different representative examples as well as provide our perspective on Se drugs and the possible future directions, promises, opportunities, and challenges of this ground-breaking area of research. ■ SIGNIFICANCE • Significance: The development of novel compounds for the treatment of numerous pathologies has become a priority due to the lack of effective therapeutic options. • Impact: This work highlights the potential of incorporating Se moieties into the scaffold of several drugs to develop novel safer bioactive compounds. • Innovation: This Perspective discusses the development of selenoderivatives of a wide array of drugs and their biological applications and proposes novel avenues to continue exploring this outstanding research area.

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Section: Selenized Small Molecule Drugsmentioning

confidence: 99%

Selenization of Small Molecule Drugs: A New Player on the Board

Morán-Serradilla,

Plano,

Sanmartín

et al. 2024

J. Med. Chem.

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“…Given the multifactorial nature of their pathogenicity, neurodegenerative diseases, such as Alzheimer's disease, appear to be able to respond positively to treatment with pleiotropic compounds, provided that they can be administered precociously through the early diagnostic stage which still needs to be improved. Some studies have recently focused on this approach [4][5][6]. Overall, the literature reports four types of pleiotropic agents designed for the potential management of Alzheimer's disease (Figure 2).…”

Section: The Application Of the Concept Of Pleiotropic Active Compoun...mentioning

confidence: 99%

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Guiselin,

Lecoutey,

Rochais

et al. 2023

Pharmaceutics

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The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.

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“…Over the years, molecules containing both melatonin scaffold and a donepezil fragment have been demonstrated to possess strong inhibitory activity against acetylcholinesterase [ 19 , 20 , 21 , 22 ]. Melatonin holds promise as a potential therapeutic agent for developing new multitarget hybrids against neurodegeneration, including AD, because it can modulate the balance of Aβ production/clearance and mitigate Aβ neurotoxicity [ 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer’s Disease

Angelova,

Georgiev,

Pencheva

et al. 2023

Pharmaceuticals

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Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or sulfonyl hydrazone (5a–l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H2O2-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood–brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.

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Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer’s Diseases: Emerging Paradigms and Strategies

Cited by 15 publications

References 91 publications

Selenization of Small Molecule Drugs: A New Player on the Board

Selenization of Small Molecule Drugs: A New Player on the Board

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer’s Disease

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