Targeted synthesis and biological activity of polypharmacophoric agents for the treatment of neurodegenerative diseases

Соколов, В. Б.; Махаева, Галина Ф.; Aksinenko, А. Yu.; Grigoriev, V. V.; Shevtsova, E. F.; Бачурин, С. О.

doi:10.1007/s11172-017-1953-y

Cited by 19 publications

(4 citation statements)

References 46 publications

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“…The prepared conjugates were subjected to primary screening using the methodology relevant to the treatment of neurodegenerative diseases that we proposed previously [6]. The system included neurotransmitter targets related to the compensation of cognitive functions, including: cholinesterases and glutamate receptors; mitochondria and the prevention of the mitochondrial permeability transition, which may provide cyto-and neuroprotection; and microtubules, whose destabilization is a specific feature of certain neurodegenerative diseases, e.g., tauopathies.…”

Section: Chemistrymentioning

confidence: 99%

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Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease

Бачурин

Shevtsova

Makhaeva

et al. 2022

IJMS

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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 of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects.

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Section: Chemistrymentioning

confidence: 99%

“…Previously, we developed a synthetic algorithm for the conjugation of several pharmacophoric ligands that act on the key stages of pathogenesis, synthesized hybrid structures, and performed screening for a broad range of biotargets participating in the pathogenesis of AD [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease

Бачурин

Shevtsova

Makhaeva

et al. 2022

IJMS

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“…In particular, compounds possessing a highly promising combination of types of activity were identified among original adamantane‐containing indoles (Figure 8). 176,177 The cognitive‐stimulation can be due to the influence on the brain cholinergic and glutamatergic systems. First of all, these compounds are selective BChE inhibitors, with IC 50 being in the micromolar range (IC 50 = 5–15 μM) 176 .…”

Section: Mitochondria As a Essential Target For Multitarget Neuroactimentioning

confidence: 99%

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Shevtsova

Maltsev

Vinogradova

et al. 2020

Medicinal Research Reviews

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The mitochondria‐targeting drugs can be conventionally divided into the following groups: those compensating for the energy deficit involved in neurodegeneration, including stimulants of mitochondrial bioenergetics and activators of mitochondrial biogenesis; and neuroprotectors, that are compounds increasing the resistance of mitochondria to opening of mitochondrial permeability transition (MPT) pores. Although compensating for the energy deficit and inhibition of MPT are obvious targets for drugs used in the very early stages of Alzheimer‐like pathology, but their use as the monotherapy for patients with severe symptoms is unlikely to be sufficiently effective. It would be optimal to combine targets that would provide the cognitive‐stimulating, the neuroprotective effects and the ability to affect specific disease‐forming mechanisms. In the design of such drugs, assessment of their potential mitochondrial‐targeted effects is of particular importance. The possibility of targeted drug design for simultaneous action on mitochondrial and neurotransmitter's receptors targets is, in particularly, based on the known interplay of various cellular pathways and the presence of common structural components. Of particular interest is directed search for multitarget drugs that would act simultaneously on mitochondrial calcium‐dependent functions, the targets (receptors, enzymes, etc.) facilitating neurotransmission, and the molecular targets related to the action of so‐called disease‐modifying factors, in particular, the formation and overcoming of the toxicity of β‐amyloid or hyperphosphorylated tau protein. The examples of such approaches realized on the level of preclinical and clinical trials are presented below.

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“…Earlier, we have proposed various options for modifi cation of biologically active structures with additional pharmacophores expanding the spectrum of biological activity of the target structures. [7][8][9] In the present work, we describe the conjugation of the drug Edaravone (1) with various pharmacologically active fragments based on bispropargylation of compound 1 and the subsequent click-reaction of copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition in order to design new potential multitarget drugs for treatment of neurodegenerative diseases. The chosen farmacoactive fragments include 1-aminoadamantane derivatives, the known drugs for treatment of neurodegenerative diseases Amantadine and Memantine, carbazole and tetrahydrocarbazole derivatives, a heterocyclic base, for example, of the drug Carprofen, and tetrahydro-γ-carboline derivatives, a fragment of the known drugs Diazolin and Dimebon, as well as many representatives of neuroprotectors.…”

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confidence: 99%

Molecular design of multitarget neuroprotective agents 5. Modification with pharmacologically active fragments of 4,4- and 1,4-dipropargyl-5-methyl-2-phenylpyrazol-3-one

2021

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Targeted synthesis and biological activity of polypharmacophoric agents for the treatment of neurodegenerative diseases

Cited by 19 publications

References 46 publications

Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease

Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Molecular design of multitarget neuroprotective agents 5. Modification with pharmacologically active fragments of 4,4- and 1,4-dipropargyl-5-methyl-2-phenylpyrazol-3-one

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