The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease

Mesiti, Francesco; Chavarria, Daniel; Gaspar, Alexandra; Alcaro, Stefano; Borges, Fernanda

doi:10.1016/j.ejmech.2019.111572

Cited by 56 publications

(27 citation statements)

References 91 publications

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“…Accordingly, in the design of multi-target drugs, a cholinesterase inhibitor is selected as one of the pharmacophores. A second pharmacophore is then attached via a spacer to the cholinesterase inhibitor [40][41][42][43][44]. Such hybrid molecules expand the range of pharmacological activities of a parent anticholinesterase compound by adding antiaggregant, antioxidant, and other desirable properties [45][46][47][48][49][50].…”

Section: Introductionmentioning

confidence: 99%

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

et al. 2020

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New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC50(BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

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Section: Introductionmentioning

confidence: 99%

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

et al. 2020

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“…Some of the most appealing analogues are the result of molecular hybridization, where the combination of multiple pharmacophores should reproduce the activity of the parent compounds while retaining a certain degree of selectivity towards the selected targets. These hybrid structures can be combined ( i ) by using a linker that spaces and anchors the biologically active moieties, ( ii ) by fusing the active sections together, ( iii ) or simply by merging the functionalities known to be involved in the target engagement [ 21 ]. The rational design behind these potential new drugs has been frequently inspired by well-known and/or approved drugs such as THA [ 22 , 23 ], Donepezil [ 24 , 25 ], or Rivastigmine, along with different natural bioactive derivatives such as resveratrol or curcumin [ 26 ], although other very interesting structural combinations/modifications have been recently identified.…”

Section: Introductionmentioning

confidence: 99%

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Maramai

Benchekroun

Gabr

et al. 2020

BioMed Research International

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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 the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

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“…Considering the extraordinarily complicated pathogenesis of AD, simultaneous impact on multi-targets are regarded as an important therapeutic strategy for treatment of this disease. (de Freitas Silva et al, 2018;Li et al, 2018;Cummings et al, 2019;Mesiti et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Nowadays, multi-targeting agents have been referred as an effective strategy for the treatment of multifactorial diseases like AD (de Freitas Silva et al, 2018;Cummings et al, 2019;Mesiti et al, 2019;Wang et al, 2019). Among several degenerative features that have been identified, neuroinflammation and cholinergic deficit are considered as the major contributing factors in the pathogenesis of AD.…”

Section: Introductionmentioning

confidence: 99%

Circumdatin D Exerts Neuroprotective Effects by Attenuating LPS-Induced Pro-Inflammatory Responses and Downregulating Acetylcholinesterase Activity In Vitro and In Vivo

Zhang

Liu

et al. 2020

Front. Pharmacol.

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Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes, of which systemic inflammation may play a key role to promote neurodegeneration, and acetylcholinesterase (AChE) is a target protein to induce cholinergic transmission. Inhibitors toward inflammation and targeting AChE are regarded to promote cholinergic signaling of the central nervous system in AD therapy. During the search for neuroprotection agents from marine-derived compounds, seven circumdatin-type alkaloids from a coral-associated fungus Aspergillus ochraceus LZDX-32-15 showed potent inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and activation of NF-kB report gene along with anti-AChE activities. Among the tested compounds, circumdatin D showed the most potent inhibitory effect against AChE activity and NO production. In vivo experiments using AD-like nematode models demonstrated that circumdatin D effectively delayed paralysis of CL4176 worms upon temperature up-shift via suppression of AChE activity and inflammatory-related gene expression. Moreover, circumdatin D interfered with inflammatory response by inhibiting the secretion of pro-inflammatory cytokines in LPS-induced BV-2 and primary microglia cells. Mechanistically, circumdatin D modulated Toll-like receptor 4 (TLR4)-mediated NF-kB, MAPKs and JAK/STAT inflammatory pathways in LPS-stimulated BV-2 cells, and protected primary neurons cells from LPS-induced neurotoxicity. Thus, circumdatin D is a potential agent for neuroprotective effects by the multi-target strategy.

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The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease

Cited by 56 publications

References 91 publications

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Circumdatin D Exerts Neuroprotective Effects by Attenuating LPS-Induced Pro-Inflammatory Responses and Downregulating Acetylcholinesterase Activity In Vitro and In Vivo

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