Alzheimer's disease is a chronic and progressive brain neurodegenerative disease affecting over 30 million people globally. Currently, no effective treatment is available due to multiple factors ...involved in the progression of AD. Given that the numerous AD-related targets in the disease network, the multi-target-directed ligands (MTDLs) strategy are considered as the promising strategy to treat AD. Herein, the multi-target compounds with/without ChEs are in clinical and in progress are reviewed. To further characterize the drug-likeness, and ADME properties are calculated using the Qikprop. This review will provide highlights for the treatment of AD.
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•This work reviews multi-target strategies with ChEs inhibition.•This work reviews multi-target strategies without ChEs inhibition.•This work predicts ADME properties of the candidate compounds.
Recently, multi‐target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3Rs) and cholinesterases are involved in ...pathophysiology of AD, identification of dual‐acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6‐chloro‐N‐methyl‐N‐3‐(4‐methylpiperazin‐1‐yl)propyl‐1H‐indole‐2‐carboxamide) and compound 4 (7‐chloro‐N‐(1‐methylpiperidin‐3‐yl)methyl‐1,2,3,4‐tetrahydroisoquinoline‐2‐carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3R EC50 = 0.73 nM; compound 4: H3R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.
H3 antagonistic activity combined with anticholinesterase properties of two computationally identified non‐imidazole compounds was assessed. Biological evaluations indicated inhibitory activity of studied compounds in nanomolar and micromolar values for H3R antagonizing and cholinesterase inhibition, respectively. The presented candidate compounds can be used for further development of novel anti‐Alzheimer agents.
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-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.
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•A novel series of 4-(Diethylamino)-Salicylaldehyde (3a-p) thiosemicarbazones was synthesized and characterized.•Probed as cholinesterase, carbonic anhydrase and α-Glycosidase ...Inhibitors.•SAR showed that aryl halides and hydroxybenzylidene moieties are critical for inhibition of enzymes.•In silico, molecular docking was carried out to study binding of active compounds with enzymes.•Pharmacokinetic properties of the most active novel compounds.
With the fading of ‘one drug-one target’ approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer’s disease.
The medicinal chemistry and pharmacological properties of the lead molecules of 92 hybrids published since 1998-Dec 2017 have been reviewed.
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Alzheimer’s disease (AD) is a genetically ...complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.
Compounds capable of interacting with single or multiple targets involved in Alzheimer’s disease (AD) pathogenesis are potential anti-Alzheimer’s agents. In our aim to develop new anti-Alzheimer’s ...agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and monoamine oxidases monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B). Four compounds are very promising: multiple AChE (IC50 = 7.31 μM), BChE (IC50 = 0.56 μM) and MAO-B (IC50 = 26.1 μM) inhibitor 10, dual AChE (IC50 = 2.25 μM) and BChE (IC50 = 0.81 μM) inhibitor 22, selective BChE (IC50 = 0.06 μM) inhibitor 13, and selective MAO-B (IC50 = 0.18 μM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid β1–42 (Aβ1–42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aβ1–42 anti-aggregation effects.
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•Novel N-alkylpiperidine carbamates were designed, synthesized and bioevaluated.•Compound 10 inhibits cholinesterases, monoamine oxidase B and is neuroprotective.•Compound 13 is a potent selective butyrycholinesterase inhibitor.•Neuroprotective compound 16 inhibits monoamine oxidase B and amyloid β aggregation.•Compound 22 inhibits both acetylcholinesterase and butyrylcholinesterase.
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in elderly people. Considering the multifactorial nature of AD, the concept of multi-target-directed ligands (MTDLs) has ...recently emerged as a new strategy for designing therapeutic agents on AD. MTDLs are confirmed to simultaneously affect diverse targets which contribute to etiology of AD. As the most potent approved drug, donepezil affects various events of AD, like inhibiting cholinesterases activities, anti-Aβ aggregation, anti-oxidative stress et al. Modifications of donepezil or hybrids with pharmacophores of donepezil in recent five years are summarized in this article. On the basis of case studies, our concerns and opinions about development of donepezil derivatives, designing of MTDLs, and perspectives for AD treatments are discussed in final part.
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•We described multi-functional cholinesterase inhibitors based on donepezil.•Compounds with high activities and diverse functions are classified by their targets.•In final part, we put forward perspectives rarely mentioned in previous articles.
As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the ...combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6 receptor (Kb = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE = 12 nM, IC50hBuChE = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.
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•Novel multi-target-directed ligands for Alzheimer's disease were developed.•The compounds combine cholinesterase inhibitory and 5-HT6 antagonist activities.•Compound 12 with balanced in vitro activity was selected for in-depth studies.•Central cholinergic activity of compound 12 was confirmed in vivo.
Tacrine was the first drug approved for the treatment of Alzheimer's disease (AD) in 1993, which was withdrawn in 2013 due to its hepatotoxicity. However, new, non-hepatotoxic tacrine derivatives ...have been constantly searched for. In this context, since 1997, we have prepared a number of diversely functionalized tacrines by changing the benzene ring present in tacrine to five- or six-membered aromatic ring cores that could present anticholinesterasic activity and additional pharmacological properties. The new compounds were designed as juxtaposed structures between tacrine and the well-known Ca2+ antagonists 1,4-dihydropyridines, with the goal of obtaining multi-target directed ligands for AD. In this account, we present our results on the PyridoTacrine (PyrTac) family of tacrine analogues, resulting from the substitution of the benzene ring by a pyridine. We highlight their pharmacological profile and review similar analogues in the literature. A first set of PyrTac showed inhibitory activity of cholinesterases (ChE) and a blocking profile of voltage-gated Ca2+ channels (VGCC). A second family with improved ChE inhibition lost VGCC blocking activity. However, the lead compound of this family (5f) presented an activating profile of the phosphatase 2A (PP2A) and showed interesting outcomes in experimental in vivo models of AD and stroke. We have identified the PyrTac ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzob 1,8naphthyridine-3-carboxylate (5f), which presents additional pharmacological properties beyond the mere cholinergic improvement. These new properties warrant attention to 5f and its further development as a new potential therapeutic agent for AD therapy.
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•Tacrine is a good scaffold to design multitarget drugs for Alzheimer's disease.•Pyridotacrines are derivatives from the replacement of the benzene-fused ring by pyridine.•Pyridotacrines avoid toxic metabolism and allow the design of multitarget compounds.•Among contributions by others, we described several families of Pyridotacrines.•Our compounds presented new biological activities of relevance for Alzheimer's disease.
•Nitrogen heterocycles as new anti-Alzheimer's (AD) agents highlighting past molecular designs.•The development of safe, low-cost and highly active therapeutic agents incorporating ...nitrogen-containing heterocycles against AD is an important research topic.•Success stories of nitrogen-containing heterocyclic compounds in AD drug discovery.•We propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD.
Alzheimer’s disease (AD) is a detrimental neurodegenerative disease that progressively worsens with time. Clinical options are limited and only provide symptomatic relief to AD patients. The search for effective anti-AD compounds is ongoing with a few already in Phase III clinical trials, yet to be approved. Heterocycles containing nitrogen are important to biological processes owing to their abundance in nature, their function as subunits of biological molecules and/or macromolecular structures, and their biological activities. The present review discusses previously used strategies, SAR, relevant in vitro and in vivo studies, and success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. Also, we propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD.
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