Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, ...galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.
In the current study, we designed, synthesized, and characterized a series of substituted pyrazolo4,3-cpyrazoles. These novel compounds were evaluated in vitro for their inhibitory activity over a ...panel of protein kinases to determine their potential therapeutic applications against Alzheimer's disease. To gain deeper insight into the binding interactions between the most potent analogues and their respective kinase targets, advanced molecular simulations were performed. In parallel, the ability of pyrazolo4,3-cpyrazoles to inhibit Aβ40 aggregation was assessed using biophysical techniques such as circular dichroism and Thioflavin T assays. Our results highlight the specific heterocycle as a highly promising and synthetically versatile scaffold for developing inhibitors of both AD-relevant kinases and amyloid-β aggregation. Although more effort is needed to assess the possibility of developing multi-target inhibitors, pyrazolo4,3-cpyrazole analogues demonstrated significant activities against their individual targets, indicating substantial capacity of the heterocyclic scaffold for further optimization toward both directions. Overall, our findings emphasize the potential of properly substituted pyrazolo4,3-cpyrazoles as multifunctional agents targeting key processes in Alzheimer's disease pathology.
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•Mono-substituted pyrazolo4,3-cpyrazoles showed promising DYRK1A and CLK1 inhibitory activity.•Di-substituted pyrazolo4,3-cpyrazoles were potent inhibitors of amyloid β aggregation.•Simulations were utilized for assessing binding geometry of most promising analogues.
Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal ...death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzodoxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ± 0.010 μM), BuChE (IC50 = 1.085 ± 0.035 μM), and significant amyloid-beta aggregation (20 μM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ± 0.055 × 10−6 cm s−1) in PAMPA assay and neuro protective properties (40 μM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Aβ1-42 induced ICV rat model). The compound 92, at a dose of 10 mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD.
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•Development of a library of 2-substituted benzodoxazol-5-amine analogs by scaffold hopping guided MTDL & their synthesis.•Synthesized derivatives were evaluated through various in-vitro and in-vivo studies.•Compounds 92 exhibited inhibition of AChE, BuChE, Aβ1-42 aggregation and neuroprotective properties.•Compound 92 represents a beneficial lead for the discovery of safe and effective disease-modifying agents for AD.
The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that ...should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
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•A novel class of fluorobenzohomoadamantanamine‒chlorotacrine hybrids was synthesized.•The hybrids are up to 44-fold more potent than 6-chlorotacrine for hAChE inhibition.•The hybrids are up to 24-fold more potent than 6-chlorotacrine for hBChE inhibition.•The hybrids are up to 2-fold more potent than memantine for NMDA antagonism.•Most of the hybrids are brain permeable, according to the PAMPA-BBB assay.
A key factor in the success of the MTDLs drug discovery approach is the selection of suitable target proteins. Based on the results of our previous research regarding dual-target inhibitors of ...AChE/GSK-3β and analysis of target proteins, in the current study, 28 hybrids were designed and synthesized. Docking studies allowed us to rationalize the binding mode of the synthesized compounds in both targets. In vitro enzyme inhibition studies identified compound GT15 as a lead molecule with preferential AChE/GSK-3β inhibition (hAChE IC50 = 1.2 ± 0.1 nM; hGSK-3β IC50 = 22.2 ± 1.4 nM). In addition, GT15 showed high kinase selectivity for GSK-3, except for DYRK1, with inhibition rate of 83.69% and 67.94% against DYRK1α and DYRK1β at a concentration of 20 μM. The compound also exhibited good permeability across the blood-brain-barrier and ability to inhibit the phosphorylation of tau protein. Upon oral administration, GT15 exhibited promising cognitive improvement in the scopolamine-induced cognitive deficit mice in the Morris water maze model. These results suggest that AChE and GSK-3 based multitargeted approach have therapeutic potential for Alzheimer’s disease.
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•A series of thiazolopyridyl tetrahydroacridines have been synthesized as AChE and GSK-3 dual inhibitors.•Potent nanomolar AChE/GSK-3β inhibitors were achieved.•The most promising hybrid have high kinase selectivity profiles for the CMGC kinase family.•The most active compounds displayed low toxicity in biological assays.•Demonstrated reversal of scopolamine-induced learning and memory impairment in ICR mice.
Alzheimer's disease (AD) is a multifactorial, irreversible, and age-related neurodegenerative disorder among the elderly. AD attracts attention due to its complex pathogenesis, morbidity and ...mortality rates, and the limitations of drugs used in the treatment of AD. Cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are used in the clinic. While tacrine, donepezil, galantamine, and rivastigmine are cholinesterase inhibitors, memantine is a non-competitive NMDA receptor antagonist. However, these drugs could not delay the progress of AD. The traditional clinical approach which is the one drug-one target concept is not entirely effective in the treatment of AD. Also, it is of high-priority to develop potent and novel anti-AD drugs by the design concept of multitarget directed ligands (MTDLs) which combine pharmacophores interacting with different pathways in AD. This article provides an overview of the noteworthy structural modifications made to tacrine to develop novel candidates for anti-Alzheimer drugs. Due to the complex pathology of AD, multifunctional tacrine-based ligands targeting different hallmarks, β-amyloid, tau protein, N-methyl-Daspartate receptor, cholinesterases, monoamine oxidases, secretases, have been studied. Here, tacrinebased derivatives including heterocyclic structures such as dihydroxypyridine, chromene, coumarin, pyrazole, triazole, tetrahydroquinolone, dipicolylamine, arylisoxazole were reported with promising anti-AD effects compared to tacrine. In vitro and in vivo assays showed that new tacrine-based hybrids, which are selective, neuroprotective, and non-hepatotoxic, might be considered as remarkable anti-AD drug candidates for further clinical studies.
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 the generation of amyloid plaques by inhibiting self-induced Aβ aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aβ. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1β, TNF-α; IC50 = 0.62 ± 0.07 μM, 1.78 ± 0.21 μM, 1.31 ± 0.28 μM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood–brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD.
Alzheimer's disease (AD) is a devastating syndrome that accounts for 60–70 % of all dementia cases, putting an enormous burden on global healthcare and economy. Unfortunately, there is no cure for ...AD, and the currently approved drugs are limited in their effects. Given the various pathological mechanisms behind AD, the “one‐target, one‐drug” paradigm for drug design became obsolete, and a new paradigm, polypharmacology, emerged. Consequently, a greater focus has been put towards multi‐target directed ligands (MTDLs), as these can regulate several targets operating in the disease network. Parallel to that, cholinesterase inhibitors have regained popularity after decades of being considered only symptomatic agents with no disease‐modifying properties. In this review, the current AD hypotheses and therapeutic targets, the concept of polypharmacology in AD pathology and the importance of cholinesterases in the pathogenesis and biochemical processes of AD are discussed, with a final overview of the current development in cholinesterase‐based MTDLs.
The multifactorial facet of Alzheimer′s disease (AD) appears as the main culprit for the lack success in finding effective therapies. This review discusses the current AD hypotheses being explored, the remerging potential of cholinesterase inhibitors, and how to improve the drugs’ effectiveness by following the new paradigm of drug design, polypharmacology, putting an emphasis on cholinesterase‐based multi‐target directed ligands (MTDLs).
Alzheimer's disease (AD) is challenging due to its irreversible declining cognitive symptoms and multifactorial nature. This work tackles targeting both acetylcholinesterase (AChE) and BuChE with a ...multitarget-directed ligand (MTDL) through design, synthesis, and biological and in silico evaluation of a series of twenty eight new 5-substituted-2-anilino-1,3,4-oxadiazole derivatives 4a-g, 5a-g, 9a-g and 13a-g dual inhibitors of the target biomolecules. In vitro cholinesterases inhibition and selectivity assay of the synthesized derivatives showed excellent nanomolar level inhibitory activities. Compound 5a, the most potent inhibitor, elicited IC50s of 46.9 and 3.5 nM against AChE and BuChE, respectively (SI = 0.07), 5 folds better than the known dual inhibitor Rivastagmine. In vivo and ex vivo investigation showed that 5a significantly inhibited MDA levels and increased GSH contents, thus, attenuating the brain tissue oxidative stress. Additionally, 5a significantly decreased AChE and BuChE levels and inhibited self-mediated β-amyloid aggregation in brains of treated rats. Histopathological and immunohistochemical evaluation demonstrated lessened damage and decreased caspase-3 and VEGF expression levels. In silico prediction of 5a's pharmacokinetics and toxicity profiles reflected promising results. Finally, 5a demonstrated tight binding interactions with the two target biomolecules upon docking along with stable complex formation with its bio-targets throughout the 100 ns MD trajectories.
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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 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs
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![The pyrazolo[4,3-c]pyrazole...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2772-4174/small "The pyrazolo[4,3-c]pyrazole core as a novel and versatile scaffold for developing dual DYRK1A-CLK1 inhibitors targeting key processes of Alzheimer’s disease pathology")
