Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aβ clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aβ42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood-brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 μM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aβ42 expressing flies and generating a better outcome than doxycycline (50 μM). Moreover, 22 proved to be able to decrease Aβ42 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual Aβ/Tau aggregation inhibition in AD.
- Klíčová slova
- aggregation inhibitors, bivalent ligands, multitarget-directed ligands, protein aggregates, tau protein, β-amyloid,
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- Drosophila melanogaster MeSH
- Drosophila MeSH
- proteiny tau MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- proteiny tau MeSH
Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 μM) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 μM) might add a piece to the puzzle of its anti-ALS molecular profile.
- Klíčová slova
- ALS, MAO, MTDLs, Polypharmacology, benzothiazoles, rasagiline, riluzole,
- MeSH
- amyotrofická laterální skleróza * farmakoterapie MeSH
- indany MeSH
- lidé MeSH
- ligandy MeSH
- neuroprotektivní látky * farmakologie terapeutické užití MeSH
- riluzol farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- indany MeSH
- ligandy MeSH
- neuroprotektivní látky * MeSH
- rasagiline MeSH Prohlížeč
- riluzol MeSH
Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aβ1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
- Klíčová slova
- Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, multitarget directed ligands, phenothiazine, tacrine,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- amyloidní beta-protein MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory farmakologie MeSH
- fenothiaziny farmakologie MeSH
- myši MeSH
- racionální návrh léčiv MeSH
- takrin * farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- amyloidní beta-protein MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- fenothiaziny MeSH
- takrin * MeSH
Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of α-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways.
- Publikační typ
- časopisecké články MeSH
A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ40 aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
- Klíčová slova
- Acetylcholinesterase, Alzheimer's disease, Aβ42 self-aggregation, Blood-brain barrier, Multi-target directed ligands, Tacrine-tryptophan hybrids, X-ray crystallographic analysis, hAChEinduced Aβ40 aggregation,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- bludiště - učení účinky léků MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- potkani Wistar MeSH
- proteinové agregáty účinky léků MeSH
- takrin chemie farmakologie MeSH
- tryptofan chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- amyloidní beta-protein MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- ligandy MeSH
- neuroprotektivní látky MeSH
- proteinové agregáty MeSH
- takrin MeSH
- tryptofan MeSH
Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (1), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. CNSL derivatives 8 and 9 display a HDAC inhibitory profile similar to 1, together with a more promising safety for 9 compared to 1. Moreover, both compounds and particularly 9 were able to effectively modulate glial cell-induced inflammation and to revert the pro-inflammatory phenotype. All these results demonstrate that the use of inexpensive food waste materials could be successfully applied for the development of accessible and sustainable drug candidates for the treatment of AD.
- Publikační typ
- časopisecké články MeSH
Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aβ self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.
- Klíčová slova
- Acetylcholinesterase, Alzheimer's disease, Amyloid, Multitarget compounds, Neuroinflammation,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein chemie MeSH
- antioxidancia chemie metabolismus farmakologie terapeutické užití MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie metabolismus farmakologie terapeutické užití MeSH
- cílená molekulární terapie * MeSH
- hematoencefalická bariéra metabolismus MeSH
- játra účinky léků MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- ligandy MeSH
- neuroprotektivní látky chemie farmakologie terapeutické užití MeSH
- peptidové fragmenty chemie MeSH
- proteinové agregáty účinky léků MeSH
- racionální návrh léčiv * MeSH
- resveratrol MeSH
- stilbeny chemie MeSH
- takrin chemie metabolismus farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- amyloid beta-protein (1-42) MeSH Prohlížeč
- amyloidní beta-protein MeSH
- antioxidancia MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- ligandy MeSH
- neuroprotektivní látky MeSH
- peptidové fragmenty MeSH
- proteinové agregáty MeSH
- resveratrol MeSH
- stilbeny MeSH
- takrin MeSH
