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.
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- Drosophila melanogaster MeSH
- Drosophila MeSH
- proteiny tau MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- antioxidancia chemie metabolismus farmakologie MeSH
- cholinesterasové inhibitory chemie metabolismus farmakologie terapeutické užití MeSH
- donepezil chemie metabolismus farmakologie terapeutické užití MeSH
- hematoencefalická bariéra diagnostické zobrazování metabolismus MeSH
- indany chemie MeSH
- lidé MeSH
- ligandy * MeSH
- nádorové buněčné linie MeSH
- neuroprotektivní látky chemie metabolismus farmakologie terapeutické užití MeSH
- oxidační stres účinky léků MeSH
- proteinové agregáty účinky léků MeSH
- racionální návrh léčiv MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Aβ aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 μM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.
- Publikační typ
- časopisecké články 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.
- 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
The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 μM), confirming the design rationale.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- Anacardium chemie metabolismus MeSH
- buněčné linie MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cytokiny metabolismus MeSH
- katalytická doména MeSH
- lidé MeSH
- ligandy * MeSH
- lipopolysacharidy farmakologie MeSH
- mikroglie cytologie účinky léků metabolismus MeSH
- neuroprotektivní látky chemie metabolismus farmakologie terapeutické užití MeSH
- ořechy chemie metabolismus MeSH
- racionální návrh léčiv MeSH
- rostlinné extrakty chemie MeSH
- simulace molekulární dynamiky MeSH
- takrin chemie metabolismus MeSH
- vazebná místa MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- blokátory kalciových kanálů farmakologie terapeutické užití MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití MeSH
- kinasa glykogensynthasy 3beta MeSH
- lidé MeSH
- ligandy MeSH
- monoaminoxidasa metabolismus MeSH
- vápníkové kanály MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
- 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
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.
- MeSH
- acetylcholin nedostatek MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- buněčné linie MeSH
- buňky PC12 MeSH
- cholinesterasové inhibitory chemie MeSH
- inhibitory cyklooxygenasy 2 chemie MeSH
- inhibitory lipoxygenas chemie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- neurony účinky léků enzymologie patologie MeSH
- racionální návrh léčiv MeSH
- semikarbazidy chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- triazoly chemie farmakologie MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- 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.
- 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
- 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
