The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   MeSH
• aminochinoliny terapeutické užití   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory * farmakologie   terapeutické užití   chemie   MeSH
• lidé MeSH
• ligandy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články 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
• GSK3B MeSH
• lidé MeSH
• ligandy MeSH
• monoaminoxidasa metabolismus   MeSH
• vápníkové kanály MeSH
• Check Tag
• lidé 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

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

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

Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• donepezil analogy a deriváty   MeSH
• lidé MeSH
• patologická konformace proteinů farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• buněčné dýchání účinky léků   MeSH
• energetický metabolismus * účinky léků   MeSH
• inhibitory MAO farmakologie   MeSH
• mitochondrie účinky léků   enzymologie   metabolismus   MeSH
• monoaminoxidasa metabolismus   MeSH
• prasata MeSH
• respirační komplex II metabolismus   MeSH
• takrin chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.

• MeSH
• acetylcholinesterasa chemie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   chemie   MeSH
• aniliny chemická syntéza   chemie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   MeSH
• kinetika MeSH
• látky ovlivňující centrální nervový systém chemická syntéza   chemie   MeSH
• lidé MeSH
• rekombinantní proteiny chemie   MeSH
• simulace molekulového dockingu MeSH
• takrin analogy a deriváty   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• antioxidancia chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• indany chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• piperidiny chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Several hallmarks such as β-amyloid (Aβ) aggregation underlying amyloid plaque formation, τ-hyperphosphorylation leading to production of neurofibrillary tangles, and decline in the number of cholinergic neurons appear to be fundamental in the pathophysiology of the disease. Other evidence points also to the involvement of oxidative stress, biometal dyshomeostasis, inflammation, and cell cycle regulatory failure. Taking into account such premises, many attractive targets for the development of anti-AD drugs have emerged. Specifically, the multifactorial nature of AD calls for multi-target-directed ligands (MTDLs) which can be beneficial by providing interactions with multiple targets. Tacrine (THA), the first clinically effective acetylcholinesterase inhibitor, was approved for the treatment of mild to moderate AD. Unfortunately, frequent adverse effects including peripheral cholinergic effects and hepatotoxicity limited its therapeutic potential. Based on the numerous biological systems involved in AD progression, this review covers THA-incorporated hybrids possessing a neuroprotective profile. In particular, it focuses on THA hybrids capable of scavenging reactive oxygen species (ROS), and derivatives which reduce the formation of Aβ-plaques either directly by confronting the Aβ1-42 selfaggregation process or indirectly by inhibiting the BACE-1 enzyme or AChE-induced Aβ1-40 aggregation. Particular interest is also addressed to THA hybrids with suppressed hepatotoxicity.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• lidé MeSH
• neuroprotektivní látky chemická syntéza   chemie   terapeutické užití   MeSH
• takrin analogy a deriváty   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH