Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease * drug therapy   metabolism   MeSH
• Biological Availability MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors * pharmacology   chemistry   chemical synthesis   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Microsomes, Liver metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Structure MeSH
• Mice MeSH
• Receptors, N-Methyl-D-Aspartate * antagonists & inhibitors   metabolism   MeSH
• Tacrine * pharmacology   chemistry   chemical synthesis   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

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
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease * drug therapy   metabolism   MeSH
• Aminoquinolines therapeutic use   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors * pharmacology   therapeutic use   chemistry   MeSH
• Humans MeSH
• Ligands MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 μM; hBChE: IC50 = 0.093 ± 0.003 μM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 μM; IC50 (hBChE) = 0.659 ± 0.077 μM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease * drug therapy   MeSH
• Amines MeSH
• Butyrylcholinesterase * metabolism   MeSH
• Cholinesterase Inhibitors pharmacology   therapeutic use   MeSH
• Monoamine Oxidase Inhibitors pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Monoamine Oxidase MeSH
• Oxidoreductases MeSH
• Drug Design MeSH
• Tacrine therapeutic use   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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.

• MeSH
• Amyotrophic Lateral Sclerosis * drug therapy   MeSH
• Indans MeSH
• Humans MeSH
• Ligands MeSH
• Neuroprotective Agents * pharmacology   therapeutic use   MeSH
• Riluzole pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The work deals with the design, synthesis and biolog-icalactivityofnewcarbamatecholinesteraseinhibitors.Itis focused on selected syntheses of new carbamate deriva-tives, which were tested for their anticholinesterase activi-ty against acetylcholinesterase as well as butyrylcholines-terase. Despite various theories in the pathogenesis of Alz-heimer's disease, drugs that can inhibit these two enzymes still represent the major approach to the treatment of this neurodegenerative disease. Many of the newly synthesized compounds have unique chemical structure. Recently, the approach to the synthesis of new cholinesterase inhibitors has focused on the preparation of potential drugs, contain-ing in their chemical structure fragments of already known drugs, commonly used in the pharmacotherapy of Alzhei-mer's disease, but also other diseases. The aim of prepar-ing these compounds is to affect several biological systems simultaneously. These multipotent compounds have been termed "multi-target-directed ligands"; the molecules of drugs used to treat Alzheimer's disease always contain a pharmacophore acting as a cholinesterase inhibitor, which represents the mainstay of therapy

• MeSH
• Acetylcholinesterase MeSH
• Alzheimer Disease diagnosis   drug therapy   pathology   MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors * chemistry   pharmacology   therapeutic use   MeSH
• Carbamates chemistry   therapeutic use   MeSH
• Humans MeSH
• Rivastigmine analogs & derivatives   therapeutic use   MeSH
• Drug Development methods   MeSH
• Check Tag
• Humans MeSH

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD.

• MeSH
• Alzheimer Disease drug therapy   MeSH
• Humans MeSH
• Naphthoquinones pharmacology   therapeutic use   MeSH
• Drug Design MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Acetylcholinesterase chemistry   metabolism   MeSH
• Alzheimer Disease drug therapy   MeSH
• Amyloid beta-Peptides antagonists & inhibitors   metabolism   MeSH
• Antioxidants chemistry   metabolism   pharmacology   MeSH
• Cholinesterase Inhibitors chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Donepezil chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Blood-Brain Barrier diagnostic imaging   metabolism   MeSH
• Indans chemistry   MeSH
• Humans MeSH
• Ligands * MeSH
• Cell Line, Tumor MeSH
• Neuroprotective Agents chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Oxidative Stress drug effects   MeSH
• Protein Aggregates drug effects   MeSH
• Drug Design MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 μM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 μM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 μM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.

• MeSH
• Antioxidants chemical synthesis   chemistry   pharmacology   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Cholinesterases metabolism   MeSH
• Electrophorus MeSH
• Hepatocytes drug effects   metabolism   MeSH
• Monoamine Oxidase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Horses MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Molecular Structure MeSH
• Monoamine Oxidase metabolism   MeSH
• Pargyline analogs & derivatives   chemical synthesis   chemistry   pharmacology   MeSH
• Rats, Wistar MeSH
• Propylamines chemical synthesis   chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Molecular Docking Simulation * MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Acetylcholinesterase chemistry   metabolism   MeSH
• Alzheimer Disease drug therapy   pathology   MeSH
• Anacardium chemistry   metabolism   MeSH
• Cell Line MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cytokines metabolism   MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Ligands * MeSH
• Lipopolysaccharides pharmacology   MeSH
• Microglia cytology   drug effects   metabolism   MeSH
• Neuroprotective Agents chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Nuts chemistry   metabolism   MeSH
• Drug Design MeSH
• Plant Extracts chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Tacrine chemistry   metabolism   MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Drug Development MeSH
• Check Tag
• Humans MeSH
• Publication type
• Introductory Journal Article MeSH
• Editorial MeSH