This review summarizes achievements in the synthesis of 1,2-disubstituted adamantane derivatives by the construction of the tricyclic framework either by total synthesis or by ring expansion/contraction reactions of corresponding adamantane homologues. It is intended to complement reviews focusing on the preparation of 1,2-disubstituted derivatives by C-H functionalization methods.

• Keywords
• adamantane, alkyl shifts, diamondoids, homoadamantane, noradamantane, protoadamantane, rearrangement, ring contraction, ring expansion, total synthesis,
• Publication type
• Journal Article MeSH
• Review MeSH

Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.

• Keywords
• 2,6,9-trisubstituted purine, adamantane, cyclin-dependent kinase, cytotoxicity, molecular docking, β-cyclodextrin,
• MeSH
• Adamantane chemistry   MeSH
• beta-Cyclodextrins chemistry   MeSH
• K562 Cells MeSH
• Cyclin-Dependent Kinase 2 antagonists & inhibitors   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Purines chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adamantane MeSH
• beta-Cyclodextrins MeSH
• CDK2 protein, human MeSH Browser
• Cyclin-Dependent Kinase 2 MeSH
• Protein Kinase Inhibitors MeSH
• Antineoplastic Agents MeSH
• Purines MeSH

Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aβ toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula.

• Keywords
• Alzheimer’s disease, Amino acids, Memantine,
• MeSH
• Alzheimer Disease drug therapy   genetics   pathology   MeSH
• Amyloid beta-Peptides drug effects   toxicity   MeSH
• Madin Darby Canine Kidney Cells MeSH
• Influenza, Human drug therapy   virology   MeSH
• Glutamic Acid metabolism   MeSH
• Humans MeSH
• Memantine analogs & derivatives   chemistry   pharmacology   MeSH
• Neuroprotective Agents chemistry   pharmacology   MeSH
• Orthomyxoviridae drug effects   pathogenicity   MeSH
• Oxidative Stress drug effects   MeSH
• Dogs MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Dogs MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• Glutamic Acid MeSH
• Memantine MeSH
• Neuroprotective Agents MeSH

A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure-activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.

• Keywords
• 3D-QSAR, LC–MS/MS., X-Ray crystallography, adamantane derivatives, amino acids, mass spectrometry, molecular docking, plasma stability,
• MeSH
• Adamantane analogs & derivatives   chemical synthesis   chemistry   pharmacology   MeSH
• Antiviral Agents chemical synthesis   chemistry   pharmacology   MeSH
• Cell Death drug effects   MeSH
• Madin Darby Canine Kidney Cells MeSH
• Differential Thermal Analysis MeSH
• Crystallography, X-Ray MeSH
• Quantitative Structure-Activity Relationship * MeSH
• Humans MeSH
• Least-Squares Analysis MeSH
• Molecular Conformation MeSH
• Orthomyxoviridae drug effects   MeSH
• Computer Simulation * MeSH
• Protein Domains MeSH
• Viral Matrix Proteins chemistry   MeSH
• Dogs MeSH
• Rimantadine blood   chemistry   MeSH
• Molecular Docking Simulation MeSH
• Drug Stability MeSH
• Temperature MeSH
• Binding Sites MeSH
• Hydrogen Bonding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Dogs MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adamantane MeSH
• Antiviral Agents MeSH
• M2 protein, Influenza A virus MeSH Browser
• Viral Matrix Proteins MeSH
• Rimantadine 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.

• Keywords
• Acetylcholinesterase, Alzheimer’s disease, donepezil, multi-target directed ligands, oxidative stress,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Donepezil MeSH
• Indans chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Piperidines chemistry   pharmacology   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antioxidants MeSH
• Cholinesterase Inhibitors MeSH
• Donepezil MeSH
• Indans MeSH
• Piperidines MeSH

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

• Keywords
• 2-methoxyhuprine, 7-MEOTA, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, huprine Y, tacrine,
• MeSH
• Acetylcholinesterase MeSH
• Enzyme Activation drug effects   MeSH
• Alzheimer Disease drug therapy   MeSH
• Aminoquinolines chemical synthesis   chemistry   pharmacology   MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Heterocyclic Compounds, 4 or More Rings chemistry   pharmacology   MeSH
• Hydrolysis MeSH
• Inhibitory Concentration 50 MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Drug Discovery * MeSH
• Permeability MeSH
• Drug Design MeSH
• Tacrine analogs & derivatives   chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-methoxytacrine MeSH Browser
• Acetylcholinesterase MeSH
• Aminoquinolines MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Heterocyclic Compounds, 4 or More Rings MeSH
• huprine Y MeSH Browser
• Tacrine MeSH

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.

• Keywords
• 6-chlorotacrine, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, enzyme inhibitor, scutellarin,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation drug effects   MeSH
• Alzheimer Disease enzymology   MeSH
• Apigenin chemistry   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Glucuronates chemistry   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Humans MeSH
• Drug Design MeSH
• Molecular Docking Simulation MeSH
• Tacrine analogs & derivatives   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 6-chlorotacrine MeSH Browser
• Acetylcholinesterase MeSH
• Apigenin MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Glucuronates MeSH
• scutellarin MeSH Browser
• Tacrine MeSH