Multicomponent reactions, particularly the Passerini reaction, serve as efficient tools for the synthesis of druglike molecules and the creation of compound libraries. Despite the effectiveness of the Passerini reaction, the limited alternatives to the crucial carboxylic acid component pose a structural constraint. Here, we have discovered that the phthalimide moiety and its derivatives react in the Passerini reaction as an acid component. We explored their potential in synthesizing diverse and intricate molecules. The phthalimide moiety stands out as a favorable building block due to its oxidative stability, heat-stable characteristics, and resistance to solvents. Our approach introduces a novel perspective to multicomponent reactions by incorporating NH-based acid components, addressing the ongoing need for the development of innovative molecular scaffolds.

• Publication type
• Journal Article MeSH

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

• Keywords
• Alzheimer’s disease, amaryllidaceae alkaloid, butyrylcholinesterase, docking studies, norbelladine-type,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Amaryllidaceae Alkaloids chemistry   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Neuroblastoma drug therapy   pathology   MeSH
• Computer Simulation MeSH
• Cell Proliferation MeSH
• Molecular Docking Simulation * MeSH
• Tyramine analogs & derivatives   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Amaryllidaceae Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• norbelladine MeSH Browser
• Tyramine MeSH

A series of novel C4-C7-tethered biscoumarin derivatives (12a-e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood-brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer's disease.

• Keywords
• A549, Alzheimer’s disease, antiproliferative activity, biscoumarin, blood–brain barrier, cholinesterase,
• MeSH
• Enzyme Activation drug effects   MeSH
• Alzheimer Disease drug therapy   MeSH
• Cell Cycle drug effects   MeSH
• A549 Cells MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Blood-Brain Barrier drug effects   metabolism   MeSH
• Coumarins chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular * MeSH
• Molecular Structure MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Chemistry Techniques, Synthetic * MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholinesterase Inhibitors MeSH
• Coumarins MeSH
• Antineoplastic Agents MeSH

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.

• Keywords
• 9-O-demethyllycorenine, Alzheimer’s disease, Amaryllidaceae, narciabduliine,
• MeSH
• Amaryllidaceae Alkaloids chemistry   pharmacology   MeSH
• Alkaloids chemistry   pharmacology   MeSH
• Alzheimer Disease MeSH
• Butyrylcholinesterase chemistry   ultrastructure   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Cholinesterases chemistry   ultrastructure   MeSH
• Circular Dichroism MeSH
• Catalytic Domain drug effects   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Cholinesterases MeSH

Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.

• Keywords
• Alzheimer’s disease, Amaryllidaceae, Narcissus pseudonarcissus cv. Carlton, alkaloids, butyrylcholinesterase, carltonine A–C, docking studies,
• MeSH
• Alkaloids chemistry   pharmacology   MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Humans MeSH
• Narcissus chemistry   MeSH
• Molecular Docking Simulation MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH

We reported a novel simplified synthetic procedure for the preparation of monosubstituted piperazine derivatives which can now be easily prepared in a one-pot-one-step way from a protonated piperazine with no need of introduction of a protecting group. Reactions, proceeding either at room or higher temperatures in common solvents, involve heterogeneous catalysis by metal ions supported on commercial polymeric resins. A general synthetic scheme was successfully applied to afford a wide range of monosubstituted piperazines. Furthermore, we picked up a set of piperazine derivatives and studied the possibilities of microwave acceleration of given synthetic reactions to make them even more efficient. Our research proceeded from a simple batch technique to the construction of a flow microwave reactor prototype and resulted in promising findings which are summarized and discussed in the article.

• Keywords
• catalysis, derivative, heterocyclic, heterogeneous, microwave, monosubstituted, piperazine, reactor, supported catalyst, synthesis,
• MeSH
• Heterocyclic Compounds chemical synthesis   chemistry   MeSH
• Catalysis MeSH
• Microwaves * MeSH
• Piperazines chemical synthesis   chemistry   MeSH
• Solvents chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Heterocyclic Compounds MeSH
• Piperazines MeSH
• Solvents MeSH

Twelve derivatives 1a-1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.

• Keywords
• Alzheimer’s disease, Amaryllidaceae, acetylcholinesterase, butyrylcholinesterase, docking studies, glycogen synthase kinase-3β inhibition, haemanthamine,
• MeSH
• Amaryllidaceae Alkaloids chemistry   metabolism   MeSH
• Alzheimer Disease metabolism   MeSH
• Amaryllidaceae chemistry   metabolism   MeSH
• Phenanthridines chemistry   metabolism   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Glycogen Synthase Kinase 3 beta metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Permeability MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Phenanthridines MeSH
• hemanthamine MeSH Browser
• Glycogen Synthase Kinase 3 beta MeSH
• Ligands 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