The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with a selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype. Notably, compounds 28 (hBChE IC50 = 0.171 ± 0.063 μM) and 33 (hBChE IC50 = 0.167 ± 0.018 μM) emerged as top-ranked hBChE inhibitors. In silico simulations elucidated the binding modes of these compounds within hBChE. CNS availability was predicted using the BBB score algorithm, corroborated by in vitro permeability assessments with the most potent derivatives. Compound 33 was also inspected for aqueous solubility, microsomal and plasma stability. Chemoinformatics analysis validated these hBChE inhibitors for oral administration, indicating favorable gastrointestinal absorption in compliance with Lipinski's and Veber's rules. Safety assessments, crucial for the chronic administration typical in AD treatment, were conducted through cytotoxicity testing on human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines.

• Publikační typ
• časopisecké články MeSH

Clivia miniata (Amaryllidaceae) is an herbaceous evergreen flowering plant that is endemic to South Africa and Swaziland and belongs to one of the top-10 traded medicinal plants in informal medicine markets in South Africa. The species has been reported as the most important component of a traditional healer's pallet of healing plants. Eighteen known Amaryllidaceae alkaloids (AAs) of various structural types, and one undescribed alkaloid of homolycorine-type, named clivimine B (3), were isolated from Clivia miniata. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR techniques and by comparison with literature data. Compounds isolated in a sufficient quantity, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BuChE; E.C. 3.1.1.8) inhibition activities.

• Klíčová slova
• Amaryllidaceae, Clivia miniata, acetylcholinesterase, butyrylcholinesterase, clivimine B,
• Publikační typ
• časopisecké články MeSH

The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.

• Klíčová slova
• 3-O-methylpancracine, Amaryllidaceae, analogues, antimycobacterial activity, cytotoxicity, galanthamine, tuberculosis,
• MeSH
• alkaloidy amarylkovitých škodlivé účinky   chemická syntéza   farmakologie   MeSH
• antibakteriální látky škodlivé účinky   chemická syntéza   farmakologie   MeSH
• buňky Hep G2 MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• antibakteriální látky MeSH

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease recognized as the most common form of dementia among elderly people. Due to the fact that the exact pathogenesis of AD still remains to be fully elucidated, the treatment is only symptomatic and available drugs are not able to modify AD progression. Considering the increase in life expectancy worldwide, AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. Due to their complex nitrogen-containing structures, alkaloids are considered to be promising candidates for use in the treatment of AD. Since the introduction of galanthamine as an antidementia drug in 2001, Amaryllidaceae alkaloids (AAs) and further isoquinoline alkaloids (IAs) have been one of the most studied groups of alkaloids. In the last few years, several compounds of new structure types have been isolated and evaluated for their biological activity connected with AD. The present review aims to comprehensively summarize recent progress on AAs and IAs since 2010 up to June 2021 as potential drugs for the treatment of AD.

• Klíčová slova
• Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, docking study, isoquinoline alkaloids, monoaminooxidase, neuroprotective activity, prolyl oligopeptidase,
• MeSH
• alkaloidy amarylkovitých metabolismus   MeSH
• Alzheimerova nemoc metabolismus   MeSH
• Amaryllidaceae chemie   MeSH
• neurodegenerativní nemoci metabolismus   MeSH
• prolyloligopeptidasy metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• prolyloligopeptidasy 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.

• Klíčová slova
• Alzheimer’s disease, amaryllidaceae alkaloid, butyrylcholinesterase, docking studies, norbelladine-type,
• MeSH
• acetylcholinesterasa chemie   MeSH
• alkaloidy amarylkovitých chemie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• neuroblastom farmakoterapie   patologie   MeSH
• počítačová simulace MeSH
• proliferace buněk MeSH
• simulace molekulového dockingu * MeSH
• tyramin analogy a deriváty   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• alkaloidy amarylkovitých MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• norbelladine MeSH Prohlížeč
• tyramin MeSH

Cholinesterases are fundamental players in the peripheral and central nervous systems [...].

• MeSH
• acetylcholinesterasa genetika   metabolismus   MeSH
• butyrylcholinesterasa genetika   metabolismus   MeSH
• centrální nervový systém cytologie   účinky léků   enzymologie   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• exprese genu MeSH
• GPI-vázané proteiny genetika   metabolismus   MeSH
• lidé MeSH
• nervový přenos MeSH
• neurodegenerativní nemoci farmakoterapie   enzymologie   genetika   patologie   MeSH
• neurony cytologie   účinky léků   enzymologie   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• periferní nervový systém cytologie   účinky léků   enzymologie   MeSH
• synapse účinky léků   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• úvodníky MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• BCHE protein, human MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• GPI-vázané proteiny MeSH
• neuroprotektivní látky 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.

• Klíčová slova
• 9-O-demethyllycorenine, Alzheimer’s disease, Amaryllidaceae, narciabduliine,
• MeSH
• alkaloidy amarylkovitých chemie   farmakologie   MeSH
• alkaloidy chemie   farmakologie   MeSH
• Alzheimerova nemoc MeSH
• butyrylcholinesterasa chemie   ultrastruktura   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• cholinesterasy chemie   ultrastruktura   MeSH
• cirkulární dichroismus MeSH
• katalytická doména účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• alkaloidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH

Lycoris Herbert, family Amaryllidaceae, is a small genus of about 20 species that are native to the warm temperate woodlands of eastern Asia, as in China, Korea, Japan, Taiwan, and the Himalayas. For many years, species of Lycoris have been subjected to extensive phytochemical and pharmacological investigations, resulting in either the isolation or identification of more than 110 Amaryllidaceae alkaloids belonging to different structural types. Amaryllidaceae alkaloids are frequently studied for their interesting biological properties, including antiviral, antibacterial, antitumor, antifungal, antimalarial, analgesic, cytotoxic, and cholinesterase inhibition activities. The present review aims to summarize comprehensively the research that has been reported on the phytochemistry and pharmacology of the genus Lycoris.

• Klíčová slova
• Amaryllidaceae, Lycoris, Lycoris radiata, alkaloids, biological activity, folk medicine,
• MeSH
• alkaloidy amarylkovitých chemie   terapeutické užití   MeSH
• Amaryllidaceae chemie   MeSH
• antimalarika chemie   terapeutické užití   MeSH
• fytonutrienty terapeutické užití   MeSH
• kořeny rostlin chemie   MeSH
• lidé MeSH
• Lycoris chemie   MeSH
• rostlinné extrakty chemie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Čína MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• antimalarika MeSH
• fytonutrienty MeSH
• rostlinné extrakty MeSH