In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure-activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood-brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301.

• Klíčová slova
• aripiprazole, blood–brain barrier, dopamine receptor, molecular modeling studies, schizophrenia,
• MeSH
• aripiprazol chemická syntéza   farmakologie   MeSH
• buněčná smrt MeSH
• centrální nervový systém účinky léků   MeSH
• chinolony chemická syntéza   chemie   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• hematoencefalická bariéra účinky léků   patologie   MeSH
• ligandy MeSH
• molekulární modely MeSH
• racionální návrh léčiv MeSH
• receptory dopaminu D2 chemie   metabolismus   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aripiprazol MeSH
• chinolony MeSH
• dihydroquinolin-2(1H)-one MeSH Prohlížeč
• ligandy MeSH
• receptory dopaminu D2 MeSH

As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Aβ aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 μM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.

• Publikační typ
• časopisecké články 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
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cytokiny MeSH
• ligandy * MeSH
• lipopolysacharidy MeSH
• neuroprotektivní látky MeSH
• rostlinné extrakty MeSH
• takrin MeSH

Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (1), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. CNSL derivatives 8 and 9 display a HDAC inhibitory profile similar to 1, together with a more promising safety for 9 compared to 1. Moreover, both compounds and particularly 9 were able to effectively modulate glial cell-induced inflammation and to revert the pro-inflammatory phenotype. All these results demonstrate that the use of inexpensive food waste materials could be successfully applied for the development of accessible and sustainable drug candidates for the treatment of AD.

• Publikační typ
• časopisecké články 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.

• Klíčová slova
• Alzheimer’s disease, Amaryllidaceae, acetylcholinesterase, butyrylcholinesterase, docking studies, glycogen synthase kinase-3β inhibition, haemanthamine,
• MeSH
• alkaloidy amarylkovitých chemie   metabolismus   MeSH
• Alzheimerova nemoc metabolismus   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• fenantridiny chemie   metabolismus   MeSH
• GSK3B metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• permeabilita 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
• fenantridiny MeSH
• GSK3B MeSH
• hemanthamine MeSH Prohlížeč
• ligandy 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.

• Klíčová slova
• Acetylcholinesterase, Alzheimer’s disease, donepezil, multi-target directed ligands, oxidative stress,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• antioxidancia chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• donepezil 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
• Názvy látek
• acetylcholinesterasa MeSH
• antioxidancia MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• indany MeSH
• piperidiny 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.

• Klíčová slova
• 2-methoxyhuprine, 7-MEOTA, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, huprine Y, tacrine,
• MeSH
• acetylcholinesterasa MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• aminochinoliny chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   farmakologie   MeSH
• hydrolýza MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• objevování léků * MeSH
• permeabilita MeSH
• racionální návrh léčiv MeSH
• takrin analogy a deriváty   chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-methoxytacrine MeSH Prohlížeč
• acetylcholinesterasa MeSH
• aminochinoliny MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• huprine Y MeSH Prohlížeč
• takrin 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.

• Klíčová slova
• 6-chlorotacrine, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, enzyme inhibitor, scutellarin,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc enzymologie   MeSH
• apigenin chemie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• glukuronáty chemie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• takrin analogy a deriváty   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 6-chlorotacrine MeSH Prohlížeč
• acetylcholinesterasa MeSH
• apigenin MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• glukuronáty MeSH
• scutellarin MeSH Prohlížeč
• takrin MeSH

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

• Klíčová slova
• Alzheimer’s disease, antioxidants, cholinesterase inhibitors, hepatotoxicity, multicomponent reactions, multitarget-directed ligands, quinazolinones,
• MeSH
• Alzheimerova nemoc prevence a kontrola   MeSH
• antioxidancia chemická syntéza   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• játra účinky léků   MeSH
• lidé MeSH
• spektrální analýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• cholinesterasové inhibitory MeSH