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.

• Klíčová slova
• Acetylcholinesterase, Amiridine, Antioxidant capacity, Butyrylcholinesterase, Multi-target directed ligands, NMDA receptors,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   MeSH
• aminochinoliny terapeutické užití   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory * farmakologie   terapeutické užití   chemie   MeSH
• lidé MeSH
• ligandy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• aminochinoliny MeSH
• amiridine MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory * MeSH
• ligandy MeSH

Imiquimod (IMQ) is an immunostimulating agent used in the treatment of basal cell carcinoma and actinic keratosis. Due to its low solubility and poor skin bioavailability, the dermal formulation of IMQ remains challenging. In analogy to tyre compounds used in Formula 1 racing, we compare four types of nanosystems belonging to three groups: (i) "hard" nanoparticles in the form of IMQ nanocrystals, (ii) "intermediate" nanoparticles in the form of liposomes and lipid nanocapsules, and (iii) "soft" nanoparticles in the form of a nanoemulsion based on oleic acid. The nanoemulsion and nanocrystals were able to incorporate the highest amount of IMQ (at least 2 wt%) compared to liposomes (0.03 wt%) and lipid nanocapsules (0.08 wt%). Regarding size, liposomes, and lipid nanocapsules were rather small (around 40 nm) whereas nanocrystals and nanoemulsion were larger (around 200 nm). All developed nanoformulations showed high efficiency to deliver IMQ into the skin tissue without undesirable subsequent permeation through the skin to acceptor. Especially, the 2 wt% IMQ nanoemulsion accumulated 129 μg/g IMQ in the skin, compared to 34 μg/g of a 5 wt% commercial cream. The effects of the respective nanoparticulate systems were discussed with respect to their possible diffusion kinetics (Brownian motion vs. settling) in the aqueous phase.

• Klíčová slova
• Ex vivo permeation study, Imiquimod, Lipid nanocapsules, Liposomes, Nanocrystals, Nanoemulsion, Oleic acid,
• MeSH
• imichimod chemie   MeSH
• kůže metabolismus   MeSH
• lipidy farmakologie   MeSH
• liposomy * farmakologie   MeSH
• nanokapsle * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imichimod MeSH
• lipidy MeSH
• liposomy * MeSH
• nanokapsle * MeSH

Cryptococcus neoformans is an opportunistic fungal pathogen that can cause life-threatening invasive fungal infections. As its prevalence and drug resistance continue to rise, cryptococcosis requires new treatment options. Tapping into the potential antifungal effects of traditional drugs or combination therapy has become one of the options. This study was the first to examine the interaction of hydroxychloroquine (HCQ) and itraconazole (ITR) on Cryptococcus neoformans in vitro and in vivo. Our results showed that HCQ alone and in combination with ITR exhibited antifungal activity against C. neoformans planktonic cells. When HCQ was combined with ITR, the minimal inhibitory concentration (MIC) value of HCQ decreased to 32 μg/mL, and the MIC value of ITR decreased from 0.25 μg/mL to 0.06-0.25 μg/mL. The time-killing curve showed that the combined application of HCQ and ITR significantly shortened the killing time, dynamically defining the antifungal activity. The minimum biofilm clearance concentration (MBEC) of HCQ was only 32 μg/mL, which was significantly lower than the MIC of HCQ for planktonic cells. When combined with ITR, the MBEC of ITR decreased from 128 μg/mL to 2-1 μg/mL, and the MBEC of HCQ decreased from 32 μg/mL to 4 μg/mL, indicating a synergistic antifungal biofilm effect. In comparison to ITR alone, the combination of HCQ and ITR treatment increased the survival of C. neoformans-infected Galleria mellonella larvae and decreased the fungal burden of infected larvae. Mechanistic investigations revealed that HCQ might damage C. neoformans cell membranes, impact the structure of fungal cells, cause extracellular material leakage, and have a potent affinity for attaching to the C. neoformans genomic DNA. In conclusion, HCQ has potential clinical application in the treatment of cryptococcosis.

• Klíčová slova
• Antifungal activity, Cryptococcus neoformans, Hydroxychloroquine, Itraconazole, Synergism,
• MeSH
• antifungální látky farmakologie   terapeutické užití   MeSH
• Cryptococcus neoformans * MeSH
• hydroxychlorochin farmakologie   terapeutické užití   MeSH
• itrakonazol farmakologie   MeSH
• kryptokokóza * farmakoterapie   mikrobiologie   MeSH
• mikrobiální testy citlivosti MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antifungální látky MeSH
• hydroxychlorochin MeSH
• itrakonazol MeSH

Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9/NF-κB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumourassociated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.

• Klíčová slova
• Chloroquine, apoptosis, chemotherapy, hydroxychloroquine, metastasis, non-small cell lung cancer, repurposing drugs in oncology,
• MeSH
• antimalarika * farmakologie   terapeutické užití   MeSH
• chlorochin farmakologie   terapeutické užití   MeSH
• hydroxychlorochin * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• nádorové mikroprostředí MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antimalarika * MeSH
• chlorochin MeSH
• hydroxychlorochin * MeSH

In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies.

• Klíčová slova
• autoimmunity, glomerulonephritis, inflammation, lupus, standards,
• MeSH
• biopsie MeSH
• dítě MeSH
• hydroxychlorochin terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• ledviny patologie   MeSH
• lidé MeSH
• membranózní glomerulonefritida * farmakoterapie   MeSH
• nefritida při lupus erythematodes * diagnóza   farmakoterapie   patologie   MeSH
• těhotenství MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hydroxychlorochin MeSH
• imunosupresiva MeSH

A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 µM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.

• Klíčová slova
• CoMSA, arginase inhibition, arylcinnamamides, lipophilicity, molecular docking, similarity-activity landscape index,
• MeSH
• antimalarika * farmakologie   MeSH
• arginasa farmakologie   MeSH
• chlorochin farmakologie   MeSH
• Plasmodium falciparum MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antimalarika * MeSH
• arginasa MeSH
• chlorochin MeSH

Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC50 from 0.58 to 31 µM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC50 = 0.58 µM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) demonstrated efficacy in the IC50 range from 2.0 to 4.3 µM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-Blue™ NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising Plasmodium selective substances for further investigations.

• Klíčová slova
• Plasmodium, antiplasmodial activity, cinnamanilides, structure-activity relationships,
• MeSH
• antagonisté kyseliny listové * MeSH
• antimalarika * farmakologie   MeSH
• chlorochin farmakologie   MeSH
• lidé MeSH
• tropická malárie * MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté kyseliny listové * MeSH
• antimalarika * MeSH
• chlorochin MeSH

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) -as potential multifunctional agents for the treatment of Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a-c exhibited an IC50(AChE) = 2.9-1.4 µM, IC50(BChE) = 0.13-0.067 µM, and 14-18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 self-aggregation, whereas compounds 5c-e (m = 4, 5, 6) showed mild (13-17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2-2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood-brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c-e appear promising for future optimization and development as multitarget anti-AD agents.

• Klíčová slova
• ADMET, Alzheimer’s disease (AD), N-acylamide, acetylcholinesterase (AChE), amiridine, antioxidants, butyrylcholinesterase (BChE), neuroprotection, thiourea, β-amyloid (Aβ42),
• MeSH
• acetylcholinesterasa MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• aminochinoliny chemie   MeSH
• antioxidancia chemie   farmakologie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• GPI-vázané proteiny antagonisté a inhibitory   MeSH
• kinetika MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• aminochinoliny MeSH
• amiridine MeSH Prohlížeč
• antioxidancia MeSH
• BCHE protein, human MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• GPI-vázané proteiny MeSH
• neuroprotektivní látky MeSH

We collected a multi-centric retrospective dataset of patients (N = 213) who were admitted to ten hospitals in Czech Republic and tested positive for SARS-CoV-2 during the early phases of the pandemic in March-October 2020. The dataset contains baseline patient characteristics, breathing support required, pharmacological treatment received and multiple markers on daily resolution. Patients in the dataset were treated with hydroxychloroquine (N = 108), azithromycin (N = 72), favipiravir (N = 9), convalescent plasma (N = 7), dexamethasone (N = 4) and remdesivir (N = 3), often in combination. To explore association between treatments and patient outcomes we performed multiverse analysis, observing how the conclusions change between defensible choices of statistical model, predictors included in the model and other analytical degrees of freedom. Weak evidence to constrain the potential efficacy of azithromycin and favipiravir can be extracted from the data. Additionally, we performed external validation of several proposed prognostic models for Covid-19 severity showing that they mostly perform unsatisfactorily on our dataset.

• MeSH
• adenosinmonofosfát analogy a deriváty   terapeutické užití   MeSH
• alanin analogy a deriváty   MeSH
• amidy terapeutické užití   MeSH
• antivirové látky terapeutické užití   MeSH
• azithromycin terapeutické užití   MeSH
• COVID-19 * epidemiologie   MeSH
• dexamethason terapeutické užití   MeSH
• dospělí MeSH
• farmakoterapie COVID-19 * MeSH
• hospitalizace MeSH
• hydroxychlorochin terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• progrese nemoci * MeSH
• retrospektivní studie MeSH
• SARS-CoV-2 * izolace a purifikace   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• adenosinmonofosfát MeSH
• alanin MeSH
• amidy MeSH
• antivirové látky MeSH
• azithromycin MeSH
• dexamethason MeSH
• hydroxychlorochin MeSH
• remdesivir MeSH Prohlížeč

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

• MeSH
• adenin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• adenosin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• adenosinmonofosfát škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• alanin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• amidy škodlivé účinky   metabolismus   farmakologie   MeSH
• antivirové látky škodlivé účinky   metabolismus   farmakologie   MeSH
• chlorochin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• COVID-19 metabolismus   MeSH
• dusíkaté sloučeniny škodlivé účinky   metabolismus   farmakologie   MeSH
• farmakoterapie COVID-19 * MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• objevování léků * MeSH
• pyraziny škodlivé účinky   metabolismus   farmakologie   MeSH
• pyrrolidiny škodlivé účinky   metabolismus   farmakologie   MeSH
• racionální návrh léčiv MeSH
• ribavirin škodlivé účinky   metabolismus   farmakologie   MeSH
• SARS-CoV-2 účinky léků   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• thiazoly škodlivé účinky   metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• adenosin MeSH
• adenosinmonofosfát MeSH
• alanin MeSH
• amidy MeSH
• antivirové látky MeSH
• chlorochin MeSH
• dusíkaté sloučeniny MeSH
• favipiravir MeSH Prohlížeč
• galidesivir MeSH Prohlížeč
• nitazoxanide MeSH Prohlížeč
• pyraziny MeSH
• pyrrolidiny MeSH
• remdesivir MeSH Prohlížeč
• ribavirin MeSH
• thiazoly MeSH