The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC50 values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid 12 with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.

• Klíčová slova
• Endonuclease, Flavonoid, Influenza, Inhibitors, RNA polymerase,
• MeSH
• antivirové látky * farmakologie   chemická syntéza   chemie   MeSH
• endonukleasy * antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů * farmakologie   chemická syntéza   chemie   MeSH
• luteolin * farmakologie   chemická syntéza   chemie   MeSH
• molekulární struktura MeSH
• racionální návrh léčiv * MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky * MeSH
• endonukleasy * MeSH
• inhibitory enzymů * MeSH
• luteolin * MeSH

Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein-protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein-protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

• Klíčová slova
• Autophagy, Autophagy inhibition, Protein–protein interaction, Small molecule,
• MeSH
• autofagie účinky léků   MeSH
• kaseinkinasa II antagonisté a inhibitory   metabolismus   MeSH
• knihovny malých molekul * chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• proteiny spojené s autofagií * metabolismus   antagonisté a inhibitory   MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kaseinkinasa II MeSH
• knihovny malých molekul * MeSH
• proteiny spojené s autofagií * MeSH

In human cells, receptor-interacting protein kinase 2 (RIPK2) is mainly known to mediate downstream enzymatic cascades from the nucleotide-binding oligomerization domain-containing receptors 1 and 2 (NOD1/2), which are regulators of pro-inflammatory signaling. Thus, the targeted inhibition of RIPK2 has been proposed as a pharmacological strategy for the treatment of a variety of pathologies, in particular inflammatory and autoimmune diseases. In this work, we designed and developed novel thieno[2,3d]pyrimidine derivatives, in order to explore their activity and selectivity as RIPK2 inhibitors. Primary in vitro evaluations of the new molecules against purified RIPKs (RIPK1-4) demonstrated outstanding inhibitory potency and selectivity for the enzyme RIPK2. Moreover, investigations for efficacy against the RIPK2-NOD1/2 signaling pathways, conducted in living cells, showed their potency could be tuned towards a low nanomolar range. This could be achieved by solely varying the substitutions at position 6 of the thieno[2,3d]pyrimidine scaffold. A subset of lead inhibitors were ultimately evaluated for selectivity against 58 human kinases other than RIPKs, displaying great specificities. We therefore obtained new inhibitors that might serve as starting point for the preparation of targeted tools, which could be useful to gain a better understanding of biological roles and clinical potential of RIPK2.

• Klíčová slova
• Kinase inhibitor, NOD, RIPK2, Receptor-interacting protein kinase 2, Thieno[2,3d]pyrimidine derivative,
• MeSH
• lidé MeSH
• protein-serin-threoninkinasa 2 interagující s receptory * antagonisté a inhibitory   metabolismus   MeSH
• signální transdukce * MeSH
• zánět * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protein-serin-threoninkinasa 2 interagující s receptory * MeSH
• RIPK2 protein, human MeSH Prohlížeč
• thieno(2,3-d)pyrimidine MeSH Prohlížeč

Mutation of FLT3 protein kinase is often associated with deregulated cell proliferation in acute myeloid leukemia and the inhibition of this kinase is a potential therapeutic strategy. We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines prepared in an effort to study their biological activity particularly toward FLT3-ITD and its downstream regulators as well as toward CDK2 and CDK9. Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition. Further biochemical analyses and molecular docking confirmed FLT3 as a cellular target of 10b.

• Klíčová slova
• Acute myeloid leukemia, Antitumour activity, FLT3, Pyrazolo[1,5-a]pyrimidines,
• MeSH
• akutní myeloidní leukemie * farmakoterapie   MeSH
• apoptóza MeSH
• inhibitory proteinkinas chemie   MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• proliferace buněk MeSH
• pyrimidiny * chemie   MeSH
• simulace molekulového dockingu MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• pyrimidiny * MeSH
• tyrosinkinasa 3 podobná fms MeSH

Novel 4-aminoquinazoline-6-carboxamide derivatives bearing differently substituted aryl or heteroaryl groups at position 7 in the core were rationally designed, synthesized and evaluated for biological activity in vitro as phosphatidylinositol 4-kinase IIα (PI4K2A) inhibitors. The straightforward approach described here enabled the sequential, modular synthesis and broad functionalization of the scaffold in a mere six steps. The SAR investigation reported here is based on detailed structural analysis of the conserved binding mode of ATP and other adenine derivatives to the catalytic site of type II PI4Ks, combined with extensive docking studies. Several compounds exhibited significant activity against PI4K2A. Moreover, we solved a crystal structure of PI4K2B in complex with one of our lead ligand candidates, which validated the ligand binding site and pose predicted by our docking-based ligand model. These discoveries suggest that our structure-based approach may be further developed and employed to synthesize new inhibitors with optimized potency and selectivity for this class of PI4Ks.

• Klíčová slova
• ATP-binding site, PI4K2A inhibitor, Phosphatidylinositol 4-kinase class II, Quinazoline derivative, SAR investigation,
• MeSH
• 1-fosfatidylinositol-4-kinasa * chemie   metabolismus   MeSH
• adenin MeSH
• adenosintrifosfát * metabolismus   MeSH
• ligandy MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-fosfatidylinositol-4-kinasa * MeSH
• 4-aminoquinazoline MeSH Prohlížeč
• adenin MeSH
• adenosintrifosfát * MeSH
• ligandy MeSH

Deregulation of protein kinases is often associated with uncontrolled cell proliferation in various tumours and the inhibition of kinase activity remains an important target for anti-tumour drug development. Here, we report a novel series of 2-aminocyclohexylamino-6-(substituted benzylamino/anilino)-9-cyclopentylpurine derivatives conjugated with putrescine, spermidine or spermine moiety in an effort to expand library of highly potent 2,6,9-trisubstituted purine kinase inhibitors. Presented aniline-type conjugates exhibit significant cytotoxic activity in MV4-11 and EOL-1 cell lines which correlates with FLT3-ITD and PDGFRα inhibition. Furthermore, 6-anilinopurines affected MAPK and STAT pathways in the treated MV4-11 cells and induced cell cycle arrest in the G1 phase. 6-Benzylaminopurines showed comparable CDK2 inhibitory activity to 6-anilinopurines, however, the PDGFRα and FLT3-ITD inhibition was strongly suppressed. Our results show that novel compounds containing aniline in the structure can be involved in the development of potent tyrosine kinase inhibitors with strong activity toward acute myeloid leukemia or chronic eosinophilic leukemia.

• Klíčová slova
• 2, 6, 9-trisubstituted purines, FLT3-ITD, Kinase inhibitor, PDGFRα,
• MeSH
• inhibitory proteinkinas chemická syntéza   chemie   farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• proteinkinasy metabolismus   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• proteinkinasy MeSH
• protinádorové látky MeSH
• puriny MeSH

Alzheimeŕs disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.

• Klíčová slova
• Acetylcholinesterase, Alzheimeŕs disease, Amaryllidaceae alkaloid, Butyrylcholinesterase, Docking studies, Montanine-type,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• alkaloidy chemická syntéza   chemie   farmakologie   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• isochinoliny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• alkaloidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• isochinoliny MeSH
• montanine MeSH Prohlížeč

The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Aβ) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.

• Klíčová slova
• Acetylcholinesterase, Alzheimer's disease, Amyloid-beta, Multi-target directed ligands, huprine Y, l-Tryptophan,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• aminochinoliny chemie   farmakologie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• tryptofan chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• aminochinoliny MeSH
• amyloidní beta-protein MeSH
• cholinesterasové inhibitory MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• huprine Y MeSH Prohlížeč
• neuroprotektivní látky MeSH
• tryptofan MeSH

Trypanosoma brucei parasites cause Human African Trypanosomiasis and the current drugs for its treatment are often inefficient and toxic. This urges the need to development of new antitrypanosomal agents. We report the synthesis and biological profiling of 3'-deoxy-3'-fluororibonucleosides derived from 7-deazaadenine nucleosides bearing diverse substituents at position 7. They were synthesized through glycosylation of 6-chloro-7-bromo- or -7-iodo-7-deazapurine with protected 3'-fluororibose followed by cross-coupling reactions at position 7 and/or deprotection. Most of the title nucleosides displayed micromolar or submicromolar activity against Trypanosoma brucei brucei. The most active were the 7-bromo- and 7-iododerivatives which exerted double-digit nanomolar activity against T. b. brucei and T. b. gambiense and no cytotoxicity and thus represent promising candidates for further development.

• Klíčová slova
• Anti-trypanosomal agents, Antiparasitic, Deazapurines, Fluorinated compounds, Nucleosides,
• MeSH
• fibroblasty účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• parazitické testy citlivosti MeSH
• ribonukleosidy chemická syntéza   farmakologie   toxicita   MeSH
• trypanocidální látky chemická syntéza   farmakologie   toxicita   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei gambiense účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ribonukleosidy MeSH
• trypanocidální látky MeSH

The compounds from eight different thiazolidine and thiazole series were assessed as potential antileishmanial scaffolds. They were tested for antileishmanial activity against promastigotes of Leishmania major using in vitro primary screen and dose response assays. The compounds from six thiazolidine and thiazole series were identified as the hits with antileishmanial activity against L. major. However, the analyses of structure-activity relations (SARs) showed that the interpretable SARs were obtained only for phenyl-indole hybrids (compounds C1, C2, C3 and C5) as the most effective compounds against L. major promastigotes (IC50 < 10 µM) with low toxicity to human fibroblasts. For the scaffold of these compounds, the most significant SAR patterns were: free N3 position of thiazolidinone core, absence of big fragments at the C5 position of thiazolidinone core and presence of halogen atoms or nitro group in the phenyl ring of phenyl-indole fragment. As previous studies showed that these compounds also have activity against the two Trypanosoma species, Trypanosoma brucei and Trypanosoma gambiense, their scaffold could be associated with a broader antiparasitic activity.

• Klíčová slova
• Antileishmanial activity, Indoles, SAR, Thiazole core, Thiazolidinone core,
• MeSH
• fibroblasty účinky léků   MeSH
• knihovny malých molekul chemie   farmakologie   toxicita   MeSH
• Leishmania major účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• thiazolidiny chemie   farmakologie   toxicita   MeSH
• trypanocidální látky chemie   farmakologie   toxicita   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei gambiense účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• knihovny malých molekul MeSH
• thiazolidiny MeSH
• trypanocidální látky MeSH