Ruthenium Complexes with Pyridazine Carboxylic Acid: Synthesis, Characterization, and Anti-Biofilm Activity.

As a result of drug resistance, many antimicrobial medicines become ineffective, making the infections more difficult to treat. Therefore, there is a need to develop new compounds with antibacterial activity. This role may be played, for example, by metal complexes with carboxylic acids.

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein-Protein Interaction.

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations.

Machine learning accelerates pharmacophore-based virtual screening of MAO inhibitors.

Nowadays, an efficient and robust virtual screening procedure is crucial in the drug discovery process, especially when performed on large and chemically diverse databases. Virtual screening methods, like molecular docking and classic QSAR models, are limited in their ability to handle vast numbers of compounds and to learn from scarce data, respectively. In this study, we introduce a universal methodology that uses a machine learning-based approach to predict docking scores without the need for time-consuming molecular docking procedures.

Efficient delivery of carotenoids to adipocytes with albumin.

Carotenoids are very effectively delivered by albumin to adipocytes. The uptake of carotenoids to the cells occurs in the form of self-aggregates that localize in the vicinity of the adipocyte membrane, as shown by high spatial resolution Raman spectroscopy. The binding of carotenoids to albumin and the mechanism of their transport were elucidated with the help of chiroptical spectroscopies, in tandem with molecular docking and molecular dynamics simulations.

Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for -Terphenyl Derivatives.

Although heavily studied, the subject of anti-PD-L1 small-molecule inhibitors is still elusive. Here we present a systematic overview of the principles behind successful anti-PD-L1 small-molecule inhibitor design on the example of the -terphenyl scaffold, with a particular focus on the neglected influence of the solubilizer tag on the overall affinity toward PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation in homogeneous time-resolved fluorescence and cell-based assays.

Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction.

Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and H-N HSQC nuclear magnetic resonance. Extensive structure-activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound , which exhibits micromolar potency and high ligand efficiency (LE = 0.

Dual Piperidine-Based Histamine H and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain.

In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, and , differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σRs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds.

Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu Receptor Modulation Activity and Antipsychotic-Like Properties.

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu activity in the T-REx 293 cell line expressing a recombinant human mGlu receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3)-one (, , mGlu IC = 6.

Hierarchical analysis of the target-based scoring function modification for the example of selected class A GPCRs.

Computational methods, especially molecular docking-based calculations, have become indispensable in the modern drug discovery workflow. The constantly increasing chemical space requires fast, robust but most of all highly predictive methods to search for new bioactive agents. Thus, the scoring function (SF) is a useful and broadly applied energy-based element of docking software, allowing quick and effective evaluation of a ligand's propensity to bind to selected protein targets.

Synthesis, Characterization and Biological Investigations of Half-Sandwich Ruthenium(II) Complexes Containing Benzimidazole Moiety.

Half-sandwich Ru(II) complexes belong to group of biologically active metallo-compounds with promising antimicrobial and anticancer activity. Herein, we report the synthesis and characterization of arene ruthenium complexes containing benzimidazole moiety, namely, [(η--cymene)RuCl(bimCOO)] () and [(η--cymene)RuCl(bim)] () (where bimCOO = benzimidazole-2-carboxylate and bim = 1--benzimidazole). The compounds were characterized by H NMR, C NMR, IR, UV-vis and CV.

Access to Isoquinolin-2(1)-yl-acetamides and Isoindolin-2-yl-acetamides from a Common MCR Precursor.

We achieved a divergent synthesis of isoquinolin-2(1)-yl-acetamides (16 examples, up to 90% yields) and regioselective isoindolin-2-yl-acetamides (14 examples, up to 93% yields) in moderate to good yields by reacting various substituted ethanones or terminal alkynes with Ugi-4CR intermediates via an ammonia-Ugi-4CR/Copper(I)-catalyzed annulation sequence reaction. The same intermediate thus gives 2D distant but 3D closely related scaffolds, which can be of high interest in exploiting chemistry space on a receptor. The scopes and limitations of these efficient sequence reactions are described, as well as gram-scale synthesis.

Discovery of ()--Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity .

[] showed broad-spectrum antiseizure activity across mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations.

Discovery of Cinnamylidene Derivative of Rhodanine with High Anthelmintic Activity against sp.

The treatment of parasitic infections requires the application of chemotherapy. In view of increasing resistance to currently in-use drugs, there is a constant need to search for new compounds with anthelmintic activity. A series of 16 cinnamylidene derivatives of rhodanine, including newly synthesized methoxy derivatives (-) and previously obtained chloro, nitro, and diethylamine derivatives (-), was investigated towards anthelmintic activity.

Influence of Fluorine Substitution on Nonbonding Interactions in Selected Para-Halogeno Anilines.

A series of 4-halogeno aniline derivatives was studied employing combined theoretical and experimental methods (i. e. crystal structure analysis and vibrational spectroscopies).

Asymmetric synthesis and in vivo/in vitro characterization of new hybrid anticonvulsants derived from (2,5-dioxopyrrolidin-1-yl)phenylacetamides.

In the current studies we carried out an optimized multistep asymmetric synthesis of R-enantiomers (eutomers) for a previously identified series of racemic hybrid anticonvulsants. The spatial structure of selected enantiomers was solved by the use of crystallographic methods. The compound (R)-16 was identified as a lead, which revealed broad-spectrum protective activity in a range of epilepsy models with the following ED values: the maximal electroshock (MES) test (36.

How can fluorine directly and indirectly affect the hydrogen bonding in molecular systems? - A case study for monofluoroanilines.

Hydrogen bonds (HBs) directly engaging fluorine has been extensively studied, but the indirect effect of fluorine on adjacent donors and acceptors is poorly understood and still difficult to predict. The indirect and direct effect of the fluorination of aniline on HB patterns observed in monofluoroanilines was studied via experimental (vibrational spectroscopy and crystal structure analysis) and theoretical (ab initio molecular dynamics and electrostatic surface potential) methods. It was found that a fluorine substituent decreases the strength and frequency of N-H⋯N HBs and, at the same time, increases the acidity of CH protons, enhancing the competitiveness of weaker interactions.

Room-Temperature Bistability in a Ni-Fe Chain: Electron Transfer Controlled by Temperature, Pressure, Light, and Humidity.

Bistable and stimuli-responsive molecule-based materials are promising candidates for the development of molecular switches and sensors for future technologies. The CN-bridged {NH [Ni(cyclam)][Fe(CN) ]⋅5 H O} chain exists in two valence states: Ni -Fe (1 ) and Ni -Fe (1 ) and shows unique multiresponsivity under ambient conditions to various stimuli, including temperature, pressure, light, and humidity, which generate measurable response in the form of significant changes in magnetic susceptibility and color. The electron-transfer phase transition 1 ↔1 shows room-temperature thermal hysteresis, can be induced by irradiation, and shows high sensitivity to small applied pressure, which shifts it to higher temperatures.

Fourfold symmetric MCR's the tetraisocyanide 1,3-diisocyano-2,2-bis(isocyanomethyl)propane.

Oligoisocyanides are attractive synthetic targets, however, only a few are known. Here, we describe the smallest stable tetraisocyanide possible, the 1,3-diisocyano-2,2-bis(isocyano-methyl)propane (1) with S4 symmetry. Its four-step synthesis, structure, and reactivity in unprecedented symmetric fourfold Ugi 4CR and fourfold Passerini 3CR are described.

Copper-Catalyzed Modular Assembly of Polyheterocycles.

Easy operation, readily accessible starting materials, and short syntheses of the privileged scaffold indeno[1,2-]isoquinolinone were achieved by an multicomponent reaction (MCR)-based protocol via an ammonia-Ugi-four component reaction (4CR)/copper-catalyzed annulation sequence. The optimization and scope and limitations of this short and general sequence are described. The methodology allows an efficient construction of a wide variety of indenoisoquinolinones in just two steps.

Scaffolding-Induced Property Modulation of Chemical Space.

Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge neutral cyclic derivatives.

'Atypical Ugi' tetrazoles.

Amino acid-derived isocyano amides together with TMSN3, oxocomponents and 1° or 2° amines are common substrates in the Ugi tetrazole reaction. We surprisingly found that combining these substrates gives two different constitutional isomeric Ugi products A and B. A is the expected classical Ugi product whereas B is an isomeric product ('atypical Ugi') of the same molecular weight with the tetrazole heterocycle migrated to a different position.

Influence of the position of the methyl substituent and N-oxide formation on the geometry and intermolecular interactions of 1-(phenoxyethyl)piperidin-4-ol derivatives.

Aminoalkanol derivatives have attracted much interest in the field of medicinal chemistry as part of the search for new anticonvulsant drugs. In order to study the influence of the methyl substituent and N-oxide formation on the geometry of molecules and intermolecular interactions in their crystals, three new examples have been prepared and their crystal structures determined by X-ray diffraction. 1-[(2,6-Dimethylphenoxy)ethyl]piperidin-4-ol, CHNO, 1, and 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol, CHNO, 2, crystallize in the orthorhombic system (space groups P222 and Pbca, respectively), with one molecule in the asymmetric unit, whereas the N-oxide 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol N-oxide monohydrate, CHNO·HO, 3, crystallizes in the monoclinic space group P2/c, with one N-oxide molecule and one water molecule in the asymmetric unit.

Isocyanide-Based Multicomponent Reactions of Free Phenylboronic Acids.

Boronic acids are amongst the most useful synthetic intermediates, frequently used by modern drug design. However, their access and fast synthesis of libraries are often problematic. We present a methodology on the synthesis of drug-like scaffolds via IMCRs with unprotected phenylboronic acids.

Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction.

Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal ''lid'' segment of MDM2 from the proximity of the p53-complementary interface.