This study describes 14 novel D2AAK1 derivatives exhibiting enhanced neuroprotective properties. These derivatives were tested for their inhibitory effects on AChE and MAO-B, as well as their effect on cell viability under normal conditions and under oxidative stress. D2AAK1 derivatives show strong cytoprotective effects, increasing cell viability by up to 80% under normal conditions and up to 60% under oxidative stress. These effects may involve modulation of MAPK p38 and Nrf2 pathway interactions, known to promote antioxidant and anti-apoptotic responses. In vivo studies indicated a beneficial effect of the tested derivative on memory processes in the novel object recognition test. These findings identify D2AAK1 derivatives as promising lead compounds for further development as potential treatments of memory deficits.

This review provides a comprehensive overview of recent advances in the synthesis, structural characterization, and applications of Ru(II), Ru(III), and Ru(VI) complexes, which bear tetradentate Schiff bases of salen type. Ruthenium complexes exhibit catalytic, electrochemical, and biological properties, serving as multifunctional platforms that integrate fundamental aspects of coordination chemistry with potential practical applications.

The objective of this work was the thermal and spectroscopic characterization of arbidol hydrochloride and its compatibility study in mixtures with starch derivatives (sodium starch glycolate, pregelatinized starch and β-cyclodextrin) using thermal analysis methods, i.e., differential scanning calorimetry (DSC), thermogravimetry (TGA), hot-stage microscopy (HSM) and spectroscopic methods such as Fourier transform infrared spectrometry (FTIR), X-ray powder diffraction (PXRD) and also thermogravimetry coupled with Fourier transform infrared spectrometry (TGA-FTIR). A comparison of thermoanalytical and spectroscopic data of mixtures against data of ingredients in isolation demonstrates the occurrence of changes, especially in the case of arbidol hydrochloride mixture with sodium starch glycolate, indicating incompatibility between these ingredients. In turn, FTIR spectra of mixture with pregelatinized starch and PXRD pattern of mixture with β-cyclodextrin subtle changes in bands or diffraction lines were found. Mixing arbidol hydrochloride with β-cyclodextrin probably also leads to the formation of an inclusion complex that contributes to increased solubility of active substance. However, the highest changes in the structure of arbidol hydrochloride were revealed after mixing it with sodium starch glycolate, which, as a superdisintegrant, may contribute to increasing solubility of active substance.

The broad spectrum of antiviral activity and relatively low toxicity of arbidol hydrochloride have made it an interesting subject of research. Additionally, there is no information available regarding its formulation with various excipients. Another drawback is its hydrophobic nature, which contributes to lower bioavailability in specific drug forms. Therefore, it is necessary to test its mixtures with excipients to identify those that can enhance its solubility in water. For this reason, tests of compatibility/incompatibility of mixtures of arbidol hydrochloride with starchy excipients such as dextrin, polydextrose, and hydroxypropyl starch were carried out using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), thermogravimetry coupled with Fourier transform infrared spectroscopy (TGA-FTIR), and powder X-ray diffraction (PXRD). Additionally, phase diagrams were developed for arbidol hydrochloride mixtures with starchy polymers, which enabled prediction of the solubility of this active pharmaceutical ingredient (API) in polymers and the mutual miscibility of the ingredients. The study concluded that arbidol hydrochloride may be compatible with dextrin.

This review provides an overview of the synthesis, characterization and application of coordination polymers based on N,O-donor Schiff base ligands. The coordination polymers (CPs) represent a novel class of inorganic–organic hybrid materials with tunable compositions and fascinating structures. They are composed of metal ions and organic ligands. Therefore, the nature of the metal ion and type of organic ligand is the most significant factor in constructing targeted coordination polymers with the desired properties. Due to the versatile coordination modes, N,O-donor Schiff base ligands are also used to construct various CPs.

Arylpiperazines are considered a “privileged scaffold” in medical chemistry due to their versatility and modular structure, enabling modifications towards diverse molecular targets with desired potency, selectivity, and pharmacokinetic properties. In particular, arylpiperazines are aminergic G protein-coupled receptor (GPCR) ligands and neurotransmitter transporter inhibitors, making this group of compounds attractive in central nervous system (CNS) drug discovery for treating schizophrenia, depression, sleep disorders, and Parkinson’s disease (PD). Furthermore, arylpiperazines may possess anticancer properties and can modulate some molecular targets involved in this disease. This review focuses on the structural aspects of arylpiperazines as aminergic GPCR ligands. The review centers on biologically active arylpiperazines with known X-ray structures, providing a detailed discussion of the conformations in the solid state. Next, their interactions with the aminergic GPCRs, based on experimental and molecular modelling studies, are addressed, making this review a comprehensive resource for medicinal and structural chemists working on arylpiperazines.

Treatment of schizophrenia with currently available drugs is often ineffective or results in several adverse reactions. In previous studies focusing on the search for new antipsychotic drugs, we designed and obtained a series of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptor ligands that were pharmacologically evaluated and showed promising antipsychotic activity. Evaluation of ADMET parameters is an important issue in drug development and should be performed at its early stage to avoid developing molecules with poor pharmacokinetics, that are unlikely to enter the market. For this reason, in this work we focused on the assessment of physicochemical parameters of selected compounds from the series we obtained to assess their drug-like potential. The results of thermal analysis showed that most of the tested compounds are thermally stable above 200 °C, with one compound stable up to 190 °C. Permeability through biological membranes assessed in the parallel artificial membrane permeability assay indicated that all tested compounds effectively migrate through biological membranes by means of passive diffusion. The solubility of the tested compounds was determined in PBS, reflecting physiological pH, and 0.01 M HCl, indicating their low to moderate solubility in PBS, which was significantly improved in acidic environment. The lipophilicity of the studied compounds expressed as LogD falls within the range of 1.84–2.80, what suggest that they would show good oral absorption and the ability to cross lipid barriers. The studies were supplemented with in silico prediction of ADMET parameters, which also indicate the probable high drug-likeness of the tested compounds.

Arbidol hydrochloride is an antiviral product widely used in Russia and China for the treatment of, among other diseases, influenza. In recent years, it has turned out to be highly effective against COVID-19. However, there is little knowledge about its physicochemical properties and its behavior in the presence of various pharmaceutical excipients, which could be useful in the development of new preparations by increasing its solubility and bioavailability. For this reason, binary mixtures composed of arbidol hydrochloride and selected pharmaceutical excipients such as chitosan, polyvinylpyrrolione K-30 and magnesium stearate were prepared and subjected to differential scanning calorimetry (DSC), thermogravimetry combined with Fourier transform infrared spectrometry (TGA-FTIR) and Fourier transform infrared spectrometry (FTIR) analyses. In order to obtain clarity in the interpretation of the outcomes, chemometric calculations with factor analysis (FA) were used. Additionally, a powder X-ray diffraction (PXRD) and an intrinsic dissolution rate study were performed for arbidol hydrochloride itself and in the presence of excipients. As a result of the study, it was revealed that arbidol hydrochloride may undergo polymorphic transformations and be incompatible with chitosan and magnesium stearate. However, mixing arbidol hydrochloride with polyvinylpyrrolidone K-30 guarantees the obtaining of durable and safe pharmaceutical preparations.

Schizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D2, 5-HT1A, and 5-HT2A receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds 1-16 were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds 1 and 10, selected based on their receptor profile, were subjected to in vivo tests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D2, 5-HT1A, and 5-HT2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.

Schizophrenia is a mental disorder with a complex pathomechanism involving many neurotransmitter systems. Among the currently used antipsychotics, classical drugs acting as dopamine D2 receptor antagonists, and drugs of a newer generation, the so-called atypical antipsychotics, can be distinguished. The latter are characterized by a multi-target profile of action, affecting, apart from the D2 receptor, also serotonin receptors, in particular 5HT2A and 5-HT1A. Such profile of action is considered superior in terms of both efficacy in treating symptoms and safety. In the search for new potential antipsychotics of such atypical receptor profile, an attempt was made to optimize the arylpiperazine based virtual hit, D2AAK3, which in previous studies displayed an affinity for D2, 5HT1A and 5-HT2A receptors, and showed antipsychotic activity in vivo. In this work, we present the design of D2AAK3 derivatives (1-17), their synthesis, and structural and pharmacological evaluation. The obtained compounds show affinities for the receptors of interest and their efficacy as antagonists/agonists towards them was confirmed in functional assays. For the selected compound 11, detailed structural studies were carried out using molecular modeling and X-ray methods. Additionally, ADMET parameters and in vivo antipsychotic activity, as well as influence on memory and anxiety processes were evaluated in mice, which indicated good therapeutic potential and safety profile of the studied compound.

The dopamine D2 receptor, which belongs to the family of G protein-coupled receptors (GPCR), is an important and well-validated drug target in the field of medicinal chemistry due to its wide distribution, particularly in the central nervous system, and involvement in the pathomechanism of many disorders thereof. Schizophrenia is one of the most frequent diseases associated with disorders in dopaminergic neurotransmission, and in which the D2 receptor is the main target for the drugs used. In this work, we aimed at discovering new selective D2 receptor antagonists with potential antipsychotic activity. Twenty-three compounds were synthesized, based on the scaffold represented by the D2AAK2 compound, which was discovered by our group. This compound is an interesting example of a D2 receptor ligand because of its non-classical binding to this target. Radioligand binding assays and SAR analysis indicated structural modifications of D2AAK2 that are possible to maintain its activity. These findings were further rationalized using molecular modeling. Three active derivatives were identified as D2 receptor antagonists in cAMP signaling assays, and the selected most active compound 17 was subjected to X-ray studies to investigate its stable conformation in the solid state. Finally, effects of 17 assessed in animal models confirmed its antipsychotic activity in vivo.

A new cobalt(III) complex with a pentadentate Schiff base was synthesized using a reaction of 2,2′-{(2-hydroxypropane-1,3-diyl)bis(nitriloeth-1-yl-1-ylidene)}diphenol (H3L) and cobalt(II) acetate in a methanolic solution. This synthesis resulted in the isolation of dinuclear compound [CoIII2L2] (1), which was characterized using elemental analyses and XRF, FTIR, and TG/DSC techniques. The molecular structure of the complex was confirmed using single-crystal X-ray diffraction. The structure of 1 consists of a centrosymmetric dimer in which two crystallographically equivalent cobalt(III) ions are bridged by two alkoxido oxygen atoms. In addition, each metal center is coordinated by two Schiff bases.

The aim of the study presented in this work was to obtain the new Zn-II complexes with different N2O2-, N3O4-, N2O5 and N2O3- donors Schiff bases (H2L1 (C29H26N2O2), H2L2 (C29H26N2O2), H4L3 (C30H29N3O4), H5L4 center dot H2O (C29H28N2O6), H3L5 center dot H2O (C19H24N2O4)) and characterized them by various physicochemical methods, such as: elemental analysis, spectroscopic (FTIR) and thermal analysis (TG/DSC, TG-FTIR). The synthesized homonuclear complexes were obtained as polycrystalline solids, stable at ambient temperature with the following formulas: [Zn-3(L1)(2)(CH3COO)(2)] (1), [ZnL2]center dot H2O (2), [ZnH2L3]center dot 0.5H(2)O (3), [Zn2L4(CH3COO)] (4), [Zn2L5(CH3COO)]center dot 1.5H(2)O (5). The results of FTIR spectroscopy indicate that azomethine nitrogen and phenoxide oxygen atoms participate in the coordination of zinc ions, and in some cases, the coordination sphere is supplemented with amino nitrogen atom or oxygen atoms from an acetate ion, a deprotonated hydroxyl group or a water molecule. TG/DSC and TG-FTIR analysis indicate that the thermal decomposition of the ZnII complexes is a multi-stage process depending on the applied Schiff base ligands and the used atmosphere (air or nitrogen). After heating, the complexes containing water molecules undergo a dehydration process, then an organic part is gradually defragmented and combusted/pyrolysed. The pyrolysis processes of the complexes are mainly associated with the release of water, carbon dioxide, ammonia, phenol, methane, carbon monoxide, and acetic acid (for 1, 4 and 5). Additionally, the antioxidant activities of the complexes in reducing power, FRAP (ferric reducing antioxidant power) were investigated. As a standard antioxidant compound, the ascorbic acid was used and the results were expressed as ascorbic equivalent (mu mol of ascorbic acid equivalents (AAE) per L). Schiff bases exhibit good antioxidant activity, which is enhanced or comparable when complexed with zinc ions. The exception is complex 3, which has a significantly lower reducing capacity than the corresponding free ligand (H4L3).

Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT1A and 5-HT2A receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT1A receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test.

A crystal structure and thermal characterization of a multisite Schiff base containing N2O2-inner and O4-outer coordination sites are reported. The title compound was characterized by X-ray structure analysis, 1H-NMR, 13C-NMR and ATR-FTIR spectroscopy, TG/DSC and TG-FTIR techniques. The compound crystallizes as a methanol solvate in the triclinic system, space group P1¯. The stable at room temperature compound, during heating in the air, first loses a methanol molecule. At higher temperature, the sample decomposition is associated with a strong exothermic effect and the emission of large amounts of carbon dioxide, carbon monoxide and ammonia.

The blockade of kainate receptors, in particular with non-competitive antagonists, has-due to their anticonvulsant and neuroprotective properties-therapeutic potential in many central nervous system (CNS) diseases. Deciphering the structural properties of kainate receptor ligands is crucial to designing medicinal compounds that better fit the receptor binding pockets. In light of that fact, here, we report experimental and computational structural studies of four indole derivatives that are non-competitive antagonists of GluK1/GluK2 receptors. We used X-ray studies and Hirshfeld surface analysis to determine the structure of the compounds in the solid state and quantum chemical calculations to compute HOMO and LUMO orbitals and the electrostatic potential. Moreover, non-covalent interaction maps were also calculated. It is worth emphasizing that compounds 3 and 4 are achiral molecules crystallising in non-centrosymmetric space groups, which is a relatively rare phenomenon.

New heterotrinuclear complexes with the general formula [Cu2Ln(H2L)(HL)(NO3)2]·MeOH (Ln = Ho (1), Er (2), H4L = N,N′-bis(2,3-dihydroxybenzylidene)-1,3-diaminopropane) were synthesized using compartmental Schiff base ligand in conjugation with auxiliary ligands. The compounds were characterized by elemental analysis, ATR-FTIR spectroscopy, X-ray diffraction, TG, DSC, TG-FTIR and XRD analysis. The N2O4 salen-type ligand coordinates 3d and 4f metal centers via azomethine nitrogen and phenoxo oxygen atoms, respectively, to form heteropolynuclear complexes having CuO2Ln cores. In the crystals 1 and 2, two terminal Cu(II) ions are penta-coordinated with a distorted square-pyramidal geometry and a LnIII ion with trigonal dodecahedral geometry is coordinated by eight oxygen atoms from [CuII(H2L)(NO3)]− and [CuII(HL)(NO3)]2− units. Compounds 1 and 2 are stable at room temperature. During heating, they decompose in a similar way. In the first decomposition step, they lose solvent molecules. The exothermic decomposition of ligands is connected with emission large amounts of gaseous products e.g., water, nitric oxides, carbon dioxide, carbon monoxide. The final solid products of decomposition 1 and 2 in air are mixtures of CuO and Ho2O3/Er2O3. The measurements of magnetic susceptibilities and field dependent magnetization indicate the ferromagnetic interaction between CuII and HoIII ions 1.

New cationic complexes of Cu(II) with bridged aminocarboxylates: glycine and alanine, as well as octaazamacrocyclic ligand N,N',N '',N'''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tpmc), with general formula [Cu-2(L)tpmc](ClO4)(4)center dot Y, (1): L=glycine, Y=2H(2)O and (2): L=alanine, Y=CH3CN were synthesized. Characterization of the complexes was performed by elemental analysis (C, H, N, Cu), UV/Vis, FTIR spectroscopy and magnetic measurements. The single crystal X-ray analyses results show that reported compounds were obtained as hydrates with formulae [Cu-2(gly)tpmc](ClO4)(4)center dot 6.5H(2)O (M1) and [Cu-2(ala)tpmc](ClO4)(4)center dot 5H(2)O (M2). They crystallize in the orthorhombic system, P2(1)2(1)2(1) space group. The metal centers are bridged by the carboxylate group of the glycine/alanine and bound via nitrogen atoms of tmpc. In the complex M1/M2, geometry around Cu(II) coordination sphere is square pyramidal (M1: tau(5) = 0.10/0.33; M2: tau(5) = 0.04/0.30). In the crystal structure of M1 and M2 the amino acids exist as a zwitterion. The temperature dependence of magnetic susceptibility indicated very weak ferromagnetic interaction between two Cu(II) ions. The antiproliferative effect of the complexes, the free ligands, and cis-platin, as referent cytostatic drug, were tested against human leukemia monocytic cell line (THP-1), leukemic T cell lymphoblast (JURKAT) and Human Caucasian Burkitt's lymphoma (RAMOS). The IC50 values for the complexes were from 37.9 +/- 2.6 to 63.05 +/- 0.72 mu M. (C) 2021 Published by Elsevier B.V.