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We investigate bias temperature instability (BTI) charge trapping trends in high- $k$ metal gate (HKMG) stacks with a variety of work function metals (WFMs). Most BTI models suggest charge trapping in oxide defects is modulated by the applied oxide electric field, which controls the energy barrier for the capture process, irrespective of the gate work function. However, experimental data on capacitors show enhanced or reduced charge trapping at a constant oxide electric field for different WFM stacks. We ascribe this to a different chemical interaction of the metals with the dielectric, which yields different defect profiles depending on the process thermal budget, and not to the gate work function per se. This observation is confirmed by comparing BTI degradation in nMOS and pMOS replacement gate planar transistors with three selected WFM stacks (representative of high-, standard-, and low- $V_{\mathrm{ th}}$ device flavors), and two different process thermal budgets. Furthermore, by employing the imec/T.U. Wien physics-based BTI simulation framework “Comphy,” we also show that, on top of the unavoidable chemical interaction of different metals with the underlying SiO2/HfO2 dielectric stack, different gate work functions within a typical range of relevance (4.35–4.75 eV) can yield a different charge state of the deep high- $k$ defects, and can therefore have an impact on charge trapping kinetics during BTI stress, particularly in nMOSFETs. [ABSTRACT FROM AUTHOR]

We investigate the negative-bias temperature instability (NBTI) degradation and recovery of pMOSFETs under continuously varying analog-circuit stress voltages and thereby generalize existing digital-stress NBTI studies. Starting from our ultrafast NBTI measurements and an extensive TCAD analysis, we study two physics-based compact models for analog-stress NBTI including recovery. The high accuracy of both models is evidenced from single-FET analog-stress and circuit-level ring oscillator experiments. Their numerical efficiency allows direct coupling to circuit simulators and permits to accurately account for NBTI already during circuit design. Furthermore, one of the models calculates the time-dependent NBTI variability of single-FET and of circuit performance parameters. We demonstrate our NBTI models on a ring oscillator and calculate the mean drift and statistical distribution of its oscillation frequency. [ABSTRACT FROM AUTHOR]

It is well-established that oxide defects adversely affect functionality and reliability of a wide range of microelectronic devices. In semiconductor-insulator systems, insulator defects can capture or emit charge carriers from/to the semiconductor. These defects feature several stable configurations, which may have profound implications for the rates of the charge capture and emission processes. Recently, these complex capture/emission events have been investigated experimentally in considerable detail in Si/SiO 2 devices, but their theoretical understanding still remains vague. In this paper we discuss in detail how the capture/emission processes can be simulated using the theoretical methods developed for calculating rates of charge transfer reactions between molecules and in electro-chemistry. By employing this theoretical framework we link the atomistic defect configurations to known trapping model parameters (e.g. trap levels) as well as measured capture/emission times in Si/SiO 2 devices. Using density functional theory (DFT) calculations, we investigate possible atomistic configurations for various defects in amorphous ( a )-SiO 2 implicated in being involved in the degradation of microelectronic devices. These include the oxygen vacancy and hydrogen bridge as well as the recently proposed hydroxyl E ′ center. In order to capture the effects of statistical defect-to-defect variations that are inevitably present in amorphous insulators, we analyze a large ensemble of defects both experimentally and theoretically. This large-scale investigation allows us to prioritize the candidates from our defect list based on their trap parameter distributions. For example, we can rule out the E ′ center as a possible candidate. In addition, we establish realistic ranges for the trap parameters, which are useful for model calibration and increase the credibility of simulation results by avoiding artificial solutions. Furthermore, we address the effect of nuclear tunneling, which is involved according to the theory of charge transfer reactions. Based on our DFT results, we demonstrate the impact of nuclear tunneling on the capture/emission process, including their temperature and field dependence, and also give estimates for this effect in Si/SiO 2 devices. [ABSTRACT FROM AUTHOR]

SiGe quantum-well pMOSFETs have recently been introduced for enhanced performance of transistors. Quite surprisingly, a significant reduction in negative bias temperature instability (NBTI) was also found in these devices. Furthermore, a stronger oxide field acceleration of the degradation in SiGe devices compared with Si devices was reported. These observations were speculated to be a consequence of the energetical realignment of the SiGe channel with respect to the dielectric stack. As these observations were made on large-area devices, only the average contribution of many defects to NBTI could be studied. In order to reveal the microscopic reasons responsible for the improved reliability, a detailed study of single defects is performed in nanoscale devices. To provide a detailed picture of single charge trapping, the step-height distributions for different device variants are measured and found to follow a unimodal and bimodal distribution. This finding suggests two conducting channels, one in the SiGe and one in the thin Si cap layer. We, furthermore, demonstrate that similar trap depth distributions are present among the device variants supported by a similar stress bias dependence of the capture times of the identified single defects. We conclude that NBTI is primarily determined by the dielectric stack and not by the device technology. [ABSTRACT FROM AUTHOR]

The susceptibility of conventional silicon p-channel MOS transistors to negative bias temperature instabilities (NBTIs) is a serious threat to further device scaling. One possible solution to this problem is the use of a SiGe quantum-well channel. The introduction of a SiGe layer, which is separated from the insulator by a thin Si cap layer, not only results in high mobilities but also superior reliability with respect to NBTI. In part one of this paper, we provide experimental evidence for reduced NBTI by thoroughly studying single traps in nanoscale devices. In this paper, we present detailed TCAD simulations and employ the four-state nonradiative multiphonon model to determine the energetical and spatial positions of the identified single traps. The found trap levels agree with the defect bands estimated in large-area devices. Our conclusions are also supported by the observation of similar activation energies for defects present in transistors of various device geometries. From the calibrated TCAD simulations data, an impressive boost of the time-to-failure for the SiGe transistor can be predicted and explained. [ABSTRACT FROM AUTHOR]

Mapping and visualization of all degradation modes in both n- and p-channel field effect transistors, specifically devices for dynamic random access memory periphery, is performed in the (VG, VD) bias space applicable for complementary metal-oxide-semiconductor operation. This "all-in-one" approach allows for tracking and studying in parallel all degradation regimes, including bias temperature instability, hot carrier degradation, and off-state stress, as well as the transitions between them. It should prove beneficial when developing new very large-scale integrated technologies, since it allows for simultaneous comparison and checking of all degradation regimes and promptly identifying "weak spots" of each technology option. It also allows to choose the correct criteria (voltages or fields) at a later time and postprocessing the data as necessary. [ABSTRACT FROM AUTHOR]

Amorphous indium gallium zinc oxide (a-IGZO) is becoming an increasingly important technological material. Transport in this material is conceptualized as the heavy disorder of the material causing a conduction or mobility band-edge that randomly varies and undulates in space across the entire system. Thus, transport is envisioned as being dominated by percolation physics as carriers traverse this varying band-edge landscape of "hills" and "valleys". It is then something of a missed opportunity to model such a system using only a compact approach-despite this being the primary focus of the existing literature-as such a system can easily be faithfully reproduced as a true microscopic TCAD model with a real physically varying potential. Thus, in this work, we develop such a "microscopic" TCAD model of a-IGZO and detail a number of key aspects of its implementation. We then demonstrate that it can accurately reproduce experimental results and consider the issue of the addition of non-conducting band-tail states in a numerically efficient manner. Finally, two short studies of 3D effects are undertaken to illustrate the utility of the model: specifically, the cases of variation effects as a function of device size and as a function of surface roughness scattering.

Feroxyhyte (δ-FeOOH) was synthesized and characterized using X-ray diffractometry (XRD), simultaneous thermal analysis (STA), scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM-EDS), and low-temperature nitrogen adsorption-desorption measurements. Its potential application as adsorbent of an anionic and cationic dyes such as C.I. Acid Violet 1 (AV1) and C.I. Basic Blue 3 (BB3) was investigated by determining the adsorption capacities based on the Langmuir (36.6 mg/g for AV1 and 187 mg/g for BB3), Freundlich and Dubinin-Radushkevich isotherm models. Adsorption of AV1 and BB3 by δ-FeOOH drops with the presence of additives such as cationic and anionic surfactants (CTAB, SDS) and ionic polymers (PAA, PEI). The surface and electrokinetic properties of examined suspensions were also described. They include determination of the solid surface charge density and the zeta potential, as well as values of point of zero charge and isoelectric point of feroxyhyte particles without and with adsorbed layers of organic substances. Their analysis made possible to propose the most probable structure of electrical double layer formed at the iron mineral/aqueous solution interface., (© 2024 Wiley‐VCH GmbH.)

The platelet aggregation inhibitory activity of selected xanthine-based adenosine A 2A and A 2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A 2B receptor antagonist PSB-603 and the A 2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.

The application of ureolytic bacteria for bioremediation of soil contaminated with heavy metals, including cadmium (Cd), allows for the efficient immobilization of heavy metals by precipitation or coprecipitation with carbonates. Microbially-induced carbonate precipitation process may be useful also in the case of the cultivation of crop plants in various agricultural soils with trace but legally permissible Cd concentrations, which may be still uptaken by plants. This study aimed to investigate the influence of soil supplementation with metabolites containing carbonates (MCC) produced by the ureolytic bacterium Ochrobactrum sp. POC9 on the Cd mobility in the soil as well as on the Cd uptake efficiency and general condition of crop plants ( Petroselinum crispum) . In the frame of the conducted studies (i) carbonate productivity of the POC9 strain, (ii) the efficiency of Cd immobilization in soil supplemented with MCC, (iii) crystallization of cadmium carbonate in the soil enriched with MCC, (iv) the effect of MCC on the physico-chemical and microbiological properties of soil, and (v) the effect of changes in soil properties on the morphology, growth rate, and Cd-uptake efficiency of crop plants were investigated. The experiments were conducted in soil contaminated with a low concentration of Cd to simulate the natural environmental conditions. Soil supplementation with MCC significantly reduced the bioavailability of Cd in soil with regard to control variants by about 27-65% (depending on the volume of MCC) and reduced the Cd uptake by plants by about 86% and 74% in shoots and roots, respectively. Furthermore, due to the decrease in soil toxicity and improvement of soil nutrition with other metabolites produced during the urea degradation (MCC), some microbiological properties of soil (quantity and activity of soil microorganisms), as well as the general condition of plants, were also significantly improved. Soil supplementation with MCC enabled efficient Cd stabilization and significantly reduced its toxicity for soil microbiota and plants. Thus, MCC produced by POC9 strain may be used not only as an effective Cd immobilizer in soil but also as a microbe and plant stimulators., Competing Interests: MZ and KD-A are holders of a patent application related to this work P.442546. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zakrzewska, Rzepa, Musialowski, Goszcz, Stasiuk and Debiec-Andrzejewska.)

Asthma is a heterogeneous, chronic respiratory disease characterized by airway inflammation and remodeling. Phosphodiesterase (PDE) inhibitors represent one of the intensively studied groups of potential anti-asthmatic agents due to their affecting both airway inflammation and remodeling. However, the effect of inhaled pan-PDE inhibitors on allergen induced asthma has not been reported to date. In this study we investigated the impact of two, representative strong pan-PDE inhibitors from the group of 7,8-disubstituted derivatives of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione: compound 38 and 145, on airway inflammation and remodeling in murine model of ovalbumin (OVA)-challenged allergic asthma. Female Balb/c mice were sensitized and challenged with OVA, 38 and 145 were administrated by inhalation, before each OVA challenge. The inhaled pan-PDE inhibitors markedly reduced the OVA-induced airway inflammatory cell infiltration, eosinophil recruitment, Th2 cytokine level in bronchoalveolar lavage fluid, as well as both, total and OVA-specific IgE levels in plasma. In addition, inhaled 38 and 145 decreased many typical features of airway remodeling, including goblet cell metaplasia, mucus hypersecretion, collagen overproduction and deposition, as well as Tgfb1, VEGF, and α-SMA expression in airways of allergen challenged mice. We also demonstrated that both 38 and 145 alleviate airway inflammation and remodelling by inhibition of the TGF-β/Smad signaling pathway activated in OVA-challenged mice. Taken together, these results suggest that the investigated pan-PDE inhibitors administered by inhalation are dual acting agents targeting both airway inflammation and remodeling in OVA-challenged allergic asthma and may represent promising, anti-asthmatic drug candidates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Phosphodiesterase (PDE) inhibitors represent a wide class of chemically different compounds that have been extensively studied in recent years. Their anti-inflammatory and anti-fibrotic effects are particularly desirable in the treatment of chronic respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Due to diversified expression of individual PDEs within cells and/or tissues as well as PDE signaling compartmentalization, pan-PDE inhibitors (compounds capable of simultaneously blocking various PDE subtypes) are of particular interest. Recently, a large group of 7,8-disubstituted derivatives of 1,3-dimethyl-7H-purine-2,6-dione (theophylline) was designed and synthesized. These compounds were characterized as potent pan-PDE inhibitors and their prominent anti-inflammatory and anti-fibrotic activity in vitro has been proved. Herein, we investigated a general in vitro safety profile and pharmacokinetic characteristics of two leading compounds from this group: a representative compound with N'-benzylidenebutanehydrazide moiety (38) and a representative derivative containing N-phenylbutanamide fragment (145). Both tested pan-PDE inhibitors revealed no cytotoxic, mutagenic, and genotoxic activity in vitro, showed moderate metabolic stability in mouse and human liver microsomes, as well as fell into the low or medium permeation category. Additionally, 38 and 145 revealed a lack of interaction with adenosine receptors, including A 1 , A 2A , and A 2B . Pharmacokinetic analysis revealed that both tested 7,8-disubstituted derivatives of 1,3-dimethyl-7H-purine-2,6-dione were effectively absorbed from the peritoneal cavity. Simultaneously, they were extensively distributed to mouse lungs and after intraperitoneal (i.p.) administration were detected in bronchoalveolar lavage fluid. These findings provide evidence that investigated compounds represent a new drug candidates with a favorable in vitro safety profile and satisfactory pharmacokinetic properties after a single i.p. administration. As the next step, further pharmacokinetic studies after multiple i.p. and p.o. doses will be conducted to ensure effective 38 and 145 serum and lung concentrations for a longer period of time. In summary, 7,8-disubstituted derivatives of 1,3-dimethyl-7H-purine-2,6-dione represent a promising compounds worth testing in animal models of chronic respiratory diseases, the etiology of which involves various PDE subtypes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening., Methods: Derivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated., Results: All the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats., Conclusion: The compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition., (© 2022. The Author(s).)

Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34 , being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound 34 was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound 34 displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings.

Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling process by increasing extracellular matrix secretion, acquiring migration properties, and overproducing pro-fibrotic transducers. Here, we investigated the effect of three new 8-arylalkylamino- and 8-alkoxy-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7 H -purin-7-yl- N -(5-( tert -butyl)-2-hydroxyphenyl)butanamides ( 1 , 2 , and 3 ), representing prominent pan-phosphodiesterase (pan-PDE) inhibitors on transforming growth factor type β (TGF-β)-induced alveolar epithelial type II cells (A549 cell line) of a pro-fibrotic phenotype. Our results demonstrate for the first time the strong activity of pan-PDE inhibitors in the prevention of TGF-β-induced mesenchymal markers' expression and A549 cells' migration. We also showed an increased p-CREB and decreased p-Smad-2 phosphorylation in TGF-β-induced A549 cells treated with 1 , 2 , and 3 derivatives, thereby confirming a pan-PDE inhibitor mesenchymal phenotype reducing effect in alveolar epithelial type II cells via suppression of the canonical Smad signaling pathway. Our observations confirmed that PDE inhibitors, and especially those active against various isoforms involved in the airway remodeling, constitute an interesting group of compounds modulating the pro-fibrotic response of epithelial cells.

In this study, we investigate how salinity, oxygen concentration and catchment area characteristics impact the dynamics of Fe-P-S cycling in the continental shelf sea sediments. Samples were collected from three sites representing different environmental conditions: Gdańsk Deep (southern Baltic Sea), Gotland Deep (central Baltic Sea) and Bothnian Sea (northern Baltic Sea). Sediments were analysed for their mineral composition and speciation of iron and phosphorus. The main groups of Prokaryota involved in Fe-P-S cycling in sediments were indicated. Concentrations of sulphate, hydrogen sulphide, alkalinity, chloride, calcium, phosphate and iron were measured in pore waters. We demonstrated that in the eutrophicated southern region with moderate salinity and oxygen deficit in bottom water, sediments had high potential for retaining Fe and releasing P as indicated by high concentrations of pyrite and labile forms of phosphorus, respectively. Strong salinity stratification and intermittent pelagic redoxcline in the central Baltic Sea resulted in a clearly higher rate of pyrite deposition. Sediment was enriched with Mn due to the formation of Ca-Mn carbonates driven by intensive Mn redox cycling and sulphate reduction. Because of high availability of Mn oxides connected with episodic inflows of oxic seawater from the North Sea, sulphate was present in the entire profile of the studied sediments in the Gotland Deep. Sediments in the well-oxygenated, virtually fresh and rich in land-derived iron northern Baltic Sea retained significant amounts of P in authigenic minerals. Organic matter mineralisation in the surface sediment of this area was dominated by iron reduction. The variability of environmental conditions and consequent availability of electron acceptors were the cause of regional differences in the composition of Prokaryota communities - the number of sulphate reducers in the Gdańsk and Gotland Deeps was greater than in the Bothnian Sea, where there were more Fe reducers and bacteria that oxidise Fe and S., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Phosphodiesterase (PDE) inhibitors are currently an extensively studied group of compounds that can bring many benefits in the treatment of various inflammatory and fibrotic diseases, including asthma. Herein, we describe a series of novel N'-phenyl- or N'-benzylbutanamide and N'-arylidenebutanehydrazide derivatives of 8-aminopurine-2,6-dione (27-43) and characterized them as prominent pan-PDE inhibitors. Most of the compounds exhibited antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. The most active compounds (32-35 and 38) were evaluated in human bronchial epithelial cells (HBECs) derived from asthmatics. To better map the bronchial microenvironment in asthma, HBECs after exposure to selected 8-aminopurine-2,6-dione derivatives were incubated in the presence of two proinflammatory and/or profibrotic factors: transforming growth factor type β (TGF-β) and interleukin 13 (IL-13). Compounds 32-35 and 38 significantly reduced both IL-13- and TGF-β-induced expression of proinflammatory and profibrotic mediators, respectively. Detailed analysis of their inhibition preferences for selected PDEs showed high affinity for isoenzymes important in the pathogenesis of asthma, including PDE1, PDE3, PDE4, PDE7, and PDE8. The presented data confirm that structural modifications within the 7 and 8 positions of the purine-2,6-dione core result in obtaining preferable pan-PDE inhibitors which in turn exert an excellent anti-inflammatory and anti-fibrotic effect in the bronchial epithelial cells derived from asthmatic patients. This dual-acting pan-PDE inhibitors constitute interesting and promising lead structures for further anti-asthmatic agent discovery., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lipophilicity is one of the principal QSAR parameters which influences among others the pharmacodynamics and pharmacokinetic properties of a drug candidates. In this paper, the lipophilicity of 14 amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 channel antagonists and phosphodiesterase 4/7 inhibitors with analgesic activity were investigated, using reversed-phase thin-layer chromatography method. It was observed that the retention behavior of the analyzed compounds was dependent on their structural features i.e. an aliphatic linker length, a kind of substituent at 8 position of purine-2,6-dione scaffold as well as on a substitution in a phenyl group. The experimental parameters (R M0 ) were compared with computationally calculated partition coefficient values by Principal Component Analysis (PCA). To verify the influence of lipophilic parameter of the investigated compounds on their biological activity the Kruskal-Wallis test was performed. The lowest lipophilicity was observed for the compounds with weak PDE4/7 inhibitory potency. The differences between the lipophilicity of potent inhibitors and inactive compounds were statistically significant. It was found that the presence of more lipophilic propoxy- or butoxy- substituents as well as the elongation of the aliphatic chain to propylene one between the purine-2,6-dione core and amide group were preferable for desired multifunctional activity., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: 5-HT 1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT 1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT 1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT 7 , 5-HT 2A  and D 2 receptors and ability to inhibit phosphodiesterases were evaluated. Results:  A selected 5-HT 1A receptor antagonist 20 ( K i  = 35 nM, K b  = 4.9 nM) showed procognitive and antidepressant activity in vivo . Conclusion: Novel 5-HT 1A receptor antagonists were discovered and shown as potential psychotropic drugs.

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α 2 -adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties., Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT 1A /5-HT ;7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease., Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H 2 O 2 -induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively., Results: Synthesized aminoalkanamides were characterized as potent 5-HT 1A receptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability., Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disease that affects the cognition, behavior, and daily activities of individuals. Studies indicate that this disease is characterized by several pathological mechanisms, including the accumulation of amyloid-beta peptide, hyperphosphorylation of tau protein, impairment of cholinergic neurotransmission, and increase in inflammatory responses within the central nervous system. Chronic neuroinflammation associated with AD is closely related to disturbances in metabolic processes, including insulin release and glucose metabolism. As AD is also called type III diabetes, diverse compounds having antidiabetic effects have been investigated as potential drugs for its symptomatic and disease-modifying treatment. In addition to insulin and oral antidiabetic drugs, scientific attention has been paid to cyclic-3',5'-adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) inhibitors that can modulate the concentration of glucose and related hormones and exert beneficial effects on memory, mood, and emotional processing. In this review, we present the most recent reports focusing on the involvement of cAMP-specific PDE4, PDE7, and PDE8 in glycemic and inflammatory response controls as well as the potential utility of the PDE inhibitors in the treatment of AD. Besides the results of in vitro and in vivo studies, the review also presents recent reports from clinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3β) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3β inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological and clinical profiles need to be defined., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC 50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG 35-55 -induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

This work aimed to determine the effect of various amounts of P admixtures in synthetic ferrihydrite on its thermal stability, transformation processes, and the properties of the products, at a broad range of temperatures up to 1000 °C. A detailed study was conducted using a series of synthetic ferrihydrites Fe 5 HO 8 ·4H 2 O doped with phosphates at P/Fe molar ratios of 0.2, 0.5, and 1.0. Ferrihydrite was synthesized by a reaction of Fe 2 (SO 4 ) 3 with 1 M KOH at room temperature in the presence of K 2 HPO 4 at pH 8.2. The products of the synthesis and the products of heating were characterized at various stages of transformation by using differential thermal analysis accompanied with X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy-energy dispersive X-ray spectroscopy. Coprecipitation of P with ferrihydrite results in the formation of P-doped 2-line ferrihydrite. A high P content reduces crystallinity. Phosphate significantly inhibits the thermal transformation processes. The temperature of thermal transformation increases from below 550 to 710-750 °C. Formation of intermediate maghemite and Fe-phosphates, is observed. The product of heating up to 1000 °C contains hematite associated with rodolicoite FePO 4 and grattarolaite Fe 3 PO 7 . Higher P content greatly increases the thermal stability and transformation temperature of rodolicoite as well.

A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT 1A /5-HT 7 receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT 1A /5-HT 7 receptor antagonist (5-HT 1A K i  = 8 nM, K b  = 0.04 nM; 5-HT 7 K i  = 451 nM, K b  = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC 50  = 80.4 μM; PDE7A IC 50  = 151.3 μM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β 1 (TGF-β 1 ) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

In recent years, there has been a growth in the number of products containing Ag nanoparticles (AgNPs) in many areas and their use suggests that the water-soil environment may be exposed to the contaminant with different Ag species. Therefore, the sorption of two Ag forms (i.e. Ag(I) ions and nanoparticles - AgNPs) on clay minerals (montmorillonite and kaolinite) and iron (oxyhydr)oxides (ferrihydrite) as a function of solution:mineral ratio (100:1, 250:1, 500:1), solution pH (3.0, 5.5 and 7.0) and initial Ag concentration (0.1-100 mg/dm 3 ) was studied using batch method. In addition the binding strength/mobility of the bonded Ag species was researched. The results show a great sorption potential of clay minerals for both Ag forms and lower sorption capacity of ferrihydrite, in particular for Ag(I) ions. The maximum sorption capacities of montmorillonite, kaolinite and ferrihydrite estimated from three-parameter isotherm model of Sips were 94.39 mg/g, 117.8 mg/g and 26.48 mg/g for AgNPs and 17.92 mg/g, 21.14 mg/g and 3.072 mg/g for Ag(I) ions, respectively. Aggregation process plays an important role in sorption and mobility of AgNPs. The sequential extraction study indicated different binding mechanisms of the Ag forms onto the clay minerals and ferrihydrite, which depended on the active sites of minerals as well as the Ag species nature in the solution. Ag(I) was weakly bound by clay minerals but presence of iron (oxyhydr)oxides decreased the Ag(I) mobility and bioavailability. On the other hand, AgNPs bound with the active centers of minerals in a very strong way and were not able to release into water. The study of the binding of Ag forms by clay minerals and (oxyhydr)oxides allows to determine the influence of their physicochemical and structural properties, including e.g. pore size on Ag sorption. These results allow these properties to be taken into account in the study of environmental samples, including waters and soils. Moreover, the results showed that in the study of behavior of Ag forms in contact with the minerals, in addition to the sorption capacity, the susceptibility to their release is very important. Studies on sorption/desorption of AgNPs and Ag(I) ions as a form of oxidation of AgNPs is important for understanding the transport and fate of the Ag species in soil, sediments and surface water because of different their behavior in contact with the minerals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

There was a mistake in the unit of clearance (Cl) in Table II. In addition, the descriptions of V 1(ROL) and V 1(GRMS-55) were imprecise and the reference number in the footnote below this table should be (9). The corrected Table appears below.

Purpose: This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders., Methods: Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling., Results: GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC 50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC 50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis., Conclusions: PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive impairments such as memory loss, decline in language skills, and disorientation that affects over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3',5'- Adenosine Monophosphate (cAMP) and cyclic-3',5'-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's Disease (AD) is a chronic and progressive neurodegenerative disorder that affects over 46 million people worldwide. It is characterized by a decline in cognitive abilities, including memory and thinking skills. AD patients also suffer from behavioral and psychological symptoms of dementia of which depression is the most prevalent. Currently available drugs provide modest symptomatic relief and do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of AD. Studies suggest that AD is a type of diabetes manifested in the brain. Although AD and diabetes are currently classified as separate disease entities, they share common pathophysiological mechanisms, one of them is an increased level of cytokines involved in the inflammation and the regulation of metabolic, regenerative, and neural processes. The purpose of this review was to update the most recent reports on the discovery and development of antidiabetic agents as promising drugs for the symptomatic and diseasemodifying treatment of AD. We collected the results of in vitro and in vivo studies, and recent reports from clinical trials suggesting the utility of antidiabetic agents in memory-enhancing therapy of AD. Their beneficial effects on chronic neuroinflammation, pathological hallmarks, and neuropsychiatric symptoms co-occurring with cognitive deficits are also presented. Antidiabetic agents refer to the diabetic and inflammatory hypotheses of AD and provide hope to find an effective drug for comprehensive therapy of the disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors., (Copyright © 2019 Elsevier B.V. All rights reserved.)