Related Analogues Research Articles

Alternative approaches utilizing click chemistry to develop next-generation analogs of solithromycin

The marked rise in bacterial drug resistance has created an urgent need for novel antibacterials belonging to new drug classes and ideally possessing new mechanisms of action. The superior biological activity of solithromycin against streptococci and other bacteria causative of community-acquired pneumonia pathogens, compared to telithromycin and other macrolides encouraged us to extensively explore this class of antibiotics. We, thus, present the design and synthesis of a novel series of solithromycin analogs. Three main strategies were pursued in structure-activity relationship studies covering the N-11 side chain and the desosamine motif, which are both chief elements for establishing strong interactions with the bacterial ribosome as the molecular target. Minimal inhibitory concentration assays were determined to assess the in vitro potency of the various analogs in relation to solithromycin. Two analogs exhibited improved activity compared to solithromycin against resistant strains, which can be assessed in further pre-clinical studies.

A highly efficient and selective optical detection method for Heparin that works in 100% human serum

Sensing Heparin in 100% serum matrix is a challenging task and is rarely reported in literature. Herein, we present a tetracationic porphyrin based probe that detects Heparin in 100% serum matrix, both, colorimetrically and fluorometrically, with a clinically relevant LOD. The probe also shows high selectivity towards Heparin when compared with its structurally related analogs, chondroitin sulfate and hyaluronic acid along with other relevant analytes. The porphyrin probe-Heparin complex could also be used for the detection of Protamine, which is the only clinically approved antitoxin for Heparin overdose. The easy commercial availability of the probe coupled with its other desirable attributes is expected to significantly improve its prospect in Heparin sensor applications and Heparin related bio-chemical research.

Merosesquiterpenes from the marine sponge Spongia pertusa Esper and their antifungal activities

Three new merosesquiterpenoids, 24-methylsulfinyllancoquinone B (1), pelorol A (2), and epi-langconol A (3), along with eight known related analogues, were isolated from a marine sponge Spongia pertusa Esper. The compounds were completely characterized by NMR spectroscopy and HRESIMS. Compound 1 had a friedo-drimane sesquiterpenoid skeleton bearing a rare 3-(methylsulfinyl)propan-1-amine functionality, whereas 2 and 3 were members of the drimane-type sesquiterpenoid derivatives. Compounds 1, 4, 6, 7, and 8 exhibited moderate antifungal activity against three human pathogens, namely, Candida albicans, Trichophyton mentaqrophytes, and Trichophyton rubrum, with MIC50 values ranging from 12.5 to 50 μg/mL.

Structure-antioxidant activity relationships of dendrocandin analogues determined using density functional theory.

Quantum-chemical calculations based on the density functional theory (DFT) at the B3LYP/6–311 + + G(2d,2p)//B3LYP/6–31G(d,p) level were employed to study the relationship between the antioxidant properties and chemical structures of six dendrocandin (DDCD) analogues in the gas phase and two solvents (methanol and water). The hydrogen atom transfer (HAT), electron-transfer-proton-transfer (ET-PT), and sequential proton-loss-electron-transfer (SPLET) mechanisms are explored. The highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), reactivity indices (η, μ, ω, ω+, and ω–), and molecular electrostatic potentials (MEPs) were also evaluated. The results suggest that the D ring plays an important role in mediating the antioxidant activity of DDCDs. For all the studied compounds, indicating that HAT was identified as the most favorable mechanism, whereas the SPLET mechanism was the most thermodynamically favorable pathway in polar solvents. The results of our study should aid in the development of new or modified antioxidant compounds.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11224-022-01895-2.

Non-target analysis and stability assessment of reference materials using liquid chromatography‒high-resolution mass spectrometry

Development and characterization of biological and environmental matrix certified reference materials (CRMs) for organic analytes typically relies heavily on targeted analytical methods, such as liquid chromatography (LC) with triple-quadrupole mass spectrometry detection. LC with high-resolution mass spectrometry (LC‒HRMS) can also provide high quality data for both targeted and non-targeted analytes, with the potential for retrospective data analysis. Here, we demonstrate the utility of non-target analysis (NTA) using LC‒HRMS for profiling and stability assessment of a mussel tissue matrix CRM certified for several classes of marine algal toxins (CRM-FDMT1). First, the NTA method was developed using data-dependent MS/MS acquisition and commercial metabolomics software for data processing. Of 128 toxin analogues previously reported in CRM-FDMT1, 125 were detected by LC-HRMS, with 97 triggered for MS/MS by data dependant acquisition. Automated data processing detected 119 of these compounds and 109 were retained after automated filtering of results for putative toxin analogues. Those analogues not detected were low abundance ions, or poorly resolved isomers. The method was then used to demonstrate new strategies for CRM stability assessment considering the stability of certified analytes, related toxin analogues, and unrelated matrix compounds. Several analogues from each toxin class in CRM-FDMT1 as well as other unrelated matrix compounds were observed to be significantly less stable than the certified toxins. Using this method, no instability was measured for any compounds at conditions ≤4 °C, providing a greater degree of confidence in CRM stability than could be achieved using conventional approaches to stability assessment targeting only the certified analytes. The NTA method and stability assessment approach presented are applicable to future CRM development with other matrices and organic analyte classes.

Distribution System State Estimation Using Model-Optimized Neural Networks

Maintaining reliability during power system operation relies heavily on the operator’s knowledge of the system and its current state. With the increasing complexity of power systems, full system monitoring is needed. Due to the costs to install and maintain measurement devices, a cost-effective optimal placement is normally employed, and as such, state estimation is used to complete the picture. However, in order to provide accurate state estimates in the current power system climate, the models must be fully expanded to include probabilistic uncertainties and non-linear assets. Recognizing its analogous relationship with state estimation, machine learning and its ability to summarily model unseen and complex relationships between input data is used. Thus, a power system state estimator was developed using modified long short-term (LSTM) neural networks to provide quicker and more accurate state estimates over the conventional weighted least squares-based state estimator (WLS-SE). The networks are then subject to standard polynomial scheduled weight pruning to further optimize the size and memory consumption of the neural networks. The state estimators were tested on a hybrid AC/DC distribution system composed of the IEEE 34-bus AC test system and a 9-bus DC microgrid. The conventional WLS-SE has achieved a root mean square error (RMSE) of 0.0151 p.u. for voltage magnitude estimates, while the LSTM’s were able to achieve RMSE’s between 0.0019 p.u. and 0.0087 p.u., with the latter having 75% weight sparsity, estimates about ten times faster, and half of its full memory requirement occupied.

Coherence Tests of Physical Theories

Textbooks show that the low-velocity limit of special relativity is compatible with nonrelativistic mechanics. Analogous relationships hold between general relativity and the Newtonian theory of gravitation, and between quantum mechanics and classical physics. This work shows that this approach can be extended and yield coherence tests of additional theories. It provides a few examples that show the effectiveness of this approach and demonstrate inconsistent points of some mainstream physical ideas. Furthermore, other well-established physical principles can be utilized for this end. Unfortunately, a scientific work that undertakes this assignment can hardly be found in the current mainstream literature. Several cases are discussed in detail. The results show inconsistencies of fundamental standard model theories, such as quantum chromodynamics and the electroweak theory. Inconsistencies are also proved for the Majorana neutrino and the Proca theory of a massive photon.

Chemoinformatic Exploration of "Bioinspired Metabolomes" Illuminates Diacetyl Assembly Pathways Toward Nesteretal A-Like Cage Molecules.

An appealing and challenging cage structure along with an unusual biosynthetic pathway prompted us to explore an expeditious bioinspired one-pot total synthesis of nesteretal A. An unconventional strategy was chosen, and a cascade reaction starting from diacetyl was studied. Under organocatalytic conditions mimicking an aldolase, nesteretal A and a related cage analogue were anticipated by in silico metabolization, detected, targeted, and characterized.

Design, Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors

A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1–DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC50 values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC50 values of 0.78 and 0.62 μM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure–activity relationships of thiazole-based stilbene analogs was also discussed.

EDTA analogues – unconventional inhibitors of gypsum precipitation

In the current study, EDTA (ethylenediamine-N,N,N′,N′-tetraacetic acid) and three further structurally related analogues with various spacing between the amino groups - PDTA (1,3-Diaminopropane-N,N,N′,N′-tetraacetic acid), HDTA (1,6-Diaminohexane-N,N,N′,N′-tetraacetic acid) and EGTA (Ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid) - were tested as inhibitors of gypsum crystallization. The precipitation reactions were performed at high initial supersaturation and calcium ions were present in large excess relative to the amount of the inhibitor. This way the crystallization reaction was facilitated and the degree of supersaturation was not affected by the complexation. It was found that the structural differences between the inhibitors (i.e., the spacing between the amino groups) seem to exert only a secondary effect on the efficiency of the inhibition. The optimum pH for inhibition was found to be strongly dependent on the inhibitor used. The optimum conditions for inhibition were explained in terms of the concentration of the uncomplexed ligand, which is determined by the stability of the calcium complexes with 1:1 composition as well as with the extent of proton competition. The structure, composition and morphology of the precipitating solids isolated from equilibrium mixtures at the completion of the precipitation process were also studied and the crystal faces where adsorption is most likely to happen were identified.

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction.

Paullone isomers are known as inhibitors of tubulin polymerase and cyclin dependent kinases (Cdks), which are potential targets for cancer chemotherapy. Herein we report an efficient and clean pathway to the fourth isomer, which remained elusive so far, namely 7,8-dihydroindolo[2,3-d][1]benzazepin-6(5H)-one. Moreover, we demonstrate the generality of our pathway by synthesizing two closely related analogues, one containing a bromo substituent and the other one incorporating an 8-membered instead of a 7-membered ring. The key transformation in this four-step synthesis, with an overall yield of 29%, is the Fischer indole reaction of 2-nitrophenylacetyl acetoacetate with 1-benzyl-1-phenylhydrazine in acetic acid that delivers methyl 2-(1-benzyl-3-(2-nitrophenyl)-1H-indol-2-yl)acetate in 55% yield.

Daily low dose of tadalafil improves pain and frequency in bladder pain syndrome/interstitial cystitis patients.

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease, with consequent high morbidity. Increasing evidence suggests that bladder afferent hyperexcitability, through neurogenic bladder inflammation and urothelial dysfunction, plays a key role in the pathophysiology of BPS/IC. The rationale of using phosphodiesterase type 5 inhibitors (PDE5i) would be to decrease bladder afferent hyperactivity. Detrusor relaxation, improvement of microcirculation, and a decrease in adrenergic nociceptive overactivity would be other effects in bladder tissue. We aimed to evaluate the efficacy, tolerability, and safety of a daily low dose of 5mg tadalafil in refractory BPS/IC patients. A total of 14 refractory BPS/IC female patients, previously evaluated with a physical examination, bladder diary, bladder-pain related visual analogue score, O'Leary-Sant Scores (OSS) for symptoms and problems, and quality of life (QoL) question from International Prostate Symptom Score, were treated with 5mg of tadalafil, for 3months. Re-evaluations occurred at 4 and 12weeks. Adverse events were assessed and recorded. Urinary frequency, OSS, and QoL were significantly improved at 1-month follow-up (10 6 2.5, 21.9 6 4.1, and 4 6 1.5, respectively, P < .05). Pain intensity and volume voided were significantly improved at a 3-month follow-up (3.5 6 2 and 266.7 6 60.5, P < .05). Patients referred to urinary frequency as the most important parameter improved at 4weeks, and pain at 3months. No differences between ulcerated and nonulceratedpatients were observed. Two patients dropped out due to unsatisfactory results and two due to persistent headache and/or tachycardia, but both events were resolved after discontinuing the drug. Daily low-dose tadalafil is an easy, well-tolerated, and effective treatment for refractory BPS/IC in women.

Application-Related Consideration of the Thermal Stability of [mTBDH][OAc] Compared to Amidine-Based Ionic Liquids in the Presence of Various Amounts of Water

The hydrolysis kinetics of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-enium acetate [mTBDH][OAc] was investigated in a comprehensive study by the utilization of the well-known Schlenk technique to achieve a better understanding of its stability for dry-jet wet spinning applications (e.g., Ioncell) and due to the course of operation for recovery methods like fractional distillation. Decomposition behavior as a function of temperature, time, acid–base stoichiometry, and water content was extensively analyzed and characterized by nuclear magnetic resonance spectroscopy (NMR), capillary electrophoresis (CE), and thermogravimetric analysis (TGA). Furthermore, kinetic models were formulated for the prediction of the stability and the results were compared with the closely related amidine-based analogues 1,5-diazabicyclo[4.3.0]non-5-enium acetate [DBNH][OAc] and 1,8-diazabicyclo[5.4.0]undec-7-enium acetate [DBUH][OAc].

A Revival of Metaphysics?

In this article, I seek to review Philip Gonzales’s call for a revitalization of the Catholic analogia entis, both as a fundamental philosophical principle and as a guiding metaphysical vision for the Church today, as explicated in his recent work, Reimagining the Analogia Entis: The Future of Erich Pryzwara’s Christian Vision. I will begin by offering a short synopsis of Erich Przywara’s reappraisal of analogy in relation to the work of Edmund Husserl and Martin Heidegger, followed by an exposition of Philip Gonzales’s call for a non-identical repetition of Przywara’s metaphysical vision both in philosophy and the Church at large. In closing, I will seek to offer an evaluation of Gonzales’s proposal from a supportive yet concerned horizon of postmetaphysical mindfulness.

Об одном опыте составления фразеологического словаря, его стилевых аспектах и прикладном значении для перевода

This article studies an experience of making an English-to-Russian and Russian-to-English dictionary of set expressions implemented as an application for mobile devices. Here we elaborate on its basic ideas and requirements used in modern interpreting. Further, we provide key facts about the dictionary, its structure and organization, describe the compilation process including how we established criteria for choosing relevant language units, as well as highlight their analysis method with reference to different sources. Further, considering the stylistic gradation of target-language semantic analogues in relation to source-language units offered in the dictionary, we give a separate emphasis to difficulties experienced when determining the register of set phrases. Additionally, we cover a number of their aspects which may be taken into account to decide on a stylistic category. We identify typical features of some registers and suggest criteria for differentiating between set expressions in terms of their style. Our theoretical observations are accompanied by the comparison of English and Russian units specifying their similarities and differences that were noted when composing the dictionary. Its solutions are considered from the perspective of popular interpreting techniques with regard to set phrases: use of existing target-language analogues, literal translation, and conveyance of connotative equivalents. We also promote experimental approaches that intend to help translators in their work. In conclusion, we summarize the novelties of the dictionary, estimate its user-friendliness and applicability to the practical aspects of translation and interpreting, and make suppositions about its future potential.

Synthesis of nuevamine and a cyano-chilenine analog via divergent C(sp3)-H bond functionalization of isoindolinone derivatives.

Divergent C(sp3)-H bond functionalizations of isoindolinone derivatives were developed to synthesize nuevamine, a cyano-chilenine derivative, and two related analogs. A copper-catalyzed C-H cross-dehydrogenative coupling (via cation formation) allowed the formation of a new C-C bond leading to the direct assembly of the isoindolo[1,2-a]isoquinolinone tetracyclic system of the nuevamine. The syntheses of the cyano-chilenine derivatives were carried out by installing two nitrile groups under basic conditions (via anion formation). Then, the isoindolobenzazepinic system of the chilenine skeleton was constructed by a Houben-Hoesch cyclization process. The present methodology has the advantage of not requiring the use of pre-functionalized substrates.

New ent-kaurane diterpenoid acids from Nouelia insignis Franch and their anti-inflammatory activity.

Eleven undescribed ent-kaurane-type diterpenoid acids, namely noueinsiancins A–K (1–11), together with sixteen related known analogs (12–27) were isolated from Nouelia insignis Franch. The chemical structures and absolute configurations of the new compounds were confirmed by the extensive spectroscopic data, electronic circular dichroism (ECD) data analysis and single crystal X-ray diffraction. Additionally, the anti-inflammatory assay was applied to estimate the nitric oxide (NO) inhibitory activities of all compounds by using lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro. The results revealed that 4–7 and 13–17 significantly inhibited NO production at the concentrations of 2.5 μM, 5.0 μM and 10.0 μM. Meanwhile, compounds 6 and 7 were found to down-regulate the protein expression levels of IL-6 and TNF-α in RAW 264.7 cells induced by LPS in a dose-dependent manner. In conclusion, these findings provided the reference values for exploring the new chemicals with biological activities from this genus.

Near-Infrared Phosphorescent Hybrid Organic-Inorganic Perovskite with High-Contrast Dielectric and Third-Order Nonlinear Optical Switching Functionalities.

Hybrid organic–inorganic perovskites providing integrated functionalities for multimodal switching applications are widely sought-after materials for optoelectronics. Here, we embark on a study of a novel pyrrolidinium-based cyanide perovskite of formula (C4H10N)2KCr(CN)6, which displays thermally driven bimodal switching characteristics associated with an order–disorder phase transition. Dielectric switching combines two features important from an application standpoint: high permittivity contrast (Δε′ = 38.5) and very low dielectric losses. Third-order nonlinear optical switching takes advantage of third-harmonic generation (THG) bistability, thus far unprecedented for perovskites and coordination polymers. Structurally, (C4H10N)2KCr(CN)6 stands out as the first example of a three-dimensional stable perovskite among formate-, azide-, and cyanide-based metal–organic frameworks comprising large pyrrolidinium cations. Its stability, reflected also in robust switching characteristics, has been tracked down to the Cr3+ component, the ionic radius of which provides a large enough metal–cyanide cage for the pyrrolidinium cargo. While the presence of polar pyrrolidinium cations leads to excellent switchable dielectric properties, the presence of Cr3+ is also responsible for efficient phosphorescence, which is remarkably shifted to the near-infrared region (770 to 880 nm). The presence of Cr3+ was also found indispensable to the THG switching functionality. It is also found that a closely related cobalt-based analogue doped with Cr3+ ions displays distinct near-infrared phosphorescence as well. Thus, doping with Cr3+ ions is an effective strategy to introduce phosphorescence as an additional functional property into the family of cobalt-cyanide thermally switchable dielectrics.

Alpha-lipoic acid analogues in the regulation of redox balance in epilepsy: A molecular docking and simulation study

ObjectiveOxidative stress is one of the pathophysiological mechanisms implicated in drug-resistant epilepsy. Recurrent seizures and prolonged treatment with anti-seizure medicines (ASMs) can produce reactive oxygen species (ROS) resulting in neuronal cell damage, cell toxicity, and cell death. This damage may contribute to the loss of efficacy of anti-seizure medicines. Add-on therapy with antioxidants, neuroimmunophilins, and polyphenols may thus be beneficial in drug-resistant epilepsy. In vitro and in vivo studies have shown a significant improvement in drug efficacy and seizure suppression using co-treatment of anti-seizure medication with naturally available antioxidants including alpha-lipoic acid (α-lipoic acid) from walnut; however, the underlying mechanisms of action remain to be fully understood. MethodsWe undertook molecular docking and molecular dynamics simulations to determine whether alpha-lipoic acid and related analogues interacted with the human manganese superoxide dismutase (MnSOD) protein, a member of the oxidative metabolic pathway. The 3D structure of the compounds and the protein were retrieved from protein and chemical databases, binding sites were identified and ligand-protein interactions were performed. ResultsAlpha-lipoic acid and various analogues docked within a human MnSOD binding region. Docking results were validated by molecular dynamic simulation. The CMX-2043 analogue showed strong binding with MnSOD compared to alpha-lipoic acid and other analogues. SignificanceOur findings provide new insights into additional mechanisms of action, which may in part, account for the antioxidant properties associated with alpha-lipoic acid and related analogues. The results support further in vitro and in vivo evaluation of these compounds to better understand their potential as add-on therapy for ASM treatment in epilepsy.

Emoxipine Modulates Concentration-Dependent Effects of Cytarabine and Cyclocytidine on Activation of Human T Cells

Title: Emoxipine modulates concentration-dependent effects of cytarabine and cyclocytidine on activation of human T cells.&#x0D; Introduction: Both cytarabine and cyclocytidine are used in the treatment of acute myeloid leukemia. Well known that cytarabine and other related cytosine-based nucleoside analogues are being toxic to tumor cells by increasing levels of cellular oxidative stress as it could be abrogated by antioxidants. However, very little is known both about both the effects of combinations of antimetabolites with antioxidants on the cytotoxic innate and adaptive immune cells and whether lymphocytes toxicity affects its anticancer efficiency.&#x0D; Aim: To estimate effects of cytarabine and cyclocytidine with emoxipine on in vitro activated human T cells at concentrations reached during in vivo treatment with high doses, conventional doses and low doses.&#x0D; Materials and Methods: T cells derived from blood donors were activated in vitro in cell culture medium alone or supplemented with cytarabine 0.1-10.0 μM or cyclocytidine 0.1-10.0 μM. Cell characteristics were assessed by flow cytometry.&#x0D; Results: Only cytarabine 1.0-10.0 μM had both antiproliferative and proapoptotic effects. Additionally, these cytarabine concentrations increased the γIFN-producing by CD3+CD4+ T cells and did not affect the release of this cytokine by CD3+CD8+ T cells. In contrast, the lowest concentration (0.1 μM) did not have or showed minor antiproliferative or cytotoxic effects, did not alter the release of γIFN. Cyclocytidine did not affect viability of normal peripheral blood mononuclear cells but decreased the proliferative capacity of activated normal T cells in dose-dependent manner. Additionally, cyclocytidine altered the percentage of γIFN-producing proliferative CD3+CD8+ cytotoxic T cells for any concentration tested (0.1, 1.0, 1 and 10.0 μM) meanwhile highly suppressed the number of the whole amount of CD3+CD8+ cells and did not affect the release of cytokines by CD3+CD4+ T cells.&#x0D; The study of the expression of the CD107a marker showed a significant stimulating effect of 10 µm of citarabine on the activation of subpopulations of T-lymphocytes (CD3+) and cytotoxic T-lymphocytes (CD3+CD8+).