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INTRODUCTION: Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. METHODS: This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. RESULTS: Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations

Histone deacetylases are well-established target enzymes involved in the pathology of different diseases including cancer and neurodegenerative disorders. The approved HDAC inhibitor drugs are associated with cellular toxicities. Different phenolic compounds have been shown to possess inhibitory activities against HDACs and are, therefore, considered safer alternatives to synthetic compounds. Here, we elucidated the binding mode and calculated the binding propensity of some of the top phenolic compounds against different isoforms representing different classes of Zn2+ ion-containing HDACs using the molecular docking approach. Our data reaffirmed the activity of the studied phenolic compounds against HDACs. Binding interaction analysis suggested that these compounds can block the activity of HDACs with or without binding to the active site zinc metal ion. Furthermore, molecular dynamics (MD) simulations were carried out on the selected crystal and docking complexes of each selected HDAC isoform. Analysis of root-mean-square displacement (RMSD) showed that the phenolic compounds demonstrated a stable binding mode over 50 ns in a way that is comparable to the cocrystal ligands. Together, these findings can aid future efforts in the search for natural inhibitors of HDACs.

Ibutamoren mesylate, or MK-0677, is an orally active, nonpeptide growth hormone secretagogue that has been developed to stimulate excretion of endogenous growth hormone. It has been evaluated for the treatment of a range of clinical conditions but is not available therapeutically. Nonetheless, MK-0677 is widely available to purchase online, sold as 'supplement' products. The mode of action and relative ease of purchase make MK-0677 a potential threat with regard to sports doping. The aim of this study was to investigate the metabolism of MK0677 in the horse following in vitro incubation and oral administration to two Thoroughbred racehorses, in order to identify the most appropriate analytical targets for doping control laboratories. Liquid chromatography high resolution mass spectrometry was used for metabolite identification, and subsequently, liquid chromatography-tandem mass spectrometry was used to generate full metabolite profiles for post-administration urine and plasma samples. Fourteen phase I metabolites were identified in vitro; 13 of these were subsequently detected in urine and nine in plasma collected post-administration, alongside the parent compound in both matrices. In both urine and plasma, the longest duration of detection was observed for an O-dealkylated metabolite of MK-0677, and therefore, this would be the best target for the detection of MK-0677 administration. MK-0677 and the O-dealkylated metabolite were found to be excreted largely unconjugated in urine and plasma.

Background The molecular chaperone, Hsp90, is a key player in the protein quality control system that maintains homeostasis under cellular stress conditions. It is a homodimer with ATP-dependent activity, and is a prominent member of the chaperone machinery that stabilizes, matures and (re)folds an extensive list of client proteins. Hsp90 occurs as four isoforms, cytosolic Hsp90α and Hsp90β, mitochondrial TRAP1 and Grp94 present in the endoplasmic reticulum. An aberrant role of Hsp90 has been attributed to several cancers and neurodegenerative disorders. Consequently, Hsp90 has emerged as an attractive therapeutic target. However, pan-Hsp90 inhibition often leads to detrimental dose-limiting toxicities. Novel strategies for Hsp90-targeted therapy intend to avoid this by using isoform-specific Hsp90 inhibition. In this respect, the radiosynthesis of carbon-11 labeled SNX-ab was developed and [11C]SNX-ab was evaluated as a Hsp90α,β isoform-selective PET probe, which could potentially allow to quantify in vivo Hsp90α,β expression. Results [11C]SNX-ab was synthesized with excellent radiochemical yields of 45% and high radiochemical purity (> 98%). In vitro autoradiography studies on tissue slices of healthy mouse brain, mouse B16.F10 melanoma and U87 glioblastoma using homologous (SNX-ab, SNX-0723) and heterologous (Onalespib and PU-H71) Hsp90 inhibitors demonstrated only limited reduction of tracer binding, indicating that the binding of [11C]SNX-ab was not fully Hsp90-specific. Similarly, [11C]SNX-ab binding to U87 cells was not efficiently inhibited by Hsp90 inhibitors. Ex vivo biodistribution studies in healthy mice revealed limited brain exposure of [11C]SNX-ab and predominantly hepatobiliary clearance, which was confirmed by in vivo full-body dynamic µPET studies. Conclusion Our results suggest that [11C]SNX-ab is not an ideal probe for in vivo visualization and quantification of Hsp90α/β expression levels in tumour and brain. Future research in the development of next-generation Hsp90 isoform-selective PET tracers is warranted to dissect the role played by each isoform towards disease pathology and support the development of subtype-specific Hsp90 therapeutics.

Herein, we reported on a new series of hydrazono bis-4-oxothiazolidines during the reaction of (hydrazinecarbonothioyl)hydrazinecarbothioamides with dimethyl acetylenedicarboxylate in ethanol as a solvent. The products were obtained in good yields. The structure assignment of obtained products was confirmed by NMR, mass and IR spectroscopy in addition to elemental analyses. The structure of the products was also confirmed by a single-crystal X-ray structure analysis. The possible mechanism for the reaction was also discussed.

Macrophage migration inhibitory factor (MIF) is involved in protein‐protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active site. Here, we use this site to develop proteolysis targeting chimera (PROTAC) in order to eliminate MIF from its protein‐protein interaction network. We report the first potent MIF‐directed PROTAC, denoted MD13, which induced almost complete MIF degradation at low micromolar concentrations with a DC50 around 100 nM in A549 cells. MD13 suppresses the proliferation of A549 cells, which can be explained by deactivation of the MAPK pathway and subsequent induction of cell cycle arrest at the G2/M phase. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF‐directed PROTAC (MD13) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy., Targeting macrophage migration inhibitory factor (MIF) is challenging, as it is involved in diseases via protein‐protein interactions. Here, the first potent MIF‐directed PROTAC MD13 is reported, which eliminates MIF from its protein‐protein interaction network by inducing MIF degradation. MD13 suppresses the proliferation of A549 cells by reducing MIF protein levels and MIF‐related signaling, demonstrating the potential of PROTACs in cancer therapy.

Urtica dioica agglutinin (UDA) is a carbohydrate-binding small monomeric protein isolated from stinging nettle rhizomes. It inhibits replication of a broad range of viruses, including coronaviruses, in multiple cell types, with appealing selectivity. In this work, we investigated the potential of UDA as a broad-spectrum antiviral agent against SARS-CoV-2. UDA potently blocks transduction of pseudotyped SARS-CoV-2 in A549.ACE2+-TMPRSS2 cells, with IC50 values ranging from 0.32 to 1.22 µM. Furthermore, UDA prevents viral replication of the early Wuhan-Hu-1 strain in Vero E6 cells (IC50 = 225 nM), but also the replication of SARS-CoV-2 variants of concern, including Alpha, Beta and Gamma (IC50 ranging from 115 to 171 nM). In addition, UDA exerts antiviral activity against the latest circulating Delta and Omicron variant in U87.ACE2+ cells (IC50 values are 1.6 and 0.9 µM, respectively). Importantly, when tested in Air-Liquid Interface (ALI) primary lung epithelial cell cultures, UDA preserves antiviral activity against SARS-CoV-2 (20A.EU2 variant) in the nanomolar range. Surface plasmon resonance (SPR) studies demonstrated a concentration-dependent binding of UDA to the viral spike protein of SARSCoV-2, suggesting interference of UDA with cell attachment or subsequent virus entry. Moreover, in additional mechanistic studies with cell-cell fusion assays, UDA inhibited SARS-CoV-2 spike protein-mediated membrane fusion. Finally, pseudotyped SARS-CoV-2 mutants with N-glycosylation deletions in the S2 subunit of the spike protein remained sensitive to the antiviral activity of UDA. In conclusion, our data establish UDA as a potent fusion inhibitor for the current variants of SARS-CoV-2. ispartof: Frontiers In Cellular And Infection Microbiology vol:12 ispartof: location:Switzerland edition: Lectins from plants, algae, fungi, bacteria and animals as potential therapeutic tools for SARS-CoV-2 and other pathogenic enveloped viruses, in a “one-health” perspective. status: published

Minor structural modifications of acyclic nucleoside phosphonates can dramatically affect their antiviral properties. This work discloses a shift in the selectivity spectrum of 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) nucleotides from herpesviruses toward hepatitis B virus (HBV) induced by their acyclic chain 2-substitution with a nonpolar group. Two series of racemic (R,S)-2-methyl-3-hydroxy-2-(phosphonomethoxy)propyl (MHPMP) and (R,S)-2-ethynyl-3-hydroxy-2-(phosphonomethoxy)propyl (EHPMP) nucleotides were initially synthesized. Among these, guanine-containing derivatives exhibited significant anti-HBV activities in the submicromolar range. Enantioenriched MHPMPG and EHPMPG analogues were subsequently obtained by Sharpless asymmetric epoxidation. The (S)-enantiomers possessed an 8- to 26-fold higher potency than the relative (R)-forms. A further comparison of the EC90 values indicated that (S)-EHPMPG inhibited HBV replication more effectively than its 2-methyl analogue. A phosphonodiamidate prodrug of (S)-EHPMPG was thus prepared and found to exert a remarkably high anti-HBV activity (EC50 = 9.27 nM) with excellent selectivity (SI50 > 10,787), proving to be a promising candidate for anti-HBV drug development. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:65 issue:13 ispartof: location:United States status: Published online

Cancer is a leading cause of global mortality, and its burden is growing despite the availability of standard treatment methods. Genetically and Morphologically tumor cells differ from normal cells. However, cancers arise from genetic modifications of normal cells and these cells may be nearly identical to normal cells, hence, making it difficult to selectively target tumor cells with the current standard cancer therapeutic methods. The ability of oncolytic viruses to specifically replicate within a target host cell and stimulate therapeutic response without disrupting normal cells in the immediate environment confers oncolytic virotherapy with a pharmacokinetic advantage over standard cancer therapies and this creates a pathway to reducing the global morality rate attributable to cancer. Aim: This review is aimed at illustrating the oncolytic potentials of Recombinant Poliovirus, PVSRIPO, for cancer therapy. PVSRIPO is a live attenuated, nonpathogenic virus containing the oral poliovirus Sabin type 1 in which the internal ribosomal entry site (IRES) is replaced with the IRES from human rhinovirus type 2 (HRV2). PVSRIPO leads to tumor regression by activating the host antitumor immune response and this process follows the phases of cancer immunoediting namely tumor cell elimination by immune system, balancing and regulating genetically unstable tumor cells and immune cells while preventing the escape of variant tumor cells. PVS-RIPO a derivate of Picornavirus, has a small virion size (~30 nm in diameter) which confers it with an oncolytic advantage. Furthermore, Picornaviruses have an attribute of rapid replication cycle, and this attribute enables PVSRIPO to effectively replicate and propagate in tumor cells to reverse the immunosuppressed state thereby resulting in tumor regression. The primary studies in this review have illustrated the oncolytic effect of the rapid propagation of PVSRIPO in tumor cells. Furthermore, these studies have indicated that this cytotoxicity of PVSRIPO, occurs in a time and dose dependent manner. For example, most of the studies reported that a single dose of intratumorally administered PVSRIPO was potent to delay tumor growth with a decline in tumor weight within few days. PVSRIPO is stable and safe for use in oncolytic virotherapy due to the substitution of the poliovirus’ original IRES for the HRV2 IRES. The primary studies in this review have illustrated that upon successful administration of PVSRIPO, there was no evidence of viral neuropathogenicity or virus shedding. In addition, PVSRIPO can be safely used in combination with other systemic therapies. Preventing side effect while targeting cancer has been a primary source of concern in cancer therapy and PVSRIPO fills this gap by its ability to selectively target the tumor cells without affecting non-tumor cells in the immediate environment due to its natural tropism for CD155, the poliovirus receptor (PVR).CD155 is present in a lot of cancers thereby making PVSRIPO an appropriate agent for eliminating tumor cells. Conclusion: This review has highlighted the oncolytic potentials of PVSRIPO which was evident in the resulting increased survival rates in both the animal models and clinical trials. Given these illustrations in this review, PVSRIPO is an appropriate agent for cancer therapy.

The oceans cover 70% of the Earth’s surface. The marine environment is an important source of secondary metabolites with high biodiversity. Besides other marine species, sponges with a wide range of secondary metabolites are an important potential for drug discovery. Cancer is one of the leading causes of death with high morbidity and mortality. It is very important to discover new therapeutic agents in the treatment of cancer. In recent years, studies on exploring new anticancer compounds are focused on the marine source. In this review, our target is collecting the studies about marine sponges secondary metabolites which have an anticancer effect. Among most of the isolated compounds from sponges and their semisynthetic derivatives, there are three FDA (US Food and Drug Administration) approved compounds and three compounds in clinical phase. Moreover, more than 40 compounds isolated from marine sponges have been tested for anticancer activity in recent 10 years. In conclusion marine sponges secondary metabolites are a promising and important source of the anticancer compounds.

COVID-19 has resulted in huge numbers of infections and deaths worldwide and brought the most severe disruptions to societies and economies since the Great Depression. Massive experimental and computational research effort to understand and characterize the disease and rapidly develop diagnostics, vaccines, and drugs has emerged in response to this devastating pandemic and more than 130 000 COVID-19-related research papers have been published in peer-reviewed journals or deposited in preprint servers. Much of the research effort has focused on the discovery of novel drug candidates or repurposing of existing drugs against COVID-19, and many such projects have been either exclusively computational or computer-aided experimental studies. Herein, we provide an expert overview of the key computational methods and their applications for the discovery of COVID-19 small-molecule therapeutics that have been reported in the research literature. We further outline that, after the first year the COVID-19 pandemic, it appears that drug repurposing has not produced rapid and global solutions. However, several known drugs have been used in the clinic to cure COVID-19 patients, and a few repurposed drugs continue to be considered in clinical trials, along with several novel clinical candidates. We posit that truly impactful computational tools must deliver actionable, experimentally testable hypotheses enabling the discovery of novel drugs and drug combinations, and that open science and rapid sharing of research results are critical to accelerate the development of novel, much needed therapeutics for COVID-19., We cover diverse methodologies, computational approaches, and case studies illustrating the ongoing efforts to develop viable drug candidates for treatment of COVID-19.

Significance Large DNA-encoded libraries of cyclic peptides are emerging as powerful sources of molecules to tackle challenging drug targets. The structural and functional diversity contained within these libraries is, however, little explored. Here we demonstrate that one such library contains members that use unexpectedly diverse mechanisms to recognize the same surface on the same target proteins with high affinity and specificity. This range of binding modes is much larger than observed in natural ligands of the same proteins, demonstrating the power and versatility of the technology. Our data also reveal opportunities for the development of more sophisticated approaches to achieving specificity when trying to selectively target one member of a family of closely related proteins., Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 106-fold. Crystal structures of 13 peptide–bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and β-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.

Intracellular excited-state properties of a photodynamic active Osmium-complex are investigated. The key to the excited-state relaxation is the interplay of 3MLCT and 3ILCT states on the oligothiophene-substituted ligand. We successfully tested the model derived from solution with the complex internalized in cells to bridge the gap between cuvette and in vivo measurements for the first time. This contribution describes the excited-state properties of an Osmium-complex when taken up into human cells. The complex 1 [Os(bpy)2(IP-4T)](PF6)2 with bpy=2,2′-bipyridine and IP-4T=2-{5′-[3′,4′-diethyl-(2,2′-bithien-5-yl)]-3,4-diethyl-2,2′-bithiophene}imidazo[4,5-f][1,10]phenanthroline) can be discussed as a candidate for photodynamic therapy in the biological red/NIR window. The complex is taken up by MCF7 cells and localizes rather homogeneously within in the cytoplasm. To detail the sub-ns photophysics of 1, comparative transient absorption measurements were carried out in different solvents to derive a model of the photoinduced processes. Key to rationalize the excited-state relaxation is a long-lived 3ILCT state associated with the oligothiophene chain. This model was then tested with the complex internalized into MCF7 cells, since the intracellular environment has long been suspected to take big influence on the excited state properties. In our study of 1 in cells, we were able to show that, though the overall model remained the same, the excited-state dynamics are affected strongly by the intracellular environment. Our study represents the first in depth correlation towards ex-vivo and in vivo ultrafast spectroscopy for a possible photodrug., publishedVersion

Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent inhibitors in the late 18th century, the field has advanced significantly and currently about 30% of the marketed drugs are covalent inhibitors. The numerous advantages of covalent inhibitors are counteracting the initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. The aim of this review is to provide a short historic overview and focus on recently developed covalent inhibitors (2011-2019), including structural aspects and examples on challenging targets.

In this review we provide a brief historic overview of covalent inhibitors and summarize recent advances focusing on developments in the last decade. Applications in challenging targets and future perspectives are also discussed., Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent inhibitors in the late 18th century, the field has advanced significantly and currently about 30% of the marketed drugs are covalent inhibitors. The numerous advantages of covalent inhibitors are counteracting the initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. The aim of this review is to provide a short historic overview and focus on recently developed covalent inhibitors (2011–2019), including structural aspects and examples on challenging targets.

N-Heterocyclic carbenes (NHCs) are the ligands of choice in a large variety of transformations entailing different transition metals. However, the number and variety of chiral NHCs suitable as stereo-controlling ligands in asymmetric catalysis remains limited. Herein we highlight the introduction of a modular NHC ligand family, consisting of a chiral version of the widely used IPr ligand. These chiral NHC ligands were applied in the nickel-catalyzed enantioselective C–H functionalization of N-heterocycles. Nickel-NHC catalysis unlocked the stereoselective C–H annulation of 2- and 4-pyridones, delivering fused bicyclic compounds found in many biologically active compounds. Applying a bulky, yet flexible ligand scaffold enabled the highly enantioselective C–H functionalization of pyridones under mild conditions. The introduction of a bulky chiral SIPr analogue enabled the nickel-catalyzed enantioselective C–H functionalization of indoles, yielding valuable tetrahydropyridoindoles. Additionally, pyrrolopyridines, pyrrolopyrimidines and pyrroles were efficiently functionalized, delivering chiral annulated azoles.

Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation. The best compound 6e with a sulfonyl scaffold displayed EC50 values of 0.0356 μmol/L against WT and 0.0228 μmol/L against HIV K103N mutant strain. More pronounced, it had a lower cytotoxicity (CC50 = 99.6 μmol/L), higher selectivity index (SIWT = 2799, SIK103N = 4375) and better calculated logarithm of the octanol-water partition coefficient (cLogP) than the lead compound 3. Molecular docking and dynamics provided the binding modes of these compounds with reverse transcriptase, explaining their activity. Collectively, the new compounds could be candidates for anti-HIV drug discovery.

Enzyme activity alterations have been associated with many metabolism disorders and have crucial roles in the pathogenesis of some diseases. Tyrosinase is a key enzyme in melanin biosynthesis, which is responsible for skin pigmentation to protect the skin from solar radiation. Pancreatic lipase has been considered a key enzyme for the treatment of obesity. Herein, we reported the synthesis and enzyme inhibitions of a series of sulfonates as possible tyrosinase and pancreatic lipase inhibitors. According to the calculated IC50 values, compound 3f (74.1 +/- 11.1 mu M) and compound 3c (86.6 +/- 6.9 mu M) were determined to be the best inhibitors among the synthesized compounds for the tyrosinase and pancreatic lipase enzymes, respectively. The approach yielded at extremely high level by creating very flexible structural domains for the chemically modified groups. The structural characterization of the target molecules was implemented by H-1-NMR, C-13-NMR, and HR-MS analyses. Also, molecular docking studies of the synthesized compounds with tyrosinase and pancreatic lipase enzymes were conducted using AutoDock Vina software. Additionally, the studies of the absorption distribution, metabolism, and excretion (ADME) were performed to uncover the target compounds ' pharmacokinetics, drug similarities, and medicinal properties of the novel sulfonate derivatives bearing salicylaldehyde.

Non-selective inhibition of different histone deacetylase enzymes by hydroxamic acid-based drugs causes severe side effects when used as a (long-term) cancer treatment. In this work, we searched for a potent zinc-binding group able to replace the contested hydroxamic acid by employing a lean inhibitor strategy. This instructed the synthesis of a set of HDAC6-selective inhibitors containing the more desirable mercaptoacetamide moiety. Biological evaluation of these new compounds showed an IC50 in the nanomolar range, dose-dependent HDAC6 inhibition in MM1.S cells and improved genotoxicity results, rendering these new inhibitors valuable hits for applications even beyond oncology.

Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:65 issue:4 pages:3473-3517 ispartof: location:United States status: published

Inhibition of high cholinesterase levels including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), is one of the most important strategies for the treatment of Alzheimer's disease (AD). Clinically limited drugs are used in the treatment of AD, so there is a need to find new effective inhibitors today. Therefore, in this study, synthesized six coumarin carboxamides (A1, A2, B1-B4) were evaluated against AChE and BChE by combined in silico and in vitro studies. The in vitro assessment of studied compounds revealed that A1, A2, B3, and B4 showed highest inhibition potential against AChE and BChE. As demonstrated with our structure activity relationship (SAR) study, the promising inhibition result of AChE at nanomolar concentrations was obtained with heterocyclic amines including pyrrolidine and N-methyl piperazine moieties for tertiary amide substituted coumarin compounds B3 and B4, displaying K-1 values of 9.78 nM and 8.07 nM, respectively. Thus, compounds B3 and B4 had around 5.7- and 6.9-fold more potency compared to the reference molecule, neostigmine. Moreover, coumarin-3-carboxamide derivative A1 bearing benzylmorpholine moiety on coumarin scaffold at position 3 displayed stronger inhibition potential against BChE. Furthermore, in order to better understand their molecular mechanisms in these targets, we conducted molecular docking and MD simulations. Our promising preclinical results show that the lead compounds A1, A2, B3 and B4 have high potential as effective inhibitors for the treatment of AD.

Mapping anomalies in the Earth’s magnetic field is one method used in applied geophysics, for exploring buried structures and objects. Magnetic surveys can be ground-based or made airborne, onboard airplanes, helicopters, or unmanned aerial vehicles (UAV), also known as drones. The measurements in this project were made as part of a mapping project by the Swedish Geological Survey (SGU) in the Enåsen area in Hälsingland, central Sweden. The magnetic data were collected by SGU in the field summer of 2021. The aim of this project is to model the data from UAV-borne surveys and validate them by checking the response with the measure ground-based data collected by SGU and compare several different profiles to investigate the different results from ground-based vs. UAV-borne surveys. Two models from two different UAV flight lines were made using the software Potent, to show anomalies in the magnetic field intensity. The modelling results show a relatively good correlation between the response from the model and ground-based data. However, there are detailed variations in the ground-based data that are not resolved by the UAV data. This is partly because of the height difference and partly different sampling. The magnetic anomalies in the project area were interpreted, with the help of the modelled profiles, as being caused mainly by geological units consisting of metasedimentary rock/migmatite. These units generally dip with 30-50°, some of them containing Cuand Au-mineralizations. The dip, rock type, and magnetic susceptbilities of these units match the field data from SGU relatively well and are also backed up by SGU models of electrical resistivity from the same area. Kartläggning av avvikelser i jordens magnetfält är en metod som används inom tillämpad geofysik för att upptäcka underjordiska strukturer och objekt. Magnetiska undersökningar kan utföras på marken eller från luften, med hjälp av flygplan, helikopter eller drönare. De geofysiska mätningarna i detta projekt gjordes som en del av ett karteringsprojekt av Sveriges geologiska undersökning (SGU) i Enåsen, Hälsingland. Dessa magnetiska data insamlades av SGU under sommaren 2021. Syftet med projektet är att modellera magnetiska data insamlade med hjälp av drönare, för att sedan kontrollera modellerna med magnetiska markdata insamlade av SGU i samma område. Dessa profiler jämfördes för att undersöka hur insamlad data från drönare respektive markmätningar skiljer sig. Modellerna gjordes i programvaran Potent, där anomalierna i magnetfältets intensitet. Resultaten från modelleringen visar en relativt tydlig korrelation mellan hur modellen (från insamlade drönardata) svarar mot markdata. Det förekommer dock små variationer i profilerna från markdata, som inte syns i modellerna från drönardata. Detta beror delvis på att mätningarna gjordes på olika höjd, och delvis på att proverna skiljer sig åt i viss mån. De magnetiska anomalierna i projektområdet tolkades med hjälp av de modellerade profilerna, och förmodas vara orsakade av enheter av metasedimentär bergart/migmatit. Dessa enheter stupar mestadels med 30-50°, och på vissa platser förekommer Cu- och Au-mineraliseringar. Stupningen, bergarter och den magnetiska susceptibiliteten stämmer relativt väl överens med SGU:s information från fältundersökningar, och tolkningen styrks ytterligare av SGU:s modeller av den elektriska resistiviteten i samma område.

Ece, Abdulilah/0000-0002-3087-5145; Supuran, Claudiu/0000-0003-4262-0323 WOS: 000520863700001 PubMed: 31797703 In this study, newly synthesised compounds 6, 8, 10 and other compounds (1-5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1-10 showed effective inhibition profiles with K-I values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.

In this study, the methanolic and infusion extracts of two species, Thymbra capitata and Thymus sipyleus subsp. rosulans, were tested for their chemical composition and biological abilities (antioxidant, enzyme inhibitory and anti-inflammatory effects). The extracts yielded total phenolic and flavonoid contents in the range of 83.43–127.52 mg GAE/g and 9.41–46.34 mg RE/g, respectively. HPLC analysis revealed rosmarinic acid to be a major component of the studied extracts (15.85–26.43%). The best ABTS radical scavenging ability was observed in the methanol extract of T. capitata with 379.11 mg TE/g, followed by in the methanol extract of T. sipylus (360.93 mg TE/g). In the CUPRAC assay, the highest reducing ability was also found in the methanol extract of T. capitata with 802.22 mg TE/g. The phosphomolybdenum ability ranged from 2.39 to 3.61 mmol TE/g. In terms of tyrosinase inhibitory effects, the tested methanol extracts (83.18–89.66 mg KAE/g) were higher than the tested water extracts (18.74–19.11 mg KAE/g). Regarding the BChE inhibitory effects, the methanol extracts were active on the enzyme while the water extracts showed no inhibitory effect on it. Overall, the methanolic extracts showed better enzyme inhibition compared to the infusion extracts. Molecular docking also showed the selected exhibited potential binding affinities with all enzymes, with a preference for cholinesterases. Additionally, the extracts were effective in attenuating the LPS-induced increase in COX-2 and IL-6 gene expression in isolated colon, thus indicating promising anti-inflammatory effects. The preliminary results of this study suggest that these species are good natural sources of antioxidants and also provide some scope as enzyme inhibitors, most likely due to their bioactive contents such as phenolic acids, and thus can be exploited for different applications related to health promotion and disease prevention.

Vitrimers are a subclass of covalent adaptable networks which introduce reshapeability and recyclability in thermoset materials while maintaining a high degree of chemical resistance and dimensional stability. Vitrimer materials based on vinylogous urethane (VU) chemistry have drawn a lot of attention in this area. Classically, these are obtained by the polycondensation polymerization of acetoacetate and amine monomers. Unfortunately, this also releases water, often leading to porosity defects in the initially obtained non-reprocessed cross-linked materials. Here, we demonstrate that alkyne esters (AE) can be used as alternative building blocks for VU vitrimers by a polyaddition polymerization with amines, leading to water-free formulations and straightforward access to defect-free cured VU vitrimer materials. The bond formation and dynamic bond exchange was also studied by small molecule reactions, further rationalized by a computational (DFT) approach. The resulting water-free VU vitrimers display similar material properties compared to vitrimers based on acetoacetates, although also some differences are seen, which can be related to a minor amide-bond forming side reaction. Furthermore, by use of this novel AE approach, polyaddition curing of VU epoxy vitrimers can easily be prepared in a one-pot three-component method, combining AE, amine, and epoxy monomers. This study shows that AE monomers can be used as an easy drop-in method to obtain processable epoxy materials with tunable viscoelastic properties, where the viscous flow behavior can in principle be fully tuned by varying the monomers' ratios and compositions.