Copper/Zinc-Catalyzed Stitching of 2-Carbonylanilines with Bis(ynamides): Access to Pyrrolo[2,3-b]quinolines and Its Photophysical Studies.

Herein, a one-pot desulfonylative protocol enabled by copper(II)/zinc(II) salts to access pyrrolo[2,3-b]quinolines in good to excellent yields from 2-carbonylanilines and ynamide-derived buta-1,3-diynes has been reported. Significantly, various 2-carbonylanilines carrying reactive functional groups are well tolerated. Moreover, a gram-scale synthesis and synthetic application highlight the practical utility of the current protocol. Notably, the fluorescence properties of pyrrolo[2,3-b]quinolines have been recorded, and their potential use as a fluorescent probe in the imaging of live cells has been demonstrated.

Getting around the roundworms: Identifying knowledge gaps and research priorities for the ascarids.

The ascarids are a large group of parasitic nematodes that infect a wide range of animal species. In humans, they cause neglected diseases of poverty; many animal parasites also cause zoonotic infections in people. Control measures include hygiene and anthelmintic treatments, but they are not always appropriate or effective and this creates a continuing need to search for better ways to reduce the human, welfare and economic costs of these infections. To this end, Le Studium Institute of Advanced Studies organized a two-day conference to identify major gaps in our understanding of ascarid parasites with a view to setting research priorities that would allow for improved control. The participants identified several key areas for future focus, comprising of advances in genomic analysis and the use of model organisms, especially Caenorhabditis elegans, a more thorough appreciation of the complexity of host-parasite (and parasite-parasite) communications, a search for novel anthelmintic drugs and the development of effective vaccines. The participants agreed to try and maintain informal links in the future that could form the basis for collaborative projects, and to co-operate to organize future meetings and workshops to promote ascarid research.

Discrete symmetries tested at 10-4 precision using linear polarization of photons from positronium annihilations.

Discrete symmetries play an important role in particle physics with violation of CP connected to the matter-antimatter imbalance in the Universe. We report the most precise test of P, T and CP invariance in decays of ortho-positronium, performed with methodology involving polarization of photons from these decays. Positronium, the simplest bound state of an electron and positron, is of recent interest with discrepancies reported between measured hyperfine energy structure and theory at the level of 10-4 signaling a need for better understanding of the positronium system at this level. We test discrete symmetries using photon polarizations determined via Compton scattering in the dedicated J-PET tomograph on an event-by-event basis and without the need to control the spin of the positronium with an external magnetic field, in contrast to previous experiments. Our result is consistent with QED expectations at the level of 0.0007 and one standard deviation.

One-Pot, Tandem Reductive Amination/Alkylation-Cycloamidation for Lactam Synthesis from Keto or Amino Acids.

Monotrifluoroacetoxyborane-amines, prepared by treating borane-amines with trifluoroacetic acid, have been shown to be efficient reagents for a one-pot, tandem reductive amination/alkylation-cycloamidation of keto or amino acids to achieve the synthesis of 5-aryl or 5-methyl pyrrolidin-2-ones and 6-aryl or 6-methyl piperidin-2-ones.

Twofold Heteroannulation Reactions Enabled by Gold(I)/Zinc(II) Catalysts: Synthesis of Amine-Substituted Diaryl[c,h][1,6]naphthyridines.

A straightforward and atom-economical one-pot protocol catalyzed by gold(I) and zinc(II) for the synthesis of amine-substituted diaryl[c,h][1,6]naphthyridines from two different aromatic nitriles has been showcased. This dual-catalytic strategy is highly efficient, offering an array of tetracyclic heteroaromatic products in good to excellent yields. Furthermore, the base can efficiently catalyze the second annulation step, yielding structurally unique thiophene-fused [1,6]naphthyridines in good yields.

Leveraging Zn(II) Catalyst: Synthesis of Amidoquinolines via (3 + 3) Heteroannulation of Aromatic Amines and Ynamides.

Herein, we present a Zn(II)-catalyzed (3 + 3) heteroannulation reaction between aromatic amines and 1,3-diynamides for the synthesis of amidoquinolines. A large number of aromatic amines are well tolerated, furnishing quinoline derivatives in up to excellent yield. Notably, various reactive functional groups have survived under the optimal reaction conditions, highlighting the mildness of the developed protocol. In addition, amines derived from bioactive molecules show modest reactivity.

Nitrogen Atom Transfer Enables the (5+1) Annulation Reaction to Access Aminoisoquinolines.

Herein, a catalytic synthetic transformation offering a series of -NH2 group-bearing aminoisoquinolines with moderate to good yields has been showcased. Interestingly, the nitrogen atom of the isoquinoline ring is coming from the reaction medium upon metal-assisted C≡N bond cleavage. Moreover, this (5+1) annulation reaction shows broad substrate variation. Furthermore, the derivatization of the isoquinoline core via functional group interconversions and mechanistic studies to identify the reaction intermediate have been carried out successfully.

Efficiency determination of J-PET: first plastic scintillators-based PET scanner.

BACKGROUND: The Jagiellonian Positron Emission Tomograph is the 3-layer prototype of the first scanner based on plastic scintillators, consisting of 192 half-metre-long strips with readouts at both ends. Compared to crystal-based detectors, plastic scintillators are several times cheaper and could be considered as a more economical alternative to crystal scintillators in future PETs. JPET is also a first multi-photon PET prototype. For the development of multi-photon detection, with photon characterized by the continuous energy spectrum, it is important to estimate the efficiency of J-PET as a function of energy deposition. The aim of this work is to determine the registration efficiency of the J-PET tomograph as a function of energy deposition by incident photons and the intrinsic efficiency of the J-PET scanner in detecting photons of different incident energies. In this study, 3-hit events are investigated, where 2-hits are caused by 511 keV photons emitted in [Formula: see text] annihilations, while the third hit is caused by one of the scattered photons. The scattered photon is used to accurately measure the scattering angle and thus the energy deposition. Two hits by a primary and a scattered photon are sufficient to calculate the scattering angle of a photon, while the third hit ensures the precise labeling of the 511 keV photons. RESULTS: By comparing experimental and simulated energy distribution spectra, the registration efficiency of the J-PET scanner was determined in the energy deposition range of 70-270 keV, where it varies between 20 and 100[Formula: see text]. In addition, the intrinsic efficiency of the J-PET was also determined as a function of the energy of the incident photons. CONCLUSION: A method for determining registration efficiency as a function of energy deposition and intrinsic efficiency as a function of incident photon energy of the J-PET scanner was demonstrated. This study is crucial for evaluating the performance of the scanner based on plastic scintillators and its applications as a standard and multi-photon PET systems. The method may be also used in the calibration of Compton-cameras developed for the ion-beam therapy monitoring and simultaneous multi-radionuclide imaging in nuclear medicine.

Monotrifluoroacetoxyborane-amines: chemoselective reagents for challenging reductive aminations.

Borane-amines undergo exclusive monoacetoxylation to trifluoroacetoxyborane-amines (TFAB-amines), which serve as chemoselective reagents for direct reductive amination of aldehydes and ketones. TFAB-NEt3 has been established as mild and highly selective compared to widely-used NaBH3CN and Na(AcO)3BH, even at higher temperatures with challenging substrates. A mechanism involving polyaminoborane formed via dehydroacetoxylation of TFAB-NH3 has been described.

Intense isolated attosecond pulses from two-color few-cycle laser driven relativistic surface plasma.

Ultrafast plasma dynamics play a pivotal role in the relativistic high harmonic generation, a phenomenon that can give rise to intense light fields of attosecond duration. Controlling such plasma dynamics holds key to optimize the relevant sub-cycle processes in the high-intensity regime. Here, we demonstrate that the optimal coherent combination of two intense ultrashort pulses centered at two-colors (fundamental frequency, [Formula: see text] and second harmonic, [Formula: see text]) can lead to an optimal shape in relativistic intensity driver field that yields such an extraordinarily sensitive control. Conducting a series of two-dimensional (2D) relativistic particle-in-cell (PIC) simulations carried out for currently achievable laser parameters and realistic experimental conditions, we demonstrate that an appropriate combination of [Formula: see text] along with a precise delay control can lead to more than three times enhancement in the resulting high harmonic flux. Finally, the two-color multi-cycle field synthesized with appropriate delay and polarization can all-optically suppress several attosecond bursts while favourably allowing one burst to occur, leading to the generation of intense isolated attosecond pulses without the need of any sophisticated gating techniques.

Cu(II)-catalyzed [4 + 1] and [4 + 3] annulation reactions: a modular approach to N-aryl/alkyl substituted 2,5-diamidopyrroles and diazepines.

A one-pot copper-catalyzed [4 + 1] annulation reaction of primary amines with ynamide-derived buta-1,3-diynes for the synthesis of 2,5-diamido bearing N-aryl/alkyl pyrroles in up to excellent yields has been showcased. A broad range of primary amines having highly reactive functional groups are well tolerated. Notably, sterically demanding aniline and primary aliphatic amines are excellent amine sources. Furthermore, the current protocol may yield structurally unique diazepine derivatives. The scale-up reaction and fruitful chemical elaboration of pyrrole motifs highlight the importance of this reaction.

Nodulisporic acid produces direct activation and positive allosteric modulation of AVR-14B, a glutamate-gated chloride channel from adult Brugia malayi.

Glutamate-gated chloride channels (GluCls) are unique to invertebrates and are targeted by macrocyclic lactones. In this study, we cloned an AVR-14B GluCl subunit from adult Brugia malayi, a causative agent of lymphatic filariasis in humans. To elucidate this channel's pharmacological properties, we used Xenopus laevis oocytes for expression and performed two-electrode voltage-clamp electrophysiology. The receptor was gated by the natural ligand L-glutamate (effective concentration, 50% [EC50] = 0.4 mM) and ivermectin (IVM; EC50 = 1.8 nM). We also characterized the effects of nodulisporic acid (NA) on Bma-AVR-14B and NA-produced dual effects on the receptor as an agonist and a type II positive allosteric modulator. Here we report characterization of the complex activity of NA on a nematode GluCl. Bma-AVR-14B demonstrated some unique pharmacological characteristics. IVM did not produce potentiation of L-glutamate-mediated responses but instead, reduced the channel's sensitivity for the ligand. Further electrophysiological exploration showed that IVM (at a moderate concentration of 0.1 nM) functioned as an inhibitor of both agonist and positive allosteric modulatory effects of NA. This suggests that IVM and NA share a complex interaction. The pharmacological properties of Bma-AVR-14B indicate that the channel is an important target of IVM and NA. In addition, the unique electrophysiological characteristics of Bma-AVR-14B could explain the observed variation in drug sensitivities of various nematode parasites. We have also shown the inhibitory effects of IVM and NA on adult worm motility using Worminator. RNA interference (RNAi) knockdown suggests that AVR-14 plays a role in influencing locomotion in B. malayi.

Advances in our understanding of nematode ion channels as potential anthelmintic targets.

Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In nematodes, the physiological behaviors including locomotion, navigation, feeding and reproduction, are regulated by these protein entities. Majority of the antinematodal chemotherapeutics target the ion channels to disrupt essential biological functions. Here, we have summarized current advances in our understanding of nematode ion channel pharmacology. We review cys-loop ligand gated ion channels (LGICs), including nicotinic acetylcholine receptors (nAChRs), acetylcholine-chloride gated ion channels (ACCs), glutamate-gated chloride channels (GluCls), and GABA (γ-aminobutyric acid) receptors, and other ionotropic receptors (transient receptor potential (TRP) channels and potassium ion channels). We have provided an update on the pharmacological properties of these channels from various nematodes. This article catalogs the differences in ion channel composition and resulting pharmacology in the phylum Nematoda. This diversity in ion channel subunit repertoire and pharmacology emphasizes the importance of pursuing species-specific drug target research. In this review, we have provided an overview of recent advances in techniques and functional assays available for screening ion channel properties and their application.

Synergetic copper/zinc catalysis: synthesis of aryl/heteroaryl-fused 1H-pyrrolo[3,2-c]pyridines.

Scaffolds having a 1H-pyrrolo[3,2-c]pyridine core show significant biological activity. Herein, we report a synergetic copper/zinc-catalyzed one-step annulation reaction of 2-amino (hetero)arylnitriles with ynamide-derived buta-1,3-diynes to deliver 1H-pyrrolo[3,2-c]quinoline-2,4-diamine derivatives in moderate to good yields. The annulation reaction follows a double cyclization pathway. The gram-scale synthesis of 1H-pyrrolo[3,2-c]quinoline-2,4-diamine proves the practicality of this protocol.

Multipurpose peptides: The venoms of Amazonian stinging ants contain anthelmintic ponericins with diverse predatory and defensive activities.

In the face of increasing drug resistance, the development of new anthelmintics is critical for controlling nematodes that parasitise livestock. Although hymenopteran venom toxins have attracted attention for applications in agriculture and medicine, few studies have explored their potential as anthelmintics. Here we assessed hymenopteran venoms as a possible source of new anthelmintic compounds by screening a panel of ten hymenopteran venoms against Haemonchus contortus, a major pathogenic nematode of ruminants. Using bioassay-guided fractionation coupled with liquid chromatography-tandem mass spectrometry, we identified four novel anthelmintic peptides (ponericins) from the venom of the neotropical ant Neoponera commutata and the previously described ponericin M-PONTX-Na1b from Neoponera apicalis venom. These peptides inhibit H. contortus development with IC50 values of 2.8-5.6 µM. Circular dichroism spectropolarimetry indicated that the ponericins are unstructured in aqueous solution but adopt α-helical conformations in lipid mimetic environments. We show that the ponericins induce non-specific membrane perturbation, which confers broad-spectrum antimicrobial, insecticidal, cytotoxic, hemolytic, and algogenic activities, with activity across all assays typically correlated. We also show for the first time that ponericins induce spontaneous pain behaviour when injected in mice. We propose that the broad-spectrum activity of the ponericins enables them to play both a predatory and defensive role in neoponeran ants, consistent with their high abundance in venom. This study reveals a broader functionality for ponericins than previously assumed, and highlights both the opportunities and challenges in pursuing ant venom peptides as potential therapeutics.

Incremental Learning in Modelling Process Analysis Technology (PAT)-An Important Tool in the Measuring and Control Circuit on the Way to the Smart Factory.

To meet the demands of the chemical and pharmaceutical process industry for a combination of high measurement accuracy, product selectivity, and low cost of ownership, the existing measurement and evaluation methods have to be further developed. This paper demonstrates the attempt to combine future Raman photometers with promising evaluation methods. As part of the investigations presented here, a new and easy-to-use evaluation method based on a self-learning algorithm is presented. This method can be applied to various measurement methods and is carried out here using an example of a Raman spectrometer system and an alcohol-water mixture as demonstration fluid. The spectra's chosen bands can be later transformed to low priced and even more robust Raman photometers. The evaluation method gives more precise results than the evaluation through classical methods like one primarily used in the software package Unscrambler. This technique increases the accuracy of detection and proves the concept of Raman process monitoring for determining concentrations. In the example of alcohol/water, the computation time is less, and it can be applied to continuous column monitoring.

Trimethyl Borate-Catalyzed, Solvent-Free Reductive Amination.

Solvent-free reductive amination of aldehydes and ketones with aliphatic and aromatic amines in high-to-excellent yields has been achieved with sub-stoichiometric trimethyl borate as promoter and ammonia borane as reductant.

Ivermectin: An Anthelmintic, an Insecticide, and Much More.

Here we tell the story of ivermectin, describing its anthelmintic and insecticidal actions and recent studies that have sought to reposition ivermectin for the treatment of other diseases that are not caused by helminth and insect parasites. The standard theory of its anthelmintic and insecticidal mode of action is that it is a selective positive allosteric modulator of glutamate-gated chloride channels found in nematodes and insects. At higher concentrations, ivermectin also acts as an allosteric modulator of ion channels found in host central nervous systems. In addition, in tissue culture, at concentrations higher than anthelmintic concentrations, ivermectin shows antiviral, antimalarial, antimetabolic, and anticancer effects. Caution is required before extrapolating from these preliminary repositioning experiments to clinical use, particularly for Covid-19 treatment, because of the high concentrations of ivermectin used in tissue-culture experiments.

Amine-boranes as Dual-Purpose Reagents for Direct Amidation of Carboxylic Acids.

Amine-boranes serve as dual-purpose reagents for direct amidation, activating aliphatic and aromatic carboxylic acids and, subsequently, delivering amines to provide the corresponding amides in up to 99% yields. Delivery of gaseous or low-boiling amines as their borane complexes provides a major advantage over existing methodologies. Utilizing amine-boranes containing borane incompatible functionalities allows for the preparation of functionalized amides. An intermolecular mechanism proceeding through a triacyloxyborane-amine complex is proposed.

Gold-catalyzed homo- and cross-annulation of alkynyl carboxylic acids: a facile access to substituted 4-hydroxy 2H-pyrones and total synthesis of pseudopyronine A.

A Au(i)-catalyzed homo- and cross-annulation reaction of alkynyl carboxylic acids offering 3,6-disubstituted 4-hydroxy 2H-pyrones has been demonstrated. The reaction tolerates various substituted alkynyl carboxylic acids and moderate to good yields of α-pyrone scaffolds have been observed. Later, a gram-scale reaction of the acid and the total synthesis of the natural product pseudopyronine A have been carried out successfully.