Monthly Archives: September 2023

Jellyfish‐type Dinuclear Hafnium Azido Complexes: Synthesis and Reactivity

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Jellyfish-type Dinuclear Hafnium Azido Complexes: Synthesis and Reactivity

A jellyfish-like tetraazide Hf2(μ-1,1-N3)2(N3)2 supported by a new pyrazolate-bridged ligand was designed and synthesized from a dihafnium chloride precursor reacting with NaN3, which further generated a tetranuclear hafnium imido complex from a putative dinuclear HfIV-nitridyl intermediate under reduction conditions.


Abstract

Di- and multinuclear hafnium complexes bridged by ligands have been rarely reported. In this article, a novel 3,5-disubstituted pyrazolate-bridged ligand LH5 with two [N2N]2−-type chelating side arms was designed and synthesized, which supported a series of dinuclear hafnium complexes. Dinuclear hafnium azides [LHf2(μ-1,1-N3)2(N3)2][Na(THF)4] 3 and [LHf2(μ-1,1-N3)2(N3)2][Na(2,2,2-Kryptofix)] 4 were further synthesized and structurally characterized, featuring two sets of terminal and bridging azido ligands like jellyfishes. The reactivity of 3 under reduction conditions was conducted, leading to a formation of a tetranuclear hafnium imido complex [L1Hf2(μ1-NH)(N3){μ2-K}]2 5. DFT calculations revealed that the mixed imido azide 5 was generated via an intramolecular C−H insertion from a putative dinuclear HfIV-nitridyl intermediate.

Synthesis of Some Benzothiazole Derivatives Based on 3‐Hydroxypyridine‐4‐one and Benzaldehyde and Evaluation of Their β‐Amyloid Aggregation Inhibition Using both Experimental Methods and Molecular Dynamic Simulation

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Synthesis of Some Benzothiazole Derivatives Based on 3-Hydroxypyridine-4-one and Benzaldehyde and Evaluation of Their β-Amyloid Aggregation Inhibition Using both Experimental Methods and Molecular Dynamic Simulation


Abstract

Some novel inhibitors based on the (benzo[d]thiazol-2-yl)-1-phenylmethanimine derivatives were designed to reduce the aggregation process in Alzheimer's disease. These structures seem to mimic stilbene-like scaffold, while the benzothiazole moiety “locks” the thioflavin T binding site. Other inhibitors were designed based on 2-((benzo[d]thiazol-2-ylimino)methyl)-5-(benzyloxy)-1-methylpyridin-4(H)-one derivatives.

Benzo[d]thiazol-2-amine derivatives were prepared by the reaction of aniline derivatives with ammonium thiocyanate in the presence of bromine/acetic acid. Then, the reaction of amines with benzaldehyde derivatives and 5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carbaldehyde gave the desired compounds. The plate reader-based fibrillation assay was done to evaluate the inhibition of Aβ aggregation. Also, molecular dynamic simulation was carried out to clarify the interaction manner of the designed compounds with Aβ formation.

The biological evaluation proved 5a and 7e as the best inhibitor of the Aβ aggregation. compound 5a in the concentration of 50 μM inhibited Aβ fibril formation better than 7e. MD simulation elucidated that the Aβ aggregation inhibitors in different concentrations represented different binding conformations throughout the entire or in one area of Aβ. MD showed the ligands in lower concentrations accumulate in an area of Aβ aggregations and separate one fibril from the aggregated Aβ. On the contrary, in higher concentrations, the ligands tend to be located through the entire Aβ.

Improving low‐temperature CO2 methanation by promoting Ni‐Al LDH‐derived catalysts with alkali metals

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Fossil fuels depletion and environmental impacts caused by greenhouse gas emissions such as CO2 are significant issues to secure the nature preservation within a sustainable economy. CO2 methanation is a promising process to mitigate CO2 emissions and reuse it to produce CH4, serving as fuel, chemical feedstock, and energy source. A series of LDH-derived Ni-Al catalysts promoted by Li, Mg, Ca, and La were prepared via the co-precipitation method. Characterization by N2 physisorption, X-ray diffraction (XRD) and photoelectron spectroscopy (XPS), as well as thermal techniques as temperature programmed reduction (H2-TPR), desorption (CO2-TPD, H2-TPD), and oxidation (TPO) analyses were performed. Low-temperature catalytic tests (200-400 °C) revealed that alkali metal modification improves performance even at 200 °C, where Ni55Ca11Al33 catalyst achieved 74% CO2 conversion with 100 % CH4 selectivity by enhancing basicity and metal-support interaction, high Ni dispersion and small crystallite sizes, providing proper sites to adsorb and activate CO2. Moreover, the catalysts presented excellent resistance to deactivation, maintaining high stability during 10 h on stream. These results prove that Ni-Al mixed oxides, LDH-derived catalysts performances can be further improved by incorporating alkali metals into less energy-spending, low-temperature CO2 methanation processes.

Metal‐free Photocatalytic [4+2] Annulation of Acrylamides with 2‐Benzyl‐2‐bromocarbonyls to Assemble Tetralin‐1‐carboxamides

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Comprehensive Summary

Tetralin-1-carboxamides are frequently incorporated in myriad medicinally important molecules. However, their existing synthetic routes not only suffer from some drawbacks such as tedious procedures, harsh reaction conditions, narrow substrate scope, low yields, and environmental problems, and are also based upon the elaboration of uneasily available non-linear tetralin derivatives. Herein we describe a metal- and additive-free visible light-induced [4+2] annulation of two simple linear starting materials, namely acrylamides and 2-benzyl-2-bromocarbonyls, through a cascade C(sp3)−Br/C(sp2)−H bond cleavage, double C−C bond formation, and aromatization sequence. The developed protocol provides a convenient, efficient, and green approach to a variety of tetralin-1-carboxamide derivatives with good functional group compatibility. Importantly, the resulting products could also undergo the LiCl-mediated mono-decarboxylative cyclization process to further furnish the architecturally novel bridged polycyclic imides with excellent cis-diastereoselectivities.

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Structure−Activity Relationship and Solubility Studies of N1‐Substituted Quinoxaline‐2,3‐diones as Kainate Receptor Antagonists

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Structure−Activity Relationship and Solubility Studies of N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists

This study presents the synthesis and structure-activity analysis of 21 new quinoxaline-2,3-dione derivatives as glutamate receptor ligands. Solubility studies focused on strategic structural modifications and resulted in increased solubility in water and alkaline conditions. These findings provide the potential for the development of active compounds with improved solubility.


Abstract

Kainate receptors are a class of ionotropic glutamate receptors that respond to the excitatory neurotransmitter glutamate in the central nervous system and play an important role in the development of neurodegenerative disorders and the regulation of synaptic function. In the current study, we investigated the structure- activity relationship of the series of quinoxaline-2,3-diones substituted at N1, 6, and 7 positions, as ligands of kainate homomeric receptors GluK1-3 and GluK5. Pharmacological characterization showed that all derivatives obtained exhibited micromolar affinity at GluK3 receptors with K i values in the range 0.1–4.4 μM range. The antagonistic properties of the selected analogues: N-(7-fluoro-6-iodo-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide, N-(7-(1H-imidazol-1-yl)-6-iodo-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide and N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(phenylethynyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide at GluK3 receptors, were confirmed by an intracellular calcium imaging assay. To correlate in vitro affinity data with structural features of the synthesized compounds and to understand the impact of the substituent in N1 position on ability to form additional protein-ligand interactions, molecular modeling and docking studies were carried out. Experimental solubility studies using UV spectroscopy detection have shown that 7-imidazolyl-6-iodo analogues with a sulfamoylbenzamide moiety at the N1 position are the best soluble compounds in the series, with molar solubility in TRISS buffer at pH 9 more than 3-fold higher compared to NBQX, a known AMPA/kainate antagonist.

Metabolism of (R)‐Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

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Metabolism of (R)-Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Praziquantel is an anthelmintic drug activating schistosome worms’ Transient Receptor Potential Melastatin ion channel for which the cyclohexyl moiety is a key pharmacophore and also the main site of CYP-mediated oxidative metabolism. While attempting to limit metabolism, the contribution to the overall activity of both the parent and the main metabolite of praziquantel in humans is discussed.


Abstract

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPMPZQ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPMPZQ, as well as serving as the primary site of oxidative metabolism which results in PZQ being a short-lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPMPZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.

E‐64c‐Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1’‐S2’ Area

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E-64c-Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1’-S2’ Area

With an optimized S1’-S2’ ligand, the E-64c-hydrazide derived compound efficiently inhibits the cysteine protease cathepsin C and thus suppresses the proteolytic activation of neutrophil elastase in the neutrophil precursor cell line U937.


Abstract

The zymogens of the neutrophil serine proteases elastase, proteinase 3, and cathepsin G are converted proteolytically into their pro-inflammatory active forms by the action of cathepsin C. The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E-64c-hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a n-butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1’-S2’ area was now investigated by a combinatorial approach, showing that Nle-tryptamide is a ligand superior to the initially used Leu-isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.

Screening and Synthesis of Tetrazole Derivatives that Inhibit the Growth of Cryptococcus Species

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Screening and Synthesis of Tetrazole Derivatives that Inhibit the Growth of Cryptococcus Species

The compounds 8-fluoro-7-methyl-5-(pyridin-2-yl)tetrazolo[1,5-c]pyrimidine and 5-(pyridin-2-yl)-8,9-dihydro-7H-cyclopenta[e]tetrazolo[1,5-c]pyrimidine belong to a novel class of antifungals. Both compounds with tetrazole backbone exhibit inhibitory activity that is equivalent or superior to those of conventional drugs on a weight-per-volume basis, with IC50 equalling 0.05 μM (0.012 μg mL−1) against each Cryptococcus species. Thus, tetrazole-backbone-containing compounds may be novel antifungal drugs with distinct mechanisms against cryptococcosis.antifungal agentsCandidaCryptococcushigh-throughput screeningtetrazoles


Abstract

Cryptococcosis has become a major health problem worldwide and caused morbidity and mortality in immunocompromised patients, especially those infected with human immunodeficiency virus (HIV). Despite the global distribution of cryptococcosis, the number and types of the available antifungals are limited, and the treatment outcomes in HIV patients are generally poor. In this study, we screened a compound library and identified one tetrazole derivative as an efficient inhibitor of Cryptococcus neoformans and Cryptococcus gattii. We further designed and synthesized a series of tetrazole derivatives and determined their structure-activity relationship, demonstrating that tetrazole backbone-containing compounds could be developed as novel antifungal drugs with distinct mechanisms against Cryptococcus spp. Our findings provide a starting point for novel target identification and structural optimization to develop a distinct class of therapeutics for patients with cryptococcosis.

Total Synthesis and Biological Investigation of Mindapyrroles A and B

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Total Synthesis and Biological Investigation of Mindapyrroles A and B

Antibiotics with novel and polypharmacological mechanisms of action are urgently needed. To this end, the total synthesis of mindapyrroles A and B was completed via a Friedel-Crafts alkylation. The antibacterial activity of these compounds was investigated against a panel of gram-positive and gram-negative pathogens, and their mechanism of action was determined to be different from their monomer pyoluteorin.


Abstract

In the search for antibacterial compounds that can overcome drug resistant species, molecules that enact novel or polypharmacological mechanisms of action (MoA) are needed. As a preliminary foray into molecules of this background, the total synthesis of mindapyrroles A and B was undertaken leveraging a biomimetic approach. Following their synthesis, they and their monomer pyoluteorin were tested against a range of pathogenic bacteria in minimum inhibitory concentration assays to confirm their activity. These molecules were then tested for their ability to disrupt membrane potential in S. aureus. Our findings indicate that pyoluteorin acts as a protonophore but the mindapyrroles do not. This work encapsulates the first total synthesis of mindapyrrole B and the second total synthesis of mindapyrrole A in 11 % and 30 % overall yields, respectively. It also provides insights into the antibacterial properties and different MoAs between the monomer and dimers.

High‐Contrast and Fast‐Removable 19F‐MRI Labels with Perfluoro‐tert‐Butyl Substituents

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High-Contrast and Fast-Removable 19F-MRI Labels with Perfluoro-tert-Butyl Substituents

High-contrast and fast-removable fluorinated agents C10F18H4O2 and C11F18H6 for the 19F MRI method were designed. The synthesis of these compounds is not complicated. The emulsions with these substances were developed, and in vivo MRI studies in laboratory rats were carried out. The substances are non-toxic, and they are excreted from the living organism in ~30 days.


Abstract

19F MRI is a unique technique for tracking and quantifying the indicator (19F-MRI label) in vivo without the use of ionizing radiation. Here we report new 19F-MRI labels, which are compounds with perfluoro-tert-butyl groups: 1,2-bis(perfluoro-tert-butoxy)ethane (C10F18H4O2) and 1,3-bis(perfluoro-tert-butyl)propane (C11F18H6). Both substances contain 18 equivalent 19F atoms, constituting 68.67 % and 71.25 % of the molecule, respectively. The emulsions with 19F molecules were prepared and used in 19F MRI studies in laboratory rats in vivo. The substances demonstrated high contrast properties, good biological inertness and the ability to be rapidly eliminated from the body. We showed that at a dose of 0.34 mg/g of body weight in rats, the time for complete elimination of C10F18H4O2 and C11F18H6 is ∼30 days. The results turned out to be promising for the use of the presented compounds in 19F MRI applications, especially since they are quite easy to synthesize.