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Neuromuscular blocking agents (NMBAs) are widely administered during anethesia to prevent the patient from moving and optimize surgical conditions. Timely reversal of the muscle relaxation state induced by NMBAs at the end of surgery is necessary to recover autonomous respiration and muscle function. Herein, an extended biphen[3]arene carboxylate (ExBP3C) was designed and synthesized by a supramolecular sequestration approach as a reversal agent with high efficiency and generality against several representative NMBAs. ExBP3C exhibited robust host-guest complexation toward atracurium, rocuronium, vecuronium, pancuronium, and gallamine with an association constant of up to 10 8 M -1 . A series of in vitro and in vivo safety tests preliminarily demonstrated that this synthetic macrocycle had good biocompatibility. Compared to sugammadex, post-treatment by an equivalent dose of ExBP3C could produce a more efficient reversal function. Additionally, a single dose of such a reversal agent was also able to completely recover overdose atracurium-induced heart rate abnormalities within 2 min.

The accumulation of perfluorocarboxylic acids (PFCAs) in environment and foods represents a significant threat to public health due to the long-term ingestion of contaminated food. This study introduces a novel adsorbent, the hierarchical porous hydrophilic molecularly imprinted resin (HPHMIR), which was synthesized by integrating molecular imprinting techniques with hydrophilic resins. The HPHMIR, characterized by its extensive mesoporous structure (average pore width ∼9.71 nm) and favorable imprinting factors (2.6-5.0), facilitates the effective adsorption of PFCAs from complex matrices through multiple interaction mechanisms, including hydrogen bonding and electrostatic interactions. This innovative material was employed in a 96-well plate format for solid-phase extraction (SPE), and combined with LC-MS/MS, a high-throughput method for the determination of PFCAs in milk was developed. The proposed method demonstrated exceptional performance, including excellent linearity (0.48-240 ng mL -1 ; r ≥ 0.9986), low detection limits (0.04-0.11 ng mL -1 ), high precision (relative standard deviation ≤ 9.9 %), and satisfactory recovery (75.7-118.1 %). These results highlight the efficacy of the method in extracting trace levels of PFCAs from complicated sample matrices, presenting a promising alternative for monitoring PFCA contamination and advancing public health standards., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC 50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC 50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Understanding the adsorption behavior of asphaltene molecules on the surfaces of oil reservoir solids is essential for optimizing oil recovery processes. This study employed molecular dynamics simulations to investigate the adsorption behavior of oil droplets composed of charged and neutral asphaltenes on silica surfaces. The results revealed that oil droplet containing anionic asphaltene molecules were more likely to adsorb onto silica surfaces and exhibited greater resistance to detachment compared to oil droplet containing neutral asphaltene molecules. Specifically, anionic asphaltene molecules tended to accumulate at the oil-water-silica interface, whereas neutral asphaltene molecules primarily adsorbed near the oil-water interface. These findings provide valuable insights into the differing adsorption dynamics of charged and neutral asphaltene molecules on silica surfaces., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abiraterone (Abi), an effective cytochrome oxidase P450 C17 (CYP17) inhibitor, inhibits androgen synthesis in testes, adrenal glands, and prostate tumors. However, their low bioavailability and dissolution rate due to their poor solubility and toxic side effects have hindered their clinical applications. In this study, water-soluble and injectable Abi derivatives were developed by introducing amino polycarboxylic acids into Abi, and their antiproliferation effects in vitro, mechanism of action, antitumor activities in vivo, pharmacokinetics, and toxicity were investigated. Compared to Abi, the water-soluble derivative Abi-DTPA exhibited excellent antitumor activity in vitro and in vivo. It decreased cell migration, invasion, and mitochondrial membrane potential. A mechanistic study revealed that it still targeted the CYP17 enzyme and increased the expression levels of apoptosis-related proteins, including cleaved caspase 9, cleaved PARP, and cleaved caspase 3. Abi-DTPA was the main form in the plasma and exhibited lower toxicity after intravenous administration. These findings suggest that Abi-DTPA can be used as a novel injectable anti-prostate cancer agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a K D2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Enrofloxacin (EFX) is a third-generation synthetic fluoroquinolone with a broad spectrum of antibacterial activity but suffers from low water solubility, affecting its bioavailability. This study attempts to enhance the physicochemical and biological properties of enrofloxacin by converting it into multicomponent forms using crystal engineering concepts. Cocrystallization of enrofloxacin with isomeric pyridine-2,n-dicarboxylic acids (n = 3,4,5,6) resulted in four new crystalline salts (1:1): EFX·Py2,3DCA, EFX·Py2,4DCA, EFX·Py2,5DCA·H 2 O and EFX·Py2,6DCA·H 2 O; two of these are monohydrates. The protonation of the nitrogen atom of the piperazine moiety and the presence of crystallization water molecules were confirmed by single-crystal X-ray diffraction and Fourier transform infrared spectroscopy. Thermogravimetric analysis provided information on the thermal behaviour of multicomponent forms. The biological studies showed that the obtained salts are characterized by high antibacterial activity against Gram-positive and Gram-negative bacteria, and their haemolytic activity is low. The new salts demonstrate significantly greater solubility in water compared to the parent drug, along with enhanced antibacterial activity; hence, pyridinedicarboxylic acids appear to be efficient cocrystallizing agents for improving the efficacy of pharmaceutical ingredients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The creatine transporter-1 (CRT-1/SLC6A8) maintains the uphill transport of creatine into cells against a steep concentration gradient. Cellular creatine accumulation is required to support the ATP-buffering by phosphocreatine. More than 60 compounds have been explored in the past for their ability to inhibit cellular creatine uptake, but the number of active compounds is very limited. Here, we show that all currently known inhibitors are full alternative substrates. We analyzed their structure-activity relationship for inhibition of CRT-1 to guide a rational approach to the synthesis of novel creatine transporter ligands. Measurements of both inhibition of [ 3 H]creatine uptake and transport associated currents allowed for differentiating between full and partial substrates and true inhibitors. This combined approach led to a refined understanding of the structural requirements for binding to CRT-1, which translated into the identification of three novel compounds - i.e., compound 1 (2-( N -benzylcarbamimidamido)acetic acid), MIPA572 (=carbamimidoylphenylalanine), and MIPA573 (=carbamimidoyltryptophane) that blocked CRT-1 transport, albeit with low affinity. In addition, we found two new alternative full substrates, namely MIPA574 (carbamimidoylalanine) and GiDi1257 (1-carbamimidoylazetidine-3-carboxylic acid), which was superior in affinity to all known CTR-1 ligands, and one partial substrate, namely GiDi1254 (1-carbamimidoylpiperidine-4-carboxylic acid). SIGNIFICANCE STATEMENT: The creatine transporter-1 (CRT-1) is required to maintain intracellular creatine levels. Inhibition of CRT-1 has been recently proposed as a therapeutic strategy for cancer, but pharmacological tools are scarce. In fact, all available inhibitors are alternative substrates. We tested existing and newly synthesized guanidinocarboxylic acids for CRT-1 inhibition and identified three blockers, one partial and two full substrates of CRT-1. Our results support a refined structural understanding of ligand binding to CRT-1 and provide a proof-of-principle for blockage of CRT-1., (Copyright © 2024 by The Author(s).)

The molecule of 2-Biphenyl Carboxylic Acid (2BCA), which contains peculiar features, was explored making use of density functional theory (DFT) and experimental approaches in the area of quantum computational research. The optimised structure, atomic charges, vibrational frequencies, electrical properties, electrostatic potential surface (ESP), natural bond orbital analysis and potential energy surface (PES) were obtained applying the B3LYP approach with the 6-311++ G (d,p) basis set.. The 2BCA molecule was examined for possible conformers using a PES scan. The methods applied for spectral analyses included FT-IR, FT-RAMAN, NMR, and UV-Vis results. Vibrational frequencies for all typical modes of vibration were found using the Potential Energy Distribution (PED) data. The UV-Vis spectrum was simulated using the TD-DFT technique, which is also seen empirically. The Gauge-Invariant Atomic Orbital (GIAO) approach was employed to model and study the 13 C and 1 H NMR spectra of the 2BCA molecule in a CDCL3 solution. The spectra were then exploited experimentally to establish their chemical shifts. To predict the donor and acceptor interaction, the NBO analysis was used. The electrostatic potential surface was employed to anticipate the locations of nucleophilic and electrophilic sites. Hirshfeld surfaces and their related fingerprint plots are exploited for the investigation of intermolecular interactions. Reduced Density Gradient (RDG) helps to measure and illustrate electron correlation effects, offering precise insights into chemical bonding, reactivity, and the electronic structure of 2BCA. According to Lipinski and Veber's drug similarity criteria, 2BCA exhibits the typical physicochemical and pharmacokinetic properties that make it a potential oral pharmaceutical candidate. According to the findings of a molecular docking study, the 2BCA molecule has promise as a treatment agent for the Nipah virus (PDB ID: 6 EB9), which causes severe respiratory and neurological symptoms in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Single walled carbon nanotubes (SWCNT) have recently been demonstrated as modular, near-infrared (nIR) probes for reporting hydrolase activity; however, these have been limited to naturally amphipathic substrate targets used to noncovalently functionalize the hydrophobic nanoparticles. Many relevant substrate targets are hydrophobic (such as recalcitrant biomass) and pose a challenge for modular functionalization. In this work, a facile mechanochemistry approach was used to couple insoluble substrates, such as lignin, to SWCNT using l-lysine amino acid as a linker and tip sonication as the mechanochemical energy source. The proposed coupling mechanism is ion pairing between the lysine amines and lignin carboxylic acids, as evidenced by FTIR, NMR, SEM, and elemental analyses. The limits of detection for the lignin-lysine-SWCNT (LLS) probe were established using commercial enzymes and found to be 0.25 ppm (volume basis) of the formulated product. Real-world use of the LLS probes was shown by evaluating soil hydrolase activities of soil samples gathered from different corn root proximal locations and soil types. Additionally, the probes were used to determine the effect of storage temperature on the measured enzyme response. The modularity of this mechanochemical functionalization approach is demonstrated with other substrates such as zein and 9-anthracenecarboxylic acid, which further corroborate the mechanochemical mechanism.

Many chiral carboxylic acids with α-amino, α-hydroxyl, and α-methyl groups are concurrently present in mammals establishing unique molecular phenotypes and multiple biological functions, especially host-microbiota symbiotic interactions. Their chirality-resolved simultaneous quantification is essential to reveal the biochemical details of physiology and pathophysiology, though challenging with their low abundances in some biological matrices and difficulty in enantiomer resolution. Here, we developed a method of the chirality-resolved metabolomics with sensitivity-enhanced quantitation via probe-promotion (Met-SeqPro) for analyzing these chiral carboxylic acids. We designed and synthesized a hydrazide-based novel chiral probe, ( S )-benzoyl-proline-hydrazide ( S BPH), to convert carboxylic acids into amide diastereomers to enhance their retention and chiral resolution on common C 18 columns. Using the d 5 - S BPH-labeled enantiomers as internal standards, we then developed an optimized ultrahigh-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous quantification of 60 enantiomers of 30 chiral carboxylic acids in one run. This enantiomer-resolved method showed excellent sensitivity (LOD < 4 fmol-on-column), linearity ( R 2 > 0.992), precision (CV < 15%), accuracy (|RE| < 20%), and recovery (80-120%) in multiple biological matrices. With the method, we then quantified 60 chiral carboxylic acids in human urine, plasma, feces, and A549 cells to define their metabolomic phenotypes. This provides basic data for human phenomics and a promising tool for investigating the mammal-microbiome symbiotic interactions.

Short-chain carboxylic acids (SCCAs) that are naturally produced by microbial fermentation play an essential role in delaying microbial spoilage. SCCAs are structurally diverse, but only a few of them are routinely used in food biopreservation. This study investigated the effects of environmental pH and intrinsic properties of 21 structurally different SCCAs on the antimicrobial and antibiofilm activity against Salmonella enterica . Inhibition of SCCA toward planktonic and biofilm growth of S. enterica was higher in an acidic environment (pH 4.5) that is common in fermented products, and for SCCA that possessed both a high acid dissociation strength (pK a ) (>4.0) and a positive hydrophobicity [octanol/water partition coefficient (log K ow )]. Crotonic and caproic acids were identified as SCCAs with potential as biopreservatives even at near-neutral pH. SCCA with hydrophilic groups such as lactic acid did not inhibit S. enterica at concentrations up to 50 mM, while SCCA with benzene or methyl groups or a double bond prevented S. enterica growth and biofilm formation. Stimulation of biofilm formation was observed for formic, acetic, and propionic acid close to the minimum inhibitory concentration to reduce 50% of cell density (MIC 50 ) of planktonic cells, and for citric and isocitric acid with an MIC 50 of ≥50 mM. The presence of low concentrations of formic and propionic acids during biofilm formation conferred protection during eradication possibly due to a pre-adaptation effect, yet two consecutive acid treatments were successful in eradicating biofilms if the first acid treatment was two- to threefold of the MIC 50 .IMPORTANCEThis study provides a systematic comparison on the antimicrobial and antibiofilm activity of more than 20 structurally different SCCAs against a common food pathogen. We tested the antimicrobial activity at controlled pH and identified the structure-dependent antimicrobial effects of SCCA without the confounding influence of acidification. The combined effect of pK a and log K ow was identified as an important feature that should be considered when deciding for a specific SCCA in the application as antimicrobial. Our results imply that additional phenomena such as the use of SCCA as substrate and cellular pre-adaption effects have to be taken into consideration. We finally present a two-step treatment as an efficient approach to eradicate biofilms, which can be applied for the disinfection of contact surfaces and manufacturing equipment. Results obtained here can serve as guidelines for application of SCCA to avoid the growth of food pathogens and/or to develop biopreserved food systems., Competing Interests: The authors declare no conflict of interest.

Carbon dioxide (CO 2 ) is an economically viable and abundant carbon source that can be incorporated into compounds such as C2-carboxylated 1,3-azoles relevant to the pharmaceutical, cosmetics, and pesticide industries. Of the 2.4 million commercially available C2-unsubstituted 1,3-azole compounds, less than 1 % are currently purchasable as their C2-carboxylated derivatives, highlighting the substantial gap in compound availability. This availability gap leaves ample opportunities for exploring the synthetic accessibility and use of carboxylated azoles in bioactive compounds. In this study, we analyze and quantify the relevance of C2-carboxylated 1,3-azoles in small-molecule research. An analysis of molecular databases such as ZINC, ChEMBL, COSMOS, and DrugBank identified relevant C2-carboxylated 1,3-azoles as anticoagulant and aroma-giving compounds. Moreover, a pharmacophore analysis highlights promising pharmaceutical potential associated with C2-carboxylated 1,3-azoles, revealing the ATP-sensitive inward rectifier potassium channel 1 (K ATP ) and Kinesin-like protein KIF18 A as targets that can potentially be addressed with C2-carboxylated 1,3-azoles. Moreover, we identified several bioisosteres of C2-carboxylated 1,3-azoles. In conclusion, further exploration of the chemical space of C2-carboxylated 1,3-azoles is recommended to harness their full potential in drug discovery and related fields., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The development of high-performance media for protein adsorption in bio-purification is highly desired, particularly in biological pharmaceuticals. In this study, we demonstrate a simple, versatile and mild strategy to construct a nanofibrous aerogel (NFA)-based adsorption media for protein purification. Pyromellitic dianhydride (PMDA) was selected to in-situ graft onto poly(ethylene-co-vinyl alcohol) (PE-co-PVA) nanofibers in aerogels through liquid phase grafting. The obtained PE-co-PVA/PMDA NFAs (PPNAs) possessed superb underwater elasticity, compression fatigue resistance and shape-memory performance. With an open porous network, abundant adsorption ligands, and surface hydrophilicity, the PPNAs exhibited a significant adsorption capacity of 1019.71 mg/g and a short equilibrium time of 3.0 h, surpassing that of commercial and reported nanofiber-based adsorbents. Additionally, the PPNAs demonstrated good dynamic adsorption performance for protein driven solely by gravity. Furthermore, the PPNAs showed reusability, selectivity, acid and alkaline resistance, and practical potential of extracting lysozyme form egg white solution. The successful scale-up of such aerogel-based adsorbents can open up new way for the development and design of next-generation protein adsorption media for bio-purification applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study proposes an integrated process chain to upconcentrate short-chain carboxylic acids (SCCA) like acetic, propionic, and butyric acid, produced from anaerobic fermentation of the organic fraction of municipal solid waste. The starting point is the residual biogas, which is produced from the anaerobic digestion of the solid fraction obtained after the acid fermentation. Using this biogas energy, integrated multiple-effect evaporator scenarios with varying SCCA initial concentrations from 10 to 40 g/L in the liquid fraction were simulated in Aspen Plus®. Using four-effects and starting from 20 g/L, SCCA can be upconcentrated to 526 g/L with only minor acids loss. This process requires 9.8 kWh energy/kg SCCA produced, which was provided by the biogas generated from the solid residue post-digestion. Also, the accuracy of the simulation results across different pressure ranges has been confirmed through the validation of the input model used in Aspen Plus®. The carbon footprint of this process was 1.24 kg CO 2 -eq./kg SCCA produced, which was 50% lower than the existing processes producing fossil-based SCCA. A techno-economic assessment have also been performed for different evaporator configurations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The success of a classic inorganic coordination compound, Cisplatin, cis-[Pt(NH 3 ) 2 Cl 2 ], as the first anticancer metallodrug started a field of research dedicated to discovering coordination compounds with antitumor activity, encompassing various metals. Among these, copper complexes have emerged as interesting candidates to develop drugs to treat cancer. In this work, mixed ligand complexes of Cu(II) with diimines (phenanthroline or 4-methylphenanthroline) and 3-(4-hydroxyphenyl)propanoate, phenylcarboxylate or phenylacetate were synthesized. They were characterized in the solid state, including a new crystal structure of [Cu 2 (3-(4-hydroxyphenyl)propanoate) 3 (phenanthroline) 2 ]Cl·H 2 O. The obtained complexes presented a variety of stoichiometries. In solution, complexes were partially dissociated in the corresponding Cu-diimine complex. The complexes bound to the DNA by partial intercalation and groove binding, as assessed by Circular Dichroism, relative viscosity change and UV-Vis titration. The cytotoxicity of the complexes was determined in vitro on MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (breast nontumoral), A549 (human lung epithelial carcinoma), and MRC-5 (human nontumoral lung epithelial cells), finding an activity higher than that of Cisplatin, although with less selectivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Understanding carboxylate transport through lipid membranes under physiological conditions is critical in biomedicine and biotechnology, as it allows for the emulation of biological membrane functions and can enhance the absorption of hydrophobic carboxylate-based drugs. However, the structural diversity of carboxylates has made it challenging to study their transport, and the limited available examples do not provide a comprehensive understanding of the role of the organic moiety in this process. Here, we present an in-depth analysis of the diffusion and transport of various aliphatic and aromatic carboxylates into liposomes. We assessed the influence of their size, number of carboxylate groups, and presence of hydroxyl groups. Our findings from fluorescence assays, using lucigenin and HPTS as probes, revealed that most carboxylates can spontaneously diffuse into liposomes in their protonated state, facilitated by the efflux of HNO 3 when using NaNO 3 solutions at pH 7. The Cl-ISE assay showed chloride/carboxylate exchange by a synthetic anion transporter. Clear trends were observed when the organic moiety was systematically varied, with a particular enhancement of anion transport by the presence of hydroxyl groups in the aromatic carboxylates. Our findings provide insights into the processes by which carboxylates can enter liposomes, which can contribute to understanding the transport of other biologically relevant organic anions.

Carboxylesterases serve as potent biocatalysts in the enantioselective synthesis of chiral carboxylic acids and esters. However, naturally occurring carboxylesterases exhibit limited enantioselectivity, particularly toward ethyl 3-cyclohexene-1-carboxylate (CHCE, S1), due to its nearly symmetric structure. While machine learning effectively expedites directed evolution, the lack of models for predicting the enantioselectivity for carboxylesterases has hindered progress, primarily due to challenges in obtaining high-quality training datasets. In this study, we devise a high-throughput method by coupling alcohol dehydrogenase to determine the apparent enantioselectivity of the carboxylesterase AcEst1 from Acinetobacter sp. JNU9335, generating a high-quality dataset. Leveraging seven features derived from biochemical considerations, we quantitively describe the steric, hydrophobic, hydrophilic, electrostatic, hydrogen bonding, and π-π interaction effects of residues within AcEst1. A robust gradient boosting regression tree model is trained to facilitate stereodivergent evolution, resulting in the enhanced enantioselectivity of AcEst1 toward S1. Through this approach, we successfully obtain two stereocomplementary variants, DR3 and DS6, demonstrating significantly increased and reversed enantioselectivity. Notably, DR3 and DS6 exhibit utility in the enantioselective hydrolysis of various symmetric esters. Comprehensive kinetic parameter analysis, molecular dynamics simulations, and QM/MM calculations offer insights into the kinetic and thermodynamic features underlying the manipulated enantioselectivity of DR3 and DS6., (© 2024. The Author(s).)

Herein, the electrochemical sensing efficacy of carboxylic acid functionalized multiwalled carbon nanotubes (C-MWCNT) intertwined with coexisting phases of gadolinium monosulfide (GdS) and gadolinium oxide (Gd 2 O 3 ) nanosheets is explored for the first time. The nanocomposite demonstrated splendid specificity for nonenzymatic electrochemical detection of uric acid (UA) in biological samples. It was synthesized using the coprecipitation method and thoroughly characterized. The presence of functional groups and disorder in the as-synthesized nanocomposite are confirmed using Fourier transform infrared spectroscopy and Raman spectroscopy. Furthermore, field emission scanning electron microscopy, high-resolution transmission electron microscope, X-ray powder diffraction, and X-ray photoelectron spectroscopy provides a clear understanding of the morphology, coexisting phases, and elemental composition of the as-synthesized nanocomposites. The differential pulse voltammetry technique was utilized to elaborate the electrochemical sensing of UA using a GdS-Gd 2 O 3 /C-MWCNT modified glassy carbon electrode (GCE), The sensor showed an enhanced current response by more than 2-fold compared to bare GCE. Also, the sensor's performance was further improved by dispersing the nanocomposite in an ionic liquid with the exceptional reproducibility (SD = 0.0025, n = 3). The fabricated UA sensor GdS-Gd 2 O 3 /C-MWCNT/IL/GCE demonstrated a wide linear detection range from 0.5-30 μM and 30-2000 μM, effectively covering the entire physiological range of UA in biological fluids with a limit of detection (LOD) of 0.380 μM (+3SD of blank) and a sensitivity of 356.125 μA mM -1 cm -2 . Moreover, the electrodes exhibited storage stability for 2 weeks with decrease in zero-day current by only 4.5%. The sensor was validated by quantifying UA in 12 unprocessed clinical human urine and serum samples, and its comparison with the gold standard test yielded remarkable results ( p < 0.05). Hence, the proposed nonenzymatic electrochemical UA sensor is selective, sensitive, reproducible, and stable, making it reliable for point-of-care diagnostics.

α-Amino esters are precursors to noncanonical amino acids used in developing small-molecule therapeutics, biologics, and tools in chemical biology. α-C-H amination of abundant and inexpensive carboxylic acid esters through nitrene transfer presents a direct approach to α-amino esters. Methods for nitrene-mediated amination of the protic α-C-H bonds in carboxylic acid esters, however, are underdeveloped. This gap arises because hydrogen atom abstraction (HAA) of protic C-H bonds by electrophilic metal-nitrenoids is slow: metal-nitrenoids preferentially react with polarity-matched, hydridic C-H bonds, even when weaker protic C-H bonds are present. This study describes the discovery and evolution of highly stable protoglobin nitrene transferases that catalyze the enantioselective intermolecular amination of the α-C-H bonds in carboxylic acid esters. We developed a high-throughput assay to evaluate the activity and enantioselectivity of mutant enzymes together with their sequences using the Every Variant Sequencing (evSeq) method. The assay enabled the identification of enantiodivergent enzymes that function at ambient conditions in Escherichia coli whole cells and whose activities can be enhanced by directed evolution for the amination of a range of substrates.

While remarkable progress has been made in the development of peptide medicines, many problems related to peptide synthesis remain unresolved. Previously, we reported electrochemical peptide synthesis using a phosphine as a potentially recyclable coupling reagent. However, there was room for improvement from the point of view of reaction efficiency, especially in the carboxylic acid activation step and the peptide bond formation step. To overcome these challenges, we searched for the optimal phosphine. Among phosphines with various electronic properties, we found that electron-rich triaryl phosphines improved the reaction efficiency. Consequently, we successfully performed electrochemical peptide synthesis on sterically hindered and valuable amino acids. We also synthesized oligopeptides that were challenging with our previous method. Finally, we examined the effect of substituents on the phosphine cations, and gained some insights into reactivity, which will aid researchers designing reactions involving phosphine cations., (© 2024 Wiley-VCH GmbH.)

Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C 60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C 60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Transketolase (TKL; EC 2.2.1.1) is a highly promising potential target for herbicidal applications. To identify novel TKL inhibitors, we designed and synthesized a series of 3-oxopropionamide-1-methylpyrazole carboxylate analogues and assessed their herbicidal activities. Ethyl 3-((1-((2,4-dichlorophenyl)amino)-1-oxopropan-2-yl)oxy)-1-methyl-1 H -pyrazole-5-carboxylate ( D15 ) and ethyl 1-methyl-3-((1-oxo-1-((thiophen-2-ylmethyl)amino)propan-2-yl)oxy)-1 H -pyrazole-5-carboxylate ( D20 ) exhibited superior growth inhibition activities against both the root and stem of Amaranthus retroflexus ( A. retroflexus ) compared to nicosulfuron and mesotrione. Additionally, D15 achieved an inhibition rate of more than 90% against the roots and stems of Digitaria sanguinalis ( D. sanguinalis ), outperforming the four control agents at a concentration of 200 mg/L using the small cup method. In the pre-emergence herbicidal activity test, D15 effectively inhibited D. sanguinalis by more than 90% at 150 g ai/ha, surpassing the efficacy of the control, mesotrione. Conversely, in the postemergence herbicidal activity test, D20 exhibited efficient inhibition of A. retroflexus by more than 90% at 150 g ai/ha, outperforming the control agents nicosulfuron, mesotrione, and metamifop. The results of the TKL enzyme activity test showed that the IC 50 values of compounds D15 and D20 were 0.384 and 0.655 mg/L, respectively, which were close to those of the control agents. Furthermore, molecular docking and molecular dynamics simulation studies revealed that D15 and D20 interacted favorably with the TKL of Setaria viridis . Such findings highlight the promising potential of D15 and D20 as lead TKL inhibitors for the optimization of new herbicides.

The higher prevalence of cancer and the unmet need for antioxidant/anti-inflammatory chemotherapeutic compounds with little side effect are of utmost importance. In addition, the increased likelihood of failure in clinical trials along with increasing development costs may have diminished the range of choices among newer drugs for clinical use. This has dictated the necessity to seek out novel medications by repurposing as it needs less time, effort, and resources to explore new uses of a current or unsuccessful medication. In this study, we examined the biological activity of 10 potential quinoline derivatives. Given the half-maximal inhibitory concentration (IC 50 value) in lipopolysaccharide (LPS) induced inflammation of RAW264.7 mouse macrophages, all commercial FQs and selected quinolines (quinoline-4-carboxlic and quinoline-3-carboxylic acids) exerted impressively appreciable anti-inflammation affinities versus classical NSAID indomethacin without related cytotoxicities in inflamed macrophages. Conversely, all 14 tested compounds lacked antioxidative DPPH radical scavenging capacities as compared to ascorbic acid. Gemifloxacin, considerably unlike markets FQs, indomethacin and quinoline derivatives, exerted exceptional and differential antiproliferation propensities in colorectum SW480, HCT116, and CACO2, pancreatic PANC1, prostate PC3, mammary T47D, lung A375, and melanoma A549 adherent monolayers using the sulforhodamine B colorimetric method versus antineoplastic cisplatin. All quinoline derivatives and gemifloxacin alike, but not levofloxacin, ciprofloxacin, or indomethacin, displayed substantially selective viability reduction affinities in prolonged tumor incubations of cervical HELA and mammary MCF7 cells. Specifically kynurenic acid (hydrate), quinoline-2-carboxylic acid, quinoline-4-carboxylic acid, quinoline-3-carboxylic acid, and 1,2-dihydro-2-oxo-4-quinoline carboxylic acids possessed the most remarkable growth inhibition capacities against mammary MCF7 cell line, while quinoline-2-carboxylic acid was the only quinoline derivative with significant cytotoxicity on cervical HELA cancer cells. It is highly speculated that chelation with divalent metals via co-planarity with close proximity of the COOH and the N atom could have the potential molecular mechanism for optimally promising repurposed pharmacologies. Conclusively, this study revealed the considerably profound repurposed duality of cytotoxicity and anti-inflammation pharmacologies of quinoline derivatives. Activity-guided structural modifications of the present nuclear scaffolds can be inherently linked to the betterment and enhancement of their repurposed pharmacologies., (© 2024 John Wiley & Sons A/S.)

Oil sands process-affected water (OSPW), generated by surface mining in Canada's oil sands, require treatment of environmentally persistent dissolved organic compounds before release to the watershed. Conventional chemical and mechanical treatments have not proved suitable for treating the large quantities of stored OSPW, and the biological recalcitrance of some dissolved organics may not be adequately addressed by conventional passive treatment systems. Previous work has evaluated photocatalytic treatment as a passive advanced oxidation process (P-AOP) for OSPW remediation. This work expands upon this prior research to further characterize the effects of water chemistry on the treatment rate and detoxification threshold. Under artificial sunlight, buoyant photocatalysts (BPCs) detoxified all OSPW samples within 1 week of treatment time with simultaneous treatment of polycyclic aromatic hydrocarbons, naphthenic acid fraction components (NAFCs), and un-ionized ammonia. Overall, these results further demonstrate passive photocatalysis as an effective method for treatment of OSPW contaminants of potential concern (COPCs)., Competing Interests: Declaration of competing interest T.M.C.L., Z.W.Y., and F.G. declare ownership stakes in H2nanO Inc., a company with financial interest in the subject matter of this work, as well as inventorship on a BPC patent application (PCT/IB2017/056505, US16/343,298) assigned to H2nanO. T.P., A.B., and T.W. work for COSIA member companies that produce materials and waste streams that are represented by the ones reported in this research. The other authors declare no potentially competing conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities 1,2 . A notable natural example is the fatty acid photodecarboxylase, which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons 3 . Here we report a method for the design of a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, rather than reliance on cofactor excitation 4 . Iminium ions 5 , transiently generated from enals within the active site of an engineered class I aldolase 6 , can absorb violet light and function as single-electron oxidants. Activation of chiral carboxylic acids, followed by decarboxylation, generates two radicals that undergo stereospecific cross-coupling, yielding products with two stereocentres. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the ability of the active site to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the long-standing problem of rapid racemization of chiral radicals. The resulting 'memory of chirality' scenario 7 is a rarity in enantioselective radical chemistry., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Even if the acids composition and their role in coffee still need to be clarified, acidity is one of the main sought-after features in coffee and it is becoming one of the main quality markers. Hence, the aim of this paper was to evaluate the main parameters influencing coffee acidity with a focus on carboxylic acids. To the best of our knowledge, this is the first study regarding filter coffee prepared from specialty and mainstream coffee, differently roasted and through eight diverse extraction methods. Coffee cup chemical composition in terms of organic and chlorogenic acids, caffein and physicochemical parameters were correlated with perceived sourness and mouthfeel to better understand the influence of extracted compounds on the final beverage acidity. Statistical tools revealed that a major impact of chlorogenic acids emerged in pH and titratable acidity, while the sensorial sourness appeared more correlated with organic acids concentration. Thus, these findings suggests that organic acids could be potential predictors of beverage perceived acidity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Transketolase (TKL, EC 2.2.1.1) is a key enzyme in the pentose phosphate pathway and Calvin cycle, and is expected to act as a herbicidal site-of-action. On the basis of TKL, we designed and synthesized a series of 1-oxy-propionamide-pyrazole-3-carboxylate analogues and evaluated their herbicidal activities., Results: Methyl 1-methyl-5-((1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)oxy)-1H-pyrazole-3-carboxylate (C23) and methyl 1-methyl-5-((1-oxo-1-((perfluorophenyl)amino)propan-2-yl)oxy)-1H-pyrazole-3-carboxylate (C33) were found to provide better growth-inhibition activities against Digitaria sanguinalis root than those of nicosulfuron, mesotrione and pretilachlor at 200 mg L -1 using the small-cup method. These compounds were also identified as promising compounds in pre-emergence and postemergence herbicidal-activity experiments, with relatively good inhibitory effects toward Amaranthus retroflexus and D. sanguinalis at 150 g ai ha -1 . In addition, enzyme inhibition assays and molecular docking studies revealed that C23 and C33 interact favourably with SvTKL (Setaria viridis TKL)., Conclusion: C23 and C33 are promising lead TKL inhibitors for the optimization of new herbicides. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Refractory naphthenic acids (NAs) are among the primary toxic compounds in oil sands process water (OSPW), a matrix with a complex chemical composition that poses challenges to its remediation. This study evaluated the effectiveness of calcium peroxide (CaO 2 ) combined with solar radiation (solar/CaO 2 ) as an advanced water treatment process for degrading model NAs (1,2,3,4-tetrahydronaphthalene-2-carboxylic acid, pentanoic acid, and diphenylacetic acid) in synthetic water (STW) and provide preliminary insights in treating real OSPW. Solar light and CaO 2 acted synergistically to degrade target NAs in STW (>67 of synergistic factor) following a pseudo-first-order kinetic (R 2 ≥ 0.95), with an optimal CaO 2 dosage of 0.1 g L -1 . Inorganic ions and dissolved organic matter were found to hinder the degradation of NAs by solar/CaO 2 treatment; however, the complete degradation of NAs was reached in 6.7 h of treatment. The main degradation mechanism involved the generation of hydroxyl radicals ( • OH), which contributed ∼90% to the apparent degradation rate constant (K), followed by H 2 O 2 (4-5%) and 1 O 2 (0-5%). The tentative transformation pathways of three NAs were proposed, confirming an open-ring reaction and resulting in short-chain fatty acid ions as final products. Furthermore, a reduction in acute microbial toxicity and genotoxic effect was observed in the treated samples, suggesting that solar/CaO 2 treatment exhibits high environmental compatibility. Furthermore, the solar/CaO 2 system was successfully applied as a preliminary step for real-world applications to remove natural NAs, fluorophore organic compounds, and inorganic components from OSPW, demonstrating the potential use of this technology in the advanced treatment of oil-tailing-derived NAs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Alzheimer's disease (AD) is a neurological disorder that progresses gradually but irreversibly leading to dementia and is difficult to prevent and treat. There is a considerable time window in which the progression of the disease can be intervened. Scientific advances were required to help the researchers to identify the effective methods for the prevention and treatment of disease. This research was designed to investigate potential mediators for the remedy of AD, five new carboxylate amide zinc complexes (AAZ9-AAZ13) were synthesized and characterized by spectroscopic and physicochemical techniques. The biological evaluation was carried out based on the cholinesterase inhibitory mechanism. The preparation methodology provided the effective synthesis of targeted moieties. The in vitro pharmacological activities were evaluated involving AChE/BChE inhibition and antioxidant potential. All synthesized compounds displayed activity against both enzymes in higher or comparable to the standard drug Galantamine, a reversible inhibitor but the results displayed by compound AAZ10 indicated IC 50 of 0.0013 µM (AChE) and 0.061 µM (BChE) as high values for dual AChE/BChE inhibition with potent anti-oxidant results. Structure activity relationship (SAR) indicated that the potent activity of compound AAZ10 appeared due to the presence of nitro clusters at the ortho position of an aromatic ring. The potent synthesized compound AAZ10 was also explored for the in-vivo Anti-Alzheimer activity and anti-oxidant activity. Binding approaches of all synthesized compounds were revealed through molecular docking studies concerning binding pockets of enzymes that analyzed the best posture interaction with amino acid (AA) residues providing an appreciable understanding of enzyme inhibitory mechanisms. Results indicate that synthesized zinc (II) amide carboxylates can behave as an effective remedy in the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double-click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO 2 NCO) via a modular amidation/SuFEx (sulfur-fluoride exchange) process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO 2 F) and N-acylsulfamides (RCONHSO 2 NR'R'') in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram-positive bacterium S. aureus and drug-resistant MRSA (MIC up to 6.25 μg ⋅ mL -1 ). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry., (© 2024 Wiley-VCH GmbH.)

Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of Na V 1.7 that showed high selectivity over Na V 1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na V 1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shaoyi Sun, Sultan Chowdhury, Ivan Hemeon, Abid Hasan, Michael S. Wilson, Qi Jia, Alla Y. Zenova, Mike E. Grimwood, Wei Gong, Shannon M. Decker, Paul Bichler, Jean-Christophe Andrez, Thilo Focken, Girish Bankar, Elaine Chang, Kuldip Khakh, Sophia Lin, Richard Dean, J. P. Johnson, Jr., Charles J. Cohen, and Christoph M. Dehnhardt are employees of Xenon Pharmaceuticals Inc. and may hold equity or stocks in the company. Phillipe Bergeron, Theresa Ngyuen, Sarah Howard, Jae H. Chang, David H. Hackos, Steve J. McKerrall, Ben Sellers, Dan F. Ortwine, Brian S. Safina, and Daniel P. Sutherlin are employees of Genentech Inc. and may hold equity or stocks in the company. Jiuxiang Zhu and Andrew D. White are employees of Chempartner and may hold equity or stocks in the company., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Naphthenic acids, NAs, are a major contaminant of concern and a focus of much research around remediation of oil sand process affected waters, OSPW. Using activated carbon adsorbents are an attractive option given their low cost of fabrication and implementation. A deeper evaluation of the effect NA structural differences have on uptake affinity is warranted. Here we provide an in-depth exploration of NA adsorption including many more model NA species than have been assessed previously with evaluation of adsorption kinetics and isotherms at the relevant alkaline pH of OSPW using several different carbon adsorbents with pH buffering to simulate the behaviour of real OSPW. Uptake for the NA varied considerably regardless of the activated carbon used, ranging from 350 mg/g to near zero highlighting recalcitrant NAs. The equilibrium data was explored to identify structural features of these species and key physiochemical properties that influence adsorption. We found that certain NA will be resistant to adsorption when hydrophobic adsorbents are used. Adsorption isotherm modelling helped explore interactions occurring at the interface between NA and adsorbent surfaces. We identified the importance of NA hydrophobicity for activated carbon uptake. Evidence is also presented that indicates favorable hydrogen bonding between certain NA and surface site hydroxyl groups, demonstrating the importance of adsorbent surface functionality for NA uptake. This research highlights the challenges associated with removing NAs from OSPW through adsorption and also identifies how adsorbent surface chemistry modification can be used to increase the removal efficiency of recalcitrant NA species., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This study focuses on evaluating new methods for the green extraction of saponin compounds from Polygonatum cyrtonema Hua (PCH). This study utilized a combination of carboxylic acid-based natural deep eutectic solvents (NADES) and various extraction techniques including conventional heat reflux-, ultrasound-, and microwave-assisted extraction. The primary objectives were to assess total saponin yield, antioxidant capacity, and enzyme inhibition efficiency. Additionally, the solvents and extracts were evaluated for their antibacterial activity. Oil-in-water (O/W) emulsions of NADES extracts were also characterized and analyzed for stability. Results indicated that three NADES systems were effective in extracting saponins, with choline chloride and lactic acid (ChCl-LA) system being the most efficient. The ChCl:LA extract exhibited antimicrobial and antioxidant activities superior to conventional organic solvent extracts. Additionally, it demonstrated maximum inhibitory activity (IC 50 values: 0.98 ± 0.03 and 1.46 ± 0.07 mg/mL, respectively) against α-glucosidase and α-amylase. The NADES extract as an aqueous phase significantly improved the stationarity of the O/W emulsion. Collectively, the study highlights the antimicrobial and technological advantages of NADES as a potential solvent for extracting saponin compounds from PCH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In recent years, copper carboxylate complexes have garnered significant interest for biological applications. This study focuses on 20 Cu(II) carboxylate complexes selected from our previous research. Due to the hydrophobic nature of these complexes, the 2-hydroxypropyl-β-cyclodextrin (2HPβCD) was employed as a carrier to reduce toxicity and increase solubility for controlling drug delivery. Monte Carlo calculations were performed to confirm the interaction between the optimized structures of Cu(II) complexes and 2HPβCD, forming a host-guest system. All the structures were simulated and optimized using DFT-D calculations in Material Studio 2017. The results indicated that a neutral medium is more favorable for the adsorption of these complexes into 2HPβCD. More negative binding energy values suggested strong and energetically favorable adsorption on 2HPβCD. Complexes 4, 5, and 7 exhibited the highest interaction, making them excellent candidates for drug delivery systems. DFT-D calculations were also used to investigate the release of complexes, revealing that complexes 5, 14, and 19 were difficult to release due to their lowest energy. In contrast, complexes 8, 9, and 16 were found to be most efficient to release due to weak non-covalent interactions with 2HPβCD as we can predict from binding energy obtained by DFT-D. No specific trend was observed in the interaction of the complexes with 2HPβCD. Additionally, the effects of these complexes on c-kit tyrosine kinase and Mushroom tyrosinase were studied by molecular docking. The results demonstrated that all the complexes interacted with the active site of respective receptors through hydrophobic interactions. Complexes containing 1,10-phenanthroline and 2,2-bipyrdine were identified as having a strong, spontaneous binding ability with receptors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

A library of C-3 functionalized flavones was successfully provided via palladium-catalyzed amino- and aryloxycarbonylation reactions of 3-iodoflavone ( 1 ), under mild conditions. This methodology showed good functional group tolerance using a variety of amines and phenols, under an atmospheric pressure of carbon monoxide as a carbonyl source. While the flavone-3-carboxamides ( 2a-t ) were produced in 22-79%, the flavone-3-carboxylates ( 4a'-l' ) were obtained in excellent yields (up to 88%), under identical reaction conditions, just by switching N -nucleophiles to O -nucleophiles. The convenient availability of the involved starting materials confers simplicity to this approach to design new C-3-substituted flavones of biological relevance. The solid-state structures of flavone-3-carboxamide ( 2r ) and flavone-3-ester ( 4f' ) were further studied by single-crystal XRD analysis.

Diesters of geminal diols (R-CH(O-CO-R') 2 , RR'C(OCOR″) 2 , etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related "non-classical acylals", as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

Nano zero-valent iron (NZVI) has been shown to effectively enhance the chain elongation (CE) process, addressing the issue of limited yield of medium-chain carboxylic acids (MCCA) from organic wastewater. However, the specific impact of NZVI on the metabolism of CE bacteria (CEB) is not well understood. In this study, it was aimed to investigate the mechanism by which an optimal concentration of NZVI influences CE metabolism, particularly in relation to ethanol oxidation, electron transfer, and MCCA synthesis. This was achieved through single-factor influence experiments and metagenomic analysis. The results showed that the addition of 1 g/gVSS NZVI achieved the highest MCCA yield (n-caproic acid + n-octanoic acid) at 2.02 g COD/L, which was 4.9 times higher than the control. This improvement in MCCA production induced by NZVI was attributed to several factors. Firstly, NZVI facilitated the oxidation of acetaldehyde, leading to its reduced accumulation in the system (from 18.4 % to 5.8 %), due to the optimized chemical environment created by NZVI corrosion, including near-neutral pH and a more reductive oxidation-reduction potential (ORP). Additionally, the inherent conductivity property of NZVI and the additional Fe ions released during corrosion improved the electron transfer efficiency between CEB. Lastly, both the composition of microbial communities and the abundance of unique enzyme genes confirmed the selective stimulation of NZVI on the reverse β-oxidation (RBO) pathway. These findings provide valuable insights into the role of NZVI in CEB metabolism and its potential application for enhancing MCCA production in CE bioreactors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

DNA N 6 -methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1 H -pyrazole-4-carboxylic acid derivative 29 . The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29 , we prepared a prodrug of 29 ( 29E ), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E . Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.

In this investigation, we detail the synthesis of silver nanoparticles (AgNPs) via a precise chemical vacuum deposition (CVD) methodology, aimed at augmenting the analytical performance of laser desorption/ionization mass spectrometry (LDI-MS) for the detection of low-molecular-weight analytes. Employing a precursor supply rate of 0.0014 mg/s facilitated the formation of uniformly dispersed AgNPs, characterized by SEM and AFM to have an average diameter of 33.5 ± 1.5 nm and a surface roughness ( R a ) of 11.8 nm, indicative of their homogeneous coverage and spherical morphology. XPS and SEM-EDX analyses confirmed the metallic silver composition of the nanoparticles with Ag peak splitting, reflecting the successful synthesis of metallic Ag. Comparative analytical evaluation with traditional MALDI matrices revealed that AgNPs significantly reduce signal suppression, thereby enhancing the sensitivity and specificity of LDI-MS for low-molecular-weight compounds such as triglycerides, saccharides, amino acids, and carboxylic acids. Notably, the application of AgNPs demonstrated a superior linear response for triglyceride signals with regression coefficients surpassing 0.99, markedly outperforming conventional matrices. The study further extends into quantitative analysis through nanoparticle-based laser desorption/ionization (NALDI), where AgNPs exhibited enhanced ionization efficiency, characterized by substantially lower limits of detection (LOD) and quantification (LOQ) for tested standards. Particular attention was paid to lipids with a detailed examination of their fragmentation pathways. These results highlight the significant potential of AgNPs synthesized via CVD to transform the analytical detection and quantification of low-molecular-weight compounds using NALDI. This approach offers a promising avenue for expanding the scope of analytical applications in mass spectrometry and introducing innovative methodologies for enhanced precision and sensitivity.

Schizophyllan is a triple helical β-1,3- D -glucan, and shows the cooperative order-disorder transition in the aqueous solution at the triple helix state. In this paper, the solvent stabilizing effects of two carboxylic acids, acetic acid and citric acid, on the cooperative order-disorder transition of aqueous schizophyllan solution were investigated from DSC and SEC-MALS measurements. The transition temperature (T r ) was shifted to higher temperature with increasing the molar fraction of carboxylic acid in the mixture (x). The transition enthalpy (ΔH r ) was increased with increasing x. These solvent stabilizing effects indicate that these carboxylic acid molecules were selectively associated with the branched side chains of schizophyllan to stabilize the ordered state. The composition dependencies of T r and ΔH r were analyzed by the linear cooperative transition theory to estimate the association parameters between the side chains and carboxylic acid. The theoretical parameters obtained were compared with those for the other active substances for the transition to discuss the molecular interactions between the triple helix and carboxylic acid., (© 2024 Wiley Periodicals LLC.)

Aiming at shedding light on the molecular interactions in deep eutectic solvents (DESs), the DESs based on tetrabutylammonium bromide (TBAB) as hydrogen bond acceptor (HBA) and carboxylic acids (CAs) (formic acid (FA), oxalic acid (OA), and malonic acid (MA)) as hydrogen bond donor (HBD) were investigated by both experimental and theoretical techniques. The thermal behaviors of the prepared DESs were investigated by differential scanning calorimetry (DSC) method. In order to study the hydrogen bond formation between the DESs constituents, the FT-IR analysis was carried out. The large positive deviations of the iso solvent activity lines of ternary HBA + HBD + 2-propanol mixtures determined by the isopiestic technique from the semi-ideal behavior indicate that CAs interact strongly with TBAB and therefore they can form DESs. Molecular dynamics (MD) simulations were performed to present an atomic-scale image of the components and describe the microstructure of DESs. From the MD simulations, the radial distribution functions (RDFs), coordination numbers (CNs), combined distribution functions (CDFs), and spatial distribution functions (SDFs) were calculated to investigate the interaction between the components and three-dimensional visualization of the DESs. The obtained results confirmed the importance of hydrogen bonds in the formation of TBAB/CAs DESs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Within the new circular economy paradigm, this work evaluates the performance of tailored mixed metal oxides (MMO) anodes, based on ruthenium and antimony, for their application into an electrochemically-assisted organic refinery process. This process is designed to transform pollutants into value-added products with minimal mineralization. Oxidation of synthetic wastes consisting of phenol solutions was used to validate the electrochemical conversion of phenolic wastes into carboxylates, which are then considered as bricks to be used for electrosynthesis or to produce fuels. The MMO anodes were manufactured using two synthesis routes (Pechini method and ionic liquid method), each followed by one of three different heating treatments: furnace, microwave, and CO 2 laser. The selection of the optimal electrode for the organic electrorefinery was based on a combination of physical and electrochemical properties, degradation performance of phenol to carboxylates, and long-term stability, looking for a truly sustainable solution. Results indicate that anodes synthesized by the ionic liquid (IL) method, regardless of the heating treatment, demonstrated superior performance, with larger active areas (with furnace 82 mC cm -2 , microwave 97 mC cm -2 , and laser 127 mC cm -2 ) and higher phenol degradation rates, resulting in a greater generation of carboxylates during electrolysis, yielding primarily oxalate and achieving up to 40% conversion with furnace heating. However, laser-treated anodes exhibited greater stability than furnace-made ones, attributed to the formation of an insulating TiO 2 layer. Although the electrode with the longest service life did not show the best catalytic properties for minimizing mineralization, the observed variations in coatings with identical chemical compositions highlight the importance of this research. This study positions itself at the forefront of developing more efficient and sustainable electrochemical technologies for organic waste treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Three distinctive end group-containing organotin (IV) carboxylates complexes (YDCOOSn, CLCOOSn and BZCOOSn) were designed and synthesized. Together with theoretical calculations, a thorough examination was carried out to investigate the photophysical properties of these compounds. The cytotoxicity of the synthesized compounds was tested using normal cell line GES-1 and was assessed against four cancer cell lines (A549, Hela, H1299 and HepG2). The outcomes of the experiments demonstrated that these complexes had superior selectivity than cisplatin towards cancerous cells, particularly in the A549 cell line. BZCOOSn was selected as a candidate compound for additional research because it exhibited the lowest IC 50 value and the most impressive inducing effect on cell death and G2/M phase arrest. Increased caspase-3 and -9 enzyme activity, a decline in mitochondrial membrane potential (MMP), characteristic nuclear apoptotic morphology, and an accumulation of intracellular reactive oxygen species (ROS) were seen in A549 exposed to BZCOOSn. These findings demonstrated that BZCOOSn exhibited strong cytotoxicity by triggering cell death in A549 via the mitochondrial route. Furthermore, using the scratch wound healing assay, it was discovered that BZCOOSn reduced the migration of A549 cancerous cells. These data all pointed to BZCOOSn as a possible candidate for more research and development as a chemotherapeutic drug., Competing Interests: Declaration of competing interest We certify that none of the work disclosed in this publication may have been influenced by any known conflicting financial interests or personal relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite the remarkable developments of the Ugi reaction and its variants, the use of ammonia in the Ugi reaction has long been recognized as impractical and unsuccessful. Indeed, the ammonia-Ugi reaction often requires harsh reaction conditions, such as heating and microwave irradiation, and competes with the Passerini reaction, thereby resulting in low yields. This study describes a robust and practical ammonia-Ugi reaction protocol. Using originally prepared ammonium carboxylates in trifluoroethanol, the ammonia-Ugi reaction proceeded at room temperature in high yields and showed a broad substrate scope, thus synthesizing a variety of α,α-disubstituted amino acid derivatives, including unnatural dipeptides. The reaction required no condensing agents and proceeded without racemization of the chiral stereocenter of α-amino acids. Furthermore, using this protocol, we quickly synthesized a novel dipeptide, D-Leu-Aic-NH-CH 2 Ph( p -F), which exhibited a potent inhibitory activity against α-chymotrypsin with a K i value of 0.091 μM.

Several conjugates between folic acid and a series of kinetically stable lanthanide complexes have been synthesized, using amide coupling and azide-alkyne cycloaddition methodologies to link the metal-binding domain to folate through a variety of spacer groups. While all these complexes exhibit affinity for the folate receptor, it is clear that the point of attachment to folate is essential, with linkage through the γ-carboxylic acid giving rise to significantly enhanced receptor affinity. All the conjugates studied show affinities consistent with displacing biological circulating folate derivatives, 5-methyltetrahydrofolate, from folate receptors. All the complexes exhibit luminescence with a short-lived component arising from ligand fluorescence overlaid on a much longer lived terbium-centered component. These can be separated using time-gating methods. From the results obtained, the most promising approach to achieve sensitized luminescence in these systems requires incorporating a sensitizing chromophore close to the lanthanide.

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC 50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.

The escalating levels of hazardous pharmaceutical contaminants, specifically nonsteroidal anti-inflammatory drugs (NSAIDs), in groundwater reservoir surfaces and surface waterway systems have prompted substantial scientific interest regarding their potential deleterious effects on both aquatic ecosystems and human health. Extraction of those pollutants from wastewater is quite challenging. Hence, the development of economic, sustainable, and scalable techniques for capturing and removing those pollutants is crucial to ensure water safety. Herein, we demonstrate a physicochemically stable, reusable, porous Hf(IV)-based cationic metal-organic framework (MOF), namely, 1'@MeCl for the aqueous phase adsorption-based removal of NSAIDs (diclofenac, naproxen, ibuprofen) from the wastewater environment. The highly positively charged surface of the 1'@MeCl MOF enables it to selectively extract more than 99% of diclofenac, naproxen, and ibuprofen contaminants within less than 30 s. With fast adsorption kinetics, very high adsorption capacities ( Q e ) were achieved at neutral pH for diclofenac (482.9 mg/g), naproxen (295.9 mg/g), and ibuprofen (219.5 mg/g). Moreover, the influence of changes in pH and coexisting anions on the adsorption property of the 1'@MeCl MOF was studied. Furthermore, the adsorption efficiency of 1'@MeCl in different real water environments was ensured by performing diclofenac, naproxen, and ibuprofen adsorption from tap, river, and lake water. Moreover, a 1'@MeCl -anchored cellulose acetate-chitosan membrane was developed successfully to demonstrate the membrane-based extraction of diclofenac, naproxen, and ibuprofen from contaminated water. Furthermore, a molecular-level mechanistic study was performed through experimental and computational study to propose the plausible adsorption mechanisms for diclofenac, naproxen, and ibuprofen over the surface of 1'@MeCl .

The adoption of biophotonic sensing technologies holds significant promise for application in health care and biomedical industries in all aspects of human life. Then, this piece of writing employs the powerful effective medium theory and FDTD simulation to anticipate the most favorable state and plasmonic attributes of a magnificent nanocomposite, comprising carboxylate functionalized carbon nanotubes and chitosan (CS). Furthermore, it thoroughly explores the exhibited surface plasmon resonance behaviors of this composite versus the quantity of CS variation. Subsequently, enlightening simulations are conducted on the nanocomposite with a delicate layer and a modified golden structure integrating as a composite. The intricate simulations eventually unveil an optimal combination to pave the way for crafting an exceptional specific biosensor that far surpasses its counterpart as a mere Au thin layer in terms of excellence. The proposed biosensor demonstrated linear behavior across a wide range from 0.01 μM to 150 μM and achieved a detection limit of 10 nM, with a sensitivity of 134 ◦ RIU -1 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)