Synthesis of 2-Ethylhexyl 5-Bromothiophene-2-Carboxylates; Antibacterial Activities against Salmonella Typhi, Validation via Docking Studies, Pharmacokinetics, and Structural Features Determination through DFT.

A new class of thiophene-based molecules of 5-bromothiophene-2-carboxylic acid (1) have been synthesized in current research work. All analogs 4A-4G were synthesized with optimized conditions by coupling reactions of 2-ethylhexyl 5-bromothiophene-2-carboxylate (3) with various arylboronic acids. The results indicated that the majority of compounds showed promising effective in vitro antibacterial activity. Herein, 2-ethylhexyl-5-(p-tolyl)thiophene-2-carboxylate (4F), in particular among the synthesized analogs, showed outstanding antibacterial action (MIC value 3.125 mg/mL) against XDR Salmonella Typhi compared to ciprofloxacin and ceftriaxone. The intermolecular interaction was investigated by using a molecular docking study of thiophene derivatives 4A-4G against XDR S. Typhi. The values of the binding affinity of functionalized thiophene molecules and ciprofloxacin were compared against bacterial enzyme PDB ID: 5ztj. Therefore, 4F appears to be a promising antibacterial agent and showed the highest potential value. Density functional theory (DFT) calculations were executed to examine the electronic, structural, and spectroscopic features of the newly synthesized molecules 4A-4G.

Electron bifurcation and fluoride efflux systems implicated in defluorination of perfluorinated unsaturated carboxylic acids by Acetobacterium spp.

Enzymatic cleavage of C─F bonds in per- and polyfluoroalkyl substances (PFAS) is largely unknown but avidly sought to promote systems biology for PFAS bioremediation. Here, we report the reductive defluorination of α, ß-unsaturated per- and polyfluorocarboxylic acids by Acetobacterium spp. The microbial defluorination products were structurally confirmed and showed regiospecificity and stereospecificity, consistent with their formation by enzymatic reactions. A comparison of defluorination activities among several Acetobacterium species indicated that a functional fluoride exporter was required for the detoxification of the released fluoride. Results from both in vivo inhibition tests and in silico enzyme modeling suggested the involvement of enzymes of the flavin-based electron-bifurcating caffeate reduction pathway [caffeoyl-CoA reductase (CarABCDE)] in the reductive defluorination. This is a report on specific microorganisms carrying out enzymatic reductive defluorination of PFAS, which could be linked to electron-bifurcating reductases that are environmentally widespread.

An Optimized Method for LC-MS-Based Quantification of Endogenous Organic Acids: Metabolic Perturbations in Pancreatic Cancer.

Accurate and reliable quantification of organic acids with carboxylic acid functional groups in complex biological samples remains a major analytical challenge in clinical chemistry. Issues such as spontaneous decarboxylation during ionization, poor chromatographic resolution, and retention on a reverse-phase column hinder sensitivity, specificity, and reproducibility in multiple-reaction monitoring (MRM)-based LC-MS assays. We report a targeted metabolomics method using phenylenediamine derivatization for quantifying carboxylic acid-containing metabolites (CCMs). This method achieves accurate and sensitive quantification in various biological matrices, with recovery rates from 90% to 105% and CVs ≤ 10%. It shows linearity from 0.1 ng/mL to 10 µg/mL with linear regression coefficients of 0.99 and LODs as low as 0.01 ng/mL. The library included a wide variety of structurally variant CCMs such as amino acids/conjugates, short- to medium-chain organic acids, di/tri-carboxylic acids/conjugates, fatty acids, and some ring-containing CCMs. Comparing CCM profiles of pancreatic cancer cells to normal pancreatic cells identified potential biomarkers and their correlation with key metabolic pathways. This method enables sensitive, specific, and high-throughput quantification of CCMs from small samples, supporting a wide range of applications in basic, clinical, and translational research.

Discovery and Biosynthesis of Streptolateritic Acids A-D: Acyclic Pentacarboxylic Acids from Streptomyces sp. FXJ1.172 with Promising Activity against Potato Common Scab.

Potato common scab (PCS) is a widespread plant disease that lacks effective control measures. Using a small molecule elicitor, we activate the production of a novel class of polyketide antibiotics, streptolateritic acids A-D, in Streptomyces sp. FXJ1.172. These compounds show a promising control efficacy against PCS and an unusual acyclic pentacarboxylic acid structure. A gene cluster encoding a type I modular polyketide synthase is identified to be responsible for the biosynthesis of these metabolites. A cytochrome P450 (CYP) and an aldehyde dehydrogenase (ADH) encoded by two genes in the cluster are proposed to catalyze iterative oxidation of the starter-unit-derived methyl group and three of six branching methyl groups to carboxylic acids during chain assembly. Our findings highlight how activation of silent biosynthetic gene clusters can be employed to discover completely new natural product classes able to combat PCS and new types of modular polyketide synthase-based biosynthetic machinery.

Synthesis of 1H-isoindolin-1-ones via a simple photodecarboxylative addition of carboxylates to phthalimides and evaluation of their antibiotic activity.

A variety of 3-hydroxy-isoindolin-1-one derivatives were synthesized using the photodecarboxylative addition of carboxylates to phthalimide derivatives in aqueous media. Subsequent acid-catalyzed dehydration furnished 3-(alkyl and aryl)methyleneisoindolin-1-ones with variable E-diastereoselectivity in good to excellent overall yields. Noteworthy, the parent 3-phenylmethyleneisoindolin-1-one underwent isomerization and oxidative decomposition when exposed to light and air. Selected 3-hydroxy-isoindolin-1-one and 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives showed moderate antibacterial activity that justifies future elaboration and study of these important bioactive scaffolds.

Adsorptive features of cyclohexane carboxylic naphthenic acid on a novel cross-linked polymer developed from spent coffee grounds.

Naphthenic acids (NA) are organic compounds commonly found in crude oil and produced water, known for their recalcitrance and toxicity. This study introduces a new adsorbent, a polymer derived from spent coffee grounds (SCGs), through a straightforward cross-linking method for removing cyclohexane carboxylic acid as representative NA. The adsorption kinetics followed a pseudo-second-order model for the data (0.007 g min-1 mg-1), while the equilibrium data fitted the Sips model ( q m = 140.55 mg g-1). The process's thermodynamics indicated that the target NA's adsorption was spontaneous and exothermic. The localized sterical and energetic aspects were investigated through statistical physical modeling, which corroborated that the adsorption occurred indeed in monolayer, as suggested by the Sips model, but revealed the contribution of two energies per site ( n 1 ; n 2 ). The number of molecules adsorbed per site ( n ) was highly influenced by the temperature as n 1 decreased with increasing temperature and n 2 increased. These results were experimentally demonstrated within the pH range between 4 and 6, where both C6H11COO-(aq.) and C6H11COOH(aq.) species coexisted and were adsorbed by different energy sites. The polymer produced was naturally porous and amorphous, with a low surface area of 20 to 30 m2 g-1 that presented more energetically accessible sites than other adsorbents with much higher surface areas. Thus, this study shows that the relation between surface area and high adsorption efficiency depends on the compatibility between the energetic states of the receptor sites, the speciation of the adsorbate molecules, and the temperature range studied.

Asymmetric ionic bond shielding encountering with carboxylate capturing metal ions for enhancing the flame retardant durability of regenerated cellulose fibers.

Enhancing the flame retardancy and durability of cellulose fibers, particularly environmentally friendly regenerated cellulose fibers types like Lyocell fibers, is essential for advancing their broader application. This study introduced a novel approach to address this challenge. Cationic-modified Lyocell fibers (Lyocell@CAT) were prepared by introducing quaternary ammonium structures into the molecular chain of Lyocell fibers. Simultaneously, a flame retardant, APA, containing -COO-NH4+ and -P=O(O-NH4+)2 groups was synthesized. APA was then covalently bonded to Lyocell@CAT to prepare Lyocell@CAT@APA. Even after undergoing 30 laundering cycles (LCs), Lyocell@CAT@APA maintained a LOI value of 37.2 %, exhibiting outstanding flame retardant durability. The quaternary ammonium structure within Lyocell@CAT@APA formed asymmetric ionic bonds with the phosphate and carboxylate groups in APA, effectively shielding the binding of Na+ ions with phosphate groups during laundering, thereby enhancing the durability. Additionally, the consumption of Na+ ions by carboxylate groups further prevented their binding to phosphate groups, which contributed to enhance the durability properties. Flame retardant mechanism analysis revealed that both gas and condensed phase synergistically endowed excellent flame retardancy to Lyocell fibers. Overall, this innovative strategy presented a promising prospect for developing bio-safe, durable, and flame retardant cellulose textiles.

Comparative study of polycarboxylic acids for sustainable crosslinking of silk fabrics: Evaluating flame retardancy and physical performances.

For protein fibers, polycarboxylic acids represent a green strategy to enhance durability without using formaldehyde. This study evaluated the physical and flame retardant properties of silk fabrics treated with three formaldehyde-free crosslinkers: citric acid (CA), 1,2,3,4-butanetetracarboxylic acid (BTCA), and 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTCA). Results showed that these acids bond with silk protein through esterification and amidation, improving washing durability. Particularly, PBTCA integrates phosphorus into silk, boosting flame retardancy. While BTCA led to the highest weight gain and improved wrinkle recovery, it negatively impacted the tensile strength and softness of silk fabrics. Conversely, PBTCA adeptly balanced enhanced wrinkle resistance with minimal effects on tensile strength and softness, and least affected the silk fabrics' whiteness, thus preserving its aesthetic appeal. All crosslinkers improved flame retardancy, but PBTCA displayed superior performance, achieving a limiting oxygen index of 32.4 % at an 80 g/L concentration. In vertical burning tests, PBTCA treated silk fabrics showed reductions in damage length and demonstrated self-extinguishing properties, qualifying them for a higher flame retardant grade. Phosphorus in PBTCA promotes char formation during combustion, essential for effective flame retardation and smoke reduction. This research highlights the exceptional potential of silk treated with PBTCA, showcasing its suitability for demanding applications.

Synthesis of (2R,4S)-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction.

Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.

High-throughput screening of non-conventional yeasts for conversion of organic waste to microbial oils via carboxylate platform.

Converting waste into high-value products promotes sustainability by reducing waste and creating new revenue streams. This study investigates the potential of diverse yeasts for microbial oil production by utilizing short-chain fatty acids (SCFAs) that can be produced from organic waste and focuses on identifying strains with the best SCFA utilisation, tolerance and lipid production. A collection of 1434 yeast strains was cultivated with SCFAs as the sole carbon source. Eleven strains emerged as candidates with promising growth rates and high lipid accumulation. Subsequent fermentation experiments in liquid SCFA-rich media, which focused on optimizing lipid accumulation by adjusting the carbon to nitrogen (C/N) ratio, showed an increase in lipid content at a C/N ratio of 200:1, but with a concurrent reduction in biomass. Two strains were characterized by their superior ability to produce lipids compared to the reference strain Yarrowia lipolytica CECT124: Y. lipolytica EXF-17398 and Pichia manshurica EXF-7849. Characterization of these two strains indicated that they exhibit a biotechnologically relevant balance between maximizing lipid yield and maintaining growth at high SCFA concentrations. These results emphasize the potential of using SCFAs as a sustainable feedstock for oleochemical production, offering a dual benefit of waste valorisation and microbial oil production.

Building Block-Centric Approach to DNA-Encoded Library Design.

DNA-encoded library technology grants access to nearly infinite opportunities to explore the chemical structure space for drug discovery. Successful navigation depends on the design and synthesis of libraries with appropriate physicochemical properties (PCPs) and structural diversity while aligning with practical considerations. To this end, we analyze combinatorial library design constraints including the number of chemistry cycles, bond construction strategies, and building block (BB) class selection in pursuit of ideal library designs. We compare two-cycle library designs (amino acid + carboxylic acid, primary amine + carboxylic acid) in the context of PCPs and chemical space coverage, given different BB selection strategies and constraints. We find that broad availability of amines and acids is essential for enabling the widest exploration of chemical space. Surprisingly, cost is not a driving factor, and virtually, the same chemical space can be explored with "budget" BBs.

A multi-step approach: Coupling of biodegradation and UV photocatalytic oxidation TiO2 for the treatment of naphthenic acid fraction compounds in oil sands process-affected water.

Bitumen extraction in Alberta's oil sands region uses large volumes of water, leading to an abundance of oil sands process-affected water (OSPW). OSPW contains naphthenic acid fraction compounds (NAFCs) which have been found to contribute to OSPW toxicity. This study utilized a multistep treatment, coupling biological degradation with UV photocatalytic oxidation, and nutrient addition to boost the native microbial community's degradation capacity. OSPW initially contained 40-42 mg/L NAFCs with a toxicity of 3.8-3.9 TU. Initial biodegradation (Step 1) was used to remove the easily biodegradable NAFCs (11-25% removal), followed by a light or heavy dose of oxidation (Step 2) to breakdown the recalcitrant NAFCs (66-82% removal). Lastly, post-oxidation biodegradation with nutrients (Step 3) removed the residual bioavailable NAFCs (16-31% removal). By the end of the multistep treatment, the final NAFC concentrations and toxicity ranged from 5.3 to 6.8 mg/L and 1.1-1.2 TU. Analysis showed that OPSW was limited in phosphorus (below detection limit), and the addition of nutrients improved the degradation of NAFCs. Two treatments throughout the multistep treatment never received nutrients and showed minimal NAFC degradation post-oxidation. The native microbial community survived the stress from UV photocatalytic oxidation as seen by the post-oxidation NAFC biodegradation. Microbial community diversity was reduced considerably following oxidation, but increased with nutrient addition. The microbial community consisted predominately of Proteobacteria (Gammaproteobacteria and Alphaproteobacteria), and the composition shifted depending on the level of oxidation received. Possible NAFC-degrading microbes identified after a light oxidation dose included Pseudomonas, Acinetobacter and Xanthomonadales, while Xanthobacteracea and Rhodococcus were the dominant microbes after heavy oxidation. This experiment confirms that the microbial community is capable of degrading NAFCs and withstanding oxidative stress, and that degradation is further enhanced with the addition of nutrients.

Pathological and ultrastructural changes of Bellamya bengalensis under chronic carboxylic acid exposure at environmentally relevant levels: Inferences from general unified threshold model for survival (GUTS) predictions and hepatopancreatic integrity assessment.

This study aimed to understand the effects of freshwater acidification, driven by industrial runoff, agricultural activities, and atmospheric deposition, on the freshwater mollusk Bellamya bengalensis. By systematically investigating the impact of two common carboxylic acids, acetic acid (AA) and benzoic acid (BA), this research employed diverse toxicological, pathological, and ecological assessments. We explored survival predictions through the generic unified threshold model of survival (GUTS-SD), examined oxidative stress responses, and investigated hepatopancreatic alterations. In the experimental design, Bellamya bengalensis were subjected to environmentally relevant sublethal concentrations (10%, 20% LC50) of AA (39.77 and 79.54 mg/l) and BA (31.41 and 62.82 mg/l) over 28 days. Acute toxicity tests revealed increased LC50 values, indicating heightened toxicity with prolonged exposure, particularly due to the greater potency of benzoic acid compared to acetic acid. The GUTS-SD model provided accurate predictions of time-specific effects on populations, presenting long-term exposure (100 days) LC50 values for AA (263.7 mg/l) and BA (330.9 mg/l). Sequentially, the integrated biomarker response (IBR) analysis across study intervals highlighted the 28-day interval as the most sensitive, with GST emerging as the most responsive enzyme to oxidative stress induced by AA and BA. Histopathological and ultrastructural assessments of the hepatopancreas showed severe alterations, including necrosis, vacuolation and disrupted micro-villi, which were especially pronounced in higher BA exposure concentrations. These findings highlight the health and survival impacts of carboxylic acid toxicity on Bellamya bengalensis, emphasizing the need for proactive measures to mitigate acidification in aquatic ecosystems. The broader ecological implications underscore the importance of effective management and conservation strategies to address ongoing environmental challenges.

Combined experimental and computational investigation of tetrabutylammonium bromide-carboxylic acid-based deep eutectic solvents.

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.

Oxidative Carboxylation of Lignin: Exploring Reactivity of Different Lignin Types.

The increased interest in the utilization of lignin in biobased applications is evident from the rise in lignin valorization studies. The present study explores the responsiveness of lignin toward oxidative valorization using acetic acid and hydrogen peroxide. The pristine lignins and their oxidized equivalents were analyzed comprehensively using NMR and SEC. The study revealed ring opening of phenolic rings yielding muconic acid- and ester-end groups and side-chain oxidations of the benzylic hydroxyls. Syringyl units were more responsive to these reactions than guaiacyl units. The high selectivity of the reaction yielded oligomeric oxidation products with a narrower dispersity than pristine lignins. Mild alkaline hydrolysis of methyl esters enhanced the carboxylic acid content of oxidized lignin, presenting the potential to adjust the carboxylic acid content of lignin. While oxidation reactions in lignin valorization are well documented, this study showed the feasibility of employing optimized oxidation conditions to engineer tailored lignin-based material precursors.

Design, Synthesis, and Biological Evaluation of 1,2,4-Oxadiazole Derivatives Containing an Aryl Carboxylic Acid Moiety as Potent Sarbecovirus Papain-like Protease Inhibitors.

Papain-like protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds 13f and 26r, which had PLpro inhibition activity (IC50 = 1.8 and 1.0 µM) and antiviral activity against SARS-CoV-2 (EC50 = 5.4 and 4.3 µM), exhibited good metabolic stability (t1/2 > 93.2 min) and higher plasma exposure (AUC0-t = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound 26r with moderate oral bioavailability of 39.1% and potent antiviral activity is worthy of further studies in vivo. Our findings provide a new insight for the discovery of antiviral agents targeting PLpro.

Resilience towards organic load and activated sludge variations in co-fermentation for carboxylic acid production.

Two perturbations were investigated in acidogenic co-fermentation of waste activated sludge (WAS) and food waste in continuous mesophilic fermenters: increasing the organic loading rate (OLR) and changing the WAS. A control reactor maintained an OLR of 11 gVS/(L·d), while a test reactor had a prolonged OLR change to 18 gVS/(L·d). For each OLR, two WAS were studied. The change in OLR led to differentiated fermentation product profile without compromising the fermentation yields (∼300 mgCOD/gVS). At 11 gVS/(L·d), the product profile was dominated by acetic, butyric, and propionic acids while at 18 gVS/(L·d) it shifted to acetic acid, ethanol, and caproic acid. Reverting the OLR also reverted the fermentation profile. The biomass immigration with the WAS changed the fermentation microbial structure and introduced acetic acid-consuming methanogens, which growth was only delayed by the OLR increase. Microbial monitoring and post-fermentation tests can be used for early detection of acetic acid-consuming events.

A sensitive bioanalytical ultra-high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous quantitation of lactone and carboxylate forms of topotecan in plasma and vitreous.

Topotecan (TPT) is used in the treatment of retinoblastoma, the most common malignant intraocular tumor in children. TPT undergoes pH-dependent hydrolysis of the lactone ring to the ring-opened carboxylate form, with the lactone form showing antitumor activity. A selective, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the determination of both forms of TPT in one mobile phase composition in plasma and vitreous humor matrices. The method showed an excellent linear range of 0.375-120 ng/mL for the lactone. For the carboxylate, the linear range was from 0.75 to 120 ng/mL. The matrix effect and the recovery for the lactone ranged from 98.5% to 106.0% in both matrices, for the carboxylate form, it ranged from 94.9% to 101.2%. The dynamics of the transition between TPT lactone and TPT carboxylate were evaluated at different pH environments. The stability of TPT forms was assessed in plasma and vitreous humor at 8 and 37°C and a very fast conversion of lactone to carboxylate form occurred at 37°C in both matrices. The method developed facilitates the investigation of TPT pharmacodynamics and the release kinetics in the development of the innovative local drug delivery systems.

Tungsten sulfide highly boosted Fe(III)/peroxymonosulfate system for rapid degradation of cyclohexanecarboxylic acid: Performance, mechanisms, and applications.

In this study, the Fe(III)/WS2/peroxymonosulfate (PMS) system was found to remove up to 97% of cyclohexanecarboxylic acid (CHA) within 10 min. CHA is a model compound for naphthenic acids (NAs), which are prevalent in petroleum industrial wastewater. The addition of WS2 effectively activated the Fe(III)/PMS system, significantly enhancing its ability to produce reactive oxidative species (ROS) for the oxidation of CHA. Further experimental results and characterization analyses demonstrated that the metallic element W(IV) in WS2 could provide electrons for the direct reduction of Fe(III) to Fe(II), thus rapidly activating PMS and initiating a chain redox process to produce ROS (SO4•-, •OH, and 1O2). Repeated tests and practical exploratory experiments indicated that WS2 exhibited excellent catalytic performance, reusability and anti-interference capacity, achieving efficient degradation of commercial NAs mixtures. Therefore, applying WS2 to catalyze the Fe(III)/PMS system can overcome speed limitations and facilitate simple, economical engineering applications.

Thermal oxidation mechanism of palmitic aicd.

The oxidation and degradation of fats lead to a decrease in the nutritional value of food and pose safety concerns. Saturated fatty acids also hold a significant position in the field of lipid oxidation. In this study, the oxidation products of methyl palmitate were investigated by using gas chromatography mass spectrometry (GC-MS). Seven monohydroperoxides and 72 secondary oxidation products were detected. Combined with density functional theory (DFT) calculations, the formation mechanisms of oxidation products can be summarized into four stages. The initial stage involved the formation of monohydroperoxides and alkanes, followed by the subsequent stage involving methyl x-oxo(hydroxy)hexadecanoates. The third stage involved the formation of methyl ketones, carboxylic acids, and aldehydes, while the final stage involved lactones. Meanwhile, methyl ketones were the most abundant oxidation product, approximately 25 times more abundant than aldehydes; the calculated results agreed well with the experimental results. The establishment of a comprehensive thermal oxidation mechanism for palmitic acid provided a new foundation for future lipid oxidation analyses.