Series Of Carboxylic Acids Research Articles

Successively Controlling Nanoscale Wrinkles of Ultrathin 2D Metal-Organic Frameworks Nanosheets.

The wrinkles are pervasive in ultrathin two-dimensional (2D) materials, but the regulation of wrinkles is rarely explored systematically. Here, we employed a series of carboxylic acids (from formic acid to octanoic acid) to control the wrinkles of Zr-BTB (BTB=1, 3, 5-(4-carboxylphenyl)-benzene) metal-organic framework (MOF) nanosheet. The wrinkles at the micrometer scale were observed with transmission electron microscopy. Furthermore, high-angle annular dark-field (HAADF) images showed lattice distortion in many nanoscale regions, which was precisely matched to the nano-wrinkles. With the changes of hydrophilicity/hydrophobicity, MOF-MOF and MOF-solvent interactions were possibly synergistically regulated and wrinkles with different sizes were obtained, which was supported by HAADF, molecular dynamics, and density functional theory calculation. Different wrinkle sizes resulted in different pore sizes between the Zr-BTB nanosheet interlayers, providing highly-oriented thin films and the successive optimization of kinetic diffusion pathways, proved by grazing-incidence wide-angle X-ray scattering and nitrogen adsorption. The most suitable wrinkle pore from Zr-BTB-C4 exhibited highly efficient chromatographic separation of the substituted benzene isomers. Our work provides a rational route for the modulation of nanoscale wrinkles and their stacked pores of MOF nanosheets and improves the separation abilities of MOFs.

Towards adjustable tri-response thermochromic fluorescent materials for information encryption via SO2CF3 terminal bis-tolane luminescent liquid crystals

A series of novel bis-tolane luminescence liquid crystals (LLCs) with SO2CF3 as terminal were first time achieved. These SO2CF3-based LLCs act as thermally responsive emission sources combined with a series of thermosensitive long-chain carboxylic acids with self-crystallization properties to obtain adjustable tri-response thermochromic fluorescent materials (TFMs). Notably, TFMs of (CH3)2N-2F-SO2CF3 exhibit excellent temperature sensitivity and tri-response thermochromic fluorescent character, which display outstanding thermochromic properties from 45 °C to 165 °C. These TFMs displayed an intuitively evident orange under ultraviolet (UV) irradiation then changed to orange-yellow color after adding long-chain carboxylic acids. Notably, it changed to yellow-green when heated to the long-chain carboxylic acids melting point of these phase change materials, further emitting a blue color at the mesophases transition when increasing temperature at 165 °C of (CH3)2N-2F-SO2CF3. Interestingly, the various thermochromic abilities and stimuli-responsive fluorescence of these TFMs could be regulated by substituents of LLCs and long-chain carboxylic acids. Therefore, such tri-response and high-contrasted thermochromic fluorescent character of TFMs are different from previous reports which promise candidates for information encryption.

Uncovering the toxicity mechanisms of a series of carboxylic acids in liver cells through computational and experimental approaches

Hepatotoxicity poses a significant concern in drug design due to the potential liver damage that can be caused by new drugs. Among common manifestations of hepatotoxic damage is lipid accumulation in hepatic tissue, resulting in liver steatosis or phospholipidosis. Carboxylic derivatives are prone to interfere with fatty acid metabolism and cause lipid accumulation in hepatocytes. This study investigates the toxic behaviour of 24 structurally related carboxylic acids in hepatocytes, specifically their ability to cause accumulation of fatty acids and phospholipids. Using high-content screening (HCS) assays, we identified two distinct lipid accumulation patterns. Subsequently, we developed structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) models to determine relevant molecular substructures and descriptors contributing to these adverse effects. Additionally, we calculated physicochemical properties associated with lipid accumulation in hepatocytes and examined their correlation with our chemical structure characteristics. To assess the applicability of our findings to a wide range of chemical compounds, we employed two external datasets to evaluate the distribution of our QSAR descriptors. Our study highlights the significance of subtle molecular structural variations in triggering hepatotoxicity, such as the presence of nitrogen or the specific arrangement of substitutions within the carbon chain. By employing our comprehensive approach, we pinpointed specific molecules and elucidated their mechanisms of toxicity, thus offering valuable insights to guide future toxicology investigations.

PKa as a Predictive Descriptor for Electrochemical Anion Adsorption

AbstractThe adsorption of anions onto metal surfaces is important in many applications including effective (electro)catalyst design, metal surface modification, and contaminant removal in wastewater treatment. In electrocatalysis, anions can be both reactive intermediates or site‐blocking spectators, where their adsorption strength therefore dictates the rate of reaction. In this work, we have measured the adsorption energy of a series of carboxylic acids on a Pt (111) single‐crystal electrode surface from aqueous solution. We find that the adsorption strength of the carboxylate anion is linearly correlated with its acid‐dissociation constant (pKa) and therefore the heterolytic O−H bond dissociation strength in solution. Using density functional theory modeling, we split the anion adsorption energy into a sum of the adsorption energy and electron affinity of a neutral (carboxyl) radical. Surprisingly, the adsorption energy of the carboxyl radicals are similar and therefore the large difference in electron affinity is what dictates anion adsorption strength; the greater the cost in energy to remove the electron from the anion upon adsorption, the weaker its binding. Therefore, at least within a class of anions with similar structure and surface binding atoms, both electron affinity and acidity are predictive descriptors of adsorption strength.

PKa as a Predictive Descriptor for Electrochemical Anion Adsorption.

The adsorption of anions onto metal surfaces is important in many applications including effective (electro)catalyst design, metal surface modification, and contaminant removal in wastewater treatment. In electrocatalysis, anions can be both reactive intermediates or site-blocking spectators, where their adsorption strength therefore dictates the rate of reaction. In this work, we have measured the adsorption energy of a series of carboxylic acids on a Pt (111) single-crystal electrode surface from aqueous solution. We find that the adsorption strength of the carboxylate anion is linearly correlated with its acid-dissociation constant (pKa) and therefore the heterolytic O-H bond dissociation strength in solution. Using density functional theory modeling, we split the anion adsorption energy into a sum of the adsorption energy and electron affinity of a neutral (carboxyl) radical. Surprisingly, the adsorption energy of the carboxyl radicals are similar and therefore the large difference in electron affinity is what dictates anion adsorption strength; the greater the cost in energy to remove the electron from the anion upon adsorption, the weaker its binding. Therefore, at least within a class of anions with similar structure and surface binding atoms, both electron affinity and acidity are predictive descriptors of adsorption strength.

Discovery of novel SOS1 inhibitors using machine learning.

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 μg mL-1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors.

Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors.

Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based on the structures of URAT1 inhibitors Epaminurad and Telmisartan via a strategy of pharmacophore fusion. Fifty-one novel compounds were synthesized and most of them showed obvious inhibition against human URAT1. A1 and B21 were identified as the most potent URAT1 inhibitors in series A and B, respectively. They exhibited IC50 values of 0.93 μM and 0.17 μM, which were comparable or superior to the clinical uricosuric drug benzbromarone. The results confirmed the effectiveness of ligand-based approaches in identifying novel and potent URAT1 inhibitors.

Piperazine-2-carboxylic acid derivatives as MTDLs anti-Alzheimer agents: Anticholinesterase activity, mechanistic aspect, and molecular modeling studies

Development of Multitarget-Directed Ligands (MTDLs) is a promising approach to combat the complex etiologies of Alzheimer's disease (AD). Herein we report the design, synthesis, and characterization of a new series of 1,4-bisbenzylpiperazine-2-carboxylic acid derivatives 3-5(a-g), 7a-f, 8a-s, and their piperazine-2-yl-1,3,4-oxadiazole analogs 6a-g. In vitro inhibitory effect against Electrophorus electricus acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from Equine serum was evaluated using modified Ellman’s method, considering donepezil and tacrine as reference drugs. Lineweaver–Burk plot analysis of the results proved competitive inhibition of AChE and BChE with Ki values, in low micromolar range. The free carboxylic acid series 4a-g showed enhanced selectivity for AChE. Hence, 4c, 1,4-bis (4-chlorobenzyl)-piperazinyl-2-carboxylic acid), was the most active member of this series (Ki (AChE) = 10.18 ± 1.00 µM) with clear selectivity for AChE (SI ∼ 17.90). However, the hydroxamic acids 7a-f and carboxamides 8a-s congeners were more potent and selective inhibitors of BChE (SI ∼ 5.38 – 21862.5). Extraordinarily, 1,4-bis (2-chlorobenzyl)-piperazinyl-2-hydroxamic acid 7b showed promising inhibitory activity against BChE enzyme (Ki = 1.6 ± 0.08 nM, SI = 21862.5), that was significantly superior to that elicited by donepezil (Ki = 12.5 ± 2.6 µM) and tacrine (Ki = 17.3 ± 2.3 nM). Cytotoxicity assessment of 4c and 7b, on human neuroblastoma (SH-SY5Y) cell lines, revealed lower toxicity than staurosporine and was nearly comparable to that of donepezil. Molecular docking and molecular dynamics simulation afforded unblemished insights into the structure–activity relationships for AChE and BChE inhibition. The results showed stable binding with fair H-bonding, hydrophobic and/or ionic interactions to the catalytic and peripheral anionic sites of the enzymes. In silico predicted ADME and physicochemical properties of conjugates showed good CNS bioavailability and safety parameters. In this regard, compound (7b) might be considered as a promising inhibitor of BChE with an innovative donepezil-based anti-Alzheimer activity. Further assessments of the most potent AChE and BChE inhibitors as potential MTDLs anti-Alzheimer’s agents are under investigation with our research group and will be published later.

Development of a Small Molecule Hydrogen Evolution Catalyst

Based on prior work done by Diane K. Smith et al on redox responsive 3 hydrogen bond array dimers, a fundamental investigation on the nature of proton coupled electron transfer (PCET) was done by surveying a series of new electroactive “host” H-bond dimers. In these dimers, electron transfer should induce proton transfer across a H-bond, increasing the overall strength of hydrogen bond binding the “guest” and “host”. In particular, the goal was to investigate how electrochemical behavior and binding strength changes as the relative acidity of the electro-inactive “guest” changes in a 2-hydrogen bond array. For this task, amido pyridinium derivatives will be used as the redox active "hosts" and a series of different carboxylic acid, 2-hydroxypyridine, and amide derivatives as the electro-inactive "guests". Unexpectedly, in the presence of carboxylic acids, the amido pyridinium acts as a hydrogen evolution catalyst. During guest host cyclic voltammogram (CV) titrations, there was a large anodic shift of 500 mV and a catalytic increase in current, which is characteristic of an EC mechanism (figure 2). A series of investigations into this mechanism were done following the initial discovery, including scan rate and concentration dependence CV’s, spectro-electrochemical studies, bulk electrolysis, DEMS, and DFT calculations. These studies allowed us to propose the mechanism below (figure 1) for hydrogen evolution. This presentation will detail our efforts to characterize this hydrogen evolution catalyst, the relevance of small molecule hydrogen evolution catalyst, and how we intend to modify it for synthetic purposes.Figure 1 (left image): Reduction of pyridinium amide with and without guests and proposed mechanism of hydrogen evolutionFigure 2 (right image): CV of pyridinium amide in the presence of dodecanoic acid Figure 1

New car odor: sensory and molecular characterization of odors and potential sources of smell in the vehicle interior

The typical new car smell is very distinctive. Depending on vehicle brand and class, this characteristic odor differs in intensity and elicits either approval or rejection among vehicle purchasers. Up to now, only limited information has been available on the molecular composition of the new car odor. Vehicle manufacturers (OEMs) are mainly concerned with the analysis of toxic compounds and (odorless) main components of the gas phase of the vehicle interior. In addition, OEMs usually do not have an appropriate equipment to characterize odorants by instrumental analysis. Therefore, this work deals with the investigation of odors and potential sources of smell in the vehicle interior. In the first two chapters of this thesis, odor‐active compounds of an aqueous cavity preservation were analyzed by means of solvent extraction, gas chromatography‐olfactometry (GC‐O) and odor extract dilution analysis (OEDA). Odorants of the investigated corrosion inhibitor could enter the vehicle interior via air bridges between the vehicle body and the passenger cabin and could have a considerable influence on the odor. Identification of the potent odors by twodimensional gas chromatography‐mass spectrometry coupled with olfactometry (2D‐GC‐ MS/O) revealed a series of carboxylic acids and lactones as the main odor contributors of the cavity preservation. The hardening of the cavity preservation affected a change of the odor profile due to the evaporation of odor‐potent lactones which was confirmed by a descriptive odor profile analysis. A comparison with odorants of individual materials of the vehicle interior investigated in literature revealed that both identified substance classes are present in a wide variety of materials and, consequently, contribute to the odor in the vehicle interior. In the third chapter of this thesis, odorants of the aqueous cavity preservation were investigated by means of emission test chamber experiments with the aim to obtain further insights into the odorant composition. Since no appropriate method existed to investigate odorants in a gas phase in the form of a liquid odor extract, different sampling strategies, such as chamber air absorption and adsorption, were compared. Subsequent investigations by GC‐O and OEDA revealed potent carboxylic acids and lactones in the gas phase of the heated cavity preservation using each sampling method. In addition, more detailed results were obtained in a descriptive odor profile analysis by sample presentation of chamber air in odor bags compared to a presentation in glass vessels according to VDA 270. As a result, the developed methods may be extended for the investigation of odorants in air of big vehicle assemblies or whole vehicle interiors. In the fourth and the fifth chapter of this thesis, odorants of two new car interiors with different seat covers were analyzed as general proof of principle. For this purpose, air of the vehicle interiors was investigated in a whole vehicle test stand for interior emissions by means of adsorption and subsequent elution of the volatiles. Following GC‐O and 2D‐GC‐MS/O analyses, 39 odorants were identified belonging to various substance classes such as esters, saturated and unsaturated aldehydes, unsaturated ketones, rose ketones, phenol and benzene derivatives, and pyrazines. Furthermore, ten important odorants were quantified which could be detected in a descriptive odor profile analysis. After the initial investigation, both vehicles were used by a customer in his everyday life. At specific time intervals during use, the odorant composition of the vehicle cabins was analyzed by means of sensory evaluation and instrumental analysis after sampling on the test stand for interior emissions. The knowledge of the decay behavior of the odorants allowed further pinpointing of the most important odorants that caused the typical new car odor in the two investigated cars during vehicle usage. Based on these findings, a targeted investigation of individual components regarding the identified odorants and, thus, a reduction of the exposure to smelly substances in the vehicle interior will be significantly facilitated.

Oxidation of Per- and Polyfluoroalkyl Ether Acids and Other Per- and Polyfluoroalkyl Substances by Sulfate and Hydroxyl Radicals: Kinetic Insights from Experiments and Models.

Per- and polyfluoroalkyl substances (PFAS) are widely used anthropogenic chemicals. Because of the strength of the carbon-fluorine bond, PFAS are not destroyed in typical water treatment processes. Sulfate (SO4•-) and hydroxyl (•OH) radicals can oxidize some PFAS, but the behavior of per- and polyfluoroalkyl ether acids (PFEAs) in processes involving SO4•- and •OH is poorly understood. In this study, we determined second-order rate constants (k) describing the oxidation of 18 PFAS, including 15 novel PFEAs, by SO4•- and •OH. Among the studied PFAS, 6:2 fluorotelomer sulfonate reacted most readily with •OH [k•OH = (1.1-1.2) × 107 M-1 s-1], while polyfluoroalkyl ether acids containing an -O-CFH- moiety reacted more slowly [k•OH = (0.5-1.0) × 106 M-1 s-1]. In the presence of SO4•-, polyfluoroalkyl ether acids with an -O-CFH- moiety reacted more rapidly [kSO4•- = (0.89-4.6) × 106 M-1 s-1] than perfluoroalkyl ether carboxylic acids (PFECAs) and a chloro-perfluoro-polyether carboxylic acid (ClPFPECA) [kSO4•- = (0.85-9.5) × 104 M-1 s-1]. For homologous series of perfluoroalkyl carboxylic acids, linear and branched monoether PFECAs, and multiether PFECAs, PFAS chain length had little impact on second-order rate constants. SO4•- reacted with the carboxylic acid headgroup of perfluoroalkyl carboxylic acids and PFECAs. In contrast, for polyfluoroalkyl ether carboxylic and sulfonic acids with an -O-CFH- moiety, the site of SO4•- attack was the -O-CFH- moiety. Perfluoroalkyl ether sulfonic acids were not oxidized by SO4•- and •OH under the conditions evaluated in this study.

Interphase formation with carboxylic acids as slurry additives for Si electrodes in Li-ion batteries. Part 1: performance and gas evolution

Rendering the solid electrolyte interphase and the inter-particle connections more resilient to volume changes of the active material is a key challenge for silicon electrodes. The slurry preparation in a buffered aqueous solution offers a strategy to increase the cycle life and capacity retention of silicon electrodes considerably. So far, studies have mostly been focused on a citrate buffer at pH = 3, and therefore, in this study a series of carboxylic acids is examined as potential buffers for slurry preparation in order to assess which chemical and physical properties of carboxylic acids are decisive for maximizing the capacity retention for Si as active material. In addition, the cycling stability of buffer-containing electrodes was tested in dependence of the buffer content. The results were complemented by analysis of the gas evolution using online electrochemical mass spectrometry in order to understand the SEI layer formation in presence of carboxylic acids and effect of high proton concentration.

Estrogenic Activity of Perfluoro Carboxylic and Sulfonic Acids in Rainbow Trout Estrogen Receptor Binding and Liver Slice Vtg mRNA Expression Assays.

Perfluoroalkylated substances (PFAS) such as carboxylic acids, and sulfonic acids were manufactured in high quantities and are ubiquitous environmental contaminants. These chemicals persist in the environment and tend to bioaccumulate. In the current study, the estrogenic potential of a series of perfluoro carboxylic acids and select perfluoro sulfonic acids were assessed in an in vitro rainbow trout estrogen receptor (rtER) binding assay and an ex vivo rtER dependent vitellogenin (Vtg) expression rainbow trout liver slice assay. Perfluoro carboxylic acids with perfluoroalkyl chain lengths of four to six did not significantly bind to the rtER or induce Vtg expression in liver slices. Perfluoro carboxylic acids with chain lengths of seven to ten, and sulfonic acids with seven and eight carbon chains bound to the rtER, but with low relative binding affinities. While affinity for the rtER increased with increasing chain length the highest affinity measured was only 0.0025% relative to the endogenous hormone 17ß-estradiol at 100%. Both the eight-carbon carboxylic acid and eight-carbon sulfonic acid induced Vtg expression in ex vivo liver slices. However, toxicity did not allow expression to achieve maximum efficacy relative to estradiol.

Rapid evaluation of UV and thermal aging of boiled tung oil by micro-UV/Py-GC/MS system

Boiled tung oil is the commonly used drying oil in Chinese cultural relics, and light radiation, temperature are the important factors leading to its aging. In order to investigate the photo and thermal aging behavior of boiled tung oil and determine the characteristic parameters to evaluate its aging degree, micro-UV/Py-GC/MS system has been applied in the present work to monitor the volatile aging products released by boiled tung oil film, to obtain high aging degree boiled tung oil film in short time and to investigate its composition change in different aging degree.Research results showed that volatile products released by boiled tung oil film during UV irradiation and 60 ℃ were mainly series of aldehydes, ketones, carboxylic acids and hydrocarbons with small molecule. With increase of aging time, the type of volatile products remain unchanged, but their amount gradually decreases until cannot be detected. Pyrolytical products of unaged and aged boiled tung oil is the same, but with the increase of aging degree, relative content of glycerol, dicarboxylic acids and azelaic acid in boiled tung oil film gradually increased, while the relative content of oleic, linoleic and eleostearic acid, as well as the content ratio of mono-carboxylic acids to di-carboxylic acids gradually decreased.Changes of volatile and pyrolytical products during aging process were summarized to evaluate the aging degree of boiled tung oil used in cultural relics. Boiled tung oil used in two lacquerware samples collected from the same carved lacquer panel from Fuwang Ge in the Forbidden City, and two polychrome samples separately collected from the inner and outer eave of Yanxi Tang in the Forbidden City were investigated, the aging degree evaluation results of boiled tung oil in historical samples have further confirm the reliability of summarized parameters. Research results of the present work can provide scientific support for the conservation and restoration of related cultural relics, and also lay a foundation for the in-depth study of the photo and thermal aging mechanism of boiled tung oil.

Palladium-catalysed deaminative/decarboxylative cross-coupling of organoammonium salts with carboxylic acids.

A palladium-catalysed carbon-carbon bond-forming reaction via deaminative/decarboxylative cross-coupling of organoammonium salts with carboxylic acids was developed. Under the reaction conditions, polyfluoroaromatic carboxylic acids, propiolic acids and α-cyano benzyl carboxylic acid reacted smoothly with benzyl ammonium salts to produce the corresponding carbon-carbon coupling products in good-to-excellent yields.

Fluorescence detected circular dichroism (FDCD) of a stereodynamic probe.

The use of chiroptical techniques in combination with stereodynamic probes is becoming one of the leading strategies for chiral sensing. While in most of the reported studies circular dichroism (CD) is the adopted spectroscopic technique, examples regarding the use of vibrational CD (VCD), circularly polarized luminescence (CPL), and Raman optical activity (ROA) are emerging as innovative tools. In this communication, an anthracene-decorated tris(2-pyridylmethyl)amine zinc complex (TPMA) is reported for its capability to act as a chiral sensor using either CD or fluorescence detected circular dichroism (FDCD). The latter technique offers the unique possibility to determine the enantiomeric excess of a series of carboxylic acids at sensor concentrations down to 0.1 μM. Limitations and possibilities opened by the use of this methodology, in particular regarding the specificity of the probe in the presence of another contaminant, are discussed.

1,3-dichloro-5,5-dimethylhydantoin promoted esterification of carboxylic acids under mild conditions

A novel and practical method has been discovered for the synthesis of esters from carboxylic acids promoted by 1,3-dichloro-5,5-dimethylhydantoin. Reactions proceed smoothly under mild conditions and show high efficiency with good to excellent yields. A series of carboxylic acids including simple molecules, drugs and amino acids are applicable to this method.

Synthesis and biological screening of novel series of 2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-[1,3,4]oxadiazole by conventional and non conventional techniques

Novel acid hydrazide 1 when reacted with a series of different carboxylic acids in presence of phosphorous oxychloride to give novel series of 2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-[1,3,4]oxadiazole 3a-3f. Use of conventional and non-conventional techniques is adapted to study the duration time of reaction. These oxadiazole compounds are studied by using spectral analysis like 1H NMR, FT-IR and mass spectroscopy. Further they are screened for antibacterial and anti-fungal biological activities.

Design, Synthesis, and Evaluation of a Set of Carboxylic Acid and Phosphate Prodrugs Derived from HBV Capsid Protein Allosteric Modulator NVR 3-778.

Hepatitis B virus (HBV) capsid protein (Cp) is necessary for viral replication and the maintenance of viral persistence, having become an attractive target of anti-HBV drugs. To improve the water solubility of HBV capsid protein allosteric modulator (CpAM) NVR 3-778, a series of novel carboxylic acid and phosphate prodrugs were designed and synthesized using a prodrug strategy. In vitro HBV replication assay showed that these prodrugs maintained favorable antiviral potency (EC50 = 0.28–0.42 µM), which was comparable to that of NVR 3-778 (EC50 = 0.38 µM). More importantly, the cytotoxicity of prodrug N8 (CC50 > 256 µM) was significantly reduced compared to NVR 3-778 (CC50 = 13.65 ± 0.21 µM). In addition, the water solubility of prodrug N6 was hundreds of times better than that of NVR 3-778 in three phosphate buffers with various pH levels (2.0, 7.0, 7.4). In addition, N6 demonstrated excellent plasma and blood stability in vitro and good pharmacokinetic properties in rats. Finally, the hemisuccinate prodrug N6 significantly improved the candidate drug NVR 3-778’s water solubility and increased metabolic stability while maintaining its antiviral efficacy.

Microwave and Computational Study of Pivalic Sulfuric Anhydride and the Pivalic Acid Monomer: Mechanistic Insights into the RCOOH + SO3 Reaction.

The microwave spectrum of pivalic sulfuric anhydride, (CH3)3CCOOSO2OH (PivSA), has been observed by rotational spectroscopy. The compound was formed by the reaction of SO3 with (CH3)3CCOOH (pivalic acid) in a supersonic jet in a manner analogous to that previously observed with other carboxylic acids. Computational analysis indicates that the reaction is best described as a pericyclic process coupled with a 60° rotation of the t-butyl group. Product formation can occur through either a sequential (two-step) or a concerted (one-step) pathway. The former involves an internal rotation of the t-butyl group through a 0.11 kcal/mol barrier followed by the pericyclic reaction that joins the moieties. The latter passes through a second-order saddle point in which the internal rotation and pericyclic reaction occur simultaneously. This path is the most energetically favorable, as the zero-point corrected energy at the saddle point structure is 0.16 kcal/mol below that of a putative (CH3)3CCOOH-SO3 precursor complex. Additional computational work involving a series of carboxylic acids is reported, which explores the effects of gas-phase acidity and basicity of the RCOOH reactant on reaction energetics. These calculations, together with prior experimental and theoretical studies of the acetic and trifluoroacetic derivatives, demonstrate that the basicity of the carbonyl oxygen, not the acidity of the COOH proton, is the important driving factor for the reaction. As a precursor to the experimental work on the title molecule, microwave spectra of the parent and OD forms of the pivalic acid monomer were recorded and are reported here as well. A convenient synthesis of SO3 is also described.