Synthesis and antimalarial and anticancer evaluation of 7-chlorquinoline-4-thiazoleacetic derivatives containing aryl hydrazide moieties.

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of ß-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.

The extraordinary transformation of traditional Chinese medicine: processing with liquid excipients.

Context: The Chinese medicinal materials originate from animals, plants, or minerals must undergo appropriate treatment before use as decoction pieces. Processing of Chinese medicines with liquid excipients is a pharmaceutical technique that transforms medicinal raw materials into decoction pieces which are significantly different from the original form. During processing, significant changes occur in chemical constituents, which inevitably affects clinical efficacy. At present, the liquid materials in processing mainly involve wine, vinegar, honey, saline water, ginger juice, herbal juice, etc.Objective: This review introduces the typical methods of liquid excipients processing, summarizes the influence on chemical composition, pharmacological efficacy, and expounds the ways and mechanisms of liquid excipients to change the properties of drugs, enhance the efficacy, eliminate or reduce toxicity and adverse reaction.Methods: English and Chinese literature from 1986 to 2020 was collected from databases including Web of Science, PubMed, Elsevier, Chinese Pharmacopoeia 2015, and CNKI (Chinese). Liquid excipients, processing, pharmacological effects, synergism, chemical constitution, traditional Chinese medicine (TCM) were used as the key words.Results: Liquid excipients play a key role in the application of TCM. Processing with proper liquid excipients can change the content of toxic or active components by physical or chemical transformation, decrease or increase drug dissolution, alter drug pharmacokinetics, or exert their own pharmacological effects. Thus, processing with liquid excipients is essential to ensure the safety and efficacy of TCM in clinic.Conclusion: This article could be helpful for researchers who are interested in traditional Chinese herbs processed with liquid excipients.

Changes of Physicochemical, Bioactive Compounds and Antioxidant Capacity during the Brewing Process of Zhenjiang Aromatic Vinegar.

Zhenjiang aromatic vinegar (ZAV) is a kind of traditional fermented food worldwide. In this study, the changes of physicochemical properties, total phenolic content (TPC), total flavonoid content (TFC), and total antioxidant activity (TAA) were evaluated during the brewing process of ZAV. In addition, the correlation between phenolic compound contents and antioxidant activities was investigated during the aging process (AP) of ZAV. The results showed that total acids, non-volatile acids, and amino nitrogen increased gradually during the brewing process. Reducing sugar decreased sharply at the early fermentation stage and then increased during the AP. Meanwhile, TPC, TFC, and TAA kept a very low level at the stage of alcohol fermentation (AF), and increased to the highest level at the sixth year of the AP. TAA has a high positive correlation with TPC and TFC during the brewing process of ZAV. In addition, the contents of p-hydroxybenzoic acid, vanillic acid, and catechin were higher than other phenolic compounds and reached the highest level at the sixth year of the AP, and were the main composition of phenolic compounds during the AP. Moreover, gallic acid, ferulic acid, and sinapic acid had the higher contribution at the early stage of the AP, and then declined to a lower level. Catechin, vanillic acid, and syringic acid had a higher contribution during the AP. These findings would be helpful in controlling the quality of vinegar and improving its functional properties.

Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species.

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.

Synthesis, Molecular Docking and in Vitro Screening of Some Newly Synthesized Triazolopyridine, Pyridotriazine and Pyridine⁻Pyrazole Hybrid Derivatives.

A series of novel pyridine and fused pyridine derivatives have been prepared starting from 6-(3,4-dimethylphenyl)-2-hydrazinyl-4-(thiophen-2-yl)-pyridine-3-carbonitrile 1 which on treatment with appropriate formic acid, acetic acid/ acetic anhydride, benzoyl chloride and/or carbon disulfide afforded the corresponding triazolopyridine derivatives 2⁻5. Also, treatment of hydrazide 1 with diethyloxalate, chloroacetyl chloride, chloroacetic acid and/or 1,2-dichloroethane yielded the corresponding pyridotriazine derivatives 7⁻10. Further transformation of compound 1 with a different active methylene group, namely acetyl acetone, diethylmalonate, ethyl cyanoacetate, ethyl benzoylacetate and/or ethyl acetoacetate, produced the pyridine⁻pyrazole hybrid derivatives 11⁻15. These newly synthesized compounds (1⁻15) were subjected to in silico molecular docking screenings towards GlcN-6-P synthase as the target protein. The results revealed moderate to good binding energies of the ligands on the target protein. All the newly prepared products exhibited antimicrobial and antioxidant activity.

High Acetic Acid Production Rate Obtained by Microbial Electrosynthesis from Carbon Dioxide.

High product specificity and production rate are regarded as key success parameters for large-scale applicability of a (bio)chemical reaction technology. Here, we report a significant performance enhancement in acetate formation from CO2, reaching comparable productivity levels as in industrial fermentation processes (volumetric production rate and product yield). A biocathode current density of -102 ± 1 A m(-2) and an acetic acid production rate of 685 ± 30 (g m(-2) day(-1)) have been achieved in this study. High recoveries of 94 ± 2% of the CO2 supplied as the sole carbon source and 100 ± 4% of electrons into the final product (acetic acid) were achieved after development of a mature biofilm, reaching an elevated product titer of up to 11 g L(-1). This high product specificity is remarkable for mixed microbial cultures, which would make the product downstream processing easier and the technology more attractive. This performance enhancement was enabled through the combination of a well-acclimatized and enriched microbial culture (very fast start-up after culture transfer), coupled with the use of a newly synthesized electrode material, EPD-3D. The throwing power of the electrophoretic deposition technique, a method suitable for large-scale production, was harnessed to form multiwalled carbon nanotube coatings onto reticulated vitreous carbon to generate a hierarchical porous structure.

Biotransformations of 2-hydroxy-2-(ethoxyphenylphosphinyl)acetic acid and the determination of the absolute configuration of all isomers.

2-Hydroxy-2-(ethoxyphenylphosphinyl)acetic acid, a new type of organophosphorus compound possessing two stereogenic centers, was investigated. Racemic 2-butyryloxy-2-(ethoxyphenylphosphinyl)acetic acid was synthesized and hydrolyzed using four bacterial species as biocatalysts. In all cases the reaction was more or less stereoselective and isomers bearing a phosphorus atom with an (SP)-configuration were hydrolyzed preferentially. The observed (1)H and (31)P NMR chemical shifts of Mosher esters of 2-hydroxy-2-(ethoxyphenylphosphinyl)acetic acid were correlated with the configurations of both stereogenic centers of all four stereoisomers.

A direct access to bioactive fused N-heterocyclic acetic acid derivatives.

A Cu-catalyzed new sequence involving the Ullmann type intermolecular C-C followed by an intramolecular C-N coupling and then intramolecular aza-Michael type addition (and oxidation) in a single pot afforded various fused N-heterocyclic acetic acid derivatives as inhibitors of PDE4.

Electrolytic membrane extraction enables production of fine chemicals from biorefinery sidestreams.

Short-chain carboxylates such as acetate are easily produced through mixed culture fermentation of many biological waste streams, although routinely digested to biogas and combusted rather than harvested. We developed a pipeline to extract and upgrade short-chain carboxylates to esters via membrane electrolysis and biphasic esterification. Carboxylate-rich broths are electrolyzed in a cathodic chamber from which anions flux across an anion exchange membrane into an anodic chamber, resulting in a clean acid concentrate with neither solids nor biomass. Next, the aqueous carboxylic acid concentrate reacts with added alcohol in a water-excluding phase to generate volatile esters. In a batch extraction, 96 ± 1.6% of the total acetate was extracted in 48 h from biorefinery thin stillage (5 g L(-1) acetate) at 379 g m(-2) d(-1) (36% Coulombic efficiency). With continuously regenerated thin stillage, the anolyte was concentrated to 14 g/L acetic acid, and converted at 2.64 g (acetate) L(-1) h(-1) in the first hour to ethyl acetate by the addition of excess ethanol and heating to 70 °C, with a final total conversion of 58 ± 3%. This processing pipeline enables direct production of fine chemicals following undefined mixed culture fermentation, embedding carbon in industrial chemicals rather than returning them to the atmosphere as carbon dioxide.

Mechanistic insight into the formation of acetic acid from the direct conversion of methane and carbon dioxide on zinc-modified H-ZSM-5 zeolite.

Methane and carbon dioxide are known greenhouse gases, and the conversion of these two C1-building blocks into useful fuels and chemicals is a subject of great importance. By solid-state NMR spectroscopy, we found that methane and carbon dioxide can be co-converted on a zinc-modified H-ZSM-5 zeolite (denoted as Zn/H-ZSM-5) to form acetic acid at a low temperature range of 523-773 K. Solid-state (13)C and (1)H MAS NMR investigation indicates that the unique nature of the bifunctional Zn/H-ZSM-5 catalyst is responsible for this highly selective transformation. The zinc sites efficiently activate CH4 to form zinc methyl species (-Zn-CH3), the Zn-C bond of which is further subject to the CO2 insertion to produce surface acetate species (-Zn-OOCCH3). Moreover, the Brønsted acid sites play an important role for the final formation of acetic acid by the proton transfer to the surface acetate species. The results disclosed herein may offer the new possibility for the efficient activation and selective transformation of methane at low temperatures through the co-conversion strategy. Also, the mechanistic understanding of this process will help to the rational design of robust catalytic systems for the practical conversion of greenhouse gases into useful chemicals.

Purinyl N1-directed aromatic C-H oxidation in 6-arylpurines and 6-arylpurine nucleosides.

Palladium-catalyzed C-H bond activation and oxidation of C6 arylpurines as well as C6 arylpurine nucleosides can be accomplished using Pd(OAc)2/PhI(OAc)2 in CH3CN. Despite the presence of four nitrogen atoms in the purine moiety as well as the polyoxygenated saccharide and a labile glycosidic bond in the nucleosides, these reactions can be effectively conducted. Notably, the generally more labile 2'-deoxyribonucleosides also undergo reaction. The reaction conditions can be tuned to yield either monoacetoxylated or diacetoxylated products predominantly. In the course of these investigations, a dimeric Pd(II)-containing cyclopalladated C6 naphthylpurine derivative has been obtained and crystallographically characterized. This compound is competent in catalyzing the oxidization with PhI(OAc)2, indicating its plausible intermediacy in the chemistry. The X-ray structure of a monoacetoxylated product from this reaction has also been obtained.

Design and synthesis of alkoxyindolyl-3-acetic acid analogs as peroxisome proliferator-activated receptor-γ/δ agonists.

A series of carbazole or phenoxazine containing alkoxyindole-3-acetic acid analogs were prepared as PPARγ/δ agonists and their transactivation activities for PPAR receptor subtypes (α, γ and δ) were investigated. Structure-activity relationship studies disclosed the effect of the lipophilic tail, attaching position of the alkoxy group and N-benzyl substitution at indole. Compound 1b was the most potent for PPARδ and 3b for PPARγ. Molecular modeling suggested two different binding modes of our alkoxyindole-3-acetic acid analogs providing the insight into their PPAR activity.

Theoretical study of reaction of ketene with water in the gas phase: formation of acetic acid?

Production of acetic acid via gas-phase hydration of ketene by water (uncatalyzed and in the presence of an additional water molecule) was theoretically characterized using high-level coupled-cluster methods, followed by a two-dimensional master equation analysis to compute thermal reaction rate constants. The results show that the formation of acetic acid quite likely occurs in high-temperature combustion of biomass, but that the rate of formation should be negligible under ambient atmospheric conditions.

Electrochemical reduction of CO2 to organic acids by a Pd-MWNTs gas-diffusion electrode in aqueous medium.

Pd-multiwalled carbon nanotubes (Pd-MWNTs) catalysts for the conversion of CO2 to organic acids were prepared by the ethylene glycol reduction and fully characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), and cyclic voltammetry (CV) technologies. The amorphous Pd particles with an average size of 5.7 nm were highly dispersed on the surface of carbon nanotubes. Functional groups of the MWNTs played a key role in the palladium deposition. The results indicated that Pd-MWNTs could transform CO2 into organic acid with high catalytic activity and CO2 could take part in the reduction reaction directly. Additionally, the electrochemical reduction of CO2 was investigated by a diaphragm electrolysis device, using a Pd-MWNTs gas-diffusion electrode as a cathode and a Ti/RuO2 net as an anode. The main products in present system were formic acid and acetic acid identified by ion chromatograph. The selectivity of the products could be achieved by reaction conditions changing. The optimum faraday efficiencies of formic and acetic acids formed on the Pd-MWNTs gas-diffusion electrode at 42V electrode voltages under 1 atm CO2 were 34.5% and 52.3%, respectively.

New Thyrointegrin αvß3 Antagonist with a Scalable Synthesis, Brain Penetration, and Potent Activity against Glioblastoma Multiforme.

We have previously reported that the αvß3 inhibitor P-bi-TAT, a bifunctional version of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) conjugated to polyethylene glycol (PEG) MW 4000, has excellent efficacy in a glioblastoma multiforme (GBM) mouse model. However, bioanalysis problems due to PEG polydispersity and large-scale synthesis issues led to a search for new molecules, culminating in the discovery of fb-PMT, a conjugate of tetrac and monodisperse PEG36, with a lipophilic 4-fluorobenzyl group at the opposite end of the PEG chain. fb-PMT reduces GBM tumor growth and viability by up to 98%, is suitable for large-scale synthesis, and is amenable to bioanalysis using mass spectrometry-based detection. We also showed that changes in lipophilicity at the opposite end of the PEG chain from the active tetrac component affected the proton NMR chemical shift of the tetrac moiety in D20 and brain levels of the compound after subcutaneous dosing.

Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth.

Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.

Design, Synthesis and Biological Activity of New Amides Derived from 3-Benzhydryl and 3-sec-Butyl-2,5-dioxo-pyrrolidin-1-yl-acetic Acid.

The aim of this study was to design and synthesize two new series of pyrrolidine-2,5-dione-acetamides with a benzhydryl or sec-butyl group at position 3 as potential anticonvulsants. Their anticonvulsant activity was evaluated in standard animal models of epilepsy: the maximal electroshock (MES), the 6 Hz, and the subcutaneous pentylenetetrazole (scPTZ) tests. The in vivo studies revealed the most potent anticonvulsant activity for 15 (3-(sec-butyl)-1-(2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione), with ED50 values of 80.38 mg/kg (MES) and 108.80 mg/kg (6 Hz). The plausible mechanism of action was assessed in in vitro binding assays, in which 15 interacted effectively with voltage-gated sodium (site 2) and L-type calcium channels at a concentration of 100 µM. Subsequently, the antinociceptive activity of compounds 7 and 15 was observed in the hot plate test of acute pain. Moreover, compounds 7, 11 and 15 demonstrated an analgesic effect in the formalin test of tonic pain. The hepatotoxic properties of the most effective compounds (7, 11 and 15) in HepG2 cells were also investigated.

Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1.

Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional antagonistic effect of 66 nM in a BRET and 12 nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27 microM in cAMP).

(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors.

(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids exhibit a wide range of pharmacological activities. Among them, the only derivative used in clinical practice is the aldose reductase inhibitor epalrestat. Structurally related compounds, [(5Z)-(5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)]acetic acid derivatives were prepared previously as potential antifungal agents. This study was aimed at the determination of aldose reductase inhibitory action of the compounds in comparison with epalrestat and evaluation of structure-activity relationships (SAR). The aldose reductase (ALR2) enzyme was isolated from the rat eye lenses, while aldehyde reductase (ALR1) was obtained from the kidneys. The compounds studied were found to be potent inhibitors of ALR2 with submicromolar IC50 values. (Z)-2-(5-(1-(5-butylpyrazin-2-yl)ethylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (3) was identified as the most efficacious inhibitor (over five times more potent than epalrestat) with mixed-type inhibition. All the compounds also exhibited low antiproliferative (cytotoxic) activity to the HepG2 cell line. Molecular docking simulations of 3 into the binding site of the aldose reductase enzyme identified His110, Trp111, Tyr48, and Leu300 as the crucial interaction counterparts responsible for the high-affinity binding. The selectivity factor for 3 in relation to the structurally related ALR1 was comparable to that for epalrestat. SAR conclusions suggest possible modifications to improve further inhibition efficacy, selectivity, and biological availability in the group of rhodanine carboxylic acids.

Peptides by activation of amino acids with CO on (Ni,Fe)S surfaces: implications for the origin of life.

In experiments modeling volcanic or hydrothermal settings amino acids were converted into their peptides by use of coprecipitated (Ni,Fe)S and CO in conjunction with H2S (or CH3SH) as a catalyst and condensation agent at 100 degreesC and pH 7 to 10 under anaerobic, aqueous conditions. These results demonstrate that amino acids can be activated under geochemically relevant conditions. They support a thermophilic origin of life and an early appearance of peptides in the evolution of a primordial metabolism.