Acetic Acid Moiety Research Articles

Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein–ligand interactions at COX-2 active sites indicative of therapeutic potential.

Synthesis and Biological Evaluation of α-Tocopherol Derivatives as Potential Anticancer Agents

α-Tocopheryl succinate (α-TS) and α-tocopheryloxyacetic acid (α-TEA) are potent inducers of apoptosis in cancer cells and efficient suppressors of tumors in experimental model cancer cell lines. They exhibit selective cytotoxicity against tumor cells and very limited or no toxicity toward nonmalignant cells. In the present work, a series of new α-tocopherol derivatives were synthesized as analogs of α-TS and α-TEA. The cytotoxic activity of obtained compounds was tested using three human cancer cell lines, including chronic lymphoblastic leukemia (CEM), breast adenocarcinoma (MCF7), cervical adenocarcinoma (HeLa), and normal human fibroblasts (BJ). The introduction of an alkyl substituent into the ether-linked acetic acid moiety in α-TEA increased anticancer activity. α-Tocopheryloxy-2-methylpropanoic acid with two additional geminal methyl groups was more active against CEM cells compared to α-TEA and non-toxic to normal cells. In order to acquire a deeper understanding of the biological activity of synthesized compounds, a molecular docking study was also conducted. Our research confirmed that vitamin E derivatives are interesting and valuable compounds in terms of their potential therapeutic use as anticancer agents.

Nanostructured poly(thiophene acetic acid)/Au/poly(methylene blue) interface for electrochemical immunosensing of p53 protein.

A poly(thiophene acetic acid)/Au/poly(methylene blue) nanostructured interface was electrochemically assembled step-by-step on screen-printed carbon electrodes (SPCE) for label-free detection of p53 protein. The initial electrical conductive properties of the polymeric interface were increased with an additional layer of poly(methylene blue) electropolymerized in the presence of gold nanoparticles. The nano-immunosensing architecture was prepared by covalent immobilization of anti-p53 antibodies as bioreceptors through the poly(thiophene acetic acid) moieties. The nano-immunosensor assembly was extensively characterized by ultraviolet-visible spectrophotometry, dynamic and electrophoretic light scattering, scanning electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, atomic force microscopy, cyclic voltammetry, and electrochemical impedance spectroscopy. Under optimal conditions, p53 was specifically and selectively detected by square wave voltammetry in a linear range between 1 and 100ngmL-1 with a limit ofdetection of 0.65ngmL-1. In addition, the electrochemical nano-immunosensor detected p53 in spiked human serum samples and colorectal cancer cell lysates, and the results were validated with a standard spectrophotometric method using a paired samples t test, which did not exhibit significant differences between both methods. The resultant p53 nano-immunosensor is simple to assemble, robust, and has the potential for point-of-care biomarker detection applications.

2-Oxa-5-azabicyclo[2.2.1]heptane as a Platform for Functional Diversity: Synthesis of Backbone-Constrained γ-Amino Acid Analogues

We communicate a versatile synthetic approach to C-3 disubstituted 2-oxa-5-azabicyclo[2.2.1]heptanes as carbon-atom bridged morpholines, starting with 4R-hydroxy-l-proline as a chiron. Attaching an acetic acid moiety on the C-3 carbon of the 2-oxa-5-azabicyclo[2.2.1]heptane core reveals the framework of an embedded γ-amino butyric acid (GABA). Variations in the nature of the substituent on the tertiary C-3 atom with different alkyls or aryls led to backbone-constrained analogues of the U.S. Food and Drug Administration-approved drugs baclofen and pregabalin.

Rapid and One-Step Screening of Taxane Compounds by a Two-Dimensional Carbon Microfiber Fractionation System Combined with Tandem Mass Spectrometry.

Taxane compounds have attracted wide attention due to the basic chemical structure of taxol as an alternative anticancer drug. The full-scan tandem mass spectrometry (MS/MS) fragmentation behaviors of seven taxane compounds were studied. For taxanes of Sc-T and Sc-T-Xyl types, diagnostic product ions are originated from a cleavage in the ester bond of the C13 position and the C-O bond of the C7 position, and the subsequent fragmentation pattern is similar to those of M-type taxanes with the loss of different numbers of acetic acid moieties (AcOH), benzoic acid moieties (BzOH), and H2O molecules. A rapid (7 min) and one-step screening method of two-dimensional microscale carbon fiber and active carbon fiber columns combined with tandem mass spectrometry (2DμCFs-MS/MS) was developed for the screening of taxane compounds from Taxus cuspidata samples. Before MS/MS analysis, the 2DμCFs system can group the sample extract without any pretreatment into three chromatographic-type fractions of strong, medium, and weak polarity to avoid matrix interference, such as lipids and pigments. The 2DμCFs-MS/MS can also conduct qualitative and quantitative analysis of taxane compounds, which is evaluated by limits of detection ranging from 3 to 50 ng mL-1, limits of quantitation ranging from 10 to 150 ng mL-1, satisfactory recoveries from 75.2 to 112.2%, and reproducibilities with relative standard deviations from 1.4 to 11.7%.

Molecular Functionalization of 2H-Phase MoS2 Nanosheets via an Electrolytic Route for Enhanced Catalytic Performance.

The molecular functionalization of two-dimensional MoS2 is of practical relevance with a view to, for example, facilitating its liquid-phase processing or enhancing its performance in target applications. While derivatization of metallic 1T-phase MoS2 nanosheets has been relatively well studied, progress involving their thermodynamically stable, 2H-phase counterpart has been more limited due to the lower chemical reactivity of the latter. Here, we report a simple electrolytic strategy to functionalize 2H-phase MoS2 nanosheets with molecular groups derived from organoiodides. Upon cathodic treatment of a pre-expanded MoS2 crystal in an electrolyte containing the organoiodide, water-dispersible nanosheets derivatized with acetic acid or aniline moieties (∼0.10 molecular groups inserted per surface sulfur atom) were obtained. Analysis of the functionalization process indicated it to be enabled by the external supply of electrons from the cathodic potential, although they could also be sourced from a proper reducing agent, as well as by the presence of intrinsic defects in the 2H-phase MoS2 lattice (e.g., sulfur vacancies), where the molecular groups can bind. The acetic acid-functionalized nanosheets were tested as a non-noble metal-based catalyst for nitroarene and organic dye reduction, which is of practical utility in environmental remediation and chemical synthesis, and exhibited a markedly enhanced activity, surpassing that of other (1T- or 2H-phase) MoS2 materials and most non-noble metal catalysts previously reported for this application. The reduction kinetics (reaction order) was seen to correlate with the net electric charge of the nitroarene/dye molecules, which was ascribed to the distinct abilities of the latter to diffuse to the catalyst surface. The functionalized MoS2 catalyst also worked efficiently at realistic (i.e., high) reactant concentrations, as well as with binary and ternary mixtures of the reactants, and could be immobilized on a polymeric scaffold to expedite its manipulation and reuse.

In Silico ADMET and Docking Studies of Thiazolidinedione-acetic-acid Hybrids as Antidiabetics with Cardioprotection

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties. Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively. Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively. Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

The potential antiviral activity of a novel pyrimidine derivative against Herpes Simplex Virus type-1 (HSV-1)

Context: Previous studies and the are trials to find new molecules to help in the war against viruses. We have started preparing new compounds in this field beginning with the nucleus of thiouracil for what is known from its multiple biological activity, including against viruses. objective: Evaluation antiviral activities of new synthetic pyrimidine compounds. materials and methods: Our new target compounds were prepared starting with 2-thiouracil which was hydroxy methylated to give compound 1 which in turn was chloromethylated by thionyl chloride yielding compound 2. This chloromethyl compound was then reacted with three selected aromatic amines namely, p-nitroaniline, p-fluoroaniline and 2-aminopyridine respectively, giving aminomethyl derivatives 3a-c, which were used as starting material for preparing many target compounds by reaction firstly with s-bromopropanoic acid affording pyrimido thiazine derivatives 4a-c. They were cyclocondensed with anthranilic acid giving pyrimido quinazoline derivatives 5a-c. In another pathway, they were reacted with s-amino ethanol affording imidazopyrimidine derivatives 6a-c. Also, they were S-methylated by methyl iodide giving methyl thiopyrimidine derivatives 7a-c alo were cyclocondensed with ethylbromoacetate and/or chloroacetyl chloride giving isomers of thiazolopyrimidine derivatives 8a-c and 9a-c. Finally, they S-alkylated by reaction with chloroacetic acid yielding acetic acid derivatives 10a-c. Results: Compound 3c and 10c exhibited a potent antiviral activity and, they showed insignificant differences as compared with other compounds. In addition, 10c exhibited higher efficacy as compared with acyclovir. Conclusion: The aryl methyl aminopyrimidine was the pharmacophore of these target compounds. Any change in the structure decreases the activity except the introduction of acetic acid moiety which potentiate the antiviral activity.

Nanocomposite of magnetic nanoparticles/graphene oxide decorated with acetic acid moieties on glassy carbon electrode: A facile method to detect nitrite concentration

Herein, iron oxide magnetic nanoparticles/graphene oxide decorated with acetic acid moieties (Fe3O4/GO/COOH) was synthesized and applied to fabricate a novel nitrite sensor in aqueous solutions (Fe3O4/GO/COOH/GC electrode). Acetic acid moieties were incorporated through nucleophilic reaction of chloroacetic acid with hydroxyl or epoxy groups on the surface of graphene oxide. The morphologies and compositions of fabricated nanomaterials were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction analysis (XRD) and Fourier transform infrared spectroscopy (FTIR). The Electrochemical performance of Fe3O4/GO/COOH/GC electrode was evaluated by electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and differential pulse voltammetry techniques (DPV). The Fe3O4/GO/COOH/GC electrode was employed for the determination of nitrite in aqueous solutions. The DPV results showed a linear response of modified electrode with increasing concentration of nitrite in the range of 1–85μM and 90–600μM with a correlation coefficient of 0.99. The Fe3O4/GO/COOH/GC electrode displayed a considerable sensitivity towards nitrite detection with a detection limit of 0.37μM. Our results suggest the modified electrode as an easy to use and inexpensive candidate for analysis of nitrite concentrations, especially in real samples.

Synthesis and Antimicrobial Activity of 4-S-Methyl-1,3,4-Oxadiazole Derivatives of Some Natural Amino Acids Bearing Secondary Quaternary Ammonium Salt Moieties

Secondary quaternary ammonium salts (QAS) derived from three natural amino acids (L-Leucine, L-Phenylalanine and L-Methionine) bearing 1,3,4-oxadiazole and acetic acid moieties have been synthesized and characterized by IR, 1 H and 13 C NMR. All the synthesized compounds were evaluated for their preliminary in vitro antibacterial and antifungal activity against different bacterial and fungal strains. All the synthesized compounds showed varying degrees of inhibition against the tested microorganisms. DOI: http://dx.doi.org/10.17807/orbital.v10i7.990

Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl.

EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.

An Inexpensive and Scalable Synthesis of Shld.

A synthesis of the important FKBP ligand Shld is reported. The synthesis avoids stoichiometric use of expensive and chiral reagents, maintains enantioselectivity and provides a high overall yield (39%). The main features in the method are enantioselective alkylation for preparation of the phenyl acetic acid moiety (building block A), catalytic enantioselective reduction for obtaining the chiral diaryl-1-propanol (building block C), and direct acylation of S-pipecolic tartrate rather than use of expensive Fmoc-pipecolic acid. The assembly of the building blocks A-C is reversed in comparison to previous synthesis, which also eliminates the need for protective groups.

Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase

Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Kiappvs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs.

Ultrasound-assisted oxidative-adsorptive desulfurization using highly acidic graphene oxide as a catalyst-adsorbent

Modified graphene oxide by acetic acid moiety (GO/COOH) was synthesized and employed in the ultrasound-assisted oxidative-adsorptive desulfurization processes. The modified graphene oxide was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. The fabricated material was applied to simultaneous oxidation and adsorption of dibenzothiophene (DBT) from model fuel. Adsorption studies were carried out to evaluate its potential for DBT removal. The effects of contact time, initial DBT concentration, and temperature on the removal efficiency of the catalyst-adsorbent were investigated. The equilibrium adsorption results was well-described by the Freundlich isotherm model (at room temperature) and oxidation-adsorption of DBT were achieved by GO/COOH with an outstanding adsorption capacity of 370mgg−1. The adsorption process followed a pseudo-first-order kinetic model and the adsorption kinetic data suggests that physical interactions are mainly involved on the entire adsorption process (Ea<40kJmol−1). The initial sulfur content of 1000ppm was reduced to <50ppm within 300min, achieving a sulfur removal of about 95%. As a whole, a model fuel with ultra-low sulfur content was obtained by the developed procedure and GO/COOH shows a high potential for effective desulfurization of diesel fuel asa catalyst-adsorbent.

Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.

A new solvate of epalerstat, a drug for diabetic neuropathy.

Epalerstat {systematic name: (5Z)-5-[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl-idene]-4-oxo-2-sulfanyl-idene-1,3-thia-zolidine-3-acetic acid} crystallized as an acetone monosolvate, C15H13NO3S2·C3H6O. In the epalerstat mol-ecule, the methyl-propyl-enediene moiety is inclined to the phenyl ring and the five-membered rhodamine ring by 21.4 (4) and 4.7 (4)°, respectively. In addition, the acetic acid moiety is found to be almost normal to the rhodamine ring, making a dihedral angle of 85.1 (2)°. In the crystal, a pair of O-H⋯O hydrogen bonds between the carb-oxy-lic acid groups of epalerstat mol-ecules form inversion dimers with an R22(8) loop. The dimers are linked by pairs of C-H⋯O hydrogen bonds, enclosing R22(20) loops, forming chains propagating along the [101] direction. In addition, the acetone mol-ecules are linked to the chain by a C-H⋯O hydrogen bond. Epalerstat acetone monosolvate was found to be isotypic with epalerstat tertra-hydro-furan solvate [Umeda et al. (2017 ▸). Acta Cryst. E73, 941-944].

Highly efficient and selective red-emitting Ca2+ probe based on a BODIPY fluorophore

A red-emitting Ca2+ probe based on difluoro-boron-dipyrromethene (BODIPY) fluorophore and 1,2-bis(o-aminophenoxy)ethane-N,N,-N′,N'-tetra acetic acid (BAPTA) moiety was designed and synthesized. Four electron-donating 4-methoxyphenyl groups were introduced on BODIPY to make the emission of probe more bathochromic-shifted. Upon Ca2+ binding, the probe exhibits a significant increase of red fluorescence intensity (λmax = 631 nm, ΦF = 0.18), an excellent luminescence ON/OFF ratio (43-fold) and a detection limit of 39 μM. Furthermore, this probe shows desirable sensitivity and selectivity for Ca2+ over other metal ions, which could be potentially applied for Ca2+ detection.

Microgels from microfluidic templating and photoinduced crosslinking of cinnamylidene acetic acid modified precursors

So far, a number of approaches to synthesize microgel networks have been followed, while only in few cases a detailed control of the network architecture has been possible. Here, the photoinduced [2+2] cycloaddition reaction of cinnamylidene acetic acid (CAA) moieties coupled to four-arm star shaped oligo(ethylene glycol) (OEG) precursors was explored for the creation of microgels with defined polymer network structures. Based on a rational solvent selection and precursor dispersion in glass-capillary microfluidics, microgels could be successfully prepared by the proposed synthesis approach. Model reactions confirmed a quantitative network formation. Therefore, compared to common radical polymerization for microgel crosslinking, CAA-dimerization may be an alternative approach particularly when well defined network structures are desired.

A task-specific phosphonium ionic liquid as an efficient extractant for green desulfurization of liquid fuel: An experimental and computational study

Desulfurization of fuel is essential to be done from the environmental and industrial points of view. Extractive desulfurization (EDS) is one of the most promising methods in order to meet statutory sulfur content. Among of various extractants, ionic liquids (ILs) are more suitable ones due to their desirable and compatible properties having green chemistry disciplines. This work shows that tributyl(carboxymethyl)phosphonium bromide [TBCMP][Br], as a task-specific phosphonium ionic liquid (PIL) including acetic acid moiety, is able to extract benzothiophenic compounds from liquid fuel, successfully. A series of experiments were done to determine the effect of PIL/fuel volume ratio, time, temperature, multiple extraction and initial concentration on EDS performance of [TBCMP][Br]. The efficiency of extraction for sulfur compounds was determined and obeyed the order of dibenzothiophene>benzothiophene>dimethyldibenzothiophene at 69%, 53% and 40%, respectively. For the volume ratio 0.5 in 15min at room temperature, deep desulfurization can obtain after four extraction times. Finally, the extraction mechanism of PIL, especially the role of acetic acid moiety, was studied experimentally and theoretically for the first time. The computational results show that the alpha hydrogens of methylene groups, connected to phosphonium core and hydrogen of acetic acid moiety, provide hydrogen bonding interaction which indicate [TBCMP][Br] acts as a bi-functional IL for EDS. So, the present work is supposed to create a new and promising insight into the courses of rational designs, syntheses and applications of task-specific ionic liquids for green desulfurization.

Synthesis of 2‐(Quinoxalin‐2‐ylamino‐benzotriazolyl) Pentanedioic Derivatives as Potential Anti‐Folate Agents

Anti‐folate agents had a significant impact on therapeutic treatment plans for diseases such as cancer, and bacterial and parasitic infections, notably malaria. Quinoxaline derivatives showed in vitro anticancer activity and were able to inhibit both the dihydrofolate reductase and thymidylate synthase. Here, we decided to combine the chemical properties of quinoxalines and quinoxaline 1,4‐dioxides with those of benzotriazole nucleus with the aim to evaluate the resulting biological properties. Two main new series, including more than 60 compounds, were prepared. In the first one, the benzotriazole moiety was linked through the nitrogen atoms 1, 2, or 3, to a glutaric acid substituent to simulate a glutamic moiety. In the second series, the glutaric acid was substituted with acetic acid moiety to evaluate the effects of steric hindrance. Here, we describe the multistep chemical processes to obtain all titled quinoxalines starting from commercially available diamines. The classical oxidation of selected quinoxalines was unsuccessful, and we have come to an independent synthetic pathway to obtain new derivatives linked to the benzotriazole moieties starting from synthons bearing N‐oxide functionality.