Ester Derivatives Research Articles

Synthesis of novel (S)-flurbiprofen-based esters for cancer treatment by targeting thymidine phosphorylase via Biomolecular Approaches

The current work is based on the synthesis of novel ester derivatives (1–17) of commercially available drug flurbiprofen by using two methods. In the first method, CDI (1,1-carbonyldiimidazole) as a coupling reagent was used to stimulate the acid of flurbiprofen then various substituted phenols were added to the reaction mixture in the presence triethylamine in acetonitrile solvent. While in the second method, different alkyl halides were directly treated with the acid of flurbiprofen in the occurrence of potassium carbonate as a base in DMF solvent. The reactions direction was checked through thin layer chromatography. Modern spectroscopic techniques like, HR-ESI-MS, 1H- and 13C NMR were used for structural elucidation and finally these compounds were subjected for their thymidine phosphorylase inhibitory potential. Eight compounds (1, 5, 7, 2, 12, 6, 17, and 8) amongst the series were found potent inhibitors having IC50 values of 2.3 ± 0.6 to 14.9 ± 0.3 µM better than standard 7-deazxanthine = 15.1 ± 0.1 µM. Similarly, eight compounds showed significant to less activity while compound 15 was found inactive. The docking analysis reflects excellent binding of the active molecules at the predicted allosteric site of TP and the docking results correlates well with the experimental findings.

Irciniaplysins A-D: New Psammaplysin Derivatives from Philippine Marine Sponge Ircinia sp.

Four new psammaplysin derivatives (1-4) with fatty acyl substituents, designated irciniaplysins A-D, and three known psammaplysins (5-7) were isolated from a marine sponge Ircinia sp. Their structures were elucidated using extensive spectroscopic analyses. The positions of the double bonds and the branch points of the fatty acyl side chains were determined by GC-MS analysis of their fatty acid methyl ester (FAME) derivatives. Irciniaplysins A (1) and B (2) contained an unusual long-chain fatty acyl substituent with a 5,9-diene unit. The isolated compounds were evaluated for their cytotoxic activity against the human colorectal carcinoma (HCT 116) cells, however, none of these compounds showed significant activity.

The Role of Catechol in Caffeic Acid Phenethyl Ester Derivatives for Neuroprotective Effects

AbstractNeurodegenerative disorders are chronic, progressive neurological diseases characterized by damage to neuron cells. Oxidative stress and neuroinflammation play crucial roles in inducing these disorders. Caffeic acid phenethyl ester (CAPE) and its sulfone derivatives have demonstrated antioxidant and anti‐inflammatory effects, suggesting their potential as neuroprotective agents. In this study, 8 sulfone derivatives were designed and synthesized to explore the importance of catechol and structure–activity relationship of CAPE sulfone derivatives. Hydroxyl groups in catechol were replaced by ‐NO2, ‐NH2 or ‐H, and their free radical scavenging, antioxidant, and anti‐inflammatory abilities were evaluated. It was found that the antioxidant activitiy was dominated by the catechol moiety in CAPE derivatives, while the anti‐inflammtory activity was not. Furthermore, the stabilization of catechol after affording H⋅ to eliminate free radicals possibly occurred through hydrogen bond ranther than electron transfer via p‐π conjugation. After the analysis, all the target compounds lost antioxidant properties at cellular level, and among them, the target compound (E)‐2‐amino‐4‐(2‐(phenethylsulfonyl)vinyl) phenol with p‐NH2 and m‐OH showed the best free radical scavaging acivitity and retained anti‐inflammatory activity.

Palladium‐Catalyzed Allylation of Isocyanoacetates with Vinyl‐Aziridines

AbstractThe first palladium‐catalyzed allylation of isocyanoacetates with vinyl aziridines has been developed. The reaction conditions were suitable for a variety of α‐aryl isocyanoacetates as well as N‐substituted vinyl aziridines, affording the corresponding allylation products in moderate to high yields (up to 98 %) along with excellent stereoselectivity and regioselectivity. Transformations of the allylation products into trans‐4,5‐dehydrolysine analogues and a highly functionalized proline ester derivative were further demonstrated, and a preliminary asymmetric version of the reaction has also been evaluated.

Synthesis and biological evaluation of panaxadiol ester derivatives possessing pyrazole and pyrrole moiety as HIF-1α inibitors

Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole (18a–j) and pyrrole (19a–n) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c, 19d, and 19n (IC50 = 8.70–10.44 μM) showed better HIF-1α inhibitory activity than PD (IC50 = 13.35 μM). None of these compounds showed cytotoxicity above 100 μM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.

The Kavaratamides: Discovery of Linear Lipodepsipeptides from the Marine Cyanobacterium Moorena bouillonii Using a Comparative Chemogeographic Analysis.

Kavaratamide A (1), a new linear lipodepsipeptide possessing an unusual isopropyl-O-methylpyrrolinone moiety, was discovered from the tropical marine filamentous cyanobacterium Moorena bouillonii collected from Kavaratti, India. A comparative chemogeographic analysis of M. bouillonii collected from six different geographical regions led to the prioritized isolation of this metabolite from India as distinctive among our data sets. AI-based structure annotation tools, including SMART 2.1 and DeepSAT, accelerated the structure elucidation by providing useful structural clues, and the full planar structure was elucidated based on comprehensive HRMS, MS/MS fragmentation, and NMR data interpretation. Subsequently, the absolute configuration of 1 was determined using advanced Marfey's analysis, modified Mosher's ester derivatization, and chiral-phase HPLC. The structures of kavaratamides B (2) and C (3) are proposed based on a detailed analysis of their MS/MS fragmentations. The biological activity of kavaratamide A was also investigated and found to show moderate cytotoxicity to the D283-medullablastoma cell line.

Visible‐Light‐Mediated Catalyst and Additive‐Free C(sp3)‐H Phosphorylation of Glycine Ester Derivatives

AbstractWe herein report a visible light induced dehydrogenative phosphonylation reaction of glycine derivatives and di‐aryl phosphine oxides. A diverse range of phosphine‐glycine derivatives were constructed under ambient condition in the absence of catalyst and additives. A plausible mechanism was also proposed.

Design, Synthesis, and Antitumor Activity of Isoliquiritigenin Amino Acid Ester Derivatives.

Isoliquiritigenin (ISL) is a chalcone that has shown great potential in the treatment of cancer. However, its relatively weak activity and low water solubility limit its clinical application. In this study, we designed and synthesized 21 amino acid ester derivatives of ISL and characterized the compounds using 1H NMR and 13C NMR. Among them, compound 9 (IC50 = 14.36 μM) had a better inhibitory effect on human cervical cancer (Hela) than ISL (IC50 = 126.5 μM), and it was superior to the positive drug 5-FU (IC50 = 33.59 μM). The mechanism of the action experiment showed that compound 9 could induce Hela cell apoptosis and autophagy through the PI3K/Akt/mTOR pathway.

A Dual Ni/Photoredox Cross-Coupling Approach toward Mandelic Acids.

Mandelic acid derivatives represent a valuable class of compounds due to their wide use in synthetic organic chemistry and the pharmaceutical sector. Herein, we report a novel reductive Ni/photoredox cross-coupling of readily accessible, bench stable N-alkoxyphthalimides and aryl halides to prepare unprotected mandelic acid ester derivatives. Mechanistic experiments suggest that this cross-coupling likely proceeds via a pathway that is distinct from previous reports using similar redox-active alkoxy radical precursors.

Innovative Hybrid Compounds Targeting Tuberculosis: Development, Characterization and Bioefficacy analysis of 6-substituted-2-Chloroquinoline-3-Carbaldehyde Hydrazide Ester derivatives

Innovative Hybrid Compounds Targeting Tuberculosis: Development, Characterization and Bioefficacy analysis of 6-substituted-2-Chloroquinoline-3-Carbaldehyde Hydrazide Ester derivatives

Cyclometalated half‐sandwich iridium complexes: Synthesis, characterization, and catalytic activity in preparation of esters from halides by using formate as both CO source and coupling partner

A highly efficient carbonylation of aryl halides using half‐sandwich iridium catalysis was developed, providing a new avenue for synthesizing carboxylic ester derivatives and yielding consistently impressive results. These iridium complexes demonstrated remarkable catalytic performance in the coupling reaction using phenyl formate derivatives as the source of CO, phenol, and aryl halides as the starting material in the presence of air and possessed good air and moisture stability properties. Ester products with different substituents were synthesized at low reaction temperatures without the need for an inert atmosphere, leading to high yields. The broad substrate scope, impressive catalytic activity, and mild reaction conditions suggest promising industrial applications for this catalytic system. The desired metal complexes 1–4 have been well proven by attenuated total reflectance‐Fourier transform infrared (ATR‐FTIR), nuclear magnetic resonance (NMR), and elemental analysis (EA). The molecular structure of the cyclometalated iridium complexes 2 and 3 was proven through X‐ray crystallography. Additionally, the possible mechanism of this Ir‐catalyzed process is further supported by the density functional theory (DFT) study.

Highly efficient palladium‐catalyzed hydroesterification of functionalized alkenes

Herein, we introduce a catalytic system consisting of Pd (OAc)2/Xantphos/Al (OTf)3, which exhibits excellent reactivity in catalyzing the hydroesterification of a wide range of substrates, including electron‐deficient unsaturated acids/esters, aliphatic alkenes, functionalized styrenes, and phenylacetylenes. The catalytic system featured high reactivity and selectivity, low catalyst loading, wide substrate scope, and low CO pressure. Importantly, it eliminated the need for corrosive strong Brønsted acid additives, yielding alkyl‐ or aryl‐substituted dicarboxylic acid esters and monocarboxylic acid ester derivatives that hold significant industrial and pharmaceutical value. Mechanistic studies indicate that the reaction proceeds via the palladium hydride pathway.

Metabolomic Analysis and Antiviral Screening of a Marine Algae Library Yield Jobosic Acid (2,5-Dimethyltetradecanoic Acid) as a Selective Inhibitor of SARS-CoV-2.

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae and cyanobacteria extract library was screened for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Following initial screening of 86 extracts, we performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This approach led to the isolation of an unusual saturated fatty acid, jobosic acid (2,5-dimethyltetradecanoic acid, 1). We confirmed that 1 demonstrated selective inhibitory activity toward both viral targets while retaining some activity against the spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its structure-activity relationship (SAR), the methyl and benzyl ester derivatives of 1 were semisynthetically accessed and demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. Our efforts have provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, unambiguous determination of its absolute configuration, and understanding of its specific mechanisms of action and binding site toward new therapeutic avenues for SARS-CoV-2 drug development.

Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors.

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

Heterologous activation and metabolites identification of the pks7 gene cluster from Saccharopolyspora erythraea

The microbial genome remains a huge treasure trove for the discovery of diverse natural products. Saccharopolyspora erythraea NRRL23338, the industry producer of erythromycin, has a dozen of biosynthetic gene clusters whose encoding products are unidentified. Heterologous expression of one of the polyketide clusters pks7 in Streptomyces albus B4 chassis resulted in the characterization of its function responsible for synthesizing both 6-methylsalicyclic acid and 6-ethylsalicyclic acid. Meanwhile, two new 6-ethylsalicyclic acid ester derivatives were isolated as shunt metabolites. Their structures were identified by comprehensive analysis of MS and NMR experiments. Putative functions of genes within the pks7 BGC were also discussed.

Synthesis, molecular dynamics, antimicrobial activity and wound healing application of new methylidene dyes based on pyrrolinone esters

A new methylidene dye based on the direct condensation of an aldehyde derivative with a pyrrolinone ester derivative was successfully prepared as well as its quaternary ammonium salt analogue. The structures of all synthesized dyes were confirmed using NMR, Mass and IR spectra. The absorption and emission spectra of the synthesized dyes were investigated. The synthesized methylidene dye and its cationic form showed high molar absorption coefficients and a significant emission of the cationic dye analogue solution was observed. The antibacterial affinity using the disk diffusion method was investigated for six potential skin infection causing microbial pathogens, including two Gram-negative species (Pseudomonas aeruginosa and Proteus mirabilis), two Gram-positive species (Staphylococcus aureus and Staphylococcus epidermidis), and two fungal species (Candida albicans and Rhizomucor miehei) by recording the inhibition zone as well as studying the killing time effect for the prepared dyes. The in vitro wound healing application and the effect of cationized Dye 2 on the healing progress showed very effective and faster healing at a concentration of 100 µg/mL (IC50). Molecular dynamics simulation studies of Dye 1 and Dye 2 were carried out to compute binding free energies using Generalized Born Surface Area (MM/GBSA) in molecular mechanics. Furthermore, computational studies revealed that Dye 2 showed high affinity toward the active site of DNA gyrase B, which provides a solid framework for new structure-based design initiatives.

Quantitation of succinylacetone in dry blood spot by tandem mass spectrometry without butyl ester derivatization

Quantitation of succinylacetone in dry blood spot by tandem mass spectrometry without butyl ester derivatization

Synthesis, Characterization and Antimicrobial Evaluation for New Esters Derivatives Containing Two 1, 3, 4-Oxadiazole Units

This work includes the synthesis of new ester compounds containing two 1,3,4-oxadiazole rings, 15a-c and 16a-c. This was done over seven steps, starting with p-acetamido-phenol 1 and 2-mercaptobenzoimidazole 2. The structure of the products was determined using FT-IR, 1H NMR, and mass spectroscopy. The evaluation of the antimicrobial activities of some prepared compounds was achieved against four types of bacteria (two types of gram-positive bacteria; Staphylococcus aureus and Bacillus subtilis, and two types of gram-negative bacteria, Pseudomonas aeruginosa and E. Coli), as well as against one types of fungus (C. albino). The results show moderate activit against the study bacteria, and the theoretical analysis of the toxicity demonstrates non-toxicity with acute oral human toxicity. Also, the toxicity of these compounds in rats was weak. A molecular modelling study explains that these compounds possess good binding with lung cancer proteins.

Design, synthesis, and insecticidal activity of novel terpenoid ester compounds containing bicyclo[2.2.1] heptane against Aphis gossypii Glover

To discover novel and efficient compounds against Aphis gossypii Glover, a series of novel terpene ester derivatives containing the structure of bicyclo[2.2.1]heptane were designed and synthesized using tschimganin as the lead compound. Bioactivity assays showed that most tschimganin analogs exhibited moderate to outstanding insecticidal activity against A. gossypii. In particular, compound 56 (LC50 = 0.28 μg mL−1), identified as (1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl nicotinate, exhibited the best activity, which was significantly superior to that of imidacloprid (LC50 = 0.54 μg mL−1) and sulfoxaflor (LC50 = 0.70 μg mL−1). The precise and dependable 3D-QSAR model suggests a promising direction for further design of more active tschimganin-based insecticides. Metabolomics showed that compound 56 disrupted detoxification, amino acid biosynthesis, and energy metabolism and may affect the central nervous system of A. gossypii. The results of this study indicated that tschimganin analogs are a potential new class of green insecticides that can be used for the integrated management of A. gossypii.

Structure - Guided design of arctigenin derivatives against infections of Gyrodactylus kobayashii

Gyrodactylosis is a widespread parasitic illness that affects fish in both farming and natural environments. The current chemotherapy approaches are not always satisfactory, so the development of new anthelmintic agents is necessary. Arctigenin, a natural lignan found in various plants, possesses a multitude of biological activities. Previous research has demonstrated that arctigenin targets the protein myosin in Gyrodactylus kobayashii. Building upon this interaction, we designed 31 derivatives of arctigenin using Discovery Studio. The ester derivatives exhibited significant anthelmintic activity, with C-21 displaying the highest activity, boasting an EC50 of 0.4 mg/L. Furthermore, we conducted an investigation into the mechanism by which C-21 affects the parasite and discovered that it disrupts the muscular structure of the parasite's body surface, thus inhibiting its energy production and myosin expression, ultimately leading to the parasite's demise. In conclusion, C-21 exhibits promising potential as an agent for controlling Gyrodactylus kobayashii infection.