Compounds 3e Research Articles

New N-amino-5-cyano-6-pyridones as antimicrobial small molecules endowed with DNA gyrase a inhibitory activity: design, one-pot synthesis, biological assessment and in silico insights.

A set of innovative N-amino-5-cyano-6-pyridones derivatives was developed and produced using one-pot three-component procedures. The evaluated molecules were examined for their antimicrobial efficacy. Based on the acquired findings, most of the investigated compounds had promising antimicrobial properties. Out of these derivatives of 3-cyanopyridine, compounds 3d and 3e exhibited minimum inhibitory concentrations (MIC) of 3.91µg/mL against E.coli. In vitro evaluation of DNA gyrase A displayed that molecule 3d exhibited promising potency as an inhibitor, with an IC50 value of 1.68µg/mL compared to ciprofloxacin (IC50 = 0.45µg/mL). Furthermore, it was observed that molecule 3e exhibited a moderate inhibitory effect, as indicated by its IC50 value of 3.77µg/mL. A kinetics study conducted to assess the time required to kill E. coli bacteria demonstrated that gentamycin and compounds 3d and 3e exhibited bactericidal effects within a time frame of 90-120min. Based on the ADME predictions, compounds 3d and 3e are expected to have favorable oral bioavailability and are unlikely to penetrate the blood-brain barrier. Computational mutagenicity and tumorigenicity studies were conducted on compounds 3d and 3e. The molecular docking investigation has conclusively demonstrated the binding of compounds 3d and 3e to the target DNA gyrase A enzyme, further reinforcing the existing data.

Synthesis, enzyme inhibition, and docking studies of new schiff bases of disalicylic acid methylene-based derivatives as dual-target antibacterial agents

IntroductionBacteria have acquired resistance to almost all antibiotics currently in use due to their extensive, broad, and improper utilization over a prolonged period. DNA gyrase and DHFR exhibit significant promise as targets for antibacterial therapeutics.MethodsWe have developed a series of disalicylic acid methylene/Schiff bases hybrids (6a-l) that function as antibacterial agents by targeting DNA gyrase and DHFR.Results and discussionThe findings showed that 6a-l have significant antibacterial activity against both Gram-positive and Gram-negative bacteria, with inhibition zones (IZ) comparable to or even higher than the reference Ciprofloxacin. MIC testing revealed that 6h and 6l were 1.5 times as effective than ciprofloxacin against S. aureus. Compounds 6h and 6l had MBC values of 28 and 33 nM for S. aureus, compared to Ciprofloxacin’s 45 nM, indicating that they are more potent bactericidal agents. The MIC values for compounds 6c, 6e, 6h, 6j, and 6l against A. flavus were between 14.50 and 19.50 µM, while the MIC value for fluconazole was 11.50 µM. Also, the studied compounds had MIC values between 18.20 and 22.90 µM against C. albicans, while Fluconazole had a MIC value of 17.50 µM. Compound 6h showed a MIC value of 1.70 µM against the clinical strain S. aureus (ATCC 43300) (MRSA), making it an effective antibacterial agent. Compounds 6h, 6j, and 6l inhibited E. coli DNA gyrase with IC50 values of 79, 117, and 87 nM, respectively, compared to the reference novobiocin (IC50 = 170 nM). Additionally, compounds 6h and 6l, the most potent E. coli gyrase inhibitors, showed encouraging results on DHFR. Compounds 6h and 6l exhibit IC50 values of 3.80 µM and 4.25 µM, respectively. These values are significantly lower and hence more effective than Trimethoprim’s IC50 of 5.20 µM.

Design And Synthesis Of Novel Thiazole Linked Tetrahydropyridine Analogues As Anticancer Agents.

A library of new thiazole linked tetrahydropyridines (6a-q) synthesized and screened for their invitro anticancer activity against human breast adeno carcinoma cell viz. MCF-7 and MDA-MB-231. The two compounds 6d containing -F and -Cl functions in para and meta position of phenyl ring (9.94 ± 1.02µM, 9.78 ± 1.08µM) and 6e with -Cl and -NH2 functions on pyridine ring (9.72 ± 0.91 µM,9.54 ± 0.95µM) demonstrated outstanding activity against both the cell lines when compared to Doxorubicin. The benzofuran analogue 6o presented good activity with an IC50 value of 12.19 ± 1.03µM (MCF-7) and 12.22 ± 1.07µM (MDA-MB-231). The molecular docking study of potent molecule 6e against crystal structure of breast tumor kinase presented promising docking score and binding interactions. Predicted pharmacokinetics properties of compounds 6a-q and presented boiled diagram of compounds 6d and 6e implied favourable drug-likeness properties.

Design, synthesis, and cytotoxic activity of 2-amino-1,4-naphthoquinone-benzamide derivatives as apoptosis inducers

A new series of 2-amino-1,4-naphthoquinone-benzamides 5a-n was designed based on previously reported potent cytotoxic agents. These compounds were synthesized from the reaction of 1,4-naphthoquinone, 4-aminobenzoic acid, and appropriate amine derivatives in good yields. Cytotoxic activities of the target compounds 5a-n were evaluated against three cancer cell lines MDA-MB-231, SUIT-2, and HT-29 by MTT assay and the obtained in vitro data. All newly synthesized compounds were more potent than positive control cisplatin against MDA-MB-231 cell line and less potent than this control against SUIT-2 cell line. Moreover, most of the synthesized compounds were more potent than cisplatin against HT-29 cell line. Among the synthesized compounds, compound 5e was the most potent cytotoxic agent against all the three evaluated cell lines. Moreover, cell cycle analysis showed that derivatives 5f and 5l dose-dependently increase the percentage of sub-G1 cells. Induction of apoptosis as an important mechanism of anti-cancer drugs was confirmed morphologically in the most potent new compounds 5e, 5f, 5g, and 5l by Hoechst 33,258 staining.

Molecular docking, ADME properties and synthesis of thiophene sulfonamide derivatives

This study investigates the drug-like properties of target molecules containing thiophene sulfonamide groups (7a–7s) using computational molecular docking techniques. The binding interactions of these derivatives were assessed using protein 2NSD (Enoyl acyl carrier protein reductase InhA, complexed with N-(4-methylbenzoyl)-4-benzylpiperidine, PDB DOI: 10.2210/pdb2NSD/pdb) as the receptor. Molecular docking results revealed notable docking scores for all compounds, ranging from −6 to −12 kcal/mol. Compounds 7e, 7i, and 7f, in particular, demonstrated impressive glide scores (>11 kcal/mol) and were selected for further analysis through molecular dynamics simulations, which provided deeper insights into their dynamic behavior and stability. The drug-like properties of these molecules were evaluated based on Lipinski’s Rule of Five and ADME (Absorption, Distribution, Metabolism, and Excretion) criteria and compared with known drugs. Additionally, we synthesized these target molecules (7a–7s) using Suzuki-Miyaura coupling with a nickel catalyst replacing palladium. The chemical structures of the synthesized compounds were confirmed through elemental analysis, LC-MS,1H-NMR, and 13C-NMR spectroscopy.

Novel Schiff bases of quinolin-4(1h)-one: Synthesis, antiproliferative evaluation, apoptosis, cell cycle, autophagy and molecular docking studies in human colon cancer cells

A green and efficient ultrasound-mediated protocol was developed for the synthesis of a series of novel Schiff bases derived from quinoline-4-one. The synthetic strategy involved the condensation of 4-oxo-1,4-dihydro-quinoline-3-carboxaldehyde with diverse anilines and heteroaryl amines. The synthesized compounds were characterized using spectroscopic techniques. A comprehensive in vitro cytotoxicity evaluation against HCT116 and HT-29 human colon cancer cell lines revealed that several compounds exhibited potent anticancer activity. Notably, compounds 3c and 3e demonstrated superior cytotoxicity compared to the clinical standard doxorubicin. Mechanistic studies indicated that these lead compounds induced apoptosis, necrosis, and cell cycle arrest at G1 and G2 phases. Furthermore, autophagy induction was observed. In silico ADMET predictions support the potential of compounds 3c and 3e as promising anticancer drug candidates. The molecular docking studies revealed that the Schiff bases 3c and 3e displayed good interaction with VEGFR-2 receptor. These findings underscore the quinoline-4-one scaffold as a valuable template for the development of novel antitumor agents.

New Copper(I) oxide biocatalyst based on functionalized olive stone for the synthesis of 1,4-disubstituted-1,2,3-triazoles under very mild conditions

An efficient methodology for coating silanized olive stone with copper(I) oxide has been described and fully characterized using various techniques, including X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR-ATR), X-ray fluorescence (XRF), electronic microscopy, thermogravimetric analysis (TGA), moisture content, electrophoretic mobility and particle size distribution. The applicability of this new biocatalyst in the 1,3-dipolar cycloaddition click reaction between alkynes and azides has been demonstrated leading to the obtention of a great variety of 1,4-disubstituted-1,2,3-triazoles with good to excellent conversions. The new biocatalyst showed promising features in terms of recyclability and industrial or biomedical application. It could be recycled up to five times with minimal loss of catalytic activity when synthezing compound 3a-3n. Additionally, it was effective in the multi-gram scale synthesis of compounds 3b and 3e, which were tested for the first time in cells, specifically on the human fibroblast-derived M1 cell line, demonstrating that these compounds are non-cytotoxic and thus suitable for potential uses in biomedicine.

Facile synthesis of substituted 2-styrylnaphthyridine and its derivatives via sp3C-H functionalization under mild conditions and their antimicrobial activity and Electrochemical properties.

Metal-free, synthetic approach for the Efficient synthesis of pyrazole, imidazopyridine based substituted 2-styryl-1,8-naphthyridines has developed via sp3 C-H activation of substituted 7-methyl-1,8-naphthyridines, with various aromatic/heteroaromatic aldehydes through knoevenagel condensation under mild basic (Piperidine) conditions. Further, the synthesized titled molecules tested their absorption and emission spectra, interestingly compound 3d was found to be that inspiring emission spectra at 626 nm (red shift) with impressive stokes shift 133 nm. Moreover, some of the best resultant conjugate scaffolds (compounds 3c, 3d, 3e, and 4e) analysed their electrochemical properties, thus, 3c, 3d, 3e, and 4e molecules respectively displaying medium to good redox potentials (compound 3e displays 0.3, -1.71 V respectively) and tested scanning rate (from 50 to 500 mV s−1) also. Furtherly, all synthsized derivatives analysed their biological activity, i.e., antifungal and antifungal. Among that, the compounds 3c, 3d, 3e, 3i, 3k, 3l, 5c, 5d and 5f were established excellent inhibition zone of activity against standard drugs.

Design and Synthesis of Novel Hydrazinyl Thiazoles from Biomass derived Furfurals: Their Molecular Docking, Anti-Cancer, Anti-Oxidant, and Anti-Bacterial Study

This report presents an application of simple and convenient grindstone chemistry to construct a library of pharmaceutically valuable hydrazinyl thiazole moieties using biomass-derived furfurals as key synthons. Significantly, the current green process avoids the use of catalysts and solvents for the desired conversion, achieving good to excellent product yields in a short reaction time. The synthesized compounds were evaluated for their anti-cancer activity against the human breast cancer cell line (MCF-7) using an in vitro MTT assay, which revealed significant antiproliferative activity of compounds 4d and 4e, with IC50 values of 41.06±0.06 and 38.39±0.90 μg/mL, respectively.Further, the in vitro antibacterial activity of the newly synthesized thiazole derivatives and reference drugs was assessed against both gram-negative bacteria, including Escherichia coli, and gram-positive bacteria such as Bacillus subtilis. The current research demonstrates that compounds 4d and 4e exhibit significantly enhanced antibacterial efficacy against pathogenic bacteria, with MIC values >25 μg/mL and >6.25 μg/mL for Escherichia coli, and >25 μg/mL for Bacillus subtilis for both compounds. The DPPH assay revealed that compounds 4a, 4d, and 4e were the most significant, displaying comparatively higher IC50 values of 41.58±1.28, 42.36±0.45 and 42.31±0.73 μg/mL respectively.Furthermore, the synthesized compounds were investigated through molecular docking studies, which were consistent with the in vitro results. The findings were further supported by a structure-activity relationship (SAR) study.

Identification of imidazo[1,2-a]pyridines-pyrazole-pyran hybrids as potent glucose-6-phosphate dehydrogenase (G6PD) inhibitors: Synthesis, molecular docking, DFT studies and ADME prediction

In this study, we aimed to identify new anticancer agents by synthesizing a series of Imidazo[1,2-a]pyridines fused with pyrazole-pyran scaffolds 7a–g in good yields (75–85 %) under microwave irradiation. The synthesis was performed through a one-pot, three-component cyclocondensation reaction of 2-(p-substituted)imidazo[1,2-a]pyridine-3-carbaldehyde 4a-g, malononitrile 5, and 5-methyl-2,4-dihydro-3H-pyrazol-3-one 6 in the presence of triethylamine as a catalyst in acetonitrile. The characterization of all synthesized compounds was accomplished through various spectroscopic techniques. All the synthesized compounds were investigated for their anticancer potential in vitro, using an MTT-based assay against A549 lung cancer cell lines. Compounds 7b, 7e, and 7c demonstrated notable anti-proliferative activity against the A549 cell line, while compound 7e showed a significantly lower fluorescence generation (24-fold less) in the G6PD inhibition assay compared to the other compounds.

Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3–5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation.

Synthesis of Paracetamol‐Appended Bis 1,2,3‐Triazole Analogues as Anti‐Inflammatory Agents

AbstractParacetamol‐based bis 1,2,3‐triazole analogues were synthesized involving copper‐catalyzed click chemistry protocol. The new compounds were characterized by 1H NMR, 13C NMR, and mass spectral techniques. All the compounds were evaluated for their in vitro anti‐inflammatory properties using diclofenac as standard reference. The compound 6b with chlorine and fluorine functions displayed outstanding activity with IC50 values of 7.34 ± 0.45 µM and 7.84 ± 0.47 µM, respectively. Compound 6g with methyl and fluorine functions displayed best activity with IC50 values of 9.34 ± 0.22 µM and 9.40 ± 0.35 µM, respectively. Compound 6i, 6k, 6f, 6a, 6e, 6h, 6j, and 6l exhibited promising activity with respect to diclofenac. Using PyRx tool, the molecular docking study against crystal structure of COX‐2 proved the binding efficacies with notable binding interactions.

A theoretical investigation into the impact of solvents (alkanolic and non-alkanolic), structural and spectroscopic properties, donor-acceptor insights, Hirshfeld surface, and molecular docking of the anti-tumor compound (2E)-3-[4-(dimethylamino)phenyl]-1-(3-nitrophenyl)prop-2-en-1-one

In this study, computational methods were employed to analyze the molecular structure of (2E)-3-[4-(Dimethylamino)phenyl]-1-(3-nitrophenyl)prop-2-en-1-one (DMAPNP), investigating its structural and spectroscopic properties along with its biological activity. In particular, the Frontier Molecular Orbital (FMO) and Molecular Electrostatic Potential (MEP) surfaces in alkanolic solvents (ethanediol, ethanol, and methanol) and non-alkanolic solvents (DMSO, toluene, and water) were generated to analyze the solvent-solute interactions. The H→L transition shows low oscillator strengths (0.0002 in toluene to 0.0013 in ethanediol, DMSO, and water), indicating limited significance in the absorption spectrum. In contrast, the H→L+1 transition has much higher oscillator strengths, around 0.9412 for ethanediol and 0.9385 for DMSO and toluene, suggesting a greater likelihood of absorption at these wavelengths. The simulated vibrational wavenumbers revealed the presence of CH, NO2, CN, CC, CH3, and C=O groups in DMAPNP. The calculated chemical shifts confirmed the molecular structure of DMAPNP and aligned with standard values. In Hirshfeld surface analysis, the crystal packing of DMAPNP was primarily stabilized by H…H interactions, contributing 41.3%, followed by O…H / H…O interactions at 30.9%. In Natural Bond Orbital (NBO) analysis, the interaction between C20-H38 and C15-H33 shows a stabilization energy of 1102.89 kJ/mol, highlighting σ-σ* transitions. In contrast, the C12-C16 and C15-H33 interactions exhibit a stabilization energy of 2542.16 kJ/mol, indicating substantial π-σ* contributions. In the Mulliken charge distribution, the carbon atoms C18 (-1.33704e) and C13 (1.776064e), located in the para and meta positions concerning the nitro group (NO2), exhibit the highest positive and negative potentials, respectively. Molecular docking assessed DMAPNP as a potential anti-tumor agent by inhibiting the key regulatory enzyme fructose-2,6-bisphosphatase, with a binding energy of -8.13 kcal/mol.

Synthesis and Molecular Docking Study of Hydrazone Schiff Bases of α‐Naphthalene‐Containing Alkyl Phenyl Ether Fragment as Potent α‐Amylase and α‐Glucosidase Inhibitors

AbstractIn this study, new Schiff base derivatives of α‐naphthalene acetic acid containing alkyl phenyl ether fragment have been effectively synthesized through multistep reaction process, characterized by 1H‐NMR and 13C‐NMR spectroscopy. These derivatives have been tested for their in vitro α‐amylase and α‐glucosidase inhibitory activities. In the series, 8 compounds (2j, 2f, 2e, 2m, 2a, 2b, 2l, and 2c) exhibited promising α‐amylase inhibition with IC50 values from 5.38 ± 0.36 to 14.59 ± 0.64 µg/mL. Similarly, in the case of α‐glucosidase inhibitory activity, 10 derivatives (2e, 2f, 2j, 2m, 2b, 2c, 2i, 2d, 2a, and 2l) exhibited excellent activity having IC50 values from 6.96 ± 0.39 to 16.27 ± 0.31 µg/mL, wheras the remaining derivatives exhibited good‐to‐least antidiabetic potential. The ADME properties were calculated for all Schiff base derivatives using Swiss‐ADME web tool. Furthermore, the docking studies identified the binding modes of the compounds.

First Report on Cationic Triphenylphosphonium Compounds as Mitochondriotropic H3R Ligands with Antioxidant Properties

Neurodegenerative diseases are a major public health problem due to the aging population and multifaceted pathology; therefore, the search for new therapeutic alternatives is of the utmost importance. In this sense, a series of six 1-(3-phenoxypropyl)piperidines alkyl-linked to a triphenylphosphonium cation derivative were synthesized as H3R ligands with antioxidant properties to regulate excessive mitochondrial oxidative stress and contribute to potential new therapeutic approaches for neurodegenerative diseases. Radioligand displacement studies revealed high affinity for H3R with Ki values in the low to moderate two-digit nanomolar range for all compounds. Compound 6e showed the highest affinity (Ki H3R = 14.1 nM), comparable to that of pitolisant. Antioxidative effects were evaluated as radical-scavenging properties using the ORAC assay, in which all derivatives showed low to moderate activity. On the other hand, cytotoxic effects in SH-SY5Y neuroblastoma cells were investigated using the colorimetric alamar blue assay, which revealed significant effects on cell viability with an unequivocally structure–toxicity relationship. Finally, docking and molecular simulation studies were used to determine the H3R binding form, which will allow us to further modify the compounds to establish a robust structure-activity relationship and find a lead compound with therapeutic utility in neurodegenerative diseases.

Design, microwave synthesis, characterization and antimicrobial activity of imidazolone derivatives

Overuse and misuse of antibiotics create superbugs as drug-resistant bacteria. The vital strategy is developing new antibiotics, and one of the vital compounds that proved activity as antimicrobials is imidazoles. So, we designed and synthesized a series of imidazolones via microwave radiation in excellent yield and evaluated them as antimicrobial agents with docking studies to promote and boost their activity. The results obtained from spectroscopic analyses approved the chemical structures of new compounds. The biological antimicrobial activity results was found that these compounds exert an excellent broad spectrum antimicrobial activity against many Gram-positive and Gram-negative bacteria, as well as different fungal strain including some highly human pathogenic microorganisms.Compounds 5a-5c are active against Gram-positive bacteria and compounds 5d-5f against Gram-negative bacteria, together with Candida albicans as fungi. Molecular Docking study on the active compounds 5e, 5f showed ring-stacking interactions between them as ligands and related proteins, which are compatible with other results. Gaussian 09 program is used as computational chemistry software to confirm the obtained experimental results.

Synthesis of Mannich N-Bases Based on Benzimidazole Derivatives using SiO2-OAlCl2 Catalyst and Their Potential as Antioxidant, Antibacterial, and Anticancer Agents

This research aimed to synthesis of N-base compounds based on benzimidazole derivatives and their potential as antibacterials, antioxidants, and anticancer. The synthesis was conducted in two stages, namely the intermediate (benzimidazole derivatives) and the final product (N-mannich base), using five variations of organic acids and SiO2-OAlCl2 as catalyst. The results showed that the catalyst was successfully synthesized and characterized by The Fourier transform infrared (FTIR), X-ray diffraction (XRD), and Scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS). The purity of the synthesized compounds was monitored by Thin layer chromatography (TLC), melting point test, Ultraviolet-visible (UV-Vis), FTIR, and Liquid chromatography-Mass spectrometry (LC-MS). The five intermediate compounds and five mannich base products yield 77%-89% and 65%-85%, respectively. The final products were applied through antibacterial testing against Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria) by disc diffusion. Mannich base compounds have potential antibacterial agents, but only 4A and 4E gave the best inhibition zone diameter. Meanwhile, the antioxidant testing result using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method showed the best activity in the mannich base compound 4E. The anticancer test result showed that the five mannich base compounds had potential as anticancer agents.

Bioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines

Background: Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe the development of promising new bioactive molecules through the bioisosteric replacement of a carbon atom with a sulfur atom in anti-inflammatory agents, specifically 3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)butanoate. Methods: Design and synthetic studies have led to the series of previously unknown substituted 2-[((3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)methyl)thio]carboxylic acids and their esters. These compounds were synthesized by reacting 6-chloroalkyl-3-R-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones with sulfanylalkyl carboxylic acids and their functional derivatives. The purity and structure of the obtained compounds were confirmed using a set of physicochemical methods, including elemental analysis, HPLC-MS, and 1H NMR spectroscopy. Molecular modeling, predicted toxicity, drug-likeness, and pharmacokinetics data were used to select compounds for evaluation of their effects on acute aseptic inflammation (carrageenan-induced paw edema test) and on markers of the inflammatory process. Results: The compound 2-((1-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)ethyl)thio)acetic acid (compound 2e) was identified as the most active anti-inflammatory agent (AA = 53.41%), demonstrating significant inhibition of both paw edema development and the generation of pro-inflammatory cytokines and mediators. Conclusions: Results from docking studies and analysis of “structure-affinity” correlations revealed that these compounds are promising candidates for further modification and detailed investigation of their anti-inflammatory activity

Semi-Preparation and X-ray Single-Crystal Structures of Sophocarpine-Based Isoxazoline Derivatives and Their Pesticidal Effects and Toxicology Study.

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 μg/nymph) and 5o (LD50: 0.024 μg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 μg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

Anti-cancer Activity Evaluation of Naphthalenonic and Chromanonic Spiroisoxazoline Derivatives as Selective COX-2 Inhibitors on HT29 Cell Lines

Background: Cyclooxygenase-2 (COX-2) is induced in response to proinflammatory conditions, and it is not only a key enzyme in the inflammatory process, but also seems to be highly expressed in various types of cancer cells. On the other hand, it is well documented that chemical compounds with spiro scaffolds in their structure could be effective chemical agents against cancer types. Objective: In this study, the cytotoxicity effects of spiroisoxazoline derivatives containing naphthalinone and chromanone spiro-bridge were investigated. Methods: The cytotoxicity effects of compounds 7a-7h were evaluated by performing the MTT assay on the HT-29 (colorectal cancer), MCF-7 (breast cancer), and HEK-293 (normal kidney) cell lines. After that, a compound with high yield and remarkable cytotoxic activity was selected to analyze the cell cycle and apoptosis mechanism. Results: The most effective cytotoxic activity was observed on HT-29 and MCF-7 cell lines of compounds 7b (IC50 value: 1.07±0.28 µM) and 7f (IC50 value: 11.92±1.07 µM). None of the compounds had a toxic effect on normal HEK-293 cells, except for compound 7g with an IC50 value of 21.30±16.14 µM, whose effect was much lower than that of cisplatin and doxorubicin, known as anti-cancer agents. Subsequently, compound 7e with significant yield and cytotoxic activity was investigated to evaluate cell cycle and apoptosis. The result showed that compound 7e induced significant G0/G1 cell cycle arrest and apoptosis in HT-29 cells Conclusion: The selective COX-2 inhibitor compounds with spiroisoxazoline core structure could be suitable scaffolds for cytotoxic effects.