One Pot Synthesis of New Benzimidazole Derivatives with Exceptionally High Luminescence Quantum Efficiency.

AIM AND OBJECTIVES: There are different approaches to the synthesis of benzimidazole. In this article, five new benzimidazole derivatives, BMPO, Me-BMPO, Di-MeBMPO, F-BMPO and Cl-BMPO where (BMPO=3-[(1H)-benzo[d]imidazol-2-yl]pyridin-2(1H)-one), have been prepared. Another study was carried out on luminescence properties and their potential applications for the detection of transition metal ions. MATERIALS AND METHODS: From the one-pot synthesis approach, all the derivatives of the benzimidazole compounds were obtained. The compounds were characterized using HRMS, 1HNMR, 13CNMR, and X-ray crystallography. Herein, a mechanism has been deciphered by predicting the release of HCl(g). RESULTS: All compounds showed a strong deep blue emission when dissolved in dimethylacetamide (DMA), with emission wavelengths at 423, 428, 435, 423, and 421 nm, and half-times of 3.64, 2.77, 2, 19, 3.42 and 3.52 ns, respectively. In addition, their emission quantum yields were determined to be 72, 50, 42, 73 and 80%. CONCLUSION: Five new benzimidazole derivatives, BMPO, Me-BMPO, Di-MeBIPO, F-BIPO, and Cl-BIPO, have been successfully synthesized by the one-pot synthesis method, and their structures are characterized and confirmed. The compounds exhibited exceptional luminescence by emitting a strong blue light in DMA with high fluorescence quantum yields between 42~80%.

Population pharmacokinetic study and application of ticagrelor and AR-C124910XX after percutaneous coronary intervention in Chinese patients with acute coronary syndrome.

OBJECTIVES: This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization. MATERIALS AND METHODS: Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology. RESULTS: The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased. CONCLUSION: The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.

A novel cascade catalysis for one-pot enzymatically modified isoquercitrin (EMIQ) conversion from rutin and sucrose using rationally designed gradient temperature control.

Enzymatically modified isoquercitrin (EMIQ) is a glyco-chemically modified flavonoid exhibiting notably high biological activity, such as antioxidant, anti-inflammatory and anti-allergic properties. However, the utilization of expensive substrates such as isoquercitrin and cyclodextrin in the conventional approach has hindered the industrial-scale production of EMIQ due to high cost and low yields. Hence, the development of a cost-effective and efficient method is crucial for the biological synthesis of EMIQ. In this study, a natural cascade catalytic reaction system was constructed with α-L-rhamnosidase and amylosucrase using the inexpensive substrates rutin and sucrose. Additionally, a novel approach integrating gradient temperature regulation into biological cascade reactions was implemented. Under the optimal conditions, the rutin conversion reached a remarkable 95.39% at 24 h. Meanwhile, the productivity of quercetin-3-O-tetraglucoside with the best bioavailability reached an impressive 41.69%. This study presents promising prospects for future mass production of EMIQ directly prepared from rutin and sucrose.

Crystal structure characterization, Hirshfeld surface analysis, and DFT calculation studies of 1-(6-amino-5-nitro-naphthalen-2-yl)ethanone.

The title compound, C12H10N2O3, was obtained by the de-acetyl-ation reaction of 1-(6-amino-5-nitro-naphthalen-2-yl)ethanone in a concentrated sulfuric acid methanol solution. The mol-ecule comprises a naphthalene ring system bearing an acetyl group (C-3), an amino group (C-7), and a nitro group (C-8). In the crystal, the mol-ecules are assembled into a two-dimensional network by N⋯H/H⋯N and O⋯H/H⋯O hydrogen-bonding inter-actions. n-π and π-π stacking inter-actions are the dominant inter-actions in the three-dimensional crystal packing. Hirshfeld surface analysis indicates that the most important contributions are from O⋯H/H⋯O (34.9%), H⋯H (33.7%), and C⋯H/H⋯C (11.0%) contacts. The energies of the frontier mol-ecular orbitals were computed using density functional theory (DFT) calculations at the B3LYP-D3BJ/def2-TZVP level of theory and the LUMO-HOMO energy gap of the mol-ecule is 3.765 eV.

Synthesis, crystal structure and Hirshfeld surface analysis of N-(6-acetyl-1-nitro-naphthalen-2-yl)acetamide.

The title compound, C14H12N2O4, was obtained from 2-acetyl-6-amino-naphthalene through two-step reactions of acetyl-ation and nitration. The mol-ecule comprises the naphthalene ring system consisting of functional systems bearing a acetyl group (C-2), a nitro group (C-5), and an acetyl-amino group (C-6). In the crystal, the mol-ecules are assembled into two-dimensional sheet-like structures by inter-molecular N-H⋯O and C-H⋯O hydrogen-bonding inter-actions. Hirshfeld surface analysis illustrates that the most important contributions to the crystal packing are from O⋯H/H⋯O (43.7%), H⋯H (31.0%), and C⋯H/H⋯C (8.5%) contacts.

Sensitive fluorescence detection of glyphosate and glufosinate ammonium pesticides by purine-hydrazone-Cu2+ complex.

Organophosphorus pesticides play an important role as broad-spectrum inactivating herbicides in agriculture. Developing a method for rapid and efficient organophosphorus pesticides detection is still urgent due to the increasing concern on food safety. An organo-probe (ZDA), synthesized by purine hydrazone derivative and 2,2'-dipyridylamine derivative, was applied in sensitive recognition of Cu2+ with detection limit of 300 nM. Mechanism study via density functional theory (DFT) and job's plot experiment revealed that ZDA and Cu2+ ions form a 1:2 complex quenching the fluorescence emission. Moreover, this fluorescent complex ZDA-Cu2+ was applicable for detecting glyphosate and glufosinate ammonium following fluorescence enhancement mechanism, with detection limits of 11.26 nM and 11.5 nM, respectively. Meanwhile, ZDA-Cu2+ was effective and sensitive when it is used for pesticide detection, reaching the maximum value and stabilizing in 1 min. Finally, the ZDA-Cu2+ probe could also be tolerated in cell assay environment, implying potential bio-application.

Synthesis and antifungal activity of hexahydropyrrolidoindole alkaloids.

Twenty-one hexahydropyrrolidoindole alkaloids were designed and synthesised via acylation reaction at the 3-N position from the commercially available indole-3-acetonitrile as the starting material in excellent yields. The effects of all target compounds against Verticillium dahlia, Fusarium oxysperium sp., Cytospora juglandis, Aspergillu sflavu, Aspergillus niger and Fusarium oxysporum were determined. The results of bioassays indicated that the majority of tested compounds displayed comparable or better in vitro bioactivity than the positive control. Notably, compounds 8 and 17 revealed potent activity against C. juglandis and A. sflavu, both with the same minimum inhibitory concentration value of 1.9 µg mL-1, which has fungicidal activity far exceeded that of amphotericin B and chlorothalonil.

Electrochemical decarboxylative alkylation of ß-ketoacids with phenol derivatives.

An electrochemical method for the decarboxylative alkylation of ß-ketoacids with phenol derivatives has been developed. The protocol was carried out in readily available unseparated cells at room temperature in the absence of catalysts and oxidants. The corresponding aryl ketones were obtained in satisfactory yields without additional electrolytes, and were easy to produce in gram-scale synthesis. Based on control experiments and cyclic voltammetry, a plausible reaction mechanism was proposed.

Ticagrelor Steady-State Trough Concentration in Chinese Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND AND OBJECTIVE: Platelets play a pivotal role in thrombotic events associated with acute coronary syndrome (ACS), making oral antiplatelet therapy a cornerstone in antithrombotic strategies. The dosing regimen for the oral antiplatelet drug ticagrelor warrants evaluation to ensure its appropriateness in clinical practice. Therefore, this study aimed to investigate the real-world clinical application of ticagrelor by determining the optimal therapeutic concentration of ticagrelor in Chinese patients undergoing percutaneous coronary intervention (PCI). METHODS: We enrolled a cohort of 912 patients who underwent PCI with drug-eluting stent implantation for the treatment of ACS. We measured steady-state plasma drug concentrations using high-performance liquid chromatography-tandem mass spectrometry. The therapeutic drug concentration range at steady state was established on the basis of clinical pharmacodynamic indices, with verification of reliability through concentration-effect analysis and receiver operating characteristic curve assessment. RESULTS: Analysis of plasma samples from the 912 patients revealed significant variations in the steady-state trough concentration of ticagrelor associated with factors such as gender, age, hypertension, and hyperlipidemia. On the basis of this analysis, the optimal therapeutic range for steady-state trough concentration was determined to be 240.65-335.83 ng/mL. Furthermore, the upper limit values for steady-state concentration were established at 439.97 ng/mL for male patients and 347.06 ng/mL for female patients. CONCLUSIONS: This study provides robust and reliable insights into the optimal therapeutic steady-state trough concentrations of ticagrelor in Chinese patients with post-percutaneous coronary intervention. These findings have significant implications for guiding the rational use of antiplatelet drugs and facilitating precise drug administration in Chinese patients undergoing percutaneous coronary intervention.

A systematic study to evaluate the safety of ticagrelor combined with aspirin in the treatment of PCI patients in Chinese population: A single nucleotide polymorphisms study.

The aim of this study was to identify genes and their associated loci related to ticagrelor pharmacokinetics and pharmacodynamics in Chinese patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). The study included 1115 patients with ACS who received a drug-eluting stent implantation between October 2019 and January 2021. Among them, 98 cases of adverse reactions were observed; thus, 97 cases without adverse reactions were selected as the comparison group. The steady-state serum drug concentration was determined via high-performance liquid chromatography-mass spectrometry, and 15 single nucleotide polymorphism (SNP) loci were genotyped using the SNaPshot SNP Multiplex System. Our results showed that age and sex may affect ticagrelor serum concentration in patients with ACS. In particular, the SNPs CYP3A4∗1 (rs2242480 C > T), IGT2B (rs5911 A > C), P2Y12 (rs6787801) and CYP3A5 (rs776746 C > T) may affect the steady-state blood concentration of ticagrelor after PCI in ACS patients, and CYP3A4∗1 may also be related to adverse events. In addition, we found that the SNPs PEAR1 (rs4661012 T > G) and P2Y12 (rs6787801 A > G) may be associated with dyspnea. These findings can provide a useful reference to establish guidelines for future clinical individualized dosage regimens of ticagrelor after PCI.

Synthesis of novel naphthalene-chimonanthine scaffolds hybrids with potent antibacterial or antifungal activity.

In this work, a total of 19 novel naphthalene hybrids with chimonanthine scaffolds were efficiently synthesised from indole-3-acetonitrile in good yields. The prepared compounds were evaluated for biological activity against Cryptococcus neoformans, Escherichia coli, Shigella spp, Candida albicans, Salmonella spp, and Staphylococcus aureus. The preliminary bioassays showed that most of the synthesised compounds exhibited significant antibacterial or antifungal activity. Notably, compound 8 showed potent activity against Cryptococcus neofonmans, Escherichia coli, Shigella spp, and Candida albicans than the positive control, all with the same MIC value of 3.53 µM. Compound 8 had a broad spectrum of antibacterial or antifungal activity, and will be studied further.

Visible-Light-Irradiated Multicomponent Reactions of Aliphatic Amines, Propiolate Acid Esters, and CF3 SO2 Na for Accessing ß-CF3 Enamines.

A novel one-pot two-step multicomponent reaction has been achieved for the preparation of ß-CF3 enamines by using different aliphatic amines, propiolates, and CF3 SO2 Na as starting material. In this protocol, various aliphatic amines including primary amines, cyclic or acyclic secondary amines were demonstrated to be good coupling partners, and different ß-CF3 enamines were obtained in moderate to good yields. Among them, the primary aliphatic amines only gave pure (E)-ß-CF3 enamines as products. The synthetic utility of the MCRs strategy was further demonstrated by mild conditions, gram-scale synthesis and natural sunlight-induced protocol. Preliminary mechanistic studies suggest that this trifluoromethylation of C(sp2 )-H involves radical process.

Boosting the mono-axial crystal field in stable high-coordinate Dy(III) single-ion magnets by substitution of the phenoxy axial ligand.

Synthesis of air-stable and high-performance single-molecule magnets (SMMs) is challenging. Here, a heptadentate pentapyridyldiamine (BPA-TPA) ligand and fine-tuned axial phenoxy ligands are used to synthesize two triangular dodecahedral Dy(III) complexes [Dy(BPA-TPA)(4-methoxy-PhO)](BPh4)2·3CH2Cl2 (4) and [Dy(BPA-TPA)(2,4-dimethyl-PhO)](BPh4)2·0.85CH2Cl2 (5). Both complexes have high effective barriers exceeding 400 K and magnetic hysteresis up to 8 K, which is ascribed to one strong and short Dy-O bond combined with seven weak Dy-N bonds. Ab initio calculations reveal the thermally activated quantum tunneling of magnetization through the first excited Kramers doublet, due to the presence of a strong axial Dy-O crystal ligand. Substitution of the phenoxy ligand leads to more constrained vibrations, improving the magnetic hysteresis behavior for 5.

Green One-Pot Syntheses of 2-Sulfoximidoyl-3,6-dibromo Indoles Using N-Br Sulfoximines as Both Brominating and Sulfoximinating Reagents.

A green one-pot 2,3,6-trifunctionalization of N-alkyl/aryl indoles was achieved by adding three equivalents of N-Br sulfoximine to the indole solution. A variety of 2-sulfoximidoyl-3,6-dibromo indoles were prepared with 38-94% yields using N-Br sulfoximines as both brominating and sulfoximinating reagents. Based on the results of controlled experiments, we propose that a radical substitution involving 3,6-dibromination and 2-sulfoximination occurs in the reaction process. This is first time that 2,3,6-trifunctionalization of indole in one pot has been achieved.

Synthesis and Structure-Activity Analysis of Novel Potential Antifungal Cyclotryptamine Alkaloid Derivatives.

A total of 39 novel cyclotryptamine alkaloid derivatives were prepared from 2-(1H-indol-3-yl) acetonitrile. The prepared compounds were evaluated against six plant pathogen fungi. Bioassay results revealed that most of the compounds displayed higher in vitro antifungal activities than the positive control. Notably, compound b2 displayed the broadest and most effective activity among the tested cyclotryptamine alkaloid derivatives and might be a novel potential leading compound for further development as an antifungal agent.

Synthesis and antifungal activity of novel chiral indole analogues.

Starting from L-tryptophan, 19 new N-substituted chiral indole analogs were synthesized. The prepared compounds were evaluated for biological activity against Sclerotinia sclerotiorum, Alternaria solani, Verticillium dahliae, Colletotrichum orbiculare, Cytospora juglandis and Curvularia lunata. The preliminary bioassays showed that most of the synthesized compounds exhibited fungicidal activity. Compound b13 in particular exhibited significant antifungal activity against Verticillium dahliae and Sclerotinia sclerotiorum, with the MIC value of 1.95 µg mL-1. Compound b13 also showed excellent activity against six plant pathogen fungi, and was identified as the most active on the biological assays, and will be studied further.

ASO Author Reflections: A Multiomic Novel Staging System for Esophageal Squamous Cell Carcinoma Patients.

The past eighth edition of the American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) pathologic tumor-node-metastasis (pTNM) staging system for esophageal squamous cell carcinoma (ESCC) patients, which also is the gold standard of postoperative treatment decision-making, needs to be continuously improved. To improve the efficiency of the staging system, the proteomic data from Chinese ESCC patients was combined with preoperative radiomic data and pTNM data to establish the multiomic RadpTNM and ProtRadpTNM models and compare them with the traditional pTNM staging system. The results suggest that both the RadpTNM and ProtRadpTNM models are significantly better than the traditional pTNM staging system. Future prospective multicentered cohort studies in Asian and Caucasian patients with ESCC are warranted to evaluate the efficiency of the multiomic models.

Development and Validation of a New Staging System for Esophageal Squamous Cell Carcinoma Patients Based on Combined Pathological TNM, Radiomics, and Proteomics.

OBJECTIVE: This study aimed to construct a new staging system for patients with esophageal squamous cell carcinoma (ESCC) based on combined pathological TNM (pTNM) stage, radiomics, and proteomics. METHODS: This study collected patients with radiomics and pTNM stage (Cohort 1, n = 786), among whom 103 patients also had proteomic data (Cohort 2, n = 103). The Cox regression model with the least absolute shrinkage and selection operator, and the Cox proportional hazards model were used to construct a nomogram and predictive models. Concordance index (C-index) and the integrated area under the time-dependent receiver operating characteristic (ROC) curve (IAUC) were used to evaluate the predictive models. The corresponding staging systems were further assessed using Kaplan-Meier survival curves. RESULTS: For Cohort 1, the RadpTNM4c staging systems, constructed based on combined pTNM stage and radiomic features, outperformed the pTNM4c stage in both the training dataset 1 (Train1; IAUC 0.711 vs. 0.706, p < 0.001) and the validation dataset 1 (Valid1; IAUC 0.695 vs. 0.659, p < 0.001; C-index 0.703 vs. 0.674, p = 0.029). For Cohort 2, the ProtRadpTNM2c staging system, constructed based on combined pTNM stage, radiomics, and proteomics, outperformed the pTNM2c stage in both the Train2 (IAUC 0.777 vs. 0.610, p < 0.001; C-index 0.898 vs. 0.608, p < 0.001) and Valid2 (IAUC 0.746 vs. 0.608, p < 0.001; C-index 0.889 vs. 0.641, p = 0.009) datasets. CONCLUSIONS: The ProtRadpTNM2c staging system, based on combined pTNM stage, radiomic, and proteomic features, improves the predictive performance of the classical pTNM staging system.

Synthesis and Antifungal Activity of Chimonanthus praecox Derivatives.

To search for efficient agricultural antifungal lead compounds, 39 Chimonanthus praecox derivatives were designed, synthesized, and evaluated for their antifungal activities. The structures of target compounds were fully characterized by 1H NMR, 13C NMR, and MS spectra. The preliminary bioassays revealed that some compounds exhibited excellent antifungal activities in vitro. For example, the minimum inhibitory concentration (MIC) of compound b15 against Phytophthora infestans was 1.95 µg mL-1, and the minimum inhibitory concentration (MIC) of compound b17 against Sclerotinia sclerotiorum was 1.95 µg mL-1. Therefore, compounds b15 and b17 were identified as the most promising candidates for further study.