Combinatorial Chemistry & High Throughput Screening - Volume 28, Issue 16, 2025

In this research, multicomponent reactions of cefixime, isothiocyanates, and alkyl bromides were carried out for the synthesis of new iminothiazole derivatives with high yields in water as the solvent at room temperature in the presence of catalytic amounts of Cu@KF/CP NPs as catalysts. Also, the ability of Cu@KF/Clinoptilolite nanoparticles (NPs) to adsorb and remove 4-NP and cefixime from water was investigated. The Cu@KF/Clinoptilolite nanoparticles were synthesized by employing a water extract of Petasites hybridus rhizomes.

For this experiment, all of the components obtained from Fluka and Merck were subjected to further purification. The antibiotic used in this investigation, cefixime, was obtained from a pharmaceutical facility situated in Sari, Mazandaran, Iran. The antibiotic factory is located in Sari City, Iran. All solutions were prepared using distilled water. The shape of Cu@KF/CP nanoparticles was analyzed using images obtained from a Holland Philips XL30 scanning electron microscope. An analysis was performed on the crystalline structure of Cu@KF/CP nanoparticles (NPs), and a room temperature X-ray diffraction (XRD) examination was carried out utilizing a Holland Philips Xpert X-ray powder diffractometer. The X-ray diffraction (XRD) examination was conducted using CuK radiation, which has a wavelength of 0.15406 nm. The analysis covered a 2ε angle range from 20 to 80°. The nanostructures that were produced were chemically analyzed using X-ray energy dispersive spectroscopy (EDS) with an S3700N equipment. The morphology and dimensions of Cu@KF/CP nanoparticles were characterized using a Philips EM208 transmission electron microscope operated at an acceleration voltage of 90 kV.

The primary objective of this study was to develop a sustainable approach for producing new iminothiazole derivatives 4. This was achieved using a highly efficient three-component reaction combining cefixime 1, isothiocyanates 2, and alkyl bromides 3. The reaction was carried out in water at ambient temperature, using Cu@KF/CP NPs as a highly effective catalyst, leading to excellent yields. Moreover, the study findings showed that the synthesized compounds demonstrated a significant antioxidant activity compared to conventional antioxidants. The antibacterial efficacy of the synthesized compounds was evaluated against both Gram-positive and Gram-negative bacteria. Furthermore, Cu@KF/CP nanoparticles were utilized to adsorb CFX and 4-NP from water-based solutions.

This study showcases the effective synthesis of innovative iminothiazole derivatives through the use of multicomponent reactions, involving the combination of cefixime, isothiocyanates, and alkyl bromides. The reactions were conducted in a water-based solvent. The reactions were carried out at room temperature, utilizing Cu@KF/CP NPs as catalysts. The Cu@KF/CP nanoparticles, a newly developed heterogeneous nanocatalyst, were synthesized and evaluated utilizing X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDX), and transmission electron microscopy (TEM) research techniques. Cu@KF/CP nanoparticles are utilized to adsorb CFX and 4-NP from water-based solutions. The objects were manufactured using a straightforward and uncomplicated approach. The BET surface area of Cu@KF/CP NPs was measured to be 201.8 m²/g. The experimental equilibrium data was evaluated by applying the isotherms of the Langmuir, Freundlich, Dubinin-Radushkevich, and Redlich-Peterson models. Additionally, we examined the catalytic efficiency of Cu@KF/CP nanoparticles (NPs) in reducing various colors in water.

Constipation-predominant irritable bowel syndrome (IBS-C) is a chronic functional intestinal disease that can significantly reduce patients' quality of life.

This study aims to evaluate the clinical effect and mechanism of YunPi RouGan (YPRG) prescription on IBS-C patients with liver-depression and spleen-deficiency syndrome.

42 IBS-C patients receiving treatment at Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine from May 2022 to March 2023 were recruited and randomly assigned to either the treatment or control group, with 21 patients in each group. The patients received either a YPRG prescription or a linalotide capsule for 4 weeks. A series of scales were utilized to evaluate the clinical symptoms, psychological aspects, and quality of life in IBS patients. Meanwhile, fresh fecal samples were collected to analyze the changes in gut microbiota by 16SrDNA sequencing.

In terms of clinical treatment, both YPRG prescription and the first-line drug linaclotide have similar effects for IBS-C. However, YPRG prescription has demonstrated significant improvements in several symptoms, such as abdominal distension and belching. Furthermore, it has been shown to upregulate the diversity of gut microbiota and induce changes in the types of dominant microbiota in IBS-C patients. At the phylum level, Firmicutes and Bacteroides increased, while Proteobacteria, actinobacteria, and desulphurobacteria decreased. At the genus level, Bacteroides, Spirillum, Clostridium praxis, Roxella, Para-salmonella, Haemophilus, koala bacillus, Micrococcus rare, Spirillum, and Streptococcus increased significantly.

The effect of YPRG prescription on improving the clinical symptoms of IBS-C may be attributed to its potential to regulate gut microbiota.

The incidence of depression is increasing year by year, and Zhizichi Decoction(ZZCD)has shown significant efficiency in the clinical treatment of mild depression, but its mechanism of action is still unclear. In this research, network pharmacology and metagenomics combined and metabolomics were used as research methods to explain the scientific connotation of the antidepressant effect of ZZCD from the aspects of the overall effect of organisms and microbial structure and function.

The rat model of depression was established by chronic unpredictable mild stress (CUMS), and the improvement of depressive symptoms was evaluated by behavioral and histopathological methods. Network pharmacology predicted possible targets and important pathways of ZZCD. Metabolomics revealed its possible related biological pathways. Metagenomics showed the disturbance of ZZCD on intestinal microbial diversity structure and associated biological functions in depressed rats.

ZZCD can improve the behavioral performance of CUMS rats, and can significantly regulate the content of 5-HT, NE and other neurotransmitters in serum and brain tissue, and improve the damaged state of neurons in the hippocampus. Network pharmacology predicts that it mainly acts on biological processes such as inflammatory response and oxidative stress response. Metabolomics found that it affected metabolic pathways such as amino acid metabolism and lipid metabolism. The results of metagenomics showed that it significantly regulated the abundance of Firmicutes and Bacteroidetes. The above results predicted that it may affect signaling pathways such as the nervous system, inflammatory diseases and cell processing.

ZZCD may play an antidepressant role by regulating intestinal probiotics, energy metabolism, and inflammation reduction. This provides a scientific basis for the clinical application of ZZCD in traditional Chinese medicine and also makes it an optional alternative for the treatment of depression.

Tobacco use is a major global health issue linked to psychiatric illnesses and high mortality rates. Nicotine, the primary compound absorbed during smoking, causes harm to various organs, particularly the brain. The current study examined the modulatory effect of Teucrium polium extract (TPE) on nicotine-induced biochemical and histological changes in the brains of mice.

Twenty-four mice were divided into four groups and were treated for three weeks. Group one was the control; Group two received 100 mg/kg TPE orally; Group three was subcutaneously injected with 2.5 mg/kg nicotine, and Group four received both nicotine and TPE.

The brain tissue of the nicotine-induced group showed histopathological alterations and oxidative stress as indicated by increased lipid peroxidation and nitric oxide levels concomitant with decreased glutathione content and superoxide dismutase activity. DNA fragmentation was also detected by comet assay. Treatment with TPE significantly decreased oxidative stress and DNA fragmentation while increasing antioxidant biomarkers. Histopathological changes were also diminished.

Through the antioxidant activity of TPE, it protected against nicotine-induced neurotoxicity in mice by impacting oxidative stress, DNA fragmentation, and brain histopathological changes.

Psoriasis is an immune-mediated skin disease that occurs worldwide and is characterized by high prevalence and chronicity. Psoriasis has a complex pathogenesis and is difficult to cure. Therefore, continuous exploration of the pathogenesis of psoriasis and the search for new drug treatment methods are crucial for improving treatment efficiency and reducing psychological damage to psoriasis patients. The active ingredients in Dihuang Zicao granules (DHZCG) can effectively treat psoriasis. Therefore, this study aimed to analyze the active ingredients of DHZCG and their potential mechanisms for treating psoriasis.

The effective components of DHZCG were screened via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Genetic information for psoriasis was retrieved from the GeneCards, OMIM and DisGENET databases. Protein-Protein Interaction (PPI) analysis was performed, and component‒target‒disease networks were constructed. Important molecular biological processes and signaling pathways were screened via GO and KEGG analyses. Molecular docking of the active ingredients and key targets was performed via AutoDock Vina (1.1.2). A mouse model of psoriasis was established and divided into a control group, model group, low-dose DHZCG group (L-DHZCG), medium-dose DHZCG group (M-DHZCG), and high-dose DHZCG group (H-DHZCG). Hematoxylin and Eosin (HE) staining was performed to determine the pathological changes in the skin of each group of mice, and the Psoriasis Area Severity Index (PASI) score was used to assess skin damage. ELISA and RT‒PCR were used to measure the levels of the inflammatory factors TNF-a, IL-17A, and IL-23 in the serum and skin tissue of the mice, respectively. Western blotting was used to analyze the expression of proteins related to the AGE/RAGE signaling pathway. Immunofluorescence was used to examine the expression of the inflammatory factor NF-kB. Immunohistochemistry was used to measure IL-1β and TNF-a expression in skin tissues.

Sixty genes associated with psoriasis treatment by DHZCG, including core genes encoding IL-6, TNF-a, AKT1, IL-1β, TP53, NFKB1, BCL2, and MAPK3, were identified. Through the construction of a psoriasis mouse model, DHZCG treatment effectively reduced skin damage and significantly decreased the levels of the validated factors TNF-a, IL-17A, IL-23, IL-1b, and NF-kB in the serum and damaged skin. Furthermore, the reduction in the levels of these inflammatory factors by DHZCG is associated with the downregulation of the AGE/RAGE signaling pathway.

DHZCG reduces inflammation and alleviates psoriasis by downregulating the AGE/RAGE/NF-kB signaling pathway. This study is beneficial for providing a theoretical basis for the development of drugs for psoriasis and for offering personalized treatment strategies for the clinical management of psoriasis.

Astragalus membranaceus (AM) is a traditional Chinese medicine that has been clinically utilized as an adjunctive therapy for the treatment of myocardial ischemia and heart failure; however, its precise molecular mechanism of action remains unknown.

This study aims to investigate the potential pharmacological effects and molecular mechanism of AM in the treatment of ischemic heart failure (IHF) using network pharmacology methods, molecular docking technology, and in vitro experiments.

The active components and targets of AM were obtained from the TCMSP databases, while the disease targets of IHF were retrieved from GeneCards and OMIM databases. The analysis of overlapping targets between AM and IHF mainly included active compounds-targets network, PPI network, and GO and KEGG enrichment analysis. The association between active compounds and target proteins was verified through molecular docking. Additionally, an in vitro experimental model was used to evaluate the accuracy of the forecast results.

The network pharmacological analysis revealed that quercetin, kaempferol, 7-O-methylisomucronulatol, formononetin, and isorhamnetin were the core active components of AM in treating IHF. The core targets included AKT1, IL6, IL1B, PTGS2, CASP3, MMP9, and HIF1A. The molecular docking results demonstrated a strong binding affinity between these active components and targets. The KEGG pathway analysis suggested that the PI3K-AKT signaling pathway might play a central role in mediating AM's therapeutic effects on IHF. In vitro experiments demonstrated that AM treatment enhanced cell viability, reduced heart failure biomarkers, and suppressed cell apoptosis. Furthermore, the western blot analyses indicated that AM treatment effectively regulated AKT1 phosphorylation in an experimental model of IHF.

Through integrated network pharmacological analysis, molecular docking technology, and in vitro experimental validation, it was demonstrated that AM can effectively mitigate IHF through activating PI3K-AKT signaling pathway. These findings significantly advance our understanding of the molecular mechanisms in IHF treatment and contribute further to promoting the clinical application of AM.

Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world, characterized by high incidence, high malignancy, and low survival rate. Currently, 1/4 of adults in the world suffer from Non-Alcoholic Fatty Liver Disease (NAFLD), with an incidence rate of 27% in Asia.

We used TCGA and GEO public database data sets to conduct weighted gene co-expression network analysis to identify relevant gene modules, defined the intersection of tumorigenesis-related modules and NASH development-related modules as shared genes, and then used single-factor Cox, LASSO, and multivariate Cox regression analysis screened out core shared genes and verified their prognostic value. We further investigated the relationship between core shared genes and immune infiltration, tumor mutational load, and drug sensitivity. Finally, RT-qPCR was used to verify its mRNA expression in different cell lines.

We identified Karyopherin α 2 (KPNA2) as the core shared gene between NASH and HCC. Patients were divided into low-risk groups and high-risk groups based on the expression of KPNA2. The prognosis of the low-risk group was significantly better than that of the high-risk group. Furthermore, we found significant differences in tumor immune cell infiltration, somatic mutations, microsatellite instability, and drug sensitivity between different expression groups.

There are very few studies on the molecular mechanism of the relationship between NAFLD and HCC. Our study demonstrates that KPNA2 is a potential therapeutic target and immune-related biomarker for patients with NAFLD and HCC.

Ovarian Cancer (OC) is a lethal malignant tumor with a poor prognosis. Disulfidptosis is a newly identified form of cell death caused by disulfide stress. Targeting disulfidptosis is a new metabolic therapeutic strategy in cancer treatment. We aimed to establish a disulfidptosis-related lncRNA signature for prognosis prediction and explore its treatment values in OC patients.

Data from the TCGA and GTEx databases and a disulfidptosis gene set were used to establish a disulfidptosis-related lncRNA signature for prognosis prediction in OC patients. Then, we internally and externally (PCR) validated our model. We also built a nomogram to improve our model's predictive power. Afterward, GSEA was employed to explore our model's potential functions. The ESTIMATE, CIBERSORT, TIMER, and ssGSEA were applied to estimate the immune landscape. Finally, the drug sensitivity of certain drugs for OC patients was analyzed.

We built a prognosis model based on seven drlncRNAs, including AL157871.2, HCP5, AC027348.1, AL109615.3, AL928654.1, LINC02585, and AC011445.1. Our model performed well by internal validation. PCR data also confirmed the same trend in the lncRNA levels. Furthermore, the nomogram-integrated age, grade, stage, and risk score could accurately predict the survival outcomes of OC patients. Subsequently, GSEA unveiled that our model genes enriched the Hedgehog signaling pathway, a key regulator in OC tumorigenesis. Our predictive signature was associated with immune checkpoints, such as PD-1(P < 0.01), PD-L1(P < 0.001), and CTLA4 (P < 0.01), which might help screen out OC patients who are sensitive to immunotherapy. Small molecule drugs, such as AZD-2281, GDC-0449, imatinib, and nilotinib, might benefit OC patients with different risk scores.

Our disulfidptosis-related lncRNA signature comprised of AL157871.2, HCP5, AC027348.1, AL109615.3, AL928654.1, LINC02585, and AC011445.1 could serve as a prognostic biomarker and guidance to therapy response for OC patients.

This study aimed to initially clarify the potential mechanism of quercetin in the treatment of non-small cell lung cancer (NSCLC) based on network pharmacology, molecular docking and in vitro experiments.

TCMSP, SwissTargetPrediction, TCMIP, STITCH, and ETCM databases were applied to obtain the targets of quercetin. NSCLC-related targets were retrieved from GeneCards, OMIM, PharmGKB, TTD, and NCBI databases. Their intersection targets were imported into the STRING database to construct a protein-protein interaction (PPI) network and core targets were identified through the Cytoscape 3.10.0 soft and the CytoHubba tool. Furthermore, Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the intersection targets. A compound-targets-pathways network was subsequently constructed to screen for key targets and pathways. Molecular docking was performed with Discovery Studio software to verify the interactions between quercetin and core targets. In vitro validations were conducted employing CCK-8 assays, flow cytometry, and Western blotting (WB).

193 potential targets of quercetin for treating NSCLC were obtained. The top ten core targets identified within the PPI network included TP53, HSP90AA1, AKT1, JUN, SRC, EGFR, ACTB, TNF, MAPK1, and VEGFA. GO analysis yielded 2319 items, and KEGG analysis resulted in 211 enriched pathways. Molecular docking results demonstrated a high affinity of quercetin towards the core targets. Based on the compound-targets-pathways network and molecular docking, the PI3K/AKT/P53 pathway and its key-related proteins (PIK3R1, AKT1, and TP53) were selected for further validation. Quercetin(20 and 40 μg/mL) significantly decreased the viability of A549 NSCLC cells but not BEAS-2B normal cells via CCK-8 assays. Flow cytometry and WB analyses further corroborated that quercetin could promote apoptosis of A549 cells by downregulating and upregulating the expression of Bcl-2 and Bax (P<0.05), respectively. Notably, quercetin did not significantly alter the total protein levels of PI3K, AKT, and P53 but downregulated the phosphorylation levels of PI3K and AKT (P<0.05) and upregulated the phosphorylation level of P53 (P<0.05).

Quercetin exhibits therapeutic potential in NSCLC by regulating the PI3K/AKT/P53 pathway to promote cell apoptosis.

This study aimed to investigate the potential therapeutic efficacy of rutin in the management of psoriasis and elucidate its underlying molecular mechanisms.

A systems biology approach, utilizing network pharmacology, was employed to identify and analyze putative targets of rutin relevant to psoriasis. The impact of rutin on the Psoriasis Area and Severity Index (PASI) scores was assessed in an imiquimod (IMQ)-induced murine psoriasis model. Histopathological alterations in the skin lesions were examined using hematoxylin and eosin (H&E) staining. Expression levels of key inflammatory mediators, including Tnf, Hif1a, Ptgs2, Tlr4, Nfkb1, Mtor, and Il2, were quantified using quantitative real-time polymerase chain reaction (qRT-PCR).

A comprehensive analysis revealed 62 potential targets of rutin in the context of psoriasis, with these targets being part of 72 interconnected signaling pathways. In vivo studies demonstrated a significant reduction in PASI scores in rutin-treated mice compared to those in the control group. Additionally, rutin treatment was associated with marked improvements in skin lesions, characterized by reduced crust formation and epidermal thickness. qRT-PCR analysis indicated that rutin administration downregulated the mRNA expression of Tnf, Hif1a, Ptgs2, Tlr4, Nfkb1, Mtor, and Il2 in the lesional skin.

These findings suggest that rutin holds promise as a therapeutic agent for psoriasis, as it effectively ameliorates IMQ-induced psoriasis-like skin inflammation in mice through modulation of multiple signaling pathways and inflammatory mediators.

SH2B adaptor protein 2 (SH2B2, also named APS) is an adaptor protein implicated in the modulation of insulin signaling pathways and glucose metabolism. Its role in colon adenocarcinoma (COAD) is unknown.

Data from The Cancer Genome Atlas and Gene Expression Omnibus database were utilized to assess SH2B2 expression and its clinical significance in COAD. We investigated the associations between SH2B2 expression with genomic instability, tumor mutational burden (TMB), DNA methylation, alternative splicing, immune infiltration, and drug sensitivity. A SH2B2 knockdown model was developed to examine its impact on COAD cellular functions.

Highly expressed SH2B2 is associated with a poorer prognosis in COAD. SH2B2 expression in COAD is associated with copy number variations, microsatellite instability, methylation patterns, and alternative 5’ splicing events, but not with TMB. SH2B2 is positively correlated with mostly immune cells and the expression of PD-1 and CTLA4. The IC50 values of ten drugs were significantly correlated with SH2B2 expression. BI-2536_1086 had a strong binding affinity with SH2B2. Furthermore, the knockdown of SH2B2 reduced the proliferation, migration, and invasion of COAD cells.

SH2B2 appears to act as an oncogene in COAD and may serve as a pivotal prognostic and therapeutic target, deserving further exploration.

This study aims to explore the relevant biomarkers in breast cancer (BC).

Kinesin family member 4A (KIF4A) is a member of the Kinesin 4 subfamily of kinesin-related proteins, which has already been investigated in diverse types of tumors.

Our current study aims to investigate the involvement of KIF4A in BC.

KIF4A expression level was firstly predicted based on the data from the Cancer Genome Atlas (TCGA) and then assessed in BC cells. Subsequently, after silencing KIF4A, its effects on BC cell proliferation and metastasis, as well as on immune-related cytokines, were assessed by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) staining and quantitative Polymerase Chain Reaction (qPCR). Next, western blotting assays were used to detect the expression and phosphorylation levels of transforming growth factor-beta 1 (TGF-β1) and small mothers against decapentaplegic 3 (Smad3) in BC cells after KIF4A silencing and the role of the pathway was verified by Smad3 inhibitor (SIS3).

KIF4A was highly expressed in BC, and silencing of KIF4A repressed the proliferation and metastasis potential of in-vitro cultured BC cells, concurrent with the reduction of CDH2, VIM, and SNAIL levels, yet the increase in the expression of CDH1. In the meantime, KIF4A knockdown diminished the levels of IL4, SMAD3, and TGFB1 while promoting those of IL1B and IL6 in BC cells. Further, enhanced phosphorylation of Smad3 was observed in BC cells, and the intervention of SIS3 restrained the proliferation and metastasis potential of BC cells and reduced the expression levels of CDH2, VIM, and SNAIL whilst promoting that of CDH1. Additionally, SIS3 intervention increased IL1B and IL6 levels and decreased IL4, SMAD3 and TGFB1 levels in BC cells.

This study preliminarily explored the involvement of KIF4A and TGF-β1/Smad3 together in BC, which may provide another insight into the management of BC in clinical practice.