Combinatorial Chemistry & High Throughput Screening

Background:Pyrazole-scaffold protein kinase inhibitors (PKIs) have emerged as promising therapeutic agents for the treatment of various diseases, such as cancer, inflammatory disorders, and neurological diseases. This review article provides an overview of the pharmacological properties of pyrazole-scaffold PKIs, including their mechanism of action, selectivity, potency, and toxicity. The article also summarizes the recent developments in the design and synthesis of pyrazole-scaffold PKIs, highlighting the structural features and modifications that contribute to their pharmacological activity. In addition, the article discusses the preclinical and clinical studies of pyrazole-scaffold PKIs, including their efficacy, safety, and pharmacokinetic properties.

Methods:A comprehensive search has been conducted on several online patent databases, including the United States Patent and Trademark Office (USPTO), the European Patent Office (EPO), and the World Intellectual Property Organization (WIPO). The search was conducted using pyrazole as the keyword. The search was limited to patents filed between 2015 and 2022. Patents were included if they involved articles in the fields of protein kinase inhibitors, and included literature on some pyrazoles and their pharmacological activities.

Results:Data were extracted from each included patent on the following variables: patent title, patent number, inventors, assignee, filing date, publication date, patent type, and field of invention. Data were extracted from each patent using a standardized form to ensure consistency and accuracy.

Conclusion:The design and pharmacological evaluation of organic compounds containing pyrazole structure as biologically active substances have been done, and the key structures from the pharmacological data obtained as protein kinase inhibitors have been addressed in detail. The review concludes with a discussion on the current challenges and future directions for the development of pyrazole-scaffold PKIs as therapeutic agents. Overall, this review article provides a comprehensive summary of the pharmacological properties of pyrazole-scaffold PKIs, which will be of interest to researchers and clinicians in the field of drug discovery and development.

Background:Developing high-efficiency and low-risk small-molecule green fungicide is the key to effective control of the plant pathogenic oomycetes. Indole is an important raw material for drug synthesis. Due to its unique structural skeleton, indole, and its derivatives have exhibited a wide range of biological activities. However, a study on the synthesis of novel indole derivatives as fungicidal agents against Phytophthora capsici has not yet been reported.

Methods:The important intermediates 2a-c and 3a-c were synthesized in high yields by Vilsmeier- Haack and Knoevenagel reactions with indole as the lead compound. Furthermore, different substituted benzenesulfonyl groups were introduced into the NH position of the indole ring, and twelve indole derivatives (I-a-l) were prepared. Their structures were well characterized by 1H NMR, HRMS, and melting point.

Results:The results showed that 2-[(N-(4-nitrobenzenesulfonyl)-indole-3)-methylene]-diethyl malonate (I-d) and 2-[(N-(4-nitrobenzenesulfonyl)-5-cyanoindole-3)-methylene]-diethyl malonate (I-l) showed more anti-oomycete activity against P. capsici than the commercialized fungicide zoxamide, with corresponding EC50 values of 26.53, 23.48 and 28.16 mg/L, respectively, and the protective effect of the compounds against P. capsici in vivo further confirmed the above results.

Conclusion:The preliminary structure-activity relationship showed that the formyl group modification at the C-3 position of the indole ring was acceptable, and the different anti-oomycete activities of R1 and R2 were significantly different, with R1 being 5-CN > H > 6-Me, and R2 being 4-NO2 > 3-NO2, H > 4-Me.

Background:Ginseng-ophiopogon injection (GOI) is a clinically commonly used drug for Qi deficiency syndrome characterized by decreased physical function in China. This study aimed to clarify common pharmacological mechanisms of GOI in enhancing physical function.

Methods:We performed an integrative strategy of weight-loaded swimming tests in cold water (5.5 °C), hepatic glycogen and superoxide dismutase (SOD) detections, GC-TOF/MS-based metabolomics, multivariate statistical techniques, network pharmacology of known targets and constituents, and KEGG pathway analysis of GOI.

Results:Compared with the control group, GOI showed significant increases in the weightloaded swimming time, hepatic levels of glycogen and SOD. Additionally, 34 significantly differential serum metabolites referred to glycolysis, gluconeogenesis and arginine biosynthesis were affected by GOI. The target collection revealed 98 metabolic targets and 50 experimentreported drug targets of ingredients in GOI involved in enhancing physical function. Further, the PPI network analysis revealed that 8 ingredients of GOI, such as ginsenoside Re, ginsenoside Rf, ginsenoside Rg1, and notoginsenoside R1, were well-associated with 48 hub targets, which had good ability in enhancing physical function. Meanwhile, nine hub proteins, such as SOD, mechanistic target of Rapamycin (mTOR), and nitric oxide synthases, were confirmed to be affected by GOI. Finally, 98 enriched KEGG pathways (P(<0.01 and FDR(<0.001) of GOI were obtained from 48 hub targets of the PPI network. Among them, pathways in cancer, Chagas disease, lipid and atherosclerosis, and PI3K-Akt signaling pathway ranked top four.

Conclusions:This study provided an integrative and efficient approach to understanding the molecular mechanism of GOI in enhancing physical function.

Background:In this study, cysteine-coated magnetite nanoparticles (Fe3O4@Cys MNPs) were synthesized by chemical method and applied as a recoverable and efficient adsorbent for the removal of carmoisine dye from aqueous solutions. The synthesized MNPs were characterized by FT-IR, XRD, SEM, and TEM studies.

Methods:The effect of various experimental parameters on the dye removal efficiency was studied using Taguchi orthogonal array design (L16 array). Under the optimum conditions (pH = 2, stirring time = 30 min, adsorbent amount = 0.1 g and without salt addition), more than 92% of carmoisine was removed from the aqueous solutions.

Results:The kinetic studies showed rapid adsorption dynamics by a pseudo second-order kinetic model, confirming that diffusion controls the adsorption process. Dye adsorption equilibrium data were fitted well to the Freundlich isotherm, and the synthesized adsorbent showed high removal efficiency.

Conclusion:The obtained results showed that the synthesized MNPs act as a reusable adsorbent for carmoisine removal with an easy procedure.

Background:Chronic Kidney Disease (CKD) leads to structural and functional abnormalities of the kidneys and seriously jeopardizes human health. Shenyan Oral Liquid (SOLI), a Chinese medicinal preparation, has been reported to protect podocytes in patients with chronic kidney disease (CKD).

Objective:The objective of this study is to investigate the mechanism of action of the Chinese medicinal preparation Senyan Oral Liquid (SOLI) in the treatment of CKD by protecting podocytes through network pharmacology technology and experimental validation.

Methods:Compounds of SOLI and targets of CKD disease were collected and screened. The SOLI network of bioactive compounds targeting CKD and the protein-protein interaction (PPI) network were constructed using Cytoscape software and the STRING online database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R software Cluster Profiler package. Molecular docking was performed using Autodock software to verify the binding ability of bioactive compounds and target genes. Subsequently, the potential mechanism of SOLI on CKD predicted by network pharmacological analysis was experimentally studied and verified in an adriamycin-induced nephropathy rat model.

Results:A total of 81 targets of SOLI components acting on CKD were identified. The results of the PPI analysis clarified that five key target genes (TNF, AKT1, IL6, VEGFA, and TP53) play a critical role in the treatment of CKD by SOLI. The GO analysis and KEGG enrichment analysis indicated that SOLI acts through multiple pathways, including the PI3K/AKT signaling pathway against CKD. Molecular docking showed that the main compounds of SOLI and five key genes had strong binding affinity. In a rat model of adriamycin-induced nephropathy, SOLI significantly ameliorated disease symptoms and improved renal histopathology. Mechanistic studies showed that SOLI upregulated the expression level of Nephrin, inhibited the PI3K/AKT pathway in renal tissues, and ultimately suppressed the activation of autophagy-related proteins in CKD.

Conclusion:SOLI exerted a renoprotective effect by regulating the Nephrin-PI3K/AKT autophagy signaling pathway, and these findings provide new ideas for the development of SOLI-based therapeutic approaches for CKD.

Objective:The objective of this study is to assess the correlation between Piezo2 and tumors through a comprehensive meta-analysis and database validation.

Methods:Case-control studies investigating the association between Piezo2 and tumors were obtained from various databases, including China National Knowledge Infrastructure (CNKI), SinoMed, Embase, Web of Science, The Cochrane Library, and PubMed. The search was performed from the inception of each database up until May 2023. Two researchers independently screened the literature, extracted data, and assessed the quality of the included studies. Metaanalysis of the included literature was conducted using Stata 12.0 software. Additionally, the Gene Expression Profiling Interactive Analysis (GEPIA) database predicted a correlation between Piezo2 expression and prognostic value in tumor patients.

Results:A total of three studies, involving a combined sample size of 392 participants, were included in the meta-analysis. The findings revealed that the expression level of Piezo2 in tumor patients was not significantly associated with age, gender, or tumor size. However, it was found to be positively correlated with lymphatic invasion (OR = 7.89, 95%CI: 3.96-15.73) and negatively correlated with invasion depth (OR = 0.17, 95%CI: 0.06-0.47), TNM stage (OR = 0.48, 95%CI: 0.27-0.87), and histological grade (OR = 0.40, 95%CI: 0.21-0.77). Confirming these findings, the GEPIA database indicated that high expression of Piezo2 was associated with poor prognosis of disease-free survival in patients with colon adenocarcinoma (HR = 1.6, P = 0.049) and gastric cancer (HR = 1.6, P = 0.017).

Conclusion:Piezo2 may be associated with poor prognosis and clinicopathological parameters in tumor patients.

Background:Chagas disease kills around 10,000 people yearly, primarily in Latin America, where it is prevalent. Current treatment has limited chronic effectiveness, is unsafe, and has substantial side effects. As a result, the use of oxadiazole derivatives and similar heterocyclic compounds as bioisosteres are well known, and they are prospective candidates in the hunt for novel anti-Trypanosoma cruzi chemicals. Recent research has revealed that the cysteine protease cruzain from T. cruzi is a validated target for disease treatment.

Objective:Thus, using a molecular dynamics simulation, the current study attempted to determine if a significant interaction occurred between the enzyme cruzain and its ligand.

Results:Interactions with the catalytic site and other critical locations were observed. Also, the RMSD values suggested that the molecule under research had stable interactions with its target.

Conclusion:Finally, the findings indicate that the investigated molecule 2b can interfere enzymatic activity of cruzain, indicating that it might be a promising antichagasic drug.

Background:Cervical spondylotic radiculopathy is a serious and common degenerative disease of the cervical spine due to irritation and compression of the nerve roots of the cervical spine, resulting in a series of clinical symptoms based on sensory, motor and reflex disorders, such as numbness and pain in the neck, shoulders, upper limbs and fingers. Acupuncture is highly effective in treating CSR and has become a common treatment accepted by patients. This study aims to systematically review and analyze existing randomized controlled trials (RCTs) to evaluate the efficacy and safety of acupuncture in the treatment of CSR.

Methods:We used the following eight databases for literature data search: PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Biology Medicine Disc ( CBMdisc), Wanfang Database and China Science and Technology Journal Database (VIP). The search consisted of randomized controlled studies of acupuncture for CSR between 2000 and 2020 and the methodological quality of the included studies was assessed according to the Cochrane Collaboration's \"Risk of Bias Assessment Tool.\"RevMan 5.4 software was used for statistical analysis only. Study screening, data extraction and statistics, and assessment of the risk of bias of the included studies were performed independently by two reviewers.

Result:27 studies with 3124 patients were included. The results of the meta-analysis of the total efficiency index for acupuncture for CSR were [RR = 1.14,95% CI (1.09,1.19)]. The results of the meta-analysis of the PPI index were [MD = -0.35, 95% CI (-0.61,-0. 09)]. The results of META analysis of the total effective rate, VAS score, PRI(A) score, PRI(S) score and PRI(T) score showed heterogeneity in the studies included for each outcome index, and sources of heterogeneity were sought through subgroup analysis and sensitivity analysis to ensure more stable and reliable data results. The results of the combined meta-analysis showed that the treatment group was significantly more effective than the control group and more effective in lowering the nerves to reduce the pain index in patients with CSR, with a statistically significant difference (P(<0.05). This indicates that acupuncture treatment is superior to traction for CSR.

Conclusion:Acupuncture is significantly more effective than traction therapy in the treatment of cervical spondylosis and can reduce the pain index of patients with CSR.