Combinatorial Chemistry & High Throughput Screening - Volume 23, Issue 2, 2020

Aims and Objective: Hypertension-induced stroke and coronary artery disease are significant causes of global morbidity and mortality. Metabolic hypertension has recently become the leading cause of hypertension. Flos Chrysanthemi Indici (CIF) has a long history as a treatment of hypertension as part of traditional Chinese medicine. However, its mechanisms of activity remain largely unknown. This study was aimed to uncover the potential anti-hypertensive mechanisms of CIF based on network pharmacology. Materials and Methods: In this research, a systems pharmacology approach integrating the measurement of active compounds, target fishing, gene screening, Gene Ontology (GO) pathway analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) database analysis, and compound-target network construction were performed to explore the anti-hypertensive mechanisms of CIF. Results: These studies revealed that 12 bioactive compounds in CIF had good druggability, 5 of which were flavonoids. After screening, 8 of those 12 bioactive compounds interacted with 118 hypertensionrelated target genes, which were mapped to 218 signal pathways. Network analysis showed that these targets were associated with improving insulin resistance, improving vascular function, inhibiting renninangiotensin- aldosterone system (RAAS), inhibiting the sympathetic nervous system (SNS) and regulating other physiological processes. Conclusion: In summary, CIF is predicted to target multiple proteins and pathways to form a network that exerts systematic pharmacological effects in order to regulate blood pressure and metabolic disorder.

Background: It is one of the effective ways for pesticide innovation to develop new insecticides from natural products as lead compounds. Quinine, the main alkaloid in the bark of cinchona tree as well as in plants in the same genus, is recognized as a safe and potent botanical insecticide to many insects. The structural modification of quinine into 9R-acyloxyquinine derivatives is a potential approach for the development of novel insecticides, which showed more toxicity than quinine. However, there are no reports on the insecticidal activity of 9Racyloxyquinine derivatives to control Mythimna separata. Methods: Endeavor to discover biorational natural products-based insecticides, 20 novel 9Racyloxyquinine derivatives were prepared and assessed for their insecticidal activity against M. separata in vivo by the leaf-dipping method at 1 mg/mL. Results: Among all the compounds, especially derivatives 5i, 5k and 5t exhibited the best insecticidal activity with final mortality rates of 50.0%, 57.1%, and 53.6%, respectively. Conclusion: Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9- substitution is well tolerated; modification of out-ring double-bond is acceptable, and hydrogenation of double-bond enhances insecticidal activity; Quinine ring is essential and open of it is not acceptable. These preliminary results will pave the way for further modification of quinine in the development of potential new insecticides.

Objective: Herein, a novel heterogeneous catalytic system constructed of iron oxide and palladium nanoparticles is presented. Firstly, a convenient synthetic pathway for the preparation of this catalytic system is introduced, then the application of the fabricated nanocomposite in the Pd-catalyzed C–C coupling reactions is monitored. High reaction yields (98%) have been obtained in short reaction time, by using this catalytic system. Materials and Methods: Fe3O4/P4VP-Pd catalytic system was fabricated via an in situ method by 4- vinylpyridine (4-VP). In this regard, all the essential structural analyses such as FT-IR, EDX, VSM, and TGA have been performed on the Fe3O4/P4VP-Pd catalytic system to investigate its properties. The spherical morphology of the NPs and their uniform size have also been studied by the SEM method. Further, the reaction progress was controlled by thin-layer chromatography. Finally, NMR analysis was used to identify the synthesized biphenyl pharmaceutical derivatives. Results: High efficiency of this catalytic system has been precisely investigated and the optimal conditions were determined. The catalytic process is carried out in 20 min, under mild conditions (room temperature). Then, the purification process is easily performed via magnetic separation of the catalyst NPs. After completion of the synthesis reaction, the NPs were collected, washed, and reused several times. Conclusion: Among recently reported heterogeneous catalytic systems, Fe3O4/P4VP-Pd is recommended due to its high catalytic performance, convenience of the preparation process, excellent biocompatibility, economic benefits, and well reusability. Overall, in order to save time in the complex synthetic processes and also prevent using so many chemical reagents and solvents for the purification process, the presented catalytic system could be suitable for scaling up and applying for the industrial applications.

Aims and Objective: The infectious disease treatment remains a challenging concern owing to the increasing number of pathogenic microorganisms associated with resistance to multiple drugs. A promising approach for combating microbial infection is to combine two or more known bioactive heterocyclic pharmacophores in one molecular platform. Herein, the synthesis and biological evaluation of novel thiazole-thiazolidinone hybrids as potential antimicrobial agents were dissimilated. Materials and Methods: The preparation of the substituted 5-benzylidene-2-thiazolyimino-4- thiazolidinones was achieved in three steps from 2-amino-5-methylthiazoline. All the compounds have been screened in PASS antibacterial activity prediction and in a panel of bacteria and fungi strains. Minimum inhibitory concentration and minimum bacterial concentration were both determined by microdilution assays. Molecular modeling was conducted using Accelrys Discovery Studio 4.0 client. ToxPredict (OPEN TOX) and ProTox were used to estimate the toxicity of the title compounds. Results: PASS prediction revealed the potentiality antibacterial property of the designed thiazolethiazolidinone hybrids. All tested compounds were found to kill and to inhibit the growth of a vast variety of bacteria and fungi, and were more potent than the commercial drugs, streptomycin, ampicillin, bifomazole and ketoconazole. Further, in silico study was carried out for prospective molecular target identification and revealed favorable interaction with the target enzymes E. coli MurB and CYP51B of Aspergillus fumigatus. Toxicity prediction revealed that none of the active compounds was found toxic. Conclusion: Substituted 5-benzylidene-2-thiazolyimino-4-thiazolidinones, endowing remarkable antibacterial and antifungal properties, were identified as a novel class of antimicrobial agents and may find a potential therapeutic use to eradicate infectious diseases.

Aims and Objective: Pesticide residues seriously affect human health, so it is very important to study the degradation of pesticide residues for food safety. The degradation of pyridaben by ultraviolet (UV) irradiation was studied, the degradation characteristics and modeling were analyzed in this paper. This study was undertaken to fully reveal the degradation mechanism of UV irradiation for pyridaben residue and provided the evaluation method of degradation effect. Materials and Methods: Firstly, the fluorescence spectra of pyridaben samples were measured by LS55 fluorescence photometer, and the relationship between pyridaben concentration and the fluorescence intensity of characteristic peak was established. Then, using UV irradiation approach, the pyridaben was degraded to different degrees by controlling the irradiation time. The degradation process was characterized according to the change of fluorescence characteristic peak intensity before and after degradation. The relationship between degradation time and fluorescence intensity was established at last. Results: The results showed that the fluorescence characteristic peak of pyridaben was located at 356 nm. The pyridaben content prediction model function was obtained with the correlation coefficient of 0.9989 and the average recovery of 99.70%. The relative standard deviation (RSD%), the limit of detection (LOD) and the limit of quantity (LOQ) was 1.71%, 0.0058 ug/ml and 0.0193 ug/ml, respectively. The exponential function model between UV degradation time and fluorescence intensity was obtained, the corresponding correlation coefficient was 0.9991, and the average recovery was 100.49%. Conclusion: UV light irradiation can effectively degrade pyridaben, degradation process can be characterized by the change of fluorescence intensity, and the degradation model was tested to be accurate.

Objective: The aim of this study areto screen MicroRNAs (miRNAs) related to the prognosis of lung adenocarcinoma (LUAD) and to explore the possible molecular mechanisms. Methods: The data for a total of 535 patients with LUAD data were downloaded from The Cancer Genome Atlas (TCGA) database. The miRNAs for LUAD prognosis were screened by both Cox risk proportional regression model and Last Absolute Shrinkage and Selection Operator (LASSO) regression model. The performances of the models were verified by time-dependent Receiver Operating Characteristic (ROC) curve. The possible biological processes linked to the miRNAs’ target genes were analyzed by Gene Ontology (GO), Kyoto gene and genome encyclopedia (KEGG). Results: Among 127 differentially expressed miRNAs identified from the screening analysis, there are 111 up-regulated and 16 down-regulated miRNAs. Three of them, hsa-miR-1293, hsa-miR-490 and hsa-miR- 5571, were also significantly associated with the survival of the LUAD patients. The targets of the three miRNAs are significantly enriched in systemic lupus erythematosus pathways. Conclusion: Hsa-miR-1293, hsa-miR-490 and hsa-miR-5571 can be potentially used as novel biomarkers for the prognosis prediction of LUAD.

Objective: A facile and efficient method for synthesis of 3, 4-dihydropyrimidin-2(1H)-ones via Biginelli reaction catalyzed by a novel dicationic Brönsted acidic ionic liquid, [(EtNH2)2SO][HSO4]2, has been successfully developed. Materials and Methods: 3, 4-Dihydropyrimidin-2(1H)-ones were synthesized through one-pot condensation of aromatic aldehydes, ethyl acetoacetate, and urea under solvent-free conditions using [(EtNH2)2SO][HSO4]2 as a novel catalyst. The progress of the reaction was monitored by thin-layer chromatography (ethyl acetate / n-hexane = 1 / 5). The products have been characterized by IR, 1H NMR, 13C NMR, and also by their melting points. Results: In this research, a library of dihydropyrimidinone derivatives was synthesized via Biginelli reaction under solvent-free conditions at 120oC using [(EtNH2)2SO][HSO4]2 as a catalyst. Various aromatic aldehydes, as well as heteroaromatic aldehydes, were employed, affording good to high yields of the corresponding products and illustrating the substrate generality of the present method. In addition, the prepared dicationic Brönsted acidic ionic liquid can be easily recovered and reused. Conclusion: 1, 1’-Sulfinyldiethylammonium bis (hydrogen sulfate), as a novel dicationic ionic liquid, can act as a highly efficient catalyst for the synthesis of 3, 4-dihydropyrimidin-2(1H)-ones under solvent-free conditions.

Background: ADAMTS (A disintegrin-like metalloproteinase with thrombospondin motifs) is a group of 19 zinc-dependent metalloproteases known to function in many pathological and physiological processes, such as adhesion, cell fusion, signaling, proteolysis and ECM degradation. Objectives: The aim of this study was to demonstrate the levels of ADAMTS-4 and -5 in gingival tissues with Stage III-Grade B generalized periodontitis (SIII-GB), Stage III-Grade C generalized periodontitis (SIII-GC) and healthy-control (C) groups. Methods: The clinical measurements were recorded for each patient. A total of 63 gingival biopsy specimens were obtained from the C (n:20), SIII-GB (n:23) and SIII-GC (n:20) groups. Polymerase chain reaction (Rt-PCR) and immunohistochemical (IHC) examinations were used to determine gene and protein levels. Results: According to the results of all methods, ADAMTS-4 and -5 expressions existed in periodontitis and C groups (P> 0.05). Immunostaining for ADAMTS-4 was found to be higher in patients with periodontitis than for ADAMTS-5 (P>0.05). Gene expression levels for ADAMTS-4 and -5 seemed to be up-regulated in subjects diagnosed with periodontitis, but the results were not statistically significant (P>0.05). A positive correlation was observed between PPD and ADAMTS-4 mRNA in SIII-GC (p=0.035) and SIII-GB (p=0.015). A positive correlation was determined between ADAMTS-4 mRNA and ADAMTS-5 mRNA in SIII-GC (p=0.037) and SIII-GB (p=0.00). Conclusion: ADAMTS expression may take part in both pathological and physiological processes in the periodontal tissues, and periodontal destruction may be the result of a complex interaction of several pathways with many participants, such as ADAMTS-4 and -5, thus facilitating the exaggeration of periodontal disease.