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2-(2-arylidenehydrazinyl) thiazol-4(5H)-ones as epidermal growth factor receptor inhibitors: A combined quantitative structure activity relationship and pharmacophore study

2-(2-Arylidenehydrazinyl) thiazol-4(5H)-ones having epidermal growth factor receptor (EGFR) inhibitory activity were subjected to quantitative structure activity relationship (QSAR) (2 and 3 dimensional) analysis and pharmacophore study in the present work. The best 2 dimensional (2D) QSAR model had r2 (squared correlation coefficient), q2 (cross validated correlation coefficient) and pred_r2 (predictive correlation coefficient) values of 0.8630, 0.7652 and 0.9533 respectively with Partial least square regression (PLSR) analysis. This model showed that count of number of nitrogen atoms separated from oxygen atom by four bonds (T_N_O_4) and RadiusOfGyration (size descriptor) descriptors contribute positively and count of number of any atoms separated from carbon atom by four bonds (T_T_C_4) contributes inversely to the biological activity. The k-nearest neighbor (kNN) method produced a significant 3 dimensional (3D) QSAR model exhibiting q2 and pred_r2 values of 0.6615 and 0.8833 respectively. PLSR gave a significant 3D QSAR model having r2, q2 and pred_r2 values of 0.8449, 0.7816 and 0.7834 respectively. Both 3D QSAR models depict the need of less bulky substituents at R2 position while PLSR 3D QSAR model also portrays the need of more bulky substituent at R4 position. The identified common pharmacophore features are one aromatic (AroC) and three hydrogen bond acceptors (HAc) obtained from Molsign and Pharmagist approaches. The present work may be useful for further lead optimization and designing of potent anticancer agents.

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Isoxazole?a potent pharmacophore

Isoxazole is an azole with an oxygen atom next to the nitrogen. Isoxazole rings are found in some natural products, such as ibotenic acid and also found in a number of drugs, including COX-2 inhibitor valdecoxib. Furoxan, a nitric oxide donor is containing isoxazolyl group and found in many beta-lactamase resistant antibiotics, such as cloxacillin, dicloxacillin and flucloxacillin. The synthetic androgenic steroid danazol also has an isoxazole ring. The substituted isoxazoles are well developed in literature to possess significant biological activities. The disubstituted and trisubstituted isoxazoles have been reported to exhibit broad range of biological activities such as antimicrobial activity, analgesic activity, anti-inflammatory activity, antioxidant activity, anticancer activity, CNS (central nervous system) activity, antitubercular activity and miscellaneous activities like GABA (gamma-amino butyric acid) agonistic activity, inhibitory activity, antihypertensive activity, and glutamate transporter activity. The present review summarizes up to date information of various biological activities of isoxazole analogs.

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Sulfur containing acridine derivatives in preclinical studies with cancer cell lines

Background: The possible use of acridines as anticancer agents was first considered in the 1920?s. Since then, a large number of acridine drugs have been tested as antitumour agents, including compounds containing sulphur on the acridine chromophore. In this review, we will discuss recent studies which have investigated the anticancer activity of this class of acridine derivatives. Methods: We present the results both of our own decade-long research and also of existing research literature into the anticancer activity of acridine derivatives containing sulphur. The evidence of specific tumor-cell killing properties displayed by these compounds suggest the potential of using such molecules as anticancer therapeutics. Results: During the last decade, a number of acridine analogs have been developed by modifying the position and the nature of the substituent on the acridine core. In this paper, we published results on the anticancer activity of acridine derivatives containing sulfur (acridine thioureas, acridine thiazolidine/thiazoidinone, and acridine thiosemicarbazones/ thiosemicarbazides). In cancer chemotherapy, the mechanism of the drugs is complex, although the study of the anticancer activity of acridines has yielded exciting results. Conclusion: In this review we have summarized recent literature on the anticancer activity of acridine derivatives containing sulfur. A considerable amount of published data suggests that these compounds exhibit promising anticancer activity against selected cancer cell lines. The obtained results can be helpful in the development of new pharmaceutical agents.

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Using human neural progenitor cell models to conduct large-scale drug screens for neurological and psychiatric diseases

High-throughput drug screen (HTS) has become a viable approach for new treatment discovery in human diseases. Advances in gene editing technology and human pluripotent stem cell differentiation techniques have expanded the capability of HTS to identify potential treatments for human diseases of the central nervous system. Here, we describe techniques to use a human patient-derived neural progenitor cell luciferase reporter line to screen a large small molecule library.

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A FACILE SYNTHESIS OF 2-OXO-THIAZOLIDINES OF BIOLOGICAL INTEREST.

A facile procedure for the preparation in good yield of L-2-oxothiazolidine-4-carboxylic acid and other 2-oxothiazolidines of biological interest is described, involving reaction of suitable aminothiols with 1,1′-carbonyldiimidazole in an organic solvent.

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New salicylic acid and pyroglutamic acid conjugated derivatives confer protection to bread wheat against Zymoseptoria tritici

BACKGROUND: To promote sustainable agriculture and healthy food, research that contributes towards a new generation of eco-friendly phytosanitary compounds is increasingly encouraged. The plant hormone salicylic acid (SA) is known for its ability to induce resistance in plants against a wide range of pathogens, whereas pyroglutamic acid (PGA), a constrained analogue of gamma-aminobutyric acid, has never been studied in the context of plant protection. RESULTS: The present study investigated for the first time the protection efficacy of SA and PGA and five new conjugated derivatives against Zymoseptoria tritici, the main pathogen in wheat crops. SA and four derivatives showed significant disease severity reductions in planta (up to 49%). In vitro assays revealed that some molecules, including SA, displayed a small direct antifungal activity, whereas others, such as PGA, showed no effect. This finding suggests that, especially for molecules without any direct activity, the mode of action relies mainly on the induction of plant resistance. CONCLUSION: Further investigations are needed to identify the defence pathways involved in plant resistance mechanisms elicited or primed by the molecules. The manufacture of these products was easily achieved on a scale of tens of grams of raw materials, and is easily scalable. The synthetic pathway is simple, short and inexpensive. For all of these reasons, the production of the target molecules is attractive for producers, whereas the prospect of a generation of non-polluting compounds with lasting efficiency against Z. tritici in wheat comes at a key moment for the sustainability of agriculture.

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Preparation method and medical application Keap1-Nrf2 PPI of hydrogen peroxide responsive, inhibitor prodrug (by machine translation)

The invention discloses a preparation method of a hydrogen peroxide response type Keap1 – Nrf2 PPI inhibitor prodrug, and medical application, thereof, and the hydrogen peroxide response type Keap1 – Nrf2 PPI inhibitor prodrug pro2 has the following chemical structure. The invention utilizes H. 2 O2 A new Keap1 – Nrf2-response antioxidant prodrug, is synthesized by modifying the key carboxyl group ROS in pro2.H inhibitor in response to the thiazolidinone moiety. 2 O2 The activated prodrug pro2 can achieve both targeted activation Nrf2 and enhanced in vivo therapeutic efficacy, which is also ROS suitable for oral administration based on, activated – ROROS-cleared concept therapy first as well. H2 O2 Prodrug Example, which has properties and highly targeted properties, is expected to be useful in clinical. (by machine translation)

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Circulating levels of adipose tissue-derived inflammatory factors in elderly diabetes patients with carotid atherosclerosis: A retrospective study

Background: Inflammation has been recognized as a key feature of both type 2 diabetes mellitus (T2DM) and atherosclerosis. However, the relationships between circulating levels of novel adipose tissue-derived inflammatory factors, including resistin, vaspin, and visfatin, and the severity of atherosclerosis have not been determined. Moreover, the associations between these inflammatory factors and obesity and insulin resistance in elderly patients remain to be clarified. Methods: A cross-sectional study of 256 elderly patients with T2DM admitted in our center was performed. Baseline circulating levels of resistin, vaspin and visfatin were measured with enzyme-linked immunosorbent assays. Ultrasonic evaluations of the carotid arteries of the patients were performed to reflect the severity of systemic atherosclerosis. Patients were classified as having mild, moderate, or severe atherosclerosis according to the results of carotid ultrasonic examination. Circulating levels of the inflammatory factors listed above also were correlated with body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA-IR). Results: With more severe carotid atherosclerosis, circulating levels of resistin (mild: 2.01 ¡À 0.23; moderate: 2.89 ¡À 1.01; severe: 3.12 ¡À 1.12; p < 0.05) and visfatin (mild: 11.63 ¡À 7.48; moderate: 15.24 ¡À 2.19; severe: 17.54 ¡À 2.98; p < 0.05) gradually increased, while level of vaspin decreased (mild: 317 ¡À 23.12; moderate: 269 ¡À 32.12; severe: 229 ¡À 14.24; p < 0.05). Subsequent results of Pearson coefficient analyses indicated that all of the tested adipose tissue-derived inflammatory factors were positively correlated with the BMI and HOMA-IR of the patients (all p < 0.05), even after adjustment for hs-CRP. Conclusions: The adipose tissue-derived inflammatory factors resistin, vaspin and visfatin may be involved in the pathogenesis of atherosclerosis in elderly T2DM patients. I hope this article can help some friends in scientific research. I am very proud of our efforts over the past few months and hope to 2682-49-7, help many people in the next few years.Application of 2682-49-7

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Synthesis and evaluation of thiazolidine-2,4-dione/benzazole derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B): Antihyperglycemic activity with molecular docking study

This work presents the synthesis of two hybrid compounds (1 and 2) with thiazolidine-2,4-dione structure as a central scaffold which were further screened in combo (in vitro as PTP-1B inhibitors, in vivo antihyperglycemic activity, in silico toxicological profile and molecular docking). Compound 1 was tested in the enzymatic assay showing an IC50 = 9.6 ¡À 0.5 muM and compound 2 showed about a 50% of inhibition of PTP-1B at 20 muM. Therefore, compound 1 was chosen to test its antihyperglycemic effect in a rat model for non-insulin-dependent diabetes mellitus (NIDDM), which was determined at 50 mg/kg in a single dose. The results indicated that compound showed a significant decrease of plasma glucose levels that reached 34%, after a 7 h post-administration. Molecular docking was employed to study the inhibitory properties of thiazolidine-2,4-dione derivatives against Protein Tyrosine Phosphatase 1B (PDB ID: 1c83). Concerning to the two binding sites in this enzyme (sites A and B), compound 1 has shown the best docking score, which indicates the highest affinity. Finally, compounds 1 and 2 have demonstrated an in silico satisfactory pharmacokinetic profile. This shows that it could be a very good candidate or leader for new series of compounds with this central scaffold.

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Novel heterocyclic hybrids based on 2-pyrazoline: Synthesis and assessment of anti-inflammatory and analgesic activities

Aim and Objective: A series of new 2-pyrazoline analogues were synthesized. The structures of the synthesized compounds were elucidated by the analytical and spectroscopic data. Some selected compounds were screened for the anti-inflammatory activity by using animal model of carrageenan-induced paw edema in mice. Additionally, the analgesic and acute toxicity of these compounds were evaluated and exhibited reasonable results. The anti-oxidant and anti-inflammatory effects of these compounds were established by measuring the contents of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and tumor necrosis factor alpha (TNF-alpha) in the edema paw tissue. Materials and Methods: All chemicals and reagents used in current study were of analytical grade. Melting points were determined using APP. Digital ST 15 melting point apparatus and are uncorrected. FT-IR spectra were recorded on a Pye-Unicam SP3-100 spectrophotometer in KBr pellet. All 1H and 13C NMR spectra were recorded on AVANCE-III (400 MHz) High Performance FT-NMR Spectrometer Brucker (Switzerland) and some 1H NMR spectra were recorded on Varian EM-360L NMR Spectrophotometer (60 MHz) (USA) in CDCl3 or DMSO-d6 as solvent. Chemical shifts are reported in sigma units and the coupling constants (J) are reported in hertz. C, H, N and S analyses were performed with a Vario EL C, H, N, S Analyzer. Carrageenan (product number C1013) was obtained from Sigma-Aldrich (USA). Results: The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analyses. The results of pharmacological activity revealed that compounds 5, 6, 7, and 15 could be recognized as potential multi-potent anti-inflammatory. Conclusion: A simple and suitable method for the synthesis of new pharmacophore was reported. We have designed nineteen heterocycles related to pyrazoline ring, and evaluated eleven of them for their antiinflammatory, analgesic and acute toxicity activities. Compounds 5, 6, 7, and 15 proved to be the interesting compounds, they have high anti-inflammatory activity. However, all the selected compounds show remarkable analgesic activity.

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