Pharmacophore Modeling, Synthesis, Scaffold hopping And Biological β-Hematin Inhibition Interaction Studies for Anti-malaria Compounds

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Author(s): Neda Fayyazi, Somayeh Esmaeili, Salman Taheri, Frederico F. Ribeiro, Marcus T. Scotti, Luciana Scotti, Jahan B. Ghasemi*, Lotfollah Saghaei, Afshin Fassihi.

Journal Name: Current Topics in Medicinal Chemistry

Abstract:

Exploring potent compounds is critical to generating multi-target drug discovery. Hematin crystallization is an important mechanism of malaria. A series of chloroquine analogues were designed using a repositioning approach to develop new anticancer compounds. Protein ligand interaction fingerprints and ADMET descriptors were used to assess docking performance in virtual screenings to design chloroquine hybrid β-hematin inhibitors. A PLS algorithm was applied to correlate the molecular descriptors to IC50 values. The modeling presented excellent predictive power with correlation coefficients for calibration and cross validation of r2 = 0.93 and q2 = 0.72. Using the model, a series of 4-aminoquinlin hybrids were synthesized and evaluated for their biological activity as an external test series. These compounds were evaluated for cytotoxic cell lines and β-hematin inhibition. The target compounds exhibited high β-hematin inhibition activity and were 3-9 times more active than the positive control. Further, all compounds exhibited moderate to high cytotoxic activity. The most potent compound in the dataset was docked with hemoglobin and its pharmacophore features were generated. These features were used as input to the Pharmit server for screening with 6 databases. The compound with the best score from ChEMBL was 2016904, previously reported as a VEGFR-2 inhibitor. The 11 compounds selected presented the best Gold scores with drug-like properties and can be used for drug development.

Keywords: Multi-target; β-hematin; Fingerprint; QSAR; Hybrid synthesis; ADME/Tox; 3D Scaffold hopping.

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DOI: 10.2174/1568026619666191116160326
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Melatonin Induces Apoptosis and Inhibits the Proliferation of Cancer Cells via Reactive Oxygen Species-mediated MAPK and mTOR Pathways

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Author(s): Reena Kasi, Pei Ling Yeo, Khuen Yen Ng, Rhun Yian Koh, Gnanajothy Ponnudurai, Yee Lian Tiong, Soi Moi Chye*.

Journal Name: Clinical Cancer Drugs

Abstract:

Background: Recent human and animal studies have demonstrated the oncostatic properties of N-acetyl-5-methoxytryptamine (melatonin) in different types of cancer. However, in few cancer cell lines including colorectal cancer cell line (HT-29), acute T cell leukemia cell line (JURKAT) and cervical cancer cell line (HeLa), precise oncostatic mechanism induced by melatonin is yet to be described.

Objectives: The aim of this study is to investigate the effects of melatonin in HT-29, JURKAT and HeLa cells and to determine the underlying molecular mechanism.

Methods: Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay while cell cycle, apoptosis and membrane potential were analysed by flow cytometry. Reactive oxygen species (ROS) was detected by 2',7'‑dichlorofluorescein diacetate (DCFH-DA) staining. Protein expressions were determined by western blot.

Results: Our results showed that melatonin suppressed cell proliferation, increased the number of sub G1 hypodiploid cells and cell cycle arrest in HT-29, JURKAT and HeLa cells. Besides that, melatonin also induced early and late apoptosis, although there was marked variations in responses between different cell lines (sensitivity; HeLa > HT-29 >JURKAT). Apart from that, staining with DCHF-DA demonstrated ROS production that was induced in a dose dependent manner in HeLa, HT-29 and JURKAT cells. Moreover, the apoptotic process and oncostatic effect of melatonin was seen to be associated with extracellular-signal-regulated kinase (ERK) and stress-activated protein kinase/c-Jun NH (2)-terminal kinase (SAPK-JNK) signalling cascades in HeLa cells. In HT-29 and JURKAT cells, melatonin induced apoptosis via activation of p38 mitogen-activated protein kinases (p38), ERK and SAPK-JNK signalling pathways. In all three cell lines, apoptotic event was triggered by mammalian target of rapamycin (mTOR)-mediated activation of the downstream target rapamycin-insensitive companion of mTOR (RICTOR) and/or regulatory-associated protein of mTOR (RAPTOR) proteins.

Conclusions: Our findings confirm that melatonin induces apoptosis through reactive oxygen species-mediated dysregulated mitogen-activated protein kinase (MAPK) and mTOR signalling pathways in these cancer cell lines.

Keywords: Melatonin, apoptosis, cancer, reactive oxygen species, MAPK, mTOR

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DOI: 10.2174/2212697X06666191116151114
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Optimal Stochastic Gradient Descent With Multilayer Perceptron Based Student's Academic Performance Prediction Model

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Author(s): S Ranjeeth*, T.P. Latchoumi, P Victer Paul.

Journal Name: Recent Advances in Computer Science and Communications
Formerly: Recent Patents on Computer Science

Abstract:

Aims: The capability to predict the student's performance is highly beneficial to take remedial actions in the present educational system.

Background: In this paper, address the issue of Student Academic Performance (SAP) by the use of Machine Learning based classification model.

Objective: Education Data Classification Model.

Method: To classify the data properly, multilayer perceptron (MLP) with Deep Learning Model is employed.

Result: The simulation outcome exhibited that the MLP-SGD model offers better results over the other classifiers.

Conclusion: However, the usage of outlier detection using RBF model takes the classifier results to a next level.

Keywords: Prediction model, Outlier detection, MLP, SGD, RBF, Academic

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DOI: 10.2174/2666255813666191116150319
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Collaborative filtering recommendation algorithm based on class correlation distance

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Author(s): Hanfei Zhang*, Yumei Jian, Ping Zhou.

Journal Name: Recent Advances in Computer Science and Communications
Formerly: Recent Patents on Computer Science

Abstract:

A class correlation distance collaborative filtering recommendation algorithm is proposed to solve the problems of category judgment and distance metric in the traditional collaborative filtering recommendation algorithm, which is using the advantage of the distance between the same samples and the class related distance. First, the class correlation distance between the training samples is calculated and stored. Second, the K nearest neighbor samples are selected, the class correlation distance of training samples and the difference ratio between the test samples and training samples are calculated respectively. Finally, according to the difference ratio, we classify the different types of samples. The experimental result shows that the algorithm combined with user rating preference can get lower MAE value, and the recommendation effect is better. With the change of K value, CCDKNN algorithm is obviously better than KNN algorithm and DWKNN algorithm, and the accuracy performance is more stable. The algorithm improves the accuracy of similarity and predictability, which has better performance than the traditional algorithm.

Keywords: Class correlation distance, Difference ratio, Collaborative filtering recommendation algorithm.

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DOI: 10.2174/2666255813666191116144822
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Interleukin 1-beta is Linked to Chronic Low-grade Inflammation and Cardiovascular Risk Factors in Overweight Adolescents

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Author(s): Gisele A. Amaral, Josilene D. Alves, Adenilda C. Honorio-França, Danny L. Fagundes, Gabriel Gomes Araujo, Nubia S. Lobato, Victor V. Lima, Fernanda R. Giachini*.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Abstract:

Aim: We hypothesized that IL-1β concentrations are augmented in overweight adolescents, who do not display metabolic syndrome. Additionally, we aimed to correlate the IL-1β concentrations with several established risk factors for CVD.

Methods: Overweight or control subjects, aging from 14-18 years, were classified according their adjusted body mass index and evaluated for biochemical and anthropometric parameters. The pro-inflammatory cytokine IL-1β was assessed in serum.

Results: Increased body fat percentage, waist circumference, triglycerides, total cholesterol, Very Low-Density Lipoprotein (VLDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, Castelli I index, IL-1β, and IL-8 levels, whereas were observed in overweight adolescents. No differences were observed in systolic blood pressure, diastolic blood pressure, glucose or High-Density Lipoprotein (HDL) cholesterol. Positive correlations between IL-1β with anthropometric and or biochemical parameters were found.

Conclusion: In conclusion, increased IL-1β levels correlate to dyslipidemic factors and may further support low-grade inflammation. IL-1β may further predict the early onset of cardiovascular disease within this population, taking into consideration its important regulatory role.

Keywords: Childhood, obesity, cytokine, inflammation, cardiovascular disease, dyslipemic factors

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DOI: 10.2174/1871530319666191116141159
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Exosomes in Sepsis and Inflammatory Tissue Injury.

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Author(s): Eun Jeong Park*, Michael G. Appiah, Phyoe Kyawe Myint, Arong Gaowa, Eiji Kawamoto, Motomu Shimaoka*.

Journal Name: Current Pharmaceutical Design

Abstract:

Sepsis is the leading cause of death in medical intensive care units, and thus represents a serious healthcare problem worldwide. Sepsis is often caused by the aberrant host responses to infection, which induce dysregulated inflammation that leads to life-threatening multiple organ failures. Mediators such as pro-inflammatory cytokines that drive the sepsis pathogenesis have been extensively studied. Exosomes, biological lipid bilayer nanoparticles secreted via the endosomal pathway of cells, have recently emerged as important cargos that carry multiple mediators critical for the pathogenesis of sepsis-associated organ dysfunctions. Here we will review the current knowledge on the exosomes in the sepsis and relevant inflammatory tissue injuries.

Keywords: Sepsis, Septic shock, Inflammatory tissue injury, Exosome, Extracellular vesicle, Integrin, miRNA

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DOI: 10.2174/1381612825666191116125525
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Synthesis of a new Dioxaspiro[bicyclo[3.3.1]nonane-oxabicyclo[6.2.0]deca-1(10),8-dien-4-one derivative using some chemical strategies

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Author(s): Figueroa-Valverde Lauro*, Rosas-Nexticapa Marcela, Lopez-Ramos Maria, Diaz Cedillo Francisco, Mateu-Armand Virginia, Garcimarero-Espino E. Alejandra, Borges-Ballote Yaritza, Ortiz-Ake Yazmin.

Journal Name: Letters in Organic Chemistry

Abstract:

Aims: Synthesis a new 3-Oxa-bicyclo[6.2.0]deca-1(10),8-dien-4-one derivative.

Background: There are several protocols for the preparation of bicyclic-derivatives; however, some methods use reagents dangerous and require specials conditions.

Objective: Synthesis a new 3-Oxa-bicyclo[6.2.0]deca-1(10),8-dien-4-one derivative

Method: Etherification, ii) reduction, iii) amidation, iv) imination and v) 2+2 addition.

Result: The structure of all compounds obtained was confirmed by spectroscopic and spectrometric methods.conclusiona facile method for the preparation of a 3-Oxa-bicyclo[6.2.0]deca-1(10),8-dien-4-one derivative using some chemical strategies is reported.

Keywords: Steroid , bicyclo , Oxa , dienone, Chemical , derivative

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DOI: 10.2174/1570178617666191116123359
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A Novel FSK Generator Using A Second Generation Current Controlled Conveyor

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Author(s): Syed Zahiruddin, Avireni Srinivasulu*, Musala Sarada.

Journal Name: Nanoscience & Nanotechnology-Asia

Abstract:

The interest concern towards the development of enabling technology towards new current mode devices has forced the designers and researchers for the invention of devices, which has having the characteristics like such as low power, robustness, compactness, efficiency and scalability. Second Generation Current Controlled Conveyor (CCCII) is the prevailing current mode device of the times today. Since its invention by A. Fabre, it has prominent applications in the field of analog signal processing and in biomedical applications too. In this manuscript, CCCII is used as an enabling device to design a Frequency Shift Keying (FSK) Generator. The proposed topology is designed using a single active device CCCII with least passive components. The circuit enjoys the features of like electronic tunability of frequency using the bias current.

Conclusion: It can be concluded that the FSK generator circuit designed using single CCCII confers better results in contrast to the existing structures. The maximum power consumption is 0.196 mW. The proposed circuit has the benefit of simple configuration, which is very much proficient for IC fabrication.

Keywords: Second Generation Current Controlled Conveyor, CCCII, Current Feedback Operational Amplifier, CFOA, Operational Transconductance Amplifier, OTA, FSK Generator.

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DOI: 10.2174/2210681209666191116121454
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One Step Fabrication of Three Metals Zif and its Application for Adsorption of Levofloxacin in Aqueous Solution

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Author(s): Abdolraouf Samadi- Maybodi*, Afshin Rahmati.

Journal Name: Current Analytical Chemistry

Abstract:

Background : Zeolitic imidazolate frameworks with three metals of Zn, Co and Ag (ZIF-3M) and ZIF-67 were synthesized at room temperature and characterized with different techniques such as FESEM, BET, EDX and XRD. Then, the synthesized nanoparticles were successfully applied for removal of levofloxacin of aqueous solutions.

Methods: To optimize the significant factors (i.e., pH, adsorbent dose and contact time) the response surface methodology (RSM) was implemented based on Box-Behnken design (BBD).in each step, an appropriate amount of adsorbent was added to 30 ppm of a solution containing levofloxacin and the pH was adjusted to desired value with 0.1 M HCl or 0.1 M NaOH. The mixture was stirred at room temperature and then centrifuged at 7500 rpm for 3 min.

Results: The optimal conditions for each variable were performed using Box-Behnken design. Results revealed ZIF-3M nanoparticles more efficiently remove the levofloxacin than that ZIF-67 in aqueous solution.

Conclusion: In this research, new three metal ZIF (ZIF-3M) nanoparticle was synthesized with Ag, Zn and Co in aqueous solution and characterized with different techniques. Results indicated successful synthesize with preserving ZIF framework. Results specified ZIF-3M has more ability for removal of levofloxacin than that ZIF-67. Isotherm studies were showed that the most suitable model for the adsorption of levofloxacin onto ZIF-3M has a good agreement with the Langmuier model.

Keywords: Zeolitic imidazolate frameworks, three metals ZIF, Levofloxacine, Box-Behnken design, Adsorption, Free solvent synthesis

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DOI: 10.2174/1573411015666191116120818
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Selective and Sensitive UHPLC Method for the Trace Analysis of Formaldehyde in Drug Substance Using Fused-core Column Technology and Detailed Pre-column Derivatization study

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Author(s): Ravi Kiran Panchakarla, Punna Rao Ravi*, Kondapalli Venkata Gowri Chandra Sekhar.

Journal Name: Current Pharmaceutical Analysis

Abstract:

Background: Formaldehyde is a key intermediate/reagent in the synthesis of many significant pharmaceutical compounds. It is genotoxic as it interacts with the DNA, RNA and hence there is a pressing need to develop sensitive analytical methods for its trace level determination.

Objective: The present study aims to develop a simple and robust Ultra-High-Performance Liquid Chromatographic (UHPLC) method for the trace level quantification of a carcinogen-formaldehyde, in pharmaceutical drug substance.

Methods: This method was developed on a conventional pre-column derivatization technique with brady’s reagent followed by fast analysis on fused core C18 Ascentis Express (150 × 4.6 mm, 2.7 μm) column using ultraviolet (UV) detection. Optimization of the derivatization reaction time was conducted in different pH conditions. The optimized analytical method was fully validated in accordance with the current international conference on harmonization (ICH) Q2 guidelines, which demonstrated the developed method to be fast, specific, linear, sensitive, repeatable, accurate and convenient for routine quality control.

Results: The developed method was linear, accurate and precise in the concentration of 12.8 ng/mL to 510.7 ng/mL. The LOD and LOQ were found to be 3.8 ng/mL and 12.8 ng/mL respectively.

Conclusion: The developed UHPLC can be used effectively for trace level quantification of formaldehyde in drug substances or drug products.

Keywords: Active pharmaceutical ingredient, derivatization, formaldehyde, fused core column technology, UHPLC and validation.

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DOI: 10.2174/1573412916666191116115424
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