Combinatorial Chemistry & High Throughput Screening - Volume 24, Issue 9, 2021

It has been a while since the disease of cancer was discovered in 16th and 17th century but still, this disease is one of the most lethal diseases in the world, which is taking a great number of lives every year. Cancer statistics suggest that there are still a lot of improvements that we have to make in the field of cancer treatment in order to overcome this deadly disease. Currently, nanotechnology has provided some more effective methods in this field, which has gained a lot of attention. Novel drug delivery systems that work using nanoparticles might be the answer to many unsolved questions in treating cancer. Chitosan is a natural glucose polymer which has the potential to be utilized as a proper drug carrier due to its advantageous features. Chitosan-based delivery systems are able to affect cancerous cells in many pathways. Wnt signaling pathways, which are one of the most essential ingredients of cancer pathogenesis, can be the target of chitosan nanoformulations. In this paper, we discussed the specific impacts of chitosan and its nanoformulations on each component of the Wnt/catenin pathway. Our conclusions might give novel insights for designing more efficient therapeutic approaches for several kinds of cancer.

Background and Objective: A Tibetan traditional herb named Swertia mussotii Franch., also called “Zangyinchen” by the local people of the Qinghai-Tibet area, has been used to protect the liver from injury for many years. However, the curative effect and molecular mechanism of the herb have not been demonstrated clearly. Materials and Methods: In our study, serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels were examined after S. mussotii Franch. treatment of the acute liver injury on the carbon tetrachloride-induced rat model. Then, proteome analysis was conducted to explore the potential mechanism of SMT for hepatoprotective effects after iTRAQLC-MS/MS analysis (isobaric tag for relative and absolute quantification-liquid chromatography-mass spectrometer with tandem mass spectrometry). Results: Serum results showed that alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels of rats with acute liver injury were all improved with SMT treatment. Moreover, proteome analysis suggested that, with S. mussotii Franch. treatment, the levels of lipid catabolic process and lipid homeostasis were all enhanced. Furthermore, the results of protein-protein interaction (PPI) analysis illustrated that the proteins assembled in PPI networks were found to be significantly enriched in response to lipid, negative regulation of lipase activity, and in response to lipopolysaccharides. Furthermore, the down-regulated MRP14 and MRP8 proteins were found to be involved in the lipid metabolism, which may indicate the mechanism of SMT for the protection of the liver from ALI induced by carbon tetrachloride. Conclusion: SMT herb could play a role in hepatoprotection and alleviating the acute liver injury by impacting the lipid metabolism associated with the biological process.

Background: Conventional high-throughput chemical screens in conjunction with genome-wide gene expression profiling proves to be successful in novel anti-cancer agent discovery and provides comprehensive insights into the mechanisms of action and off-target effects of single small-molecule compound. However, systematic evaluation on heterogeneous transcriptional responses of different cancer cell types to thousands of independent perturbations in a bioinformatics way is still limited. Method: Here, we introduce cancer transcriptome modifying potential (CTMP) which uses “Connectivity Score” to quantify and compare the effects of approved antineoplastic drugs on transcriptionally restoring dysregulated (both up- and down-) gene expressions at cancer state towards normal state. As a proof-of-concept, we applied this CTMP computational evaluation on > 10,000 small-molecule compounds using >200,000 Library of Integrated Network-based Cellular Signatures (LINCS) expression profiles generated upon 4 different cancer cell lines. We screened and proposed a candidate list of cancer transcriptome modifying therapeutics (CTMTs), among which the approved on-market drugs are further validated using GDSC drug sensitivity data, highlighting their potential to facilitate direct antineoplastic repositioning. Results: In total, we calculated CTMPs of 85 on-market antineoplastic drugs and ~15,000 smallmolecule compounds using 253,813 transcriptomes across four cancer cell lines of lung, melanoma, prostate, and colon. Our results reveal that regardless of the chemical structure and targeted proteins majority of approved antineoplastic drugs present significant bilateral CTMPs across all 4 cancer cell lines. Bilateral CTMP-based systematic screen further indicates that candidate CTMTs are limited and most notably cancer-type specific. In particular, for each cancer cell type we proposed 3~5 CTMTs that are approved drugs with potent sensitivity data to support development in antineoplastic indications. Conclusion: Our work establishes CTMP to evaluate the antineoplastic property of small-molecule compounds and suggests CTMP-based systematic screen of cancer type-specific CTMTs as a feasible strategy in drug repositioning for precise anti-cancer purposes.

Background: Head and neck squamous cell carcinoma (HNSCC) is a common cancer that is characterized by a complex pathogenesis. Only limited data are available on the primary pathogenic genes and pathways in HNSCC. Objective: This study aimed to identify potential biomarkers of HNSCC and explore its underlying mechanisms. Methods: We screened differentially expressed genes (DEGs) using the Gene Expression Omnibus(GEO) database. Gene Ontology (GO) and Reactome pathway enrichment were analyzed using the STRING database. The protein-protein interaction network of the DEGs was reconstructed using Cytoscape software in STRING. The ONCOMINE and UNLCAN databases were used to identify the expression of hub genes. In addition, we employed UNLCAN to correlate tumor grade with key genes. Results: Finally, the effect of hub genes on overall survival (OS) was analyzed using the Kaplan- Meier method. In total, 22 DEGs were identified. These were related to the mitotic cell cycle, mitotic G1-G1, and S phases, G2/M transition, NOTCH signaling, and regulation of TP53 activity. Seven hub genes were screened with Cytoscape. Increased expression of five hub genes (AURKA, BIRC5, MKI67, UBE2C, and TOP2A) was related to a higher tumor grade and worse OS. Conclusion: We have identified five key genes that may help us understand the carcinogenic mechanisms related to the cell cycle in HNSCC. These genes may be used as biomarkers for survival and treatment of HNSCC.

Aims: Dendrobine is a major alkaloid present mainly in dendrobium nobile Lindl. It has been reported to have analgesic, antipyretic, lower heart rate and blood pressure and other pharmacologic activities. Despite its critical pharmacological function, its metabolite profiling is still unclear. Methods: In this study, the in vivo metabolite profiling of dendrobine in rats was investigated using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS). The metabolites were predicted using MetabolitePilotTM software with a mass defect filter (MDF) technique. These predicted metabolites were further analyzed by MS² spectra and compared with the detailed fragmentation pathway of the dendrobine standard and literature data. Results: Total of 59 metabolites were identified for the first time in rat plasma and urine after oral administration of dendrobine. Demethylated, dehydrogenated, hydroxylated, ketonizated and glucuronide were the major metabolic pathways. Conclusion: This research provides scientific and reliable support for full understanding of the metabolic fate of dendrobine in vivo.

Objective: Shufeng Jiedu capsule (SFJDC) is a well-known Chinese patent drug that is recommended as a basic prescription and applied widely in the clinical treatment of COVID-19. However, the exact molecular mechanism of SFJDC remains unclear. The present study aims to determine the potential pharmacological mechanisms of SFJDC in the treatment of COVID-19 based on network pharmacology. Methods: The network pharmacology-based strategy includes collection and analysis of active compounds and target genes, network construction, identification of key compounds and hub target genes, KEGG and GO enrichment, recognition and analysis of main modules, as well as molecule docking. Results: A total of 214 active chemical compounds and 339 target genes of SFJDC were collected. Of note, 5 key compounds (β -sitosterol, luteolin, kaempferol, quercetin, and stigmasterol) and 10 hub target genes (TP53, AKT1, NCOA1, EGFR, PRKCA, ANXA1, CTNNB1, NCOA2, RELA and FOS) were identified based on network analysis. The hub target genes mainly enriched in pathways including MAPK signaling pathway, PI3K-Akt signaling pathway and cAMP signaling pathway, which could be the underlying pharmacological mechanisms of SFJDC for treating COVID-19. Moreover, the key compounds had high binding activity with three typical target proteins including ACE2, 2OFZ, and 1SSK. Conclusion: By network pharmacology analysis, SFJDC was found to effectively improve immune function and reduce inflammatory responses based on its key compounds, hub target genes, and the relevant pathways. These findings may provide valuable evidence for explaining how SFJDC exerting the therapeutic effects on COVID-19, providing a holistic view for further clinical application.

Background: Prediction biomarkers associated with prognosis and lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) are needed to facilitate clinicians in choosing appropriate therapies. Objective: We hope to identify key genes associated with LNM and prognosis in PTC. Methods: GSE29265, GSE33630, GSE3467, GSE3678 and GSE58545 gene expression profiles were acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between PTC tissues and normal thyroid tissues were selected with the GEO2R tool, and common DEGs among the five datasets were integrated with Venn software online. A proteinprotein interaction (PPI) network of the common DEGs was visualized. We analyzed the PPI network and determined core genes using the Cytoscape software. Furthermore, we employed UALCAN to verify the expression and promoter methylation status of the core genes in thyroid carcinoma (THCA). Additionally, the Kaplan–Meier plotter online tool was used to analyze the relationship between overall survival and core gene expressions in THCA. Results: TNS3, DUSP6, DUSP4 and PTPRE were identified as core genes. Expression of these 4 genes and the promoter methylation status of DUSP4 and PTPRE were strongly associated with LNM (P<0.05). High expression of 3 genes (DUSP6, DUSP4 and PTPRE) was related to a significantly better survival than low expression of the 3 genes in THCA. In contrast, high TNS3 expression was related to significantly worse survival (P<0.05). Conclusion: TNS3, DUSP6, DUSP4, PTPRE and DUSP4 and PTPRE promoter methylation status might be useful predictive biomarkers of LNM in PTC. Additionally, these genes may be prognostic biomarkers in PTC.

Aim and Objective: An analytical method for the determination of mobocertinib, an investigational tyrosine kinase inhibitor, was developed and optimized by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rat plasma. Materials and Methods: Plasma samples were pretreated by the protein precipitation method with a methanol solution of osimertinib as the internal standard (IS). Chromatographic separation was performed using an Inertsil ODS-3 column (50 mm × 4.6 mm, I.D. 5 μm) with the temperature maintained at 40°C. The mobile phase consisted of water (containing 0.1% formic acid) and methanol in a gradient mode at a flow rate of 0.5 mL/min. Mass spectrometric detection was carried out in the selected reaction monitoring (SRM) mode with positive electrospray ionization, and the mass transitions of mobocertinib and osimertinib were m/z 587.01 → 71.88 and m/z 499.80 → 71.94, respectively. The method was validated in terms of selectivity, linearity, accuracy and precision, extraction recovery and matrix effect, stability and carryover as per the guidelines for bioanalytical method validation (FDA, 2018). The method was applied to the pharmacokinetic study of mobocertinib in rats by oral gavage at the doses of 2, 6, and 18 mg/kg. A total of 216 plasma samples from 18 rats were analyzed. Results: The results showed good linearity over the range of 1-1000 ng/mL (R2 = 0.9957). The intra-batch accuracy was within 94.65-102.59% and the precision was within 5.49-10.46%. The inter-batch accuracy was within 97.08-102.25% with a precision of 7.54-10.13%. The extraction recovery and matrix factor were acceptable for the bioanalysis of mobocertinib. Additionally, mobocertinib was found to be stable under the detected conditions. Mobocertinib showed linear pharmacokinetic characteristics following oral administration to rats at 2.0-18.0 mg/kg. Conclusion: The developed and validated method was successfully employed in the pharmacokinetic study in rats following oral administration of mobocertinib at the doses of 2, 6, and 18 mg/kg.

Background: In Traditional Chinese Medicine (TCM), the heads and tails of Angelica sinensis (Oliv.) Diels (AS) is used in treating different diseases due to their different pharmaceutical efficacies. The underline mechanisms, however, have not been fully explored. Objective: Novel mechanisms responsible for the discrepant activities between AS heads and tails were explored by a combined strategy of transcriptomes and metabolomics. Methods: Six pairs of the heads and tails of AS roots were collected in Min County, China. Total RNA and metabolites, which were used for RNA-seq and untargeted metabolomics analysis, were respectively isolated from each AS sample (0.1 g) by Trizol and methanol reagent. Subsequently, differentially expressed genes (DEGs) and discrepant pharmaceutical metabolites were identified for comparing AS heads and tails. Key DEGs and metabolites were quantified by RT-qPCR and targeted metabolomics experiment. Results: Comprehensive analysis of transcriptomes and metabolomics results suggested that five KEGG pathways with significant differences included 57 DEGs. Especially, fourteen DEGs and six key metabolites were related to the metabolic regulation of Phenylpropanoid biosynthesis (PB) pathway. Results of RT-qPCR and targeted metabolomics indicated that higher levels of expression of crucial genes in PB pathway, such as PAL, CAD, COMT and peroxidase in the tail of AS, were positively correlated with levels of ferulic acid-related metabolites. The average content of ferulic acid in tails (569.58±162.39 nmol/g) was higher than those in the heads (168.73 ± 67.30 nmol/g) (P#130;0.01); Caffeic acid in tails (3.82 ± 0.88 nmol/g) vs heads (1.37 ± 0.41 nmol/g) (P#130;0.01), and Cinnamic acid in tails (0.24 ± 0.09 nmol/g) vs heads (0.14 ± 0.02 nmol/g) (P#130;0.05). Conclusion: Our work demonstrated that overexpressed genes and accumulated metabolites derived from the PB pathway might be responsible for the discrepant pharmaceutical efficacies between AS heads and tails.

Aim: In this study, we evaluated the prognostic value of four calculated inflammatory ratios in patients with colorectal cancer. Materials and Methods: A six-year retrospective study was conducted on subjects admitted for colorectal cancer at "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology Cluj-Napoca, Romania, from January 2014 until September 2019. The medical charts of patients diagnosed with colorectal cancer were used as the source of raw data and for the calculation of four ratios (neutrophil-to-lymphocyte ratio-NLR, derived neutrophil-to-lymphocyte ratio-dNLR, platelet-to-lymphocyte ratio-PLR, and systemic immune-inflammation index-SII), considered as prognostic markers related to mortality in colorectal cancer. Results: One thousand six hundred and eighty-eight patients, with ages ranging from 17 to 98 years, were evaluated. NLR and dNLR displayed significantly higher values among patients who died (NLR: 4.2 for deceased vs. 3.4 for alive, P-value=0.0224; dNLR: 2.7 for deceased vs. 2.3 for alive, Pvalue= 0.0566). Ischemic cardiomyopathy (odds ratio (OR)=2.70), liver cirrhosis (OR=7.84), postoperative complications (OR=2.39), and neutrophil-to-lymphocyte ratio (OR=1.08) proved to be significant prognostic factors for the primary outcome, independent of age and gender. Conclusion: Patients with high NLR, post-operative complications, ischemic cardiomyopathy, and/or liver cirrhosis are the candidates to a less favorable outcome among subjects with colorectal cancer regardless the age and gender.

Aim and Objective: This study aimed to explore the plasma free amino acid (FAA) and carnitine levels in pregnant women with cesarean scar pregnancy (CSP), and to compare them with those of healthy pregnant women. Materials and Methods: This prospective and randomized controlled study was conducted in patients admitted to Harran University Medical Faculty Hospital Obstetrics Clinic between January 2018 and January 2019. A total of 60 patients were included in the study, and the patients were divided into two groups: the CSP group (n = 30) and the healthy pregnant group as the control group (n = 30). The blood samples were taken from the participants between 7 - 12 weeks of gestation. Twenty-seven carnitines and their esters and 14 FAAs were analysed by liquid chromatography – mass spectrometry (LC-MS/MS). Results: The mean plasma concentrations of some carnitines, including C2, C5, C5-OH, C5-DC, C6, C8-1, C12, C14, C14-1, C14-2, C16, C16-1, C18, and C18-1 were significantly higher in the CSP group than in the control group. However, other carnitines, including C0, C3, C4, C4-DC, C5- 1, C6-DC, C8, C8-DC, C10, C10-1, C18-1-OH, and C18-2, were similar in both groups. The plasma levels of some FAAs, including Methyl Glutaryl, Leu, Met, Phe, Arg, Orn, and Glu values, were significantly higher in the CSP group than in the control group. However, there was no statistical significance in other FAA levels, including Val, Asa, Tyr, Asp, Ala, Cit, and Gly between the two groups. Additionally, Pearson’s correlation analysis showed that there were significantly positive correlations between many FAA and carnitine values. Conclusion: Since several plasma carnitines and FAA levels were higher in the CSP group than in the control group, we think that scar pregnancy increases the metabolic need for myometrial invasion. Also, we think that these results may be useful in clinical practice for CSP diagnosis.

Background: It is possible that patients with pneumonia may also have sepsis and the separation of these two clinical entities may cause some trouble to clinicians. Objective: In order to separate a patient with pneumonia and a patient with sepsis, we qualify thiol/disulfide homeostasis as a potential biomarker. Methods: This study was designed between February 2018 – February 2019 prospectively. All patients in the intensive care unit with pneumonia and sepsis were enrolled in the study. At the time of hospitalization, thiol/disulfide homeostasis was measured. Patients diagnosed with sepsis and pneumonia were compared, in regards to thiol/disulfide homeostasis. Results: During research period, 103 patients with sepsis and 120 patients with pneumonia were enrolled into the study. When we compared native-thiol, total-thiol, and disulfide levels in both sepsis and pneumonia patients, we had similar results (p>0.05). In sepsis group, index-1 (disulfide/native thiol ratio) and index-2 (disulfide/total thiol ratio) were found to be statistically higher than the pneumonia group, and index-3 (native thiol/total thiol ratio) was statistically lower than the pneumonia group (p=0.020, p= 0.021, p=0.021, respectively). Conclusion: In this study, we showed that thiol/disulfide homeostasis could be used as new markers in the early period in order to separate patients with sepsis and patients with pneumonia.

Objective: In this study, amine-functionalized magnetite Kit-6 silica nanocomposite (Fe3O4@SiO2@ Kit-6-NH2) was synthesized as an adsorbent for removing Carmoisine food dye from aqueous solutions. Methods: The nanocomposite was chemically synthesized and was characterized by X-ray diffraction analysis (XRD), vibrating sample magnetometery (VSM), energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). Taguchi orthogonal array experimental design method was used to optimize the experimental conditions, including adsorbent amount, pH of the solution, amount of salt, the volume of sample and contact time. Pseudo first-order, pseudo second-order, intra-particle diffusion and Elovich kinetic models were investigated to study the kinetic parameters of the sorption process. Results: The kinetic data corresponded to the pseudo second-order kinetic model with R2 = 0.9999. Also, adsorption data were analyzed using Langmuir, Freundlich and Temkin isotherm models. The results indicated that the data were well fitted to the Freundlich isotherm model (R2 = 0.9984, n=1.0786). The reusability tests showed that the proposed nanocomposite could be used for more than 8 cycles with removal efficiency higher than 90%. Conclusion: The applicability study of the proposed nanocomposite proved its ability for efficient removal of Carmoisine dye from real aqueous samples.

Aims and Objective: In the current study, environmentally benign and cost-effective procedures were suggested for the preparation of carboxy group functionalized imidazolium salts, including [Cmmim]BF4 - or [Cmmim]Br- as a new, reusable Brønsted acidic ionic liquid (BAIL) catalyst. Then, the catalytic performance of [Cmmim]BF4 - or [Cmmim]Br- were successfully inspected towards the three-components onepot preparation of pyrano[2,3-d]pyrimidinone derivatives 4a-4q. The mentioned procedures show short reaction times, easy work-up procedure, green conditions, high yields of the products, high potent of recovering, and reusing capability. The current study is useful and adequate for the application and development of imidazolium salts on the basis of green chemistry principles. Materials and Methods: An aromatic aldehyde (1 mmol), barbituric acid (1 mmol), and malononitrile (1 mmol) were placed in a round-bottomed flask containing ethanol (5 mL). BAILs A and B (0.1 mmol, 10 mol%) were added to the mixture. The suspension was magnetically stirred at room temperature for an appropriate time (Table 2). After completion of the reaction, which was monitored by TLC (n-hexane:ethyl acetate = 3:1), the pure product was filtered off to separate the catalyst, washed with water, and recrystallized from ethanol to afford the pure compound. After separation of the product, the catalyst was recovered by evaporation of water, washed with Et2O, dried under vacuum for 2 h, and reused for the same reaction. Results: The mentioned procedure shows short reaction times, easy work-up procedure, green conditions, high yields of the products, and high potent of recovering and reusing capability. Conclusion: In this study, we unveiled the synthesis of a new acetic acid functionalized ionic liquids [Cmmim]BF4 - BAIL A or [Cmmim]Br- BAIL B and their application for the preparation of pyrano[2,3-d]pyrimidinone derivatives via a three-component reaction among various aromatic aldehydes, barbituric acid, and malononitrile under mild and metal-free conditions. A wide range of pyrano[2,3-d]pyrimidinone derivatives bearing diverse functional groups was obtained in short reaction and excellent yields. Operational simplicity, recoverability, and reusability of catalysts, cheap and chemically stable reagents, high catalytic activity, easy work-up, and the eco-friendly procedure, make this method environmentally benign and cost-effective.

Aim and Objective: Diabetes mellitus is associated with inflammation and increased oxidative stress. In the current study, we aimed to investigate the relationship between type 2 diabetes mellitus (T2DM) and serum pro-oxidant-antioxidant balance (PAB) in a large populationbased study. Methods: In this cross-sectional study, 7888 individuals were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study. Participants were divided into three groups based on their serum PAB values (levels < 36.4, 36.4-82.6 and > 82.6 HK). Serum PAB values were measured using a colorimetric method and enzyme-linked immune sorbent assay (ELISA). Results: Serum PAB in subjects with and without diabetes was reported 76.85 ± 61.07 HK and 69.51 ± 55.50 HK. In subjects with a serum PAB > 82.6 HK the risk of T2DM was 1.2 fold higher in comparison to subjects with a serum PAB < 36.4 HK (OR: 1.26, 95% CI: 1.09 – 1.47, P-value: 0.002). This association remained significant after adjustment for confounding factors in multivariable analysis (OR: 1.19, 95% CI: 1.02 – 1.38, P-value: 0.027). Conclusion: Increased pro-oxidant levels may be a major complication of T2DM in our study subjects and PAB could be an indicator of higher oxidative stress in T2DM patients from northeastern Iran.

Aim and Objective: A recent study has revealed that non-structural protein 1 (Nsp1) of the SARS-CoV-2 is one of the novel targets for developing new antiviral drugs. To date, there is no significant exact medication available to treat Covid-19. As a result, both the death toll and the number of people affecting by this disease are increasing with each passing day. 35 phytochemicals having antiviral properties were taken to get the best compounds against Nsp1 Materials and Methods: As no PDB structure of this protein is available, homology modeling was done to predict the probable structure. After homology modeling, the best model was taken according to C-score and TM- score and then validated using different web servers. After validation, docking of these compounds was done using AutoDock vina, vega zz, and PyRx, and consensus docking score was considered to select molecules after docking. Finally, the orbitals energy calculation of these compounds was done to check their activity and the binding interactions of these molecules also analyzed. Results: Molecules having a consensus score of -8kcal/mol or more negative were kept for further study and it was seen that 16 molecules had the given criteria. Then, drug-likeness filtration was done according to Lipinski’s rule of five and 11 molecules remained. Out of these 11 molecules, 5 molecules had satisfactory ADMET properties. Calculation of orbital energy revealed their activity. Conclusion: It is expected that this research might be helpful for the development of new antiviral drugs active against SARS-CoV-2 targeting Nsp1.

Background and Objective: Perimenopause is a physiological occurrence in women, and is characterized by endocrine and biochemical changes. During perimenopause phase, many derangements or abnormal health conditions start developing as a result of hormonal changes. These derangements in health conditions and biochemical changes lead to higher incidence of metabolic syndrome (MetS) occurrence with or without bone involvement. There is a scarcity of information on MetS in Enugu, Southern Nigeria and there is no available data on the correlation of selected bone-related biochemicals with endocrine parameters and MetS in perimenopausal women from the region. Material and Methods: We consecutively sampled 200 apparently healthy women, and categorized them into 120 perimenopausal women (age (x) = 50years) and a second group of 80 women in premenopause (age (x) = 35years). Measurement of anthropometric indices like blood pressure, height, weight and waist circumference were taken. Fasting blood samples were collected for the estimation of endocrine parameters (estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone (LH)) using enzyme linked immunosorbent assay (ELISA) technique. The lipid profile, fasting plasma glucose (FPG), uric acid, inorganic phosphate, calcium and alkaline phosphatase levels were determined using standard biochemical methods. The evaluation of MetS was carried out in the women using the three different criteria: World Health Organization (WHO), National Cholesterol Education Program- Adult Treatment Panel 111 (NCEP-ATP 111) and International Diabetes Federation (IDF). For statistical analysis, Student’s t-test, Pearson correlation and Chi-square were used to compare categorical and continuous variables. Results: Calcium was predominantly high in the three criteria (p<0.05). LH and FSH showed a positive correlation with FPG while E2 was negatively associated with FPG. Similarly, LH showed a positive association with inorganic phosphate while E2 was negatively associated with alkaline phosphatase (p<0.05). Conclusion: Perimenopausal women are at higher risk of developing osteoporosis than premenopausal women. This emphasizes the need for timely diagnosis of osteoporosis in perimenopausal women.

Aim and Objective: Nowadays, developing effective antibiotics for bacterial control has become difficult due to increased resistance to the available medicines in the market. Essential oils possess interesting biological properties as some of their components have very powerful antiviral and antibacterial properties. Carthamus caeruleus is a plant that has antibacterial and antioxidant activity due to the presence of an acetylenic compound, Carlina oxide. The aim of this work was to provide, for the first time, the chemical modifications to the structure of Carlina oxide and the insilico study of these analogues. Materials and Methods: The essential oil of Carthamus caeruleus was extracted by steam distillation in a Clevenger-type apparatus. Carlina oxide component was separated by column chromatography. Five new analogues were synthetized and identified by spectroscopic analyses (RMN, IR and SM). Molecular docking simulation study was performed using Molecular Operating Environment software (MOE) on three enzymes of bacterial origin (Streptococcus pyogenesis and Enterococcus faecalis). Results: Five new compounds derived from Carlina oxide were synthesized (IM8-IM12), and their structures were characterized by infrared (IR), 1H and 13C nuclear magnetic resonance (NMR). The new synthesized compounds were evaluated as mSpeB, DHFR from Enterococcus faecalis and DNA gyrase inhibitors by a docking analysis using MOE. These results show interesting ligand interactions with the three enzymes, and the best result was attributed to the complexes formed with IM9, which had the lowest score. Conclusion: In fact, these new compounds could lead to powerful approaches for the research and development of new antibiotics.

Introduction: Enzymatic degradation of peptidoglycan, a structural cell wall component of Gram-positive bacteria, has attracted considerable attention being a specific target for many known antibiotics. Methods: Peptidoglycan hydrolases are involved in bacterial lysis through peptidoglycan degradation. β-N-acetyl-glucosaminidase, a peptidoglycan hydrolase, acts on O-glycosidic bonds formed by N-acetylglucosamine and N-acetyl muramic acid residues of peptidoglycan. Aim of present study was to study the action of β -N-acetylglucosaminidase, on methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-negative bacteria. Results: We investigated its dynamic behaviour using molecular dynamics simulation and observed that serine and alanine residues are involved in catalytic reaction in addition to aspartic acid, histidine, lysine and arginine residues. When simulated in its bound state, the RMSD values were found lesser than crystal form in the time stamp of 1000 picoseconds revealing its stability. Structure remained stably folded over 1000 picoseconds without undergoing any major change further confirming the stability of complex. Conclusion: It can be concluded that enzymes belonging to this category can serve as a tool in eradicating Gram-positive pathogens and associated infections.