Combinatorial Chemistry & High Throughput Screening - Volume 23, Issue 3, 2020

Background: The selective targeting of CREB-cAMP-responsive element-binding protein (CBP) has recently evolved as a vital therapeutic approach for curtailing its aberrant upregulation associated with the development of prostate cancer. Inhibition of CBP has been discovered to be an important therapeutic option in androgen receptor signalling pathway mediated prostate cancer. Y08197, a novel selective inhibitor of CBP, has shown promising therapeutic outcome in prostate carcinogenesis over non-selective analogues such as CPI-637. Methods/Results: Herein, we used molecular dynamics simulation to gain insights into the mechanistic and selective targeting of Y08197 at the bromodomain active site. Molecular Mechanics/ Poisson-Boltzmann Surface Area (MM/PBSA) analysis revealed a similar inhibitory effect between Y08197 and CPI-637. Furthermore, in exploring the selective affinity of Y08197 towards CBP in combination with Bromodomain and PHD finger-containing protein 1(BRPF1), our findings highlighted Asp1116 as the ‘culprit’ residue responsible for this selective targeting. Upon binding, Asp1116 assumed a conformation that altered the architecture of the bromodomain active site, thereby orienting the helices around the active site in a more compacted position. In addition to some specific structural perturbations mediated by Asp1116 on the dynamics of CBP, our study revealed that the strong hydrogen bond interaction (N-H...O) elicited in CBP-Y08197 sequestered Y08197 tightly into the CBP bromodomain active site. Conclusion: Conclusively, the inhibition and selective pattern of Y08197 can be replicated in future structure-based CBP inhibitors and other bromodomain implicated in carcinogenesis.

Aims and Objective: This study aimed to investigate the value of Thiol/Disulfide homeostasis in pediatric diabetic ketoacidosis patients suffering from type 1 diabetes mellitus. Materials and Methods: This study featured children who were diagnosed with diabetic ketoacidosis and who were consecutively admitted to pediatric intensive care within one year of their diagnosis. Thiol/disulfide homeostasis was evaluated in 45 pediatric patients suffering from DKA, as well as 45 healthy controls of parallel gender and age. Thiol/disulfide homeostasis parameters were measured using a novel automated measurement method and the correlation between demographic data and parameters was measured. Results: Pediatric patients were found to have low native thiols, total thiols and disulfide levels with type 1 diabetes after DKA (331.82±106.40, 362.71±113.31, 17.02±5.33 μmol/L, respectively) as compared to the control group (445.08±24.41, 481.21± 28.47, 18.06±5.12 μmol/L, respectively). Conclusion: Thiol/disulfide homeostasis was distorted in pediatric patients with DKA. Furthermore, it was found that they are not likely to return to normal, immediately after treatment.

Aims and Objective: Clinoptilolite is one of the natural zeolites. Clinoptilolite particles have a high surface area, negative surface charge, cation adsorption and exchange capacities. Barium sulfate (BaSO4) and bismuth subnitrate (Bi5H9N4O22) suspensions have been used for upper and lower gastrointestinal imaging but Ba2+ and Bi3+ ions are toxic. In the present study, the feasibility of the application of Ba2+- and Bi3+-loaded clinoptilolite micro- and nano-particles in medical imaging was investigated. Materials and Methods: Nanoparticles and microparticles of natural clinoptilolite were loaded with Ba2+ and Bi3+ ions. Radiopacities of loaded particles were measured and compared with those of BaSO4 and Bi5H9N4O22. Results: Ba2+- and Bi3+-loaded clinoptilolite nanoparticles and microparticles showed more intense X-ray opacities than BaSO4 and Bi5H9N4O22 with equimolar concentrations. Moreover, Ba2+- and Bi3+-loaded clinoptilolite nanoparticles more intensely absorbed X-ray than respective loaded microparticles. Conclusion: The present study proposes Ba2+- and Bi3+-loaded clinoptilolite nanoparticles and microparticles as new, safe, efficient, and inexpensive contrast agents.

Background: Tomato is considered a model plant in genetics and is one of the most economically important crops of all those that exist in the world. Several species of fungi are reported on tomato fruit, causing damage both during cultivation and after harvest. Some of the appropriate actions that could be initiated to resolve the problem are to develop and search for new antimicrobial substances isolated from the bioactive natural products, such as essential oils. Aims and Objective: The aim of this work was to determine the chemical composition of essential oils of Ammoides verticillata, Allium sativum and Curcuma longa, to evaluate their in-vitro antifungal activities and in-vivo antifungal effect of essential oils to prevent the diseases caused by tomato. Materials and Methods: The essential oils obtained from aerial parts of plants were analyzed by GC/MS and tested for their antifungal activities against Penicillium expansum, Fusarium solani, Rhizopus stolonifer and Alternaria alternata using the radial growth technique method. The effectiveness in-vivo of the association between Allium sativum and Curcuma longa essential oils was also investigated on tomatoes inoculated by fungi. Results: The essential oil from A. verticilata was mainly composed of phenolic compounds (54.4%), the A. sativum oil was mainly composed of sulfur compounds (91.5%) and C. longa oil was dominated by oxygenated monoterpenes (82.0%). The obtained results in-vitro antifungal revealed that individual essential oils of A. verticillata and A. sativum were more active than the essential oil of C. longa against all screened microorganisms. An important antifungal effect of A. sativum and C. longa essential oils blend was obtained against P. expansum (100%), F. solani (95.2%), R. stolonifer (95.1%) and A. alternata (48.5%). Furthermore, A. sativum and C. longa essential oils blends have demonstrated promising in-vivo antifungal activity to control infection of tomato against P. expansum and R. stolonifer. Conclusion: A. sativum and C. longa essential oil blends can be used as a natural food preservative and alternative to chemical fungicides to protect stored tomato against many phytopathogens.

Aims and Objective: This study explains the FT-IR, XRD, XRF, SEM/EDX, TGA, and DSC/DTA characterization of commercially available kaolin clay. The objective of this paper is to explore the prominent utilization of kandites clay and useful chemical aspects for the modification of kaolin clay minerals. Materials and Methods: The untreated kaolin sample has been procured in this experimental work from AksharChem, Gujrat, India. The kaolin clay was treated with 4M hydrochloric acid. FT-IR, XRD, XRF, SEM/EDX, TGA, and DSC/DTA characterization methods have been used. Results: Loss on ignition was found at 10.89%. The fingerprint region of the acid-treated sample has broad and more bending vibrations than untreated samples. The high weight percentage of Ti and CaCO3 were spotted in the scanning electron micrograph by both atomic % and weight %. The FT-IR revealed the functional group of Al-O, A1-OH, and Si-O. Conclusion: The morphology indicates that the presences of large particles are in the form of agglomerates. It was found that impurity like scandium vanished and manganese traced by the same atomic % 0.01 of zinc which had no presence after acid treatment. Thermogravimetric analysis indicates the sharp increments in heat flow in-between temperatures 0°C to 200°C and consequently increments in between 500°C to 550°C, a suitable range for the pyrolysis. Low amount of alumina and high amount of silica has been found out. TGA and DTA analysis satisfy the waste plastic valorization temperature ranges.

Background: Activated inflammation and oxidant stress during cerebral ischemia reperfusion injury (IRI) lead to brain damage. Astaxanthin (ASX) is a type of carotenoid with a strong antioxidant effect. Objective: The aim of this study was to investigate the role of ASX on brain IRI. Methods: A total of 42 adult male Sprague-Dawley rats were divided into 3 groups as control (n=14) group, IRI (n=14) group and IRI + ASX (n=14) group. Cerebral ischemia was instituted by occluding middle cerebral artery for 120 minutes and subsequently, reperfusion was performed for 48 hours. Oxidant parameter levels and protein degradation products were evaluated. Hippocampal and cortex cell apoptosis, neuronal cell count, neurological deficit score were evaluated. Results: In the IRI group, oxidant parameter levels and protein degradation products in the tissue were increased compared to control group. However, these values were significantly decreased in the IRI + ASX group (p<0.05). There was a significant decrease in hippocampal and cortex cell apoptosis and a significant increase in the number of neuronal cells in the IRI + ASX group compared to the IRI group alone (p<0.05). The neurological deficit score which was significantly lower in the IRI group compared to the control group was found to be significantly improved in the IRI + ASX group (p<0.05). Conclusion: Astaxanthin protects the brain from oxidative damage and reduces neuronal deficits due to IRI injury.

Background: Halogenated corticosteroids are widely used in medicine, and the global need of these steroidal APIs is estimated to be 40 – 70 tons, annually. Vietnam currently imports the pharmaceutical compounds up to 90%, in particular 100% of steroidal drugs. Currently, industrial production is based on the chemical syntheses of corticosteroids from either 16- dehydropregnenolone acetate (obtained from diosgenin) or androstenedione (obtained from phytosterol). The development of shorter synthetic schemes and more economically feasible technologies is of great significance. Introduction of 1(2)-double bond at the final stages of the corticosteroids synthesis results inpoor yield. 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione (tetraene acetate) is a key intermediate in the synthesis of highly active halogenated corticosteroids such as dexamethasone and other halogenated corticosteroids. 21-acetoxypregna-1,4,9(11),16- tetraene-3,20-dione is a key intermediate in the synthesis of dexamethasone from the readily available and cheap 9α-hydroxyandrost-4-ene-3,17-dione. Objective: The purpose of this study was the development of an efficient and shorter procedure for the synthesis of 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, which is a product of a bio-oxidative degradation of the side chain of phytosterols. Methods: Pregnane side chain was constructed using cyanohydrin method. For 1(2)- dehydrogenation, selene dioxide was applied for the introduction of Δ1(2)-double bond. Other stages of the synthesis were epimerization, Stork’s iodination procedure and dehydration. Result: 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione was prepared from 9α- hydroxyandrostenedione in yield more than 46%. Conclusion: An efficient and practically feasible procedure for the synthesis of 21-acetoxypregna- 1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, a key intermediate for the synthesis of 9-haloidated corticoids, has been developed. The procedure can be applied for the production of value-added 9-haloidated corticoids.

Background: Plant secondary metabolites play an essential role in the discovery of novel insecticide due to their unique sources and potential target sites. Paeonol, the main phenolic components in Moutan Cortex, is recognized as a safe and potent botanical insecticide to many insects. The structural modification of paeonol in this study into phenylsulfonylhydrazone derivatives is proved an effective approach for the development of novel insecticides, those derivatives being more toxic than paeonol. However, there have been no reports on the insecticidal activity of paeonol-based phenylsulfonylhydrazone derivatives in controlling Mythimna separata. Methods: We have been working to discover biorational natural products-based insecticides. Twelve novel paeonol-based phenylsulfonylhydrazone derivatives have been successfully prepared by structural modification of paeonol, and the insecticidal activity against M. separata by the leafdipping method at the concentration of 1 mg/mL has been evaluated. Results: Insecticidal activity revealed that out of 12 title compounds, derivatives 5c and 5f displayed the best against M. separate with the FMR both of 53.6% than toosendanin (FMR = 50.0%). Conclusion: The results suggested that for the paeonol-based phenylsulfonylhydrazone series derivatives, the proper substituent of arylsulfonyl R at the hydroxyl position of paeonol was very important for their insecticidal activity. These preliminary results will pave the way for further modification of paeonol in the development of potential new insecticides.

Aim and Objective: Five-Flavor Sophora flavescens Enteric-Coated Capsules (FSEC) are the only proprietary Chinese medicine approved for the treatment of ulcerative colitis (UC) in China. Phase II and III clinical trials have shown that the curative effect of FSEC in relieving UC was not inferior to that of mesalazine granules and enteric-coated tablets, but its pharmacological mechanism is unclear. Therefore, the network pharmacology is used to reveal the more comprehensive effective components and targets of FSEC in the treatment of UC. Methods: We screened the components of FSEC based on the TCMSP database, determined the action targets of these compounds through target fishing, and integrated the UC disease targets of several disease gene databases. The FSEC-UC composite targets were obtained by matching the two results, and then a PPI network was constructed to analyze the relationship between these targets, and the core targets were selected by topological correlation parameters. Finally, GO-BP and KEGG enrichment analyses were carried out using the clusterProfiler software package. Results: One hundred and sixty active components of FSEC were identified and 77 targets were obtained. Of these, 30 core targets were the main targets of FESC in the treatment of UC. And quercetin, kaempferol, luteolin and mangiferin were regarded as the core active components of FSEC. The results screened by GO and KEGG enrichment analysis showed that FSEC played a comprehensive therapeutic role in immune recognition, anti-inflammation and antioxidation mainly through IL-17, TNF, Toll-like receptor, NF-kappa B, and Th17 cell differentiation. Conclusion: The molecular mechanism of UC remission induced by FSEC was predicted by network pharmacology. These findings provide an important theoretical basis for further study of the effective substances and mechanism of FSEC in the treatment of UC.

Aim and Objective: One of the challenges to conventional therapies against Mycobacterium tuberculosis is the development of multi-drug resistant pathogenic strains. This study was undertaken to explore new therapeutic targets for the revolutionary antivirulence therapy utilizing the pathogen’s essential hypothetical proteins, serving as virulence factors, which is the essential first step in novel drug designing. Methods: Functional annotations of essential hypothetical proteins from Mycobacterium tuberculosis (H37Rv strain) were performed through domain annotation, Gene Ontology analysis, physicochemical characterization and prediction of subcellular localization. Virulence factors among the essential hypothetical proteins were predicted, among which pathogen-specific drug target candidates, non-homologous to human and gut microbiota, were identified. This was followed by druggability and spectrum analysis of the identified targets. Results and Conclusion: The study successfully assigned functions of 83 essential hypothetical proteins of Mycobacterium tuberculosis, among which 25 were identified as virulence factors. Out of 25, 12 virulence factors were observed as potential pathogen-specific drug target candidates. Nine potential targets had druggable properties and rest three were considered as novel targets. Exploration of these targets will provide new insights into future drug development. Characterization of subcellular localizations revealed that most of the predicted targets were cytoplasmic which could be ideal for intracellular drugs, while two drug targets were membranebound, ideal for vaccines. Spectrum analysis identified one broad-spectrum and 11 narrowspectrum targets. This study would, therefore, instigate designing novel therapeutics for antivirulence therapy, which have the potential to serve as revolutionary treatment instead of conventional antibiotic therapies to overcome the lethality of antibiotic-resistant strains.