Search results for: curcumin analogues

Authors: Gagan Kumar, Koijam M. Devi, Amarendra K. Sarma, Dibakar Roy Chowdhury

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Research in metamaterials has been gaining momentum over the past decade owing to its ability in controlling electromagnetic wave properties through careful design at the sub-wavelength scale. The metamaterials have led to several important phenomena which are useful in a variety of applications. One such phenomenon is the electromagnetically induced transparency (EIT) effect in which a narrow transparency region is created in an otherwise absorptive spectrum. In our work, we explore plasmon induced transparency (PIT) in terahertz metamaterials which is analogues to EIT effect. The PIT effect is achieved using the plasmonic metamaterials in which a unit cell is comprised of two C (2C) shaped resonators and a cut-wire (CW). When terahertz wave of a particular polarization is normally incident on the proposed metamaterials geometry, it strongly couples with the cut wire, resulting in the excitation of the bright mode. However due to the specific polarization of the incident beam, the fundamental modes of the C-shaped resonators are not excited by the incident terahertz, hence they are termed as the dark mode. The PIT effect occurs as a result of interference between the bright and the dark mode. In order to observe PIT effect, both the bright and dark modes should have similar resonant frequencies with a little deviation. We further have examined that the PIT window can be modulated by displacing the C-shaped resonators w.r.t. the cut-wire. The numerical observations for different coupling configurations can be explained through an equivalent lumped element circuit model. Moving ahead the PIT effect is further explored in a metamaterial comprising of a cross like structure and four C-shaped resonators. For such configuration, equally strong PIT effect is observed for two orthogonally polarized lights. Therefore, such metamaterials demonstrate a polarization independent PIT response w.r.t the incident terahertz radiation. The proposed study could be significant in the development of slow light devices and polarization independent sensing applications.

Keywords: terahertz, metamaterial, split ring resonator, plasmon

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Authors: Dafna Knani, Sarit S. Sivan

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Aggrecan, one of the main components of the intervertebral disc (IVD), belongs to the family of proteoglycans (PGs) that are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein. Its primary function is to maintain tissue hydration and hence disc height under the high loads imposed by muscle activity and body weight. Significant PG loss is one of the first indications of disc degeneration. A possible solution to recover disc functions is by injecting a synthetic hydrogel into the joint cavity, hence mimicking the role of PGs. One of the hydrogels proposed is GAG-analogues, based on sulfate-containing polymers, which are responsible for hydration in disc tissue. In the present work, we used molecular dynamics (MD) to study the effect of the hydrogel crosslinking (type and degree) on the swelling behavior of the suggested GAG-analogue biomimetics by calculation of cohesive energy density (CED), solubility parameter, enthalpy of mixing (ΔEmix) and the interactions between the molecules at the pure form and as a mixture with water. The simulation results showed that hydrophobicity plays an important role in the swelling of the hydrogel, as indicated by the linear correlation observed between solubility parameter values of the copolymers and crosslinker weight ratio (w/w); this correlation was found useful in predicting the amount of PEGDA needed for the desirable hydration behavior of (CS)₄-peptide. Enthalpy of mixing calculations showed that all the GAG analogs, (CS)₄ and (CS)₄-peptide are water-soluble; radial distribution function analysis revealed that they form interactions with water molecules, which is important for the hydration process. To conclude, our simulation results, beyond supporting the experimental data, can be used as a useful predictive tool in the future development of biomaterials, such as disc replacement.

Keywords: molecular dynamics, proteoglycans, enthalpy of mixing, swelling

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Authors: Narayana Murthy Akurathi, Vijaya Lakshmi Marella

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The literature is reviewed with regard to online Super critical fluid extraction (SFE) coupled directly with supercritical fluid chromatography (SFC) -mass spectrometry that have typically more sensitive than conventional LC-MS/MS and GC-MS/MS. It is becoming increasingly interesting to use on-line techniques that combine sample preparation, separation and detection in one analytical set up. This provides less human intervention, uses small amount of sample and organic solvent and yields enhanced analyte enrichment in a shorter time. The sample extraction is performed under light shielding and anaerobic conditions, preventing the degradation of thermo labile analytes. It may be able to analyze compounds over a wide polarity range as SFC generally uses carbon dioxide which was collected as a by-product of other chemical reactions or is collected from the atmosphere as it contributes no new chemicals to the environment. The diffusion of solutes in supercritical fluids is about ten times greater than that in liquids and about three times less than in gases which results in a decrease in resistance to mass transfer in the column and allows for fast high resolution separations. The drawback of SFC when using carbon dioxide as mobile phase is that the direct introduction of water samples poses a series of problems, water must therefore be eliminated before it reaches the analytical column. Hundreds of compounds analysed simultaneously by simple enclosing in an extraction vessel. This is mainly applicable for pharmaceutical industry where it can analyse fatty acids and phospholipids that have many analogues as their UV spectrum is very similar, trace additives in polymers, cleaning validation can be conducted by putting swab sample in an extraction vessel, analysing hundreds of pesticides with good resolution.

Keywords: super critical fluid extraction (SFE), super critical fluid chromatography (SFC), LCMS/MS, GCMS/MS

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Authors: O.Ofoegbu, S. Roongnapa, A.N. Eboatu

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Most polluted environments, most challengingly, aerosol types, contain a cocktail of different toxicants. Multi-templating of matrices have been the recent target by researchers in a bid to solving complex mixed-toxicant challenges using single or common remediation systems. This investigation looks at the effect of such multi-templated system vis-a-vis the synthesis by non-covalent interaction, of a molecularly imprinted polymer architecture using nicotine and its structural analogue Phenylalanine amide individually and, in the blend, (50:50), as template materials in a Chitosan-Methacrylic acid functional monomer matrix. The temperature for polymerization is 60OC and time for polymerization, 12hrs (water bath heating), 4mins for (microwave heating). The characteristic thermal properties of the molecularly imprinted materials are investigated using Simultaneous Thermal Analysis (STA) profiling, while the absorption and separation efficiencies based on the relative retention times and peak areas of templates were studied amongst other properties. Transmission Electron Microscopy (TEM) results obtained, show the creation of heterogeneous nanocavities, regardless, the introduction of Caffeine a close structural analogue presented near-zero perfusion. This confirms the selectivity and specificity of the templated polymers despite its dual-templated nature. The STA results presented the materials as having decomposition temperatures above 250OC and a relative loss in mass of less than19% over a period within 50mins of heating. Consequent to this outcome, multi-templated systems can be fabricated to sequester specifically and selectively targeted toxicants in a mixed toxicant populated system effectively.

Keywords: chitosan, dual-templated, methacrylic acid, mixed-toxicants, molecularly-imprinted-polymer

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Authors: Anshu Bahl, Saroj Kaler, Shivani Gupta, S B Ray

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Background: Somatostatin is an endogenous regulatory neuropeptide. Somatostatin and its analogues play an important role in neuropathic and inflammatory pain. Neuropeptide Y is extensively distributed in the mammalian nervous system. NPY has an important role in blood pressure, circadian rhythm, obesity, appetite and memory. The purpose was to investigate somatostatin and NPY expression in dorsal root ganglia during pain. The plantar incision model in rats is similar to postoperative pain in humans. Methods: 24 adult male Sprague dawley rats were distributed randomly into two groups – Control (n=6) and incision (n=18) groups. Using Hargreaves apparatus, thermal hyperalgesia behavioural test for nociception was done under basal condition and after surgical incision in right hind paw at different time periods (day 1, 3 and 5). The plantar incision was performed as per standard protocol. Perfusion was done using 4% paraformaldehyde followed by extraction of dorsal root ganglia at L4 level. The tissue was processed for immunohistochemical localisation for somatostatin and neuropeptide Y. Results: Post incisional groups (day 1, 3 and 5) exhibited significant decrease of paw withdrawal latency as compared to control groups. Somatostatin expression was noted under basal conditions. It decreased on day 1, but again gradually increased on day 3 and further on day five post incision. The expression of Neuropeptide Y was noted in the cytoplasm of dorsal root ganglia under basal conditions. Compared to control group, expression of neuropeptide Y decreased on day one after incision, but again gradually increased on day 3. Maximum expression was noted on day five post incision. Conclusion: Decrease in paw withdrawal latency indicated nociception, particularly on day 1. In comparison to control, somatostatin and NPY expression was decreased on day one post incision. This could be correlated with increased axoplasmic flow towards the spinal cord. Somatostatin and NPY expression was maximum on day five post incision. This could be due to decreased migration from the site of synthesis towards the spinal cord.

Keywords: dorsal root ganglia, neuropeptide y, postoperative pain, somatostatin

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Authors: Kailash Pattanaik, Giribala Mohanty

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Dhanujatra is a folk performance of ODISHA, India, that transports the participants, on lookers and all alike into a mythical atmosphere for eleven days and nights as well. In this performance the whole town becomes stage. The uniqueness of the festival lies in the fact that all the episodes of this Jatra enacted in different parts of the town making it the largest open air theatre in the world. The paper would emphasize on the uniqueness and the impact of this performance.Different episodes are enacted at different places in the regime. So, Dhanujatra does not confine itself to a fixed static or dead stage, as in case of other Jatra’s; it rather becomes the stage for the world at large. For that, it is said that, Worlds biggest open air theatre held in the tiny town called Bargarh in the western part of Orissa. The play moves sequentially day after day and the audience moves from locale to locale. Here it is analogues to the Ramleela of Ramnagar of Benars. Parallal enactment is a significant feature of this Jatra. From the second day, parallal performances take place in both Bargarh town and Ambapalli epitomising ‘Mathura’ and ‘Gokul’ respectively. Krishna is born in the prison on the second day of the jatra. Basudeb exchanges the child with the Nanda’s newborn baby in Gokul. In this way, parallal performances go on both in Mathura and Gokul. The ordinary persons who act as the mythological characters, or become historical heroes or the legendary Saints or Bhaktas in a Jatra in the evening, lead the lives of ordinary persons during day time. The dramatic personas of those individuals are shed with the end of the Jatra. On the contrary, the persons who act as the main characters of Dhanujatra are exceptions in this regard. They are identified as the characters they enact for the whole period of performance, both in the evenings and during daytime. It is worth mentioning that generally in the folk performances there is an ample scope to touch upon or interpret or comment or satirize the issues of contemporary relevance with the sole purpose to convey some specific message. Dhanujatra is no exception to that.

Keywords: folk performance, Jatra, parallel enactment, open-air stage, Odisha

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Authors: Jun Hyung Lee, Robin B. Guevarra, Jin Ho Cho, Bo-Ra Kim, Jiwon Shin, Doo Wan Kim, Young Hwa Kim, Minho Song, Hyeun Bum Kim

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Salmonella is one of the most important swine pathogens, causing acute or chronic digestive diseases, such as enteritis. The acute form of enteritis is common in young pigs of 2-4 months of age. Salmonellosis in swine causes a huge economic burden to swine industry by reducing production. Therefore, it is necessary that swine industries should strive to decrease Salmonellosis in pigs in order to reduce economic losses. Thus, we tested three types of natural plant extracts(PEs) to evaluate antibacterial effects against Salmonella enterica Typhimurium isolated from the piglet with Salmonellosis. Three PEs including turmeric oleoresin (containing curcumin 79 to 85%), capsicum oleoresin (containing capsaicin 40%-40.1%), and garlic essential oil (100% natural garlic) were tested using the direct contact agar diffusion test, minimum inhibitory concentration test, growth curve assay, and heat stability test. The tests were conducted with PEs at each concentration of 2.5%, 5%, and 10%. For the heat stability test, PEs with 10% concentration were incubated at each 4, 20, 40, 60, 80, and 100 °C for 1 hour; then the direct contact agar diffusion test was used. For the positive and negative controls, 0.5N HCl and 1XPBS were used. All the experiments were duplicated. In the direct contact agar diffusion test, garlic essential oil with 2.5%, 5%, and 10% concentration showed inhibit zones of 1.5cm, 2.7cm, and 2.8cm diameters compared to that of 3.5cm diameter for 0.5N HCl. The minimum inhibited concentration of garlic essential oil was 2.5%. Growth curve assay showed that the garlic essential oil was able to inhibit Salmonella growth significantly after 4hours. The garlic essential oil retained the ability to inhibit Salmonella growth after heat treatment at each temperature. However, turmeric and capsicum oleoresins were not able to significantly inhibit Salmonella growth by all the tests. Even though further in-vivo tests will be needed to verify effects of garlic essential oil for the Salmonellosis prevention for piglets, our results showed that the garlic essential oil could be used as a potential natural agent to prevent Salmonellosis in swine.

Keywords: garlic essential oil, pig, salmonellosis, Salmonella enterica

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Authors: Jun Hyung Lee, Robin B. Guevarra, Jin Ho Cho, Bo-Ra Kim, Jiwon Shin, Doo Wan Kim, Young Hwa Kim, Minho Song, Hyeun Bum Kim

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Colibacillosis is one of the major health problems in young piglets ultimately resulting in their death, and it is common especially in young piglets. For the swine industry, colibacillosis is one of the important economic burdens. Therefore, it is necessary for the swine industries to prevent Colibacillosis in piglets in order to reduce economic losses. Thus, we tested three types of natural plant extracts (PEs) to evaluate antibacterial effects against Shiga toxin-producing Escherichia coli (STEC) isolated from the piglet. Three PEs including turmeric oleoresin (containing curcumin 79 to 85%), capsicum oleoresin (containing capsaicin 40%-40.1%), and garlic essential oil (100% natural garlic) were tested using the direct contact agar diffusion test, minimum inhibitory concentration test, growth curve assay, and heat stability test. The tests were conducted with PEs at each concentration of 2.5%, 5%, and 10%. For the heat stability test, PEs with 10% concentration were incubated at each 4, 20, 40, 60, 80, and 100 °C for 1 hour, then the direct contact agar diffusion test was used. For the positive and negative controls, 0.5N HCl and 1XPBS were used. All the experiments were duplicated. In the direct contact agar diffusion test, garlic essential oil with 2.5%, 5%, and 10% concentration showed inhibit zones of 1.1cm, 3.0cm, and 3.6 cm in diameters compared to that of 3.5cm diameter for 0.5N HCl. The minimum inhibited concentration of garlic essential oil was 2.5%. Growth curve assay showed that the garlic essential oil was able to inhibit STEC growth significantly after 4 hours. The garlic essential oil retained the ability to inhibit STEC growth after heat treatment at each temperature. However, turmeric and capsicum oleoresins were not able to significantly inhibit STEC growth by all the tests. Even though further tests using the piglets will be required to evaluate effects of garlic essential oil for the Colibacillosis prevention for piglets, our results showed that the garlic essential oil could be used as a potential natural agent to prevent Colibacillosis in swine.

Keywords: garlic essential oil, pig, Colibacillosis, Escherichia coli

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Authors: E. E. Tereshatov, M. Yu. Boltoeva, V. Mazan, M. F. Volia, C. M. Folden III

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Room temperature ionic liquids (RTILs) are a class of liquid organic salts with melting points below 20 °C that are considered to be environmentally friendly ‘designers’ solvents. Pure hydrophobic ILs are known to extract metallic species from aqueous solutions. The closest analogues of ionic liquids are deep eutectic solvents (DESs), which are a eutectic mixture of at least two compounds with a melting point lower than that of each individual component. DESs are acknowledged to be attractive for organic synthesis and metal processing. Thus, these non-volatile and less toxic compounds are of interest for critical metal extraction. The US Department of Energy and the European Commission consider indium as a key metal. Its chemical homologue, thallium, is also an important material for some applications and environmental safety. The aim of this work is to systematically investigate In and Tl extraction from aqueous solutions into pure fluorinated ILs and hydrophobic DESs. The dependence of the Tl extraction efficiency on the structure and composition of the ionic liquid ions, metal oxidation state, and initial metal and aqueous acid concentrations have been studied. The extraction efficiency of the TlXz3–z anionic species (where X = Cl– and/or Br–) is greater for ionic liquids with more hydrophobic cations. Unexpectedly high distribution ratios (> 103) of Tl(III) were determined even by applying a pure ionic liquid as receiving phase. An improved mathematical model based on ion exchange and ion pair formation mechanisms has been developed to describe the co-extraction of two different anionic species, and the relative contributions of each mechanism have been determined. The first evidence of indium extraction into new quaternary ammonium- and menthol-based hydrophobic DESs from hydrochloric and oxalic acid solutions with distribution ratios up to 103 will be provided. Data obtained allow us to interpret the mechanism of thallium and indium extraction into ILs and DESs media. The understanding of Tl and In chemical behavior in these new media is imperative for the further improvement of separation and purification of these elements.

Keywords: deep eutectic solvents, indium, ionic liquids, thallium

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Authors: Sunil K. Jena, Sanjaya K. Samal, Mahesh Chand, Abhay T. Sangamwar

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Tamoxifen (TMX) and its analogues are approved as a first line therapy for the treatment of estrogen receptor-positive tumors. However, clinical development of TMX has been hampered by its low bioavailability and severe hepatotoxicity. Herein, we attempt to design a new drug delivery vehicle that could enhance the pharmacokinetic performance of TMX. Initially, high-molecular weight carboxymethyl chitosan was hydrolyzed to low-molecular weight carboxymethyl chitosan (LMW CMC) with hydrogen peroxide under the catalysis of phosphotungstic acid. Amphiphilic block copolymers of LMW CMC were synthesized via amidation reaction between the carboxyl group of α-tocopherol succinate (TS) and an amine group of LMW CMC. These amphiphilic block copolymers were self-assembled to nanosize core-shell-structural micelles in the aqueous medium. The critical micelle concentration (CMC) decreased with the increasing substitution of TS on LMW CMC, which ranged from 1.58 × 10-6 to 7.94 × 10-8 g/mL. Maximum TMX loading up to 8.08 ± 0.98% was achieved with Cmc-TS4.5 (TMX/Cmc-TS4.5 with 1:8 weight ratio). Both blank and TMX-loaded polymeric micelles (TMX-PM) of Cmc-TS4.5 exhibits spherical shape with the particle size below 200 nm. TMX-PM has been found to be stable in the gastrointestinal conditions and released only 44.5% of the total drug content by the first 72 h in simulated gastric fluid (SGF), pH 1.2. However, the presence of pepsin does not significantly increased the TMX release in SGF, pH 1.2, released only about 46.2% by the first 72 h suggesting its inability to cleave the peptide bond. In contrast, the release of TMX from TMX-PM4.5 in SIF, pH 6.8 (without pancreatin) was slow and sustained, released only about 10.43% of the total drug content within the first 30 min and nearly about 12.41% by the first 72 h. The presence of pancreatin in SIF, pH 6.8 led to an improvement in drug release. About 28.09% of incorporated TMX was released in the presence of pancreatin in 72 h. A cytotoxicity study demonstrated that TMX-PM exhibited time-delayed cytotoxicity in human MCF-7 breast cancer cells. Pharmacokinetic studies on Sprague-Dawley rats revealed a remarkable increase in oral bioavailability (1.87-fold) with significant (p < 0.0001) enhancement in AUC0-72 h, t1/2 and MRT of TMX-PM4.5 than that of TMX-suspension. Thus, the results suggested that CMC-TS micelles are a promising carrier for TMX delivery.

Keywords: carboxymethyl chitosan, d-α-tocopherol succinate, pharmacokinetic, polymeric micelles, tamoxifen

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Authors: Vadim V. Zefirov, Victor E. Sizov, Marina A. Pigaleva, Igor V. Elmanovich, Mikhail S. Kondratenko, Marat O. Gallyamov

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This work presents a novel method for treating porous hydrophobic polyolefin membranes using supercritical carbon dioxide that allows usage of the modified membrane in redox flow batteries with an aqueous electrolyte. Polyolefin membranes are well known and widely used, however, they cannot be used as separators in redox flow batteries with an aqueous electrolyte since they have insufficient wettability, and therefore do not provide sufficient proton conductivity. The main aim of the presented work was the development of hydrophilic composites based on cheap membranes and precursors. Supercritical fluid was used as a medium for the deposition of the hydrophilic phase on the hydrophobic surface of the membrane. Due to the absence of negative capillary effects in a supercritical medium, a homogeneous composite is obtained as a result of synthesis. The in-situ synthesized silicon oxide nanoparticles and the chitosan polymer layer act as the hydrophilic phase and not only increase the affinity of the membrane towards the electrolyte, but also reduce the pore size of the polymer matrix, which positively affects the ion selectivity of the membrane. The composite material obtained as a result of synthesis has enhanced hydrophilic properties and is capable of providing proton conductivity in redox flow batteries. The morphology of the obtained composites was characterized by electron microscopy. To analyze the phase composition, infrared spectroscopy was used. The hydrophilic properties were studied by water contact angle measurements. In addition, the proton conductivity and ion selectivity of the obtained samples were studied, and tests in real redox flow batteries were performed. As a result, modified membrane was characterised in detail and moreover it was shown that modified cheap polyolefin membranes have pronounced proton conductivity and high ion selectivity, so their performance in a real redox flow battery approaches expensive commercial analogues, reaching 70% of energy efficiency.

Keywords: carbon dioxide, chitosan, polymer membrane, redox flow batteries, silica nanoparticles, supercritical fluid

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Authors: Simona Grasso, Gabrielle Smith, Sophie Bowers, Oluseyi Moses Ajayi, Mark Swainson

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Hybrid meat analogues are meat products whereby a proportion of meat has been partially replaced by more sustainable protein sources. These products could bridge the gap between meat and meat-free products, providing convenience, and allowing consumers to continue using meat products as they conventionally would, while lowering their overall meat intake. The study aimed to investigate the effect of introducing texturized soy protein (TSP) at different levels (15% and 30%) with and without nutritional yeast as flavour enhancer on the sensory and instrumental quality of beef meatballs, compared to a soy and yeast-free control. Proximate analysis, yield, colour, instrumental texture, and sensory quality were investigated. The addition of soy and yeast did not have significant effects on the overall protein content, but the total fat and moisture content went down with increasing soy substitution. Samples with 30% TSP had significantly higher yield than the other recipes. In terms of colour, a* redness values tended to go down and b* yellowness values tended to go up with increasing soy addition. The addition of increasing levels of soy and yeast modified the structure of meatballs resulting in a progressive decrease in hardness and chewiness compared to control. Sixty participants assessed the samples using Check-all-that-apply (CATA) questions and hedonic scales. The texture of all TSP-containing samples received significantly higher acceptability scores than control, while 15% TSP with yeast received significantly higher flavour and overall acceptability scores than control. Control samples were significantly more often associated than the other recipes to the term 'hard' and the least associated to 'soft' and 'crumbly and easy to cut'. All recipes were similarly associated to the terms 'weak meaty', 'strong meaty', 'characteristic' and 'unusual'. Correspondence analysis separated the meatballs in three distinct groups: 1) control; 2) 30%TSP with yeast; and 3) 15%TSP, 15%TSP with yeast and 30%TSP located together on the sensory map, showing similarity. Adding 15-30% TSP with or without yeast inclusion could be beneficial for the development of future meat hybrids with acceptable sensory quality. These results can provide encouragement for the use of the hybrid concept by the meat industry to promote the partial substitution of meat in flexitarians’ diets.

Keywords: CATA, hybrid meat products, texturised soy protein, yeast

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Authors: Melanie Ostermann, Eivind Birkeland, Ying Xue, Alexander Sauter, Mihaela R. Cimpan

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Background: New reliable and robust techniques to assess biological effects of nanomaterials (NMs) in vitro are needed to speed up safety analysis and to identify key physicochemical parameters of NMs, which are responsible for their acute cytotoxicity. The central aim of this study was to validate and evaluate the applicability and reliability of an impedance-based flow cytometry (IFC) technique for the high-throughput screening of NMs. Methods: Eight inorganic NMs from the European Commission Joint Research Centre Repository were used: NM-302 and NM-300k (Ag: 200 nm rods and 16.7 nm spheres, respectively), NM-200 and NM- 203 (SiO₂: 18.3 nm and 24.7 nm amorphous, respectively), NM-100 and NM-101 (TiO₂: 100 nm and 6 nm anatase, respectively), and NM-110 and NM-111 (ZnO: 147 nm and 141 nm, respectively). The aim was to assess the biological effects of these materials on human monoblastoid (U937) cells. Dispersions of NMs were prepared as described in the NANOGENOTOX dispersion protocol and cells were exposed to NMs at relevant concentrations (2, 10, 20, 50, and 100 µg/mL) for 24 hrs. The change in electrical impedance was measured at 0.5, 2, 6, and 12 MHz using the IFC AmphaZ30 (Amphasys AG, Switzerland). A traditional toxicity assay, Trypan Blue Dye Exclusion assay, and dark-field microscopy were used to validate the IFC method. Results: Spherical Ag particles (NM-300K) showed the highest toxic effect on U937 cells followed by ZnO (NM-111 ≥ NM-110) particles. Silica particles were moderate to non-toxic at all used concentrations under these conditions. A higher toxic effect was seen with smaller sized TiO2 particles (NM-101) compared to their larger analogues (NM-100). No interferences between the IFC and the used NMs were seen. Uptake and internalization of NMs were observed after 24 hours exposure, confirming actual NM-cell interactions. Conclusion: Results collected with the IFC demonstrate the applicability of this method for rapid nanotoxicity assessment, which proved to be less prone to nano-related interference issues compared to some traditional toxicity assays. Furthermore, this label-free and novel technique shows good potential for up-scaling in directions of an automated high-throughput screening and for future NM toxicity assessment. This work was supported by the EC FP7 NANoREG (Grant Agreement NMP4-LA-2013-310584), the Research Council of Norway, project NorNANoREG (239199/O70), the EuroNanoMed II 'GEMN' project (246672), and the UH-Nett Vest project.

Keywords: cytotoxicity, high-throughput, impedance, nanomaterials

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Authors: Syed Asif Hassan, Tabrej Khan

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Multiple sclerosis (MS) is a chronic demyelinating autoimmune disorder, of the central nervous system (CNS). In the present scenario, the current therapies either do not halt the progression of the disease or have side effects which limit the usage of current Disease Modifying Therapies (DMTs) for a longer period of time. Therefore, keeping the current treatment failure schema, we are focusing on screening novel analogues of the available DMTs that specifically bind and inhibit the Sphingosine1-phosphate receptor1 (S1PR1) thereby hindering the lymphocyte propagation toward CNS. The novel drug-like analogs molecule will decrease the frequency of relapses (recurrence of the symptoms associated with MS) with higher efficacy and lower toxicity to human system. In this study, an integrated approach involving ligand-based virtual screening protocol (Ultrafast Shape Recognition with CREDO Atom Types (USRCAT)) to identify the non-toxic drug like analogs of the approved DMTs were employed. The potency of the drug-like analog molecules to cross the Blood Brain Barrier (BBB) was estimated. Besides, molecular docking and simulation using Auto Dock Vina 1.1.2 and GOLD 3.01 were performed using the X-ray crystal structure of Mtb LprG protein to calculate the affinity and specificity of the analogs with the given LprG protein. The docking results were further confirmed by DSX (DrugScore eXtented), a robust program to evaluate the binding energy of ligands bound to the ligand binding domain of the Mtb LprG lipoprotein. The ligand, which has a higher hypothetical affinity, also has greater negative value. Further, the non-specific ligands were screened out using the structural filter proposed by Baell and Holloway. Based on the USRCAT, Lipinski’s values, toxicity and BBB analysis, the drug-like analogs of fingolimod and BG-12 showed that RTL and CHEMBL1771640, respectively are non-toxic and permeable to BBB. The successful docking and DSX analysis showed that RTL and CHEMBL1771640 could bind to the binding pocket of S1PR1 receptor protein of human with greater affinity than as compared to their parent compound (Fingolimod). In this study, we also found that all the drug-like analogs of the standard MS drugs passed the Bell and Holloway filter.

Keywords: antagonist, binding affinity, chemotherapeutics, drug-like, multiple sclerosis, S1PR1 receptor protein

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Authors: Daniel Todorov, Anton Hinkov, Petya Angelova, Kalina Shishkova, Venelin Tsvetkov, Stoyan Shishkov

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Human herpes viruses (HHV) are ubiquitous pathogens with a pandemic spread across the globe. HHV type 1 is the main causative agent of cold sores and fever blisters around the mouth and on the face, whereas HHV type 2 is generally responsible for genital herpes outbreaks. The treatment of both viruses is more or less successful with antivirals from the nucleoside analogues group. Their wide application increasingly leads to the emergence of resistant mutants In the past, medicinal plants have been used to treat a number of infectious and non-infectious diseases. Their diversity and ability to produce the vast variety of secondary metabolites according to the characteristics of the environment give them the potential to help us in our warfare with viral infections. The variable chemical characteristics and complex composition is an advantage in the treatment of herpes since the emergence of resistant mutants is significantly complicated. The screening process is difficult due to the lack of standardization. That is why it is especially important to follow the mechanism of antiviral action of plants. On the one hand, it may be expected to interact with its compounds, resulting in enhanced antiviral effects, and the most appropriate environmental conditions can be chosen to maximize the amount of active secondary metabolites. During our study, we followed the activity of various plant extracts on the viral replication cycle as well as their effect on the extracellular virion. We obtained our results following the logical sequence of the experimental settings - determining the cytotoxicity of the extracts, evaluating the overall effect on viral replication and extracellular virion.During our research, we have screened a variety of plant extracts for their antiviral activity against both virus replication and the virion itself. We investigated the effect of the extracts on the individual stages of the viral replication cycle - viral adsorption, penetration and the effect on replication depending on the time of addition. If there are positive results in the later experiments, we had studied the activity over viral adsorption, penetration and the effect of replication according to the time of addition. Our results indicate that some of the extracts from the Lamium album have several targets. The first stages of the viral life cycle are most affected. Several of our active antiviral agents have shown an effect on extracellular virion and adsorption and penetration processes. Our research over the last decade has shown several curative antiviral plants - some of which are from the Lamiacea family. The rich set of active ingredients of the plants in this family makes them a good source of antiviral preparation.

Keywords: human herpes virus, antiviral activity, Lamium album, Nepeta nuda

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Authors: R. Khare, R. V. Gelamo, M. A. More, D. J. Late, Chandra Sekhar Rout

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Graphene emerges out as a promising material for various applications ranging from complementary integrated circuits to optically transparent electrode for displays and sensors. The excellent conductivity and atomic sharp edges of unique two-dimensional structure makes graphene a propitious field emitter. Graphene analogues of other 2D layered materials have emerged in material science and nanotechnology due to the enriched physics and novel enhanced properties they present. There are several advantages of using 2D nanomaterials in field emission based devices, including a thickness of only a few atomic layers, high aspect ratio (the ratio of lateral size to sheet thickness), excellent electrical properties, extraordinary mechanical strength and ease of synthesis. Furthermore, the presence of edges can enhance the tunneling probability for the electrons in layered nanomaterials similar to that seen in nanotubes. Here we report electron emission properties of multilayer graphene and effect of plasma (CO2, O2, Ar and N2) treatment. The plasma treated multilayer graphene shows an enhanced field emission behavior with a low turn on field of 0.18 V/μm and high emission current density of 1.89 mA/cm2 at an applied field of 0.35 V/μm. Further, we report the field emission studies of layered WS2/RGO and SnS2/RGO composites. The turn on field required to draw a field emission current density of 1μA/cm2 is found to be 3.5, 2.3 and 2 V/μm for WS2, RGO and the WS2/RGO composite respectively. The enhanced field emission behavior observed for the WS2/RGO nanocomposite is attributed to a high field enhancement factor of 2978, which is associated with the surface protrusions of the single-to-few layer thick sheets of the nanocomposite. The highest current density of ~800 µA/cm2 is drawn at an applied field of 4.1 V/μm from a few layers of the WS2/RGO nanocomposite. Furthermore, first-principles density functional calculations suggest that the enhanced field emission may also be due to an overlap of the electronic structures of WS2 and RGO, where graphene-like states are dumped in the region of the WS2 fundamental gap. Similarly, the turn on field required to draw an emission current density of 1µA/cm2 is significantly low (almost half the value) for the SnS2/RGO nanocomposite (2.65 V/µm) compared to pristine SnS2 (4.8 V/µm) nanosheets. The field enhancement factor β (~3200 for SnS2 and ~3700 for SnS2/RGO composite) was calculated from Fowler-Nordheim (FN) plots and indicates emission from the nanometric geometry of the emitter. The field emission current versus time plot shows overall good emission stability for the SnS2/RGO emitter. The DFT calculations reveal that the enhanced field emission properties of SnS2/RGO composites are because of a substantial lowering of work function of SnS2 when supported by graphene, which is in response to p-type doping of the graphene substrate. Graphene and 2D analogue materials emerge as a potential candidate for future field emission applications.

Keywords: graphene, layered material, field emission, plasma, doping

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Authors: Sudhanshu Sharma

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Lisinopril, 1-[N-{(s)-I-carboxy-3 phenyl propyl}-L-proline dehydrate is a lysine analog of enalaprilat, the active metabolite of enalapril. It is long-acting, non-sulhydryl angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of hypertension and congestive heart failure in daily dosage 10-80 mg. Pharmacological activity of lisinopril has been proved in various experimental and clinical studies. Owing to its importance and widespread use, efforts have been made towards the development of simple and reliable analytical methods. As per our literature survey, lisinopril in pharmaceutical formulations has been determined by various analytical methodologies like polaragraphy, potentiometry, and spectrophotometry, but most of these analytical methods are not too suitable for the Identification of lisinopril from clinical samples because of the interferences caused by the amino acids and amino groups containing metabolites present in biological samples. This report is an attempt in the direction of developing a simple and reliable method for on plate identification and quantification of lisinopril in pharmaceutical formulations as well as from human urine samples using silica gel H layers developed with a new mobile phase comprising of micellar solutions of N-cetyl-N, N, N-trimethylammonium bromide (CTAB). Micellar solutions have found numerous practical applications in many areas of separation science. Micellar liquid chromatography (MLC) has gained immense popularity and wider applicability due to operational simplicity, cost effectiveness, relatively non-toxicity and enhanced separation efficiency, low aggressiveness. Incorporation of aqueous micellar solutions as mobile phase was pioneered by Armstrong and Terrill as they accentuated the importance of TLC where simultaneous separation of ionic or non-ionic species in a variety of matrices is required. A peculiarity of the micellar mobile phases (MMPs) is that they have no macroscopic analogues, as a result the typical separations can be easily achieved by using MMPs than aqueous organic mobile phases. Previously MMPs were successfully employed in TLC based critical separations of aromatic hydrocarbons, nucleotides, vitamin K1 and K5, o-, m- and p- aminophenol, amino acids, separation of penicillins. The human urine analysis for identification of selected drugs and their metabolites has emerged as an important investigation tool in forensic drug analysis. Among all chromatographic methods available only thin layer chromatography (TLC) enables a simple fast and effective separation of the complex mixtures present in various biological samples and is recommended as an approved testing for forensic drug analysis by federal Law. TLC proved its applicability during successful separation of bio-active amines, carbohydrates, enzymes, porphyrins, and their precursors, alkaloid and drugs from urine samples.

Keywords: lisnopril, surfactant, chromatography, micellar solutions

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Authors: Natalia V. Beloglazova, Pieterjan Lenain, Martin Hedstrom, Dietmar Knopp, Sarah De Saeger

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In recent years polycyclic aromatic hydrocarbons (PAHs), which represent a hazard to humans and entire ecosystem, have been receiving an increased interest due to their mutagenic, carcinogenic and endocrine disrupting properties. They are formed in all incomplete combustion processes of organic matter and, as a consequence, ubiquitous in the environment. Benzo(a)pyrene (BaP) is on the priority list published by the Environmental Agency (US EPA) as the first PAH to be identified as a carcinogen and has often been used as a marker for PAHs contamination in general. It can be found in different types of water samples, therefore, the European Commission set up a limit value of 10 ng L–1 (10 ppt) for BAP in water intended for human consumption. Generally, different chromatographic techniques are used for PAHs determination, but these assays require pre-concentration of analyte, create large amounts of solvent waste, and are relatively time consuming and difficult to perform on-site. An alternative robust, stand-alone, and preferably cheap solution is needed. For example, a sensing unit which can be submerged in a river to monitor and continuously sample BaP. An affinity sensor based on capacitive transduction was developed. Natural antibodies or their synthetic analogues can be used as ligands. Ideally the sensor should operate independently over a longer period of time, e.g. several weeks or months, therefore the use of molecularly imprinted polymers (MIPs) was discussed. MIPs are synthetic antibodies which are selective for a chosen target molecule. Their robustness allows application in environments for which biological recognition elements are unsuitable or denature. They can be reused multiple times, which is essential to meet the stand-alone requirement. BaP is a highly lipophilic compound and does not contain any functional groups in its structure, thus excluding non-covalent imprinting methods based on ionic interactions. Instead, the MIPs syntheses were based on non-covalent hydrophobic and π-π interactions. Different polymerization strategies were compared and the best results were demonstrated by the MIPs produced using electropolymerization. 4-vinylpyridin (VP) and divinylbenzene (DVB) were used as monomer and cross-linker in the polymerization reaction. The selectivity and recovery of the MIP were compared to a non-imprinted polymer (NIP). Electrodes were functionalized with natural receptor (monoclonal anti-BaP antibody) and with MIPs selective towards BaP. Different sets of electrodes were evaluated and their properties such as sensitivity, selectivity and linear range were determined and compared. It was found that both receptor can reach the cut-off level comparable to the established ML, and despite the fact that the antibody showed the better cross-reactivity and affinity, MIPs were more convenient receptor due to their ability to regenerate and stability in river till 7 days.

Keywords: antibody, benzo(a)pyrene, capacitive sensor, MIPs, river water

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Authors: Maryam Nazari

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COVID-19 is a respiratory disease triggered by the novel coronavirus, SARS-CoV-2, that has reached pandemic status today. Acute inflammation and immune cells infiltration into lung injuries result in multi-organ failure. The presence of other non-communicable diseases (NCDs) with systemic inflammation derived from COVID-19 may exacerbate the patient's situation and increase the risk for adverse effects and mortality. This pandemic is a novel situation and the scientific community at this time is looking for vaccines or drugs to treat the pathology. One of the biggest challenges is focused on reducing inflammation without compromising the correct immune response of the patient. In this regard, addressing the nutritional factors should not be overlooked not only as a matter of avoiding the presence of NCDs with severe infections but also as an adjunctive way to modulate the inflammatory status of the patients. Despite the pivotal role of nutrition in modifying immune response, due to the novelty of the COVID-19 disease, information about the effects of specific dietary agents is limited in this area. From the macronutrients point of view, protein deficiency (quantity or quality) has negative effects on the number of functional immunoglobulins and gut-associated lymphoid tissue (GALT). High biological value proteins or some amino acids like arginine and glutamine are well known for their ability to augment the immune system. Among lipids, fish oil has the ability to inactivate enveloped viruses, suppress pro-inflammatory prostaglandin production and block platelet-activating factors and their receptors. In addition, protectin D1, which is an Omega-3 PUFAs derivation, is a novel antiviral drug. So it seems that these fatty acids can reduce the severity and/or improve recovery of patients with COVID-19. Carbohydrates with lower glycemic index and fibers are associated with lower levels of inflammatory cytokines (CRP, TNF-α, and IL-6). Short-Chain Fatty acids not only exert a direct anti-inflammatory effect but also provide appropriate gut microbial, which is important in gastrointestinal issues related to COVID-19. From the micronutrients point of view, Vitamins A, C, D, E, iron, magnesium, zinc, selenium and copper play a vital role in the maintenance of immune function. Inadequate status in these nutrients may result in decreased resistance against COVID-19 infection. There are specific bioactive compounds in the diet that interact with the ACE2 receptor, which is the gateway for SARS and SARS-CoV-2, and thus controls the viral infection. Regarding this, the potential benefits of probiotics, resveratrol (a polyphenol found in grape), oleoylethanolamide (derived from oleic acid), and natural peroxisome proliferator-activated receptor γ agonists in foodstuffs (like curcumin, pomegranate, hot pepper) are suggested. Yet, it should be pointed out that most of these results have been reported in animal models and further human studies are needed to be verified.

Keywords: Covid-19, inflammation, nutrition, dietary agents

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Authors: Parisa Shirzadeh

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Drug delivery systems in which drugs are traditionally used, multi-stage and at specified intervals by patients, do not meet the needs of the world's up-to-date drug delivery. In today's world, we are dealing with a huge number of recombinant peptide and protean drugs and analogues of hormones in the body, most of which are made with genetic engineering techniques. Most of these drugs are used to treat critical diseases such as cancer. Due to the limitations of the traditional method, researchers sought to find ways to solve the problems of the traditional method to a large extent. Following these efforts, controlled drug release systems were introduced, which have many advantages. Using controlled release of the drug in the body, the concentration of the drug is kept at a certain level, and in a short time, it is done at a higher rate. Graphene is a natural material that is biodegradable, non-toxic, and natural compared to carbon nanotubes; its price is lower than carbon nanotubes and is cost-effective for industrialization. On the other hand, the presence of highly effective surfaces and wide surfaces of graphene plates makes it more effective to modify graphene than carbon nanotubes. Graphene oxide is often synthesized using concentrated oxidizers such as sulfuric acid, nitric acid, and potassium permanganate based on Hummer 1 method. In comparison with the initial graphene, the resulting graphene oxide is heavier and has carboxyl, hydroxyl, and epoxy groups. Therefore, graphene oxide is very hydrophilic and easily dissolves in water and creates a stable solution. On the other hand, because the hydroxyl, carboxyl, and epoxy groups created on the surface are highly reactive, they have the ability to work with other functional groups such as amines, esters, polymers, etc. Connect and bring new features to the surface of graphene. In fact, it can be concluded that the creation of hydroxyl groups, Carboxyl, and epoxy and in fact graphene oxidation is the first step and step in creating other functional groups on the surface of graphene. Chitosan is a natural polymer and does not cause toxicity in the body. Due to its chemical structure and having OH and NH groups, it is suitable for binding to graphene oxide and increasing its solubility in aqueous solutions. Graphene oxide (GO) has been modified by chitosan (CS) covalently, developed for control release of doxorubicin (DOX). In this study, GO is produced by the hummer method under acidic conditions. Then, it is chlorinated by oxalyl chloride to increase its reactivity against amine. After that, in the presence of chitosan, the amino reaction was performed to form amide transplantation, and the doxorubicin was connected to the carrier surface by π-π interaction in buffer phosphate. GO, GO-CS, and GO-CS-DOX characterized by FT-IR, RAMAN, TGA, and SEM. The ability to load and release is determined by UV-Visible spectroscopy. The loading result showed a high capacity of DOX absorption (99%) and pH dependence identified as a result of DOX release from GO-CS nanosheet at pH 5.3 and 7.4, which show a fast release rate in acidic conditions.

Keywords: graphene oxide, chitosan, nanosheet, controlled drug release, doxorubicin

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Authors: Rusudan Chagelishvili, Nino Sulava, Tamar Beridze, Nana Rezesidze, Nikoloz Tatuashvili

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The South Caucasus is one of the most important centers of prehistoric metallurgy, known for its Colchian bronze culture. Modern Lechkhumi – historical Mountainous Colchis where the existence of prehistoric metallurgy is confirmed by the discovery of many artifacts is a part of this area. Studies focused on prehistoric smelting sites, related artefacts, and ore deposits have been conducted during last ten years in Lechkhumi. More than 20 prehistoric smelting sites and artefacts associated with metallurgical activities (ore roasting furnaces, slags, crucible, and tuyères fragments) have been identified so far. Within the framework of integrated studies was established that these sites were operating in 13-9 centuries B.C. and used for copper smelting. Palynological studies of slags revealed that chestnut (Castanea sativa) and hornbeam (Carpinus sp.) wood were used as smelting fuel. Geological exploration-analytical studies revealed that copper ore mining, processing, and smelting sites were distributed close to each other. Despite recent complex data, the signs of prehistoric mines (trenches) haven’t been found in this part of the study area so far. Since 2018 the archaeological-geological exploration has been focused on the southern part of Lechkhumi and covered the areas of villages Okureshi and Opitara. Several copper smelting sites (Okureshi 1 and 2, Opitara 1), as well as a Colchian Bronze culture settlement, have been identified here. Three mine workings have been found in the narrow gorge of the river Rtkhmelebisgele in the vicinities of the village Opitara. In order to establish a link between the Opitara-Okureshi archaeometallurgical sites, Late Bronze Age settlements, and mines, various scientific analytical methods -mineralized rock and slags petrography and atomic absorption spectrophotometry (AAS) analysis have been applied. The careful examination of Opitara mine workings revealed that there is a striking difference between the mine #1 on the right bank of the river and mines #2 and #3 on the left bank. The first one has all characteristic features of the Soviet period mine working (e. g. high portal with angular ribs and roof showing signs of blasting). In contrast, mines #2 and #3, which are located very close to each other, have round-shaped portals/entrances, low roofs, and fairly smooth ribs and are filled with thick layers of river sediments and collapsed weathered rock mass. A thorough review of the publications related to prehistoric mine workings revealed some striking similarities between mines #2 and #3 with their worldwide analogues. Apparently, the ore extraction from these mines was conducted by fire-setting applying primitive tools. It was also established that mines are cut in Jurassic mineralized volcanic rocks. Ore minerals (chalcopyrite, pyrite, galena) are related to calcite and quartz veins. The results obtained through the petrochemical and petrography studies of mineralized rock samples from Opitara mines and prehistoric slags are in complete correlation with each other, establishing the direct link between copper mining and smelting within the study area. Acknowledgment: This work was supported by the Shota Rustaveli National Science Foundation of Georgia (grant # FR-19-13022).

Keywords: archaeometallurgy, Mountainous Colchis, mining, ore minerals

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Authors: Martin Cvek, Miroslav Mrlik, Michal Sedlacik, Tomas Plachy

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Magnetorheological elastomers (MREs) are multi-phase composite materials containing micron-sized ferromagnetic particles dispersed in an elastomeric matrix. Their properties such as modulus, damping, magneto-striction, and electrical conductivity can be controlled by an external magnetic field and/or pressure. These features of the MREs are used in the development of damping devices, shock attenuators, artificial muscles, sensors or active elements of electric circuits. However, imperfections on the particle/matrix interfaces result in the lower performance of the MREs when compared with theoretical values. Moreover, magnetic particles are susceptible to corrosion agents such as acid rains or sea humidity. Therefore, the modification of particles is an effective tool for the improvement of MRE performance due to enhanced compatibility between particles and matrix as well as improvements of their thermo-oxidation and chemical stability. In this study, the carbonyl iron (CI) particles were controllably modified with poly(trimethylsilyloxyethyl methacrylate) (PHEMATMS) nano-grafts to develop magnetic core–shell structures exhibiting proper wetting with various elastomeric matrices resulting in improved performance within a frame of rheological, magneto-piezoresistance, pressure-piezoresistance, or radio-absorbing properties. The desired molecular weight of PHEMATMS nano-grafts was precisely tailored using surface-initiated atom transfer radical polymerization (ATRP). The CI particles were firstly functionalized using a 3-aminopropyltriethoxysilane agent, followed by esterification reaction with α-bromoisobutyryl bromide. The ATRP was performed in the anisole medium using ethyl α-bromoisobutyrate as a macroinitiator, N, N´, N´´, N´´-pentamethyldiethylenetriamine as a ligand, and copper bromide as an initiator. To explore the effect PHEMATMS molecular weights on final properties, two variants of core-shell structures with different nano-graft lengths were synthesized, while the reaction kinetics were designed through proper reactant feed ratios and polymerization times. The PHEMATMS nano-grafts were characterized by nuclear magnetic resonance and gel permeation chromatography proving information to their monomer conversions, molecular chain lengths, and low polydispersity indexes (1.28 and 1.35) as the results of the executed ATRP. The successful modifications were confirmed via Fourier transform infrared- and energy-dispersive spectroscopies while expected wavenumber outputs and element presences, respectively, of constituted PHEMATMS nano-grafts, were occurring in the spectra. The surface morphology of bare CI and their PHEMATMS-grafted analogues was further studied by scanning electron microscopy, and the thicknesses of grafted polymeric layers were directly observed by transmission electron microscopy. The contact angles as a measure of particle/matrix compatibility were investigated employing the static sessile drop method. The PHEMATMS nano-grafts enhanced compatibility of hydrophilic CI with low-surface-energy hydrophobic polymer matrix in terms of their wettability and dispersibility in an elastomeric matrix. Thus, the presence of possible defects at the particle/matrix interface is reduced, and higher performance of modified MREs is expected.

Keywords: atom transfer radical polymerization, core-shell, particle modification, wettability

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Authors: Agnieszka E. Laudy, Karolina Stępien, Sergiusz Lulinski, Krzysztof Durka, Stefan Tyski

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1,3-dihydro-1-hydroxy-2,1-benzoxaborole and its derivatives are a particularly interesting group of synthetic agents and were successfully employed in supramolecular chemistry medicine. The first important compounds, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole and 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole were identified as potent antifungal agents. In contrast, (S)-3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole hydrochloride is in the second phase of clinical trials as a drug for the treatment of Gram-negative bacterial infections of the Enterobacteriaceae family and Pseudomonas aeruginosa. Equally important and difficult task is to search for compounds active against Gram-negative bacilli, which have multi-drug-resistance efflux pumps actively removing many of the antibiotics from bacterial cells. We have examined whether halogen-substituted benzoxaborole-based derivatives and their analogues possess antibacterial activity and are substrates for multi-drug-resistance efflux pumps. The antibacterial activity of 1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-benzosiloxaborole and 10 halogen-substituted its derivatives, as well as 1,2-phenylenediboronic acid and 3 synthesised fluoro-substituted its analogs, were evaluated. The activity against the reference strains of Gram-positive (n=5) and Gram-negative bacteria (n=10) was screened by the disc-diffusion test (0.4 mg of tested compounds was applied onto paper disc). The minimal inhibitory concentration values and the minimal bactericidal concentration values were estimated according to The Clinical and Laboratory Standards Institute and The European Committee on Antimicrobial Susceptibility Testing recommendations. During the minimal inhibitory concentration values determination with or without phenylalanine-arginine beta-naphthylamide (50 mg/L) efflux pump inhibitor, the concentrations of tested compounds ranged 0.39-400 mg/L in the broth medium supplemented with 1 mM magnesium sulfate. Generally, the studied benzosiloxaboroles and benzoxadiboroles showed a higher activity against Gram-positive cocci than against Gram-negative rods. Moreover, benzosiloxaboroles have the higher activity than benzoxadiboroles compounds. In this study, we demonstrated that substitution (mono-, di- or tetra-) of 1,3-dihydro-3-hydroxy-1,1-dimethyl-1,2,3-benzosiloxaborole with halogen groups resulted in an increase in antimicrobial activity as compared to the parent substance. Interestingly, the 6,7-dichloro-substituted parent substance was found to be the most potent against Gram-positive cocci: Staphylococcus sp. (minimal inhibitory concentration 6.25 mg/L) and Enterococcus sp. (minimal inhibitory concentration 25 mg/L). On the other hand, mono- and dichloro-substituted compounds were the most actively removed by efflux pumps present in Gram-negative bacteria mainly from Enterobacteriaceae family. In the presence of efflux pump inhibitor the minimal inhibitory concentration values of chloro-substituted benzosiloxaboroles decreased from 400 mg/L to 3.12 mg/L. Of note, the highest increase in bacterial susceptibility to tested compounds in the presence of phenylalanine-arginine beta-naphthylamide was observed for 6-chloro-, 6,7-dichloro- and 6,7-difluoro-substituted benzosiloxaboroles. In the case of Escherichia coli, Enterobacter cloacae and P. aeruginosa strains at least a 32-fold decrease in the minimal inhibitory concentration values of these agents were observed. These data demonstrate structure-activity relationships of the tested derivatives and highlight the need for further search for benzoxaboroles and related compounds with significant antimicrobial properties. Moreover, the influence of phenylalanine-arginine beta-naphthylamide on the susceptibility of Gram-negative rods to studied benzosiloxaboroles indicate that some tested agents are substrates for efflux pumps in Gram-negative rods.

Keywords: antibacterial activity, benzosiloxaboroles, efflux pumps, phenylalanine-arginine beta-naphthylamide

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