Synthesis of some novel pyrazolo[1,5‐a]pyrimidine, 1,2,4‐triazolo[1,5‐a]pyrimidine,pyrido[2,3‐d]pyrimidine,pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives incorporating a thiazolo[3,2‐a]benzimidazole moiety

E‐3‐(N,N‐Dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 2 ) was synthesized by the reaction of 1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)ethanone ( 1 ) with dimethylformamide‐dimethylacetal. The reaction of 2 with 5‐amino‐3‐phenyl‐1H‐pyrazole ( 4a ) or 3‐amino‐1,2,4‐(1H)‐triazole ( 4b ) furnished pyrazolo[1,5‐a]pyrimidine and 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives 6a and 6b , while the reaction of enaminone 2 with 6‐aminopyrimidine derivatives 7a,b afforded pyrido[2,3‐d]pyrimidine derivatives 9a,b , respectively. The diazonium salts 11a or 11b coupled with compound 2 to yield the pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives 13a and 13b . Some of the newly synthesized compounds exhibited a moderate effect against some bacterial and fungal species.     

Microcantilever sensing and actuation with end-grafted stimulus-responsive elastin-like polypeptides

Stimulus-responsive elastin-like polypeptides (ELPs) grafted onto surfaces are of significant technical interest because they can be exploited for force generation, in sensing applications, or as molecular switches with tunable properties. Changes in the conformational state of grafted ELPs, induced by a phase transition or changes in osmotic pressure, lead to significant changes in the surface stress in the ELP graft layer and translate into detectable changes in microcantilever deflection. In this study, we investigate the conformational mechanics of ELPs in response to changes in solution pH and ionic strength using atomic force microscopy (AFM) microcantilever deflection and quartz crystal microbalance (QCM) measurements. We show that the use of genetically encoded, surface-grafted ELPs is exciting for cantilever actuation and sensing because commonly available microfabricated cantilever springs offer a simple and nonintrusive way to detect changes in solvent type, temperature, and pH, promising great potential for sensing applications in microfluidic devices.     

Determination of 2-methoxyestradiol in human plasma, using liquid chromatography/tandem mass spectrometry

A liquid chromatography/tandem mass spectrometric (LC/MS/MS) assay was developed for the quantitative determination of 2-methoxyestradiol (2ME2) in human plasma. Sample pretreatment involved liquid-liquid extraction with ethyl acetate of 0.3-mL aliquots of plasma spiked with the internal standard, deuterated 2ME2 (2ME2-d5). Separation was achieved on a Zorbax Eclipse C18 column (2.1 x 50 mm, i.d., 5 microm) at room temperature using a gradient elution with methanol and water at a flow rate of 0.25 mL/min. Detection was performed using atmospheric pressure chemical ionization MS/MS by monitoring the ion transitions from m/z 303.1 --> 136.8 (2ME2) and m/z 308.1 --> 138.8 (2ME2-d5). Calibration curves were linear in the concentration range of 1-100 ng/mL. The accuracy and precision values, obtained from three different sets of quality control samples analyzed in quintuplicate on four separate occasions, ranged from 105-108% and from 3.62-5.68%, respectively. This assay was subsequently used for the determination of 2ME2 concentration in plasma of a patient with cancer after a single oral administration of 2ME2 at a dose of 2200 mg.     

5‐Phenyl‐1,3,4‐oxadiazole‐2‐thiol/polyamide‐montmorillonite microbicides nanocomposites as drug delivery system

The preparation and structural characterization of polymeric microbicides consisting of 5‐phenyl‐1,3,4‐oxadiazole‐2‐thiol covalently bound to polyamide based on diethyl‐2,3‐dihydroxysuccinate and polyoxypropylenetriamine Jeffamine (T₄₀₃) are described. Two different mole ratios of 5‐phenyl‐1,3,4‐oxadiazole‐2‐thiol was reacted with chloroacetylated diethyl‐2,3‐dihydroxysuccinate followed by polycondensation with Jeffamine (T₄₀₃). The nanocomposites were prepared by modification of microbicide polyamides to yield polymers with phosphonium salt or amine hydrochloride salt followed by ion exchange process between the phosphonium salt or amine hydrochloride of the polyamides and the intermellar sodium cation of the clay mineral montmorillonite. The monomers were characterized by mass spectrum, proton nuclear magnetic resonance. The polymers showed good or moderate antimicrobial activities. Nanocomposites were characterized by Fourier transformed infrared spectroscopy, X‐ray diffraction, thermal gravimetric analysis, and transmission electron microscope. The swelling behavior and release of 5‐phenyl‐1,3,4‐oxadiazole‐2‐thiol in different pH values (2.3, 5.8, and 7.4) were studied. A slow release, ranging from 12% to 28% after 50 hours was recorded from nanocomposites. However, the release profile reached almost 70% from polyamides. The antimicrobial activity of the polyamides was studied against gram‐negative bacteria, gram‐positive bacteria, yeast, and the filamentous fungi by well diffusion method. The polyamides showed better antimicrobial activities than 5‐phenyl‐1,3,4‐oxadiazole‐2‐thiol.     

The regioselectivity in the formation of pyrazolines and pyrazoles from nitrile imines

The 1,3-cycloaddition of the nitrile imines 2a-e to the carbon-carbon double bond in benzalacetophenone leads to the formation of 4-phenyl-5-benzoylpyrazolines 3a-e which were converted into 4-phenyl-5-benzoylpyrazoles 5a-e upon treatment with chloranil in xylene. However, the cycloaddition of 2a-e to the carbon-carbon double bond in the enol tautomer of dibenzoylmethane gives the regioisomers 5-phenyl-5-hydroxy-4-benzoylpyrazolines which loose elements of water to yield 4-benzoyl-5-phenylpyrazoles 6a-e . The orientations in these reactions are interpretted in terms of the Frontier Molecular Orbital theory. The structures of the products 3 , 5 and 6 were substantiated by their chemical reactions and alternate synthesis wherever possible.     

Specific and nonspecific interaction forces between Escherichia coli and silicon nitride, determined by poisson statistical analysis

The nature of the physical interactions between Escherichia coli JM109 and a model surface (silicon nitride) was investigated in water via atomic force microscopy (AFM). AFM force measurements on bacteria can represent the combined effects of van der Waals and electrostatic forces, hydrogen bonding, steric interactions, and perhaps ligand-receptor type bonds. It can be difficult to decouple these forces into their individual components since both specific (chemical or short-range forces such as hydrogen bonding) and nonspecific (long-range colloidal) forces may be present in the overall profiles. An analysis is presented based on the application of Poisson statistics to AFM adhesion data, to decouple the specific and nonspecific interactions. Comparisons with classical DLVO theory and a modified form of a van der Waals expression for rough surfaces were made in order to help explain the nature of the interactions. The only specific forces in the system were due to hydrogen bonding, which from the Poisson analysis were found to be -0.125 nN. The nonspecific forces of 0.155 nN represent an overall repulsive interaction. These nonspecific forces are comparable to the forces calculated from DLVO theory, in which electrostatic-double layer interactions are added to van der Waals attractions calculated at the distance of closest approach, as long as the van der Waals model for "rough" spherical surfaces is used. Calculated electrostatic-double layer and van der Waals interactions summed to 0.116 nN. In contrast, if the classic (i.e., smooth) sphere-sphere model was used to predict the van der Waals forces, the sum of electrostatic and van der Waals forces was -7.11 nN, which appears to be a large overprediction. The Poisson statistical analysis of adhesion forces may be very useful in applications of bacterial adhesion, because it represents an easy way to determine the magnitude of hydrogen bonding in a given system and it allows the fundamental forces to be easily broken into their components.     

Tungsten Oxide Nanoplates; the Novelty in Targeting Metalloproteinase-7 Gene in Both Cervix and Colon Cancer Cells

In this study, we synthesized tungsten oxide (WO₃) nanoplates, both crystallographic phases and the morphology of the samples were determined by powder x-ray diffraction and the scanning electron microscopy, respectively. The obtained data clarified that, the all prepared WO₃·H₂O samples were composed of large quantity of nanoplates. The cytotoxicity patterns of nanoplates were checked on both normal and cancer mammalian cell lines. Both nanoplates cytotoxicity did not exceed the 50 % inhibitory concentration (IC50) on the all normal tested cells even by using concentrations up to 1 mg/ml. In addition, orthorhombic tungsten oxide nanoplate was more potent against both Caco2 and Hela cells by showing inhibition percentages in cellular viability 64.749 and 72.27, respectively, and with cancer selectivity index reached 3.2 and 2.6 on both colon and cervix cancer, respectively. The anticancer effects of nanoplates were translated to alteration in both pro-apoptotic and anti-apoptotic genes expressions. Tungsten oxide nanoplates down regulated the expression of B cell lymphoma 2 (Bcl-2) and metalloproteinase-7 (MMP7) genes. In addition, orthorhombic tungsten oxide nanoplates showed more potentiation in IL2 and IL8 induction (40.43 pg/ml) and upregulation of TNF-α gene expression but with lower folds than Escherichia coli lipopolysaccharide (LPS) induction.     

Chemometric Investigation and Antimicrobial Activity of Salvia rosmarinus Spenn Essential Oils

To ensure the better production and sustainable management of natural resources, a chemometric investigation was conducted to examine the effect of cooperative and harvesting periods on the crop yields and chemical compositions of Salvia rosmarinus Spenn essential oils in the Oriental region of Morocco. The samples were collected from three cooperatives over nine time periods from January 2018 to April 2019. The chemical composition of Salvia rosmarinus Spenn essential oils was analyzed by gas chromatography coupled with mass spectrometry. The data from this study were processed by multivariate analyses, including principal component analysis (PCA) and hierarchical cluster analysis (HCA). The disc diffusion technique and a determination of the minimal inhibitory concentration were performed to study the antibacterial properties of the oils. Statistical analysis showed that the cooperative and harvest period have a significant effect on yields. The highest yield of essential oil was recorded in April 2019 at cooperative C1. The PCA and the HCA results were divided into two groups: Group A for the summer season and group B for the winter season. The samples collected during summer were characterized by a high amount of 1,8-cineole component and a high yield of essential oil, whereas the samples collected during winter were qualified by a high amount of α-pinene component and a low yield of essential oil. The antibacterial activity of Salvia rosmarinus Spenn essential oils showed that Mycobacterium smegmatis ATCC23857 and Bacillus subtilis ATCC 23857 are the most susceptible strains, stopping growth at 1/500 (v/v). The least susceptible strain is Escherichia coli ATCC25922, with an MIC value corresponding to 1/250 (v/v). The findings of this study could have a positive economic impact on the exploitation of rosemary in the Oriental region, especially during the best harvest periods, as they indicate how to obtain the best yields of oils richest in 1,8-cineole and α-pinene chemotypes.     

Synthesis and reactions of indane‐1,3‐dione‐2‐thiocarboxanilides with hydrazonoyl halides and active chloromethylene compounds

A novel synthesis of thiadiazoline derivatives 12 and 14 via treatment of indane‐1,3‐dione‐2‐thiocarboxanilides ( 5 ) with hydrazonoyl halides 1 and 2 is reported. Also, active chloromethylene compounds 15 react with 5 to give thiazole derivatives 19 . © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:585–591, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10132     

Nanogold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets,HO-1 and γ-GCS

The development of the field of nanotechnology has revolutionized various aspects in the fields of modern sciences. Nano-medicine is one of the primary fields for the application of nanotechnology techniques. The current study sheds light on the reno-protective impacts of gold nano-particles; nanogold (AuNPs) against 5-flurouracil (5-FU)-induced renal toxicity. Indeed, the use of 5-FU has been associated with kidney injury which greatly curbs its therapeutic application. In the current study, 5-FU injection was associated with a significant escalation in the indices of renal injury, i.e., creatinine and urea. Alongside this, histopathological and ultra-histopathological changes confirmed the onset of renal injury. Both gene and/or protein expression of nuclear factor erythroid 2–related factor 2 (Nrf-2) and downstream antioxidant enzymes revealed consistent paralleled anomalies. AuNPs administration induced a significant renal protection on functional, biochemical, and structural levels. Renal expression of the major sensor of the cellular oxidative status Nrf-2 escalated with a paralleled reduction in the renal expression of the other contributor to this axis, known as Kelch-like ECH-associated protein 1 (Keap-1). On the level of the effector downstream targets, heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (γ-GCS) AuNPs significantly restored their gene and protein expression. Additionally, combination of AuNPs with 5-FU showed better cytotoxic effect on MCF-7 cells compared to monotreatments. Thus, it can be inferred that AuNPs conferred reno-protective impact against 5-FU with an evident modulatory impact on Nrf-2/Keap-1 and its downstream effectors, HO-1 and γ-GCS, suggesting its potential use in 5-FU regimens to improve its therapeutic outcomes and minimize its underlying nephrotoxicity.