Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A–H). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC50 of the tested compounds revealed series B, D, E and G with nanomolar range of IC50 values (6.00–81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC50 = 18.13–41.41 nM). Compound 11b (series G, oxadiazole-based derivatives with terminal 4-NO2 substituted phenyl ring and rigid linker) was the most potent analogue with IC50 value of 18.13 nM. Structure–activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound (11b). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation

Colorimetric Method for Determination of some 1,4-Dihydropyridine Drugs in their Tablets and Capsules

A simple, accurate and selective colorimetric method was developed and validated for determination of five 1,4-dihydropyridine drugs (1,4-DHP) using Tetrabutylammonium hydroxide reagent (TBAH). The proposed method was based on addition of TBAH to the studied drugs then produced yellow colors were measured spectrophotometrically. Different variables affecting the reactions conditions carefully studied and optimized and under the optimum conditions, Beer's law was obeyed in the concentration range of 2.50-40.0 µg/mL and the limits of detection were ranged from 0.750-1.956 µg/mL. The proposed method was successfully extended to pharmaceutical preparations tablets or capsules and the results which obtained were comparable with that obtained by the reference methods

Self-ratiometric fluorescence approach based on plant extract-assisted synthesized silver nanoparticles for the determination of vanillin

The current study designed and applied a novel self-ratiometric fuorescent nanosensor composed of green-synthesized silver nanoparticles (Ag-NPs) to determine vanillin in adult and infant foods and human plasma. A straightforward microwaveassisted approach is proposed for synthesizing Ag-NPs in less than 1 min using a reducing agent, tailed pepper seed extract. The synthesized Ag-NPs had a strong fuorescence with an intense emission band at 360 nm and a shoulder peak at 430 nm when excited at 265 nm. Upon interaction with vanillin, the fuorescence peak of Ag-NPs at 360 nm decreases in a concentration-dependent manner while being shifted to a longer wavelength, 385 nm. Meanwhile, the shoulder fuorescence peak at 430 nm is only slightly afected by vanillin addition. Thus, a new Ag-NP self-ratiometric probe was designed and validated for vanillin determination using the peak at 385 nm and the shoulder peak at 430 as two built-in reference peaks. The optimized system accurately measured vanillin with a detection limit of 9.0 ng/mL and a linear range of 0.05–8.0 μg/ mL without needing pre-derivatization or high-cost instrumentation. The method successfully measured vanillin in adult and infant milk formula, biscuits, and human plasma samples with high percentage recoveries (95.3–104.6%) and excellent precision (relative SD; ≤3.85%).Microchimica Acta, 191(1), art. no. 16; 202

Flow Injection Sensing Strategy for Determining Cationic Surfactants in Commodity and Water Samples

The formation of stable binary water-soluble sub-micellar aggregates of cetyltrimethylammonium bromide-copper-pyrocatechol violet complex (CTAB-Cu-PCV) diminishes the stability and absorbance of the Cu-PCV complex. A new flow injection spectrophotometric sensing strategy used for the determination of CTAB in commodity personal care antiseptics and water samples has been established relying on the above-mentioned concept. Based on the reduction of the absorption of the Cu-PCV solution by the injection of CTAB solution at pH 6.0 and 430 nm, a linear absorbance decrease was observed over the CTAB concentration range of 2.0 to 100.0 µg mL−1 (r = 0.987). The analysis method showed limits of detection (3.3 ơ) and quantification (10 ơ) of 0.08 and 0.27 µg mL−1, respectively. The precision (RSD) for five replicate determinations was 7.9 and 3.7% at 10 and 50 µg mL−1, respectively. The developed method was applied successfully to the determination of CTAB in personal care products, namely skin lotion and vaginal wash, in addition to water samples. The corresponding RSD (n = 5) values were ≤8.2%

Sustainable PVP-Capped Silver Nanoparticles as a Free-Standing Nanozyme Sensor for Visual and Spectrophotometric Detection of Hg2+ in Water Samples: A Green Analytical Method

In the proposed method, microwave-assist heating and AgNO3/trisodium citrate were used to create the polyvinylpyrrolidone-capped silver nanoparticles (PVP-AgNPs) sensor. This sensor had a peroxidase-like activity that could catalytically oxidize O-phenylenediamine (OPD, colourless) into 2,3-diaminophenazine (ox-OPD, greenish-yellow colour) in the presence of H2O2, otherwise, in the presence of Hg2+, this pass has been effectively inhibited. The degree of colour fading was directly correlated with Hg2+ concentration. These results indicated the selectivity of Hg2+ ions toward PVP-AgNPs after establishing the PVP-AgNPs/OPD/H2O2 system. This selectivity was proved by the negative results obtained from other mon-, di-, and trivalent ions such as Na+, K+, Ca2+, Mg2+, Ba2+, Co2+, Ni2+, Cd2+, and Cr3+, instead of Hg2+. Consequently, a reliable, selective, and eco-effective spectrophotometric approach was designed for the detection of Hg2+ in various types of water samples. LOD was extended to lower than 0.1 µM, and a fading in the obtained colour was shown by the naked eye at a concentration higher than 1.5 µM of Hg2+. The elemental details for preparing the used PVP-AgNPs, such as particle size, morphology, polydispersity index (PdI), and their UV-visible spectrum, were identified by SEM technique, TEM, UV-visible spectrophotometer, and zeta-sizer device. Thus, the peroxidase mimicking the activity of OPD/H2O2 was confirmed by a fluorescence technique. The greenness profile of this work was confirmed after applying a reported assessment tool

Sustainable PVP-Capped Silver Nanoparticles as a Free-Standing Nanozyme Sensor for Visual and Spectrophotometric Detection of Hg²⁺ in Water Samples: A Green Analytical Method

In the proposed method, microwave-assist heating and AgNO3/trisodium citrate were used to create the polyvinylpyrrolidone-capped silver nanoparticles (PVP-AgNPs) sensor. This sensor had a peroxidase-like activity that could catalytically oxidize O-phenylenediamine (OPD, colourless) into 2,3-diaminophenazine (ox-OPD, greenish-yellow colour) in the presence of H2O2, otherwise, in the presence of Hg2+, this pass has been effectively inhibited. The degree of colour fading was directly correlated with Hg2+ concentration. These results indicated the selectivity of Hg2+ ions toward PVP-AgNPs after establishing the PVP-AgNPs/OPD/H2O2 system. This selectivity was proved by the negative results obtained from other mon-, di-, and trivalent ions such as Na+, K+, Ca2+, Mg2+, Ba2+, Co2+, Ni2+, Cd2+, and Cr3+, instead of Hg2+. Consequently, a reliable, selective, and eco-effective spectrophotometric approach was designed for the detection of Hg2+ in various types of water samples. LOD was extended to lower than 0.1 µM, and a fading in the obtained colour was shown by the naked eye at a concentration higher than 1.5 µM of Hg2+. The elemental details for preparing the used PVP-AgNPs, such as particle size, morphology, polydispersity index (PdI), and their UV-visible spectrum, were identified by SEM technique, TEM, UV-visible spectrophotometer, and zeta-sizer device. Thus, the peroxidase mimicking the activity of OPD/H2O2 was confirmed by a fluorescence technique. The greenness profile of this work was confirmed after applying a reported assessment tool

Green Bio-Analytical Study of Gabapentin in Human Plasma Coupled with Pharmacokinetic and Bioequivalence Assessment Using UPLC-MS/MS

Gabapentin (GAB) is a cyclohexane acetic acid, structurally related to the neurotransmitter gamma-aminobutyric acid (GABA), and considered the principal inhibitory neurotransmitter in the central nervous system (CNS) of mammals. An ultra-performance liquid chromatography–tandem mass spectrophotometry (UPLC-MS/MS) method for assessing pregabalin (PRE) in human plasma, was developed and validated, via PRE usage as an internal standard. The plasma underwent protein precipitation using methanol, prior to analysis. Chromatographic separation was completed using a mobile phase of methanol: 0.1% formic acid solution, (65:35, v/v), at a flow rate of 0.2 mL/min, with an isocratic approach, on an Agilent Eclipse plus column (50 × 2.1 mm and 1.8 μm), in 1.6 min of running time. An Agilent triple quadrupole was used for mass analysis, to detect the ion transitions for GAB and PER, respectively, at m/z of 172.1 → 154.1 and 160.10 → 142.10. The calibration curve, over the linear range of 0.050–10.0 μg/mL, showed a high correlation coefficient, r = 0.9993. The limits of detection and quantitation were 13.37 ng/mL and 40.52 ng/mL, respectively, based on the standard deviation and slope equation. The results for intra- and inter-day measurement accuracy and precision were in acceptable ranges. The method was extended into the assessment of oral administrations of GAB at different doses, of one 600 mg/tablet and two capsules (each one of them has 300 mg of GAB), to volunteers who were used in pharmacokinetics and bioequivalent studies. The AGREE assessment tool was used to visualize the proposed method’s greenness degree, which revealed a high AGREE rating score, supporting the accepted method’s greenness profile