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The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1 H -pyrazolo[3,4- c ]pyridazin-3-amine ( 4 ) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4 . Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4- c ]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

All-solid-state potentiometric sensors have attracted great attention over other types of potentiometric sensors due to their outstanding properties such as enhanced portability, simplicity of handling, affordability and flexibility. Herein, a novel solid-contact ion-selective electrode (SC-ISE) based on poly(3,4-ethylenedioxythiophene) (PEDOT) as the ion-to-electron transducer was designed and characterized for rapid detection of harmine. The harmine-sensing membrane was based on the use of synthesized imprinted bio-mimics as a selective material for this recognition. The imprinted receptors were synthesized using acrylamide (AA) and ethylene glycol dimethacrylate (EGDMA) as functional monomer and cross-linker, respectively. The polymerization process was carried out at 70 °C in the presence of dibenzoyl peroxide (DBO) as an initiator. The sensing membrane in addition to the solid-contact layer was applied to a glassy-carbon disc as an electronic conductor. All performance characteristics of the presented electrode in terms of linearity, detection limit, pH range, response time and selectivity were evaluated. The sensor revealed a wide linearity over the range 2.0 × 10 -7 -1.0 × 10 -2 M, with a detection limit of 0.02 µg/mL and a sensitivity slope of 59.2 ± 0.8 mV/hamine concentration decade. A 40 mM Britton-Robinson (BR) buffer solution at pH of 6 was used for all harmine measurements. The electrode showed good selectivity towards harmine over other common interfering ions, and maintained a stable electrochemical response over two weeks. After applying the validation requirements, the proposed method revealed good performance characteristics. Method precision, accuracy, bias, trueness, repeatability, reproducibility, and uncertainty were also evaluated. These analytical capabilities support the fast and direct assessment of harmine in different urine specimens. The analytical results were compared with the standard liquid chromatographic method. The results obtained demonstrated that PEDOT/PSS was a promising solid-contact ion-to-electron transducer material in the development of harmine-ISE. The electrodes manifested enhanced stability and low cost, which provides a wide number of potential applications for pharmaceutical and forensic analysis.

A simple, rapid, sensitive, and precise reversed-phase liquid chromatographic method was developed and validated for the simultaneous determination of four direct-acting antivirals, sofosbuvir (SF), ledipasvir (LD), declatasvir (DC), and simeprevir (SM), in their respective pharmaceutical formulations. Effective chromatographic separation was achieved on an Agilent Eclipse plus C8 column (250 mm × 4.6 mm, 5 µm) at 40 °C with gradient elution using a mobile phase composed of acetonitrile:phosphate buffer (pH 6.5). The quantification of SF and DC was based on peak area measurements at 260 nm, while the quantification of LD and SM was achieved at 330 nm. The linearity was acceptable from 1.0 to 20.0 μg/mL for the studied drugs, with correlation coefficients >0.999. The analytical performance of the newly proposed HPLC procedure was thoroughly validated according to ICH guidelines in terms of linearity, precision (RSD%, 0.39-1.57), accuracy (98.05-101.90%), specificity, limit of detection (LOD) (0.022-0.039 μg/mL), limit of quantification (LOQ) (0.067-0.118 μg/mL), and robustness. The validated HPLC method was successfully used to analyze the abovementioned drugs in their pure and dosage forms without interference from common excipients present in commercial formulations.

Herein, a novel validated potentiometric method is presented for the first time for citicoline determination. The method is based on measuring the potential using new constructed citicoline electrodes. The electrodes are based on the use of citicolinium/phosphomolybdate [Cit] 2 [PM] (sensor I) and citicolinium/tetraphenylborate [Cit][TPB] (sensor II) ion association complexes. These sensory materials were dispersed in plasticized polyvinyl chloride (PVC) polymeric membranes. The sensors revealed a Nernstian response with the slopes 55.9 ± 1.8( r 2 = 0.9994) and 51.8 ± 0.9 ( r 2 = 0.9991) mV/decade over a linearity range of 6.3 × 10 -6 -1.0 × 10 -3 and 1.0 × 10 -5 -1.0 × 10 -3 M and detection limits of 3.16 × 10 -6 and 7.1 × 10 -6 M for sensors I and II, respectively. To ensure the existence of monovalent citicoline, all measurements were performed in 50 mM acetate buffer at pH 3.5. All presented electrodes showed good performance characteristics such as rapid response, good selectivity, high potential-stability and long life-span. Method verification and validation in terms of response linearity, quantification limit, accuracy, bias, trueness, robustness, within-day variability and between-days variability were evaluated. The method was introduced for citicoline determination in different pharmaceutical formulations and compared with the standard high performance liquid chromatography (HPLC) method.

A simple potentiometric sensor is described for accurate, precise, and rapid determination of sulfite additives in beverages. The sensor is based on the use of cobalt phthalocyanine as a recognition material, dispersed in a plasticized poly(vinyl chloride) matrix membrane. o -Nitrophenyl octyl ether ( o -NPOE) as a membrane solvent and tri-dodecylmethyl- ammonium chloride (TDMAC) as ion discriminators are used as membrane additives. Under the optimized conditions, sulfite ion is accurately and precisely measured under batch and flow injection modes of analysis. The sensor exhibits fast and linear response for 1.0 × 10 -2 -1.0 × 10 -6 M (800-0.08 µg/mL) and 1.0 × 10 -1 -5.0 × 10 -5 M (8000-4 µg/mL) sulfite with Nernstian slopes of -27.4 ± 0.3 and -23.7 ± 0.6 mV/concentration decade under static and hydrodynamic modes of operation, respectively. Results in good agreement with the standard iodometric method are obtained.Validation of the assay method is examined in details including precision, accuracy, bias, trueness, repeatability, reproducibility, and uncertainty and good performance characteristics of the method are obtained. The sensor response is stable over the pH range of 5 to 7 without any significant interference from most common anions. The advantages offered by the proposed sensor (i.e., wide range of assay, high accuracy and precision, low detection limit, reasonable selectivity, long term response stability, fast response, and long life span and absence of any sample pretreatment steps) suggest its use in the quality control/quality assurance routine tests in beverages industries, toxicological laboratories and by inspection authorities.

To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties 2-13 was designed and synthesized and their biological activities were evaluated. Compounds 7a , 7b and 8 exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal Aspergillus flavus with minimum inhibitory concentration (MIC) values ranged from 0.95 ± 0.22 to 3.25 ± 1.00 μg/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds 7a and 7b were the most potent with IC 50 values of 10.17 ± 0.65 and 11.59 ± 0.59 μM, respectively. On the other hand, the tested compounds were less toxic against normal kidney epithelial cell lines (Vero cells). The in vitro enzyme inhibition assay of 8 displayed excellent inhibitory activity against Escherichia coli DNA B gyrase and moderate one against E. coli Topoisomerase IV (IC 50 = 0.33 ± 1.25 and 19.72 ± 1.00 µM, respectively) in comparison with novobiocin (IC 50 values 0.28 ± 1.45 and 10.65 ± 1.02 µM, respectively). Finally, the molecular docking was done to position compound 8 into the E. coli DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound 8 may serve as a potential dual E. coli DNA B and Topoisomerase IV inhibitor.

Copper ferrite nano-particles (CuFe 2 O 4 ) were synthesized, characterized, modified with polyaniline to form CuFe 2 O 4 /PANI nano-composite. They were used as new adsorbents for the removal of the hazardous mercuric ions from aqueous solutions. High resolution transmission electron microscope (HR-TEM), X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) and Brunauer-Emmett-Teller (BET) were used for the characterization of the synthesized CuFe 2 O 4 nano-particles (NPs) in presence and absence of PANI nano-composite. The synthesized CuFe 2 O 4 NPs were of spherical shape with an average size of 10.8 nm. XRD analysis displayed crystal peaks for CuFe 2 O 4 NPs and amorphous peaks CuFe 2 O 4 /PANI nano-composite due to the existence of polyaniline layer. Contact time, adsorbent dose, solution pH, adsorption kinetics, adsorption isotherm and recyclability were studied. The method at the optimum conditions exhibited high performance with high mercury removal percentage of up to 99% with a maximum adsorption capacity 12.5 and 157.1 mg/g for CuFe 2 O 4 and CuFe 2 O 4 /PANI, respectively. The adsorption processes were fitted to Langmuir isotherms. The adsorption behavior of CuFe 2 O 4 @PANI composite towards Hg 2+ ions is attributed to the soft acid-soft base strong interaction between PANI and Hg(II) ions. High stability and enhanced re-usability are offered using CuFe 2 O 4 @PANI composite due to its enhanced removal efficiency. No significant removal decrease was noticed after five adsorption-desorption cycles. In addition, it possesses an easy removal from aqueous solutions by external magnetic field after adsorption experiments. These indicated the enhancement of polyaniline to the surface of CuFe 2 O 4 toward the adsorption of mercury from aqueous solutions.

A facile eco-friendly approach for acetampirid pesticide removal is presented. The method is based on the use of micro- and mesoporous activated carbon (TPAC) as a natural adsorbent. TPAC was synthesized via chemical treatment of tangerine peels with phosphoric acid. The prepared activated carbon was characterized before and after the adsorption process using Fourier- transform infrared (FTIR), X-ray diffraction (XRD), particle size and surface area. The effects of various parameters on the adsorption of acetampirid including adsorbent dose (0.02-0.2 g), pH 2-8, initial adsorbate concentration (10-100 mg/L), contact time (10-300 min) and temperature (25-50 °C) were studied. Batch adsorption features were evaluated using Langmuir and Freundlich isotherms. The adsorption process followed the Langmuir isotherm model with a maximum adsorption capacity of 35.7 mg/g and an equilibration time within 240 min. The adsorption kinetics of acetamiprid was fitted to the pseudo-second-order kinetics model. From the thermodynamics perspective, the adsorption was found to be exothermic and spontaneous in nature. TPAC was successfully regenerated and reused for three consecutive cycles. The results of the presented study show that TPAC may be used as an effective eco-friendly, low cost and highly efficient adsorbent for the removal of acetamiprid pesticides from aqueous solutions.

As important cancer therapeutic agents, macrocyclic peptides have recently drawn great attention, mainly because they are synthetically accessible and have lower toxicity towards normal cells. In the present work, we synthesized newly macrocyclic pyridoheptapeptide derivatives. The synthesized derivatives were characterized using standard chemical and spectroscopic analytical techniques, and their anticancer activities against human breast and hepatocellular cancer cells were investigated. Results showed that compounds 1a and 1b were the most effective against hepatocellular (HepG2) and breast (MCF-7) cancer cell lines, respectively.

A series of branched tetrapeptide Schiff bases 3 - 6 were designed and synthesized from corresponding tetrapeptide hydrazide 2 as a starting material.In vitroevaluation of the synthesized compounds 4 - 6 against breast MCF-7 carcinoma cells identified their excellent anticancer potency, with IC 50 ranging from 8.12 ± 0.14 to 17.55 ± 0.27 μM in comparison with the references, cisplatin and milaplatin (IC 50 = 13.34 ± 0.11and 18.43 ± 0.13 μM, respectively). Furthermore, all derivatives demonstrated promising activity upon evaluation of theirin vitroandin vivosuppression of p53 ubiquitination and inhibition assessment for LDHA kinase. Finally, molecular docking studies were performed to predict the possible binding features of the potent derivatives within the ATP pocket of LDHA in an attempt to get a lead for developing a more potent LDHA inhibitor with anti-proliferative potency.

Screen-printed membrane sensors based on the use of paper and ceramic substrates are fabricated, characterized, and used for rapid batch and continuous monitoring of Cr III in the form of CrO 4 2- in some industrial products and wastewater samples. Strips of paper and ceramic platforms (15 × 5 mm) were covered with conductive carbon paint and then modified with polyaniline (PANI) film, to act as an ion-to-electron transducer, followed by a drop casting of plasticized poly (vinyl chloride) (PVC) Rhodamine-B chromate membrane as a recognition sensing material. In a 5.0 mmol L -1 Trizma buffer solution of pH ~8, the fabricated paper and ceramic based membrane sensors exhibited a near Nernstian response for Cr VI ion with slopes of -29.7 ± 0.5 and -28.6 ± 0.3 mV decade -1 , limit of detection 2.5 × 10 -5 and 2.4 × 10 -6 mol L -1 (1.3-0.12 µg mL -1 ), and linear concentration range 7.5 × 10 -3 -5.0 × 10 -5 and 7.5 × 10 -3 -1.0 × 10 -5 mol L -1 (390-0.5 µg mL -1 ), respectively. Both sensors exhibited fast and stable potentiometric response, excellent reproducibility, and good selectivity with respect to a number of common foreign inorganic species. Impedance spectroscopy and chronopotentiometry data revealed a small resistance and a larger double layer capacitance due to the presence of the intermediate polyaniline (PAN) conductive layer. Furthermore, the formation of a water layer between the ion selective membrane (ISM) and the underlying conductor polymer and between the conducting polymer and the carbon conducting surface was greatly reduced. The developed disposable solid-contact potentiometric sensors offer the advantages of simple design, long term potential stability, flexibility, miniaturization ability, short conditioning time, and cost effectiveness that enable mass production. The sensors were successfully used for static and hydrodynamic measurements of total chromium in some leather tanning wastewater and nickel-chrome alloy samples. The results compare favorably with data obtained by atomic absorption spectrometry., Competing Interests: The authors declare no conflict of interest.

The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6 - 14 . The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines namely, HepG2 and MCF-7) and antioxidant (by two methods; ABTS and DPPH) activities of the investigated compounds, the best quinazolinthione derivatives were 6 and 14, which exhibited excellent potencies comparable to quinazolinone derivatives 5 and 9 , respectively. Secondly, we compared the activity of four series of Schiff bases which included the quinazolinone moiety ( 11a - d ). In addition, the antiproliferative and antioxidant activities of the compounds with various aryl aldehyde hydrazone derivatives ( 11a - d ) analogs were studied. The compounds exhibited potency that increased with increasing electron donating group in p -position (OH > OMe > Cl) due to extended conjugated systems. Noteworthy, most of antiproliferative and antioxidant activities results for the tested compounds are consistent with the DFT calculations.

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8-5.7 nm) of the previously prepared benzofuran-pyrazole compound ( IV ) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC 50 doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized- BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP .

In this study, some of new thiophenyl thienopyrimidinone derivatives 2 - 15 were prepared and tested as anti-cancer agents by using thiophenyl thieno[2,3-d]pyrimidinone derivative 2 as a starting material, which was prepared from cyclization of ethyl ester derivative 1 with formamide. Treatment of 2 with ethyl- chloroacetate gave thienopyrimidinone N -ethylacetate 3 , which was reacted with hydrazine hydrate or anthranilic acid to afford acetohydrazide 4 and benzo[d][1, 3 ]oxazin-4-one 5, respectively. Condensation of 4 with aromatic aldehydes or phenylisothiocyanate yielded Schiff base derivatives 6,7 , and thiosemicarbazise 10 , which were treated with 2-mercaptoacetic acid or chloroacetic acid to give the corresponding thiazolidinones 8 , 9, and phenylimino-thiazolidinone 11 , respectively. Treatment of 4 with ethylacetoacetate or acetic acid/acetic anhydride gave pyrazole 12 and acetyl acetohydrazide 13 derivatives, respectively. The latter compound 13 was reacted with ethyl cycno-acetate or malononitrile to give 14 and 15 , respectively. In this work, we have studied the anti-cancer activity of the synthesized thienopyrimidinone derivatives against MCF-7 and MCF-10A cancer cells. Furthermore, in vivo experiments showed that the synthesized compounds significantly reduced tumor growth up to the 8 th day of treatment in comparison to control animal models. Additionally, the synthesized derivatives showed potential inhibitory effects against pim-1 kinase activities.

A series of 16-(α-alkoxyalkane)-17-hydrazino-estra-1(10),2,4-trien[17,16-c]-3-ol ( 3a - l ) and estra-1(10),2,4-trien-[17,16-c]pyrazoline-3-ol derivatives ( 4a - d ) were synthesized from corresponding arylidines 2a,b which was prepared from estrone 1 as starting material. Condensation of 1 with aldehydes gave the corresponding arylidine derivatives 2 a,b which were treated with hydrazine derivatives in alcohols to give the corresponding derivatives 3a - l , respectively. Additionally, treatment of 2 a,b with methyl- or phenylhydrazine in ethanolic potassium hydroxide afforded the corresponding N-substituted pyrazoline derivatives 4a - d , respectively. All these derivatives showed potent anti-ovarian cancer both in vitro and in vivo . The mechanism of anti-ovarian cancer was suggested to process via topoisomerase II and V600E BRAF inhibition., Competing Interests: The authors declare no conflict of interest.

A series of estrone derivatives 3 ⁻ 8 was designed and synthesized using estrone arylmethylenes 2a , b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and in vivo cytotoxic activities against breast cancer cell lines. In addition, all compounds were subjected to in vitro and in vivo inhibition assays for EGFR and VEGFR-2 kinases as well as p53 ubiquitination activity to obtain more details about their mechanism of action. Based on the promising results, a molecular docking study was investigated for the most representative compound 5a against the two targets, EGFR and VEGFR-2 kinases, to assess its binding affinity, hoping to rationalize and obtain potent anticancer agents in the future.

A series of macrocyclic pyrido-pentapeptide candidates 2 ⁻ 6 were synthesized by using N , N -bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a , b as starting material. Structures of the newly synthesized compounds were established by IR, ¹H and 13 C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC 50 values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases.

A series of estrone derivatives, 2 ⁻ 4 , were synthesized from the corresponding arylidine estrone, 2a , b , as starting materials, which were prepared by condensation of estrone (3-hydroxy-estran-17-one, 1) with 4-bromobenzaldehyde and thiophene-2-aldehyde. Treating of 2a , b with hydrazine derivatives in acetic acid or propionic acid afforded pyrazoline derivatives, 3a ⁻ f and 4a ⁻ f , respectively. Furthermore, results proved the superiority of thienyl derivatives over 4-bromophenol derivatives in terms of cytotoxic effects on MCF-7 cancer cells. In vivo xenograft breast cancer animal model experiments revealed that the synthesized derivatives can be used for decreasing tumor volume, while the most potent derivative ( 4f ) decreased the development of tumor volume by about 87.0% after 12 days.