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Mostafa M Ghorab,1 Ali S Alqahtani,2,3 Aiten M Soliman,1 Ahmed A Askar4 1Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo 11765, Egypt; 2Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 3Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 4Botany and Microbiology Department, Faculty of Science (Boys), Al-Azhar University, Cairo, EgyptCorrespondence: Mostafa M Ghorab; Ali S Alqahtani Tel +20 1067846727Email mmsghorab@yahoo.com; Alalqahtani@ksu.edu.saAim: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects.Materials and Methods: Novel quinazolinone-benzenesulfonamide derivatives 5– 18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV–Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase.Results: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25– 36 mm and 0.31– 5.0 μg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 μM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 μg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin.Conclusion: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.Keywords: quinazolinone, benzenesulfonamide, antimicrobial, nanoparticles, nanoformulations, MBC, Staphylococcus aureus DNA gyrase, docking

Mostafa M Ghorab,1,2 Mansour S Alsaid,1 Maureen Higgins,3 Albena T Dinkova-Kostova,3–5 Abdelaaty A Shahat,1,6 Nehal H Elghazawy,7 Reem K Arafa7,8 1Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2Department of Drug Radiation Research, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt; 3Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK; 4Department of Medicine, 5Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Phytochemistry Department, National Research Center, Dokki, Giza, 7Zewail City of Science and Technology, 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt Abstract: The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements pathway enables cells to survive oxidative stress conditions through regulating the expression of cytoprotective enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1). This work presents the design and synthesis of novel anilinoquinazoline derivatives (2–16a) and evaluation of their NQO1 inducer activity in murine cells. Molecular docking of the new compounds was performed to assess their ability to inhibit Keap1–Nrf2 protein–protein interaction through occupying the Keap1–Nrf2-binding domain, which leads to Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds can potentially interact with Keap1; however, 1,5-dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1,2-dihydropyrazol-3-one (9), the most potent inducer, showed the largest number of interactions with key amino acids in the binding pocket (Arg483, Tyr525, and Phe478) compared to the native ligand or any other compound in this series. Keywords: Kelch domain, molecular modeling, Keap1/Nrf2, cytoprotection, NQO1 induction

A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a-n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-β (TGF-β). Compound 3n showed a non-significant deviation of lung TGF-β1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-β and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC 50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: New quinazoline benzenesulfonamide hybrids 4a-n were synthesized to determine their cytotoxicity and effect on the miR-34a/MDM4/p53 apoptotic pathway. Materials & methods: Cytotoxicity against hepatic, breast, lung and colon cancer cell lines was estimated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: Compound 4d was the most potent against HepG2 and MCF-7 cancer cells, with potential apoptotic activity verified by a significant upregulation of miR-34a and p53 gene expressions. The apoptotic effect of 4d was further investigated and showed downregulation of miR-21 , VEGF , STAT3 and MDM4 gene expression. Conclusion: The anticancer and apoptotic activities of 4d were enhanced post irradiation by a single dose of 8 Gy γ-radiation. Docking analysis demonstrated a valuable affinity of 4d toward VEGFR2 and MDM4 active sites.

Novel series of aminopyrimidines bearing a biologically active cyclohexenone 3a-f and oxo-selaneylidene moiety 4 , besides selenadiazolopyrimidines ( 5a-e and 7 ), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC 50 14.31 ± 0.83 µM), A-549 (IC 50 30.74 ± 0.76 µM), and MCF-7 (IC 50 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC 50 4.48 ± 0.65 µM) and HSP90 (IC 50 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a . The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability.

Herein, we report the synthesis of a series of new quinazoline sulfonamide conjugates 2-16 and their evaluation as potential anticancer agents via dual targeting of EGFR T790M and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. The compounds were evaluated for their cytotoxicity against four cancer cell lines (HepG2, MCF-7, HCT116 and A549) using MTT assay. The most active compounds were further evaluated for their inhibitory activity against EGFR T790M and VEGFR-2. Compound 15 showed the most significant cytotoxic activity with IC 50  = 0.0977 µM against MCF-7 and the most potent inhibitory activity against both EGFR and VEGFR with IC 50  = 0.0728 and 0.0523 µM, respectively. Compound 15 was able to induce apoptosis in MCF-7 cells and cell cycle arrest at the G2/M phase. The relative safety profile of 15 was assessed using HEK-293 normal cell line and an ADMET profile was carried out. Radiosensitizing evaluation of 15 proved its significant ability to sensitize the cancer cell to the effect of radiation after being subjected to a single dose of 8 Gy gamma irradiation. Molecular docking studies revealed that 15 could bind to the ATP-binding site of EGF and VEGF receptors, inhibiting their activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In a search for new antioxidants, a set of new iodoquinazolinone derivatives bearing benzenesulfonamide moiety and variable acetamide pharmacophores 5-17 were designed and synthesized. The structures of the synthesized compounds were confirmed based on spectral data. Compounds 5-17 were screened using in vitro assay for their antioxidant potential and acetylcholinesterase (AChE) inhibitory activity. The 2-(6-iodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-ylthio)-N-(pyrazin-2-yl) acetamide 14 was the most active scaffold with potent AChE inhibitory activity. Compound 14 showed relative safety with a median lethal dose of 300 mg/kg (LD 50  = 300 mg/kg), in an acute toxicity study. The possible antioxidant and neuroprotective activities of 14 were evaluated in irradiated mice. Compound 14 possessed in vivo AChE inhibitory activity and was able to modify the brain neurotransmitters. It was able to cause mitigation of gamma radiation-induced oxidative stress verified by the decline in Myeloperoxidase (MPO) and increase of glutathione (GSH) levels. Also, 14 restored the alterations in behavioral tests. Molecular docking of 14 was performed inside MPO and AChE active sites and showed the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings would support that 14 could be considered a promising antioxidant with a neuromodulatory effect., (© 2023. Springer Nature Limited.)

Despite significant advances in oral drug delivery technologies, many drugs are prone to limited oral bioavailability due to biological barriers that hinder drug absorption. Pro-nanolipospheres (PNL) are a form of delivery system that can potentiate the oral bioavailability of poorly water-soluble drugs through a variety of processes, including increased drug solubility and protecting them from degradation by intestinal or hepatic first-pass metabolism. In this study, pro-nanolipospheres were employed as a delivery vehicle for improving the oral bioavailability of the lipophilic statin, atorvastatin (ATR). Various ATR-loaded PNL formulations, composed of various pharmaceutical ingredients, were prepared by the pre-concentrate method and characterized by determining particle size, surface charge, and encapsulation efficiency. An optimized formula (ATR-PT PNL) showing the smallest particle size, highest zeta potential, and highest encapsulation efficiency was selected for further in vivo investigations. The in vivo pharmacodynamic experiments demonstrated that the optimized ATR-PT PNL formulation exerted a potent hypolipidemic effect in a Poloxamer® 407-induced hyper-lipidaemia rat model by restoring normal cholesterol and triglyceride serum levels along with alleviating serum levels of LDL while elevating serum HDL levels, compared to pure drug suspensions and marketed ATR (Lipitor®). Most importantly, oral administration of the optimized ATR-PT PNL formulation showed a dramatic increase in ATR oral bioavailability, as evinced by a 1.7- and 3.6-fold rise in systemic bioavailability when compared with oral commercial ATR suspensions (Lipitor®) and pure drug suspension, respectively. Collectively, pro-nanolipospheres might represent a promising delivery vehicle for enhancing the oral bioavailability of poorly water-soluble drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Targeting CDK4/6 has advanced breast cancer treatment. Herein, new quinazolinones were synthesized with acetamide linkers as potential anti-breast cancer agents. Methods & results: In vitro cytotoxic evaluation on human breast cancer cell lines (MCF7 and MDA-MB-231) identified 1,3-benzodioxole ( 5d ) to be of the highest potency. It showed good inhibitory activity on CDK4/6. Compound 5d arrested the cell cycle at the G1-phase, caused induction of early and late apoptosis in an Annexin V-FITC assay, led to an increase in the level of caspase-3 and upregulated Bax expression and downregulated Bcl-2 in MCF7 cells. Compound 5d showed good radiosensitizing activity when combined with a single dose of 8-Gy γ-radiation. Conclusion: This study introduces quinazolinone scaffolds as new CDK4/6 inhibitors for breast cancer.

Nanostructured lipid carriers (NLCs) have been proven to significantly improve the bioavailability and efficacy of many drugs; however, they still have many limitations. These limitations could hinder their potential for enhancing the bioavailability of poorly water-soluble drugs and, therefore, require further amendments. From this perspective, we have investigated how the chitosanization and PEGylation of NLCs affected their ability to function as a delivery system for apixaban (APX). These surface modifications could enhance the ability of NLCs to improve the bioavailability and pharmacodynamic activity of the loaded drug. In vitro and in vivo studies were carried out to examine APX-loaded NLCs, chitosan-modified NLCs, and PEGylated NLCs. The three nanoarchitectures displayed a Higuchi-diffusion release pattern in vitro, in addition to having their vesicular outline proven via electron microscopy. PEGylated and chitosanized NLCs retained good stability over 3 months, versus the nonPEGylated and nonchitosanized NLCs. Interestingly, APX-loaded chitosan-modified NLCs displayed better stability than the APX-loaded PEGylated NLCs, in terms of mean vesicle size after 90 days. On the other hand, the absorption profile of APX (AUC 0-inf ) in rats pretreated with APX-loaded PEGylated NLCs (108.59 µg·mL -1 ·h -1 ) was significantly higher than the AUC 0-inf of APX in rats pretreated with APX-loaded chitosan-modified NLCs (93.397 µg·mL -1 ·h -1 ), and both were also significantly higher than AUC 0-inf of APX-Loaded NLCs (55.435 µg·mL -1 ·h -1 ). Chitosan-coated NLCs enhanced APX anticoagulant activity with increased prothrombin time and activated partial thromboplastin time by 1.6- and 1.55-folds, respectively, compared to unmodified NLCs, and by 1.23- and 1.37-folds, respectively, compared to PEGylated NLCs. The PEGylation and chitosanization of NLCs enhanced the bioavailability and anticoagulant activity of APX over the nonmodified NLCs; this highlighted the importance of both approaches.

A new series of 4-((7-methoxyquinolin-4-yl) amino)- N -(substituted) benzenesulfonamide 3(a-s) was synthesized via the reaction of 4-chloro-7-methoxyquinoline 1 with various sulfa drugs. The structural elucidation was verified based on spectroscopic data analysis. All the target compounds were screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and unicellular fungi. The results revealed that compound 3l has the highest effect on most tested bacterial and unicellular fungal strains. The highest effect of compound 3l was observed against E. coli and C. albicans with MIC = 7.812 and 31.125 µg/mL, respectively. Compounds 3c and 3d showed broad-spectrum antimicrobial activity, but the activity was lower than that of 3l . The antibiofilm activity of compound 3l was measured against different pathogenic microbes isolated from the urinary tract. Compound 3l could achieve biofilm extension at its adhesion strength. After adding 10.0 µg/mL of compound 3l , the highest percentage was 94.60% for E. coli, 91.74% for P. aeruginosa, and 98.03% for C. neoformans . Moreover, in the protein leakage assay, the quantity of cellular protein discharged from E. coli was 180.25 µg/mL after treatment with 1.0 mg/mL of compound 3l , which explains the creation of holes in the cell membrane of E. coli and proves compound 3l 's antibacterial and antibiofilm properties. Additionally, in silico ADME prediction analyses of compounds 3c , 3d, and 3l revealed promising results, indicating the presence of drug-like properties.

The present work describes a quinazolinone-based lead optimization for the development of novel purine nucleoside phosphorylase (PNP) inhibitors with quinazolinone scaffold. Nineteen compounds were proposed and docked against PNP, the best 14 compounds with highest docking and affinity scores and low RMSD values were synthesized. Synthesis of new quinazolinone derivatives with variable acetamide substituents on two positions on quinazoline ring was performed. The structures assigned to the products were concordant with the microanalytical and spectral data. In vitro cytotoxicity on human breast cancer cell line (MCF7) was performed and identified compound 6g as the most potent with IC 50 (0.99 ± 0.11 μM) which was further tested against five different breast cancer cell lines in addition to normal breast cell to determine the selectivity. Compound 6g was subjected to molecular dynamic simulation study, radiolabelling and biodistribution study to investigate its stability and selectivity toward breast cancers. The in vitro PNP inhibition results were aligned with the in silico, cytotoxicity, and biodistribution results where 6g showed the most potent PNP inhibitory activity with IC 50 (0.159 ± 0.007 μM) when compared to Peldesine (BCX-34) IC 50 (0.041 ± 0.002 μM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Sulfonamides are privileged candidates with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and could replenish the MRSA antibiotic pipeline. The initial screening of a series of quinazolinone benzenesulfonamide derivatives 5-18 against multidrug-resistant bacterial and fungal strains revealed their potent activity. The promising compounds were conjugated with ZnONPs to study the effect of nanoparticle formation on the antimicrobial, cytotoxic and immunomodulatory activity. Compounds 5 , 11 , 16 and 18 revealed promising antimicrobial and cytotoxic activities with superior safety profiles and enhanced activity upon nanoformulation. The immunomodulatory potential of compounds 5 , 11 , 16 and 18 was assessed. Compounds 5 and 11 demonstrated an increase in spleen and thymus weight and boosted the activation of CD4 + and CD8 + T lymphocytes, confirming their promising antimicrobial, cytotoxic and immunomodulatory activity.

A set of novel N-substituted-2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetamide 3-16 were designed and synthesized from 2-mercapto-3-phenylquinazolinone 2. The targeted compounds were screened for their cytotoxic activity against the hepatocellular carcinoma cell line HepG-2. Compounds 8, 9, 10, and 11 with IC 50 values of 1.11, 4.28, 5.70, and 4.69 µM, respectively, showed 5.7- to 28-fold higher activities than the positive control doxorubicin (IC 50 32.02 µM). Furthermore, compounds 8 and 9 were tested for EGFR inhibitory activity and demonstrated IC 50 values of 73.23 and 58.26  µM, respectively, when compared to erlotinib's IC 50 value of 9.79 µM. The most potent compounds, 8 and 9, were subjected to a single dose of 8 Gy of γ-radiation, and their cytotoxic efficacy was found to increase after irradiation, demonstrating the synergistic effect of γ-irradiation. Molecular docking was adopted for the most active compounds to confirm their mode of action., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Three new sets of quinazolinones bearing sulfachloropyridazine 4a-f, 6a-i and 8a-i were designed and synthesized. All the synthesized compounds were screened for their in vitro cytotoxicity against a panel of 60 cancer cell lines. The most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were evaluated as VEGFR-2 inhibitors. Compounds 8f, 8c and 6f were the most active with IC 50  = 66 ± 0.002, 108 ± 0.004 and 146 ± 0.006 nM, respectively. Compound 8f showed also moderate inhibition against PDGFR (IC 50  = 180 ± 0.009 nM), EGFR (IC 50  = 98 ± 0.004 nM), FGFR-1 (IC 50  = 82 ± 0.004 nM) and ability to reduce migration of cells in wound healing assay. Compound 8f showed cell cycle arrest at S-phase and induced early and late apoptosis in Annexien V-FITC assay. In addition, compound 8f increased the level of caspase-3 and up regulate Bax expression and down regulate Bcl-2 in UO-31 cells. The cytotoxicity of compounds 6f, 6g and 8f against UO-31 and melanoma cells was slightly affected by combination with γ-radiation. Also, compound 8f showed low toxicity against human normal renal (RPTEC) cell line. Docking studies of the most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were performed to have more insights on their binging mode within VEGFR-2 active site., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Apixaban (Apx), an oral anticoagulant drug, is a direct factor Xa inhibitor for the prophylaxis against venous thromboembolism. Apx has limited oral bioavailability and poor water solubility. The goal of this study was to improve the formulation of an Apx-loaded nanostructured lipid carrier (NLC) to increase its bioavailability and effectiveness. As solid lipid, liquid lipid, hydrophilic, and lipophilic stabilizers, stearic acid, oleic acid, Tween 80, and lecithin were used, respectively. Utilizing Box-Behnken design, the effects of three factors on NLC particle size (Y 1 ), zeta potential (Y 2 ), and entrapment efficiency percent (Y 3 ) were examined and optimized. The optimized formula was prepared, characterized, morphologically studied, and pharmacokinetically and pharmacodynamically assessed. The observed responses of the optimized Apx formula were 315.2 nm, -43.4 mV, and 89.84% for Y 1 , Y 2 , and Y 3 , respectively. Electron microscopy revealed the homogenous spherical shape of the NLC particles. The in vivo pharmacokinetic study conducted in male Wistar rats displayed an increase in AUC and C max by 8 and 2.67 folds, respectively, compared to oral Apx suspension. Moreover, the half-life was increased by 1.94 folds, and clearance was diminished by about 8 folds, which makes the NLC formula a promising sustained release system. Interestingly, the pharmacodynamic results displayed the superior effect of the optimized formula over the drug suspension with prolongation in the cuticle bleeding time. Moreover, both prothrombin time and activated partial thromboplastin time are significantly increased. So, incorporating Apx in an NLC formula significantly enhanced its oral bioavailability and pharmacodynamic activity.

We synthesised a new series of sulphonamide-bearing quinazolinone derivatives 5-18 and evaluated their in vitro cytotoxicity in various cancer cell lines (A549, HepG-2, LoVo and MCF-7) and in normal human cells (HUVEC). Compounds 6 and 10 exhibited the higher activity against all the cancer cell lines compared with 5-flourourcil as positive control. The ability of the most promising compounds 6 and 10 to induce cell cycle arrest and apoptosis in breast cancer (MCF-7) cells was evaluated by flow cytometry. Reverse transcriptase-polymerase chain reaction and western blotting were used to evaluate the expression of apoptosis-related markers. We found that the 2-tolylthioacetamide derivative 6 and the 3-ethyl phenyl thioacetamide derivative 10 exhibited cytotoxic activity comparable to that of 5-fluorouracil as reference drug in MCF-7 and LoVo colon cancer cells. Cell cycle analysis showed a concentration-dependent accumulation of cells in the sub-G1 phase upon treatment with both compounds. The Annexin V-fluorescein isothiocyanate/propidium iodide assay showed that the compounds 6 and 10 increased the early and late apoptosis cell death modes in a dose-dependent manner. These compounds downregulated the expression of B-cell lymphoma-2 (Bcl-2), while increasing that of p53, Bcl-2-like protein 4, and caspase-7, at the mRNA and protein levels. Molecular docking of compounds 6 and 10 with Bcl-2 predicted them to show moderate - high binding affinity ( 6 : -7.5 kcal/mol, 10 : -7.9 kcal/mol) and interactions with key central substrate cavity residues. Overall, compounds 6 and 10 were found to be promising anticancer and apoptosis-inducing agents.

Many quinazoline derivatives with pharmacological properties, such as anticancer activity, have been synthesized. Fourteen quinazoline derivatives bearing a substituted sulfonamide moiety ( 4a-n ) were previously synthesized and fully characterized. These compounds exerted antiproliferative activity against cell lines derived from solid tumors. Herein, the antileukemic activities of these compounds ( 4a-n ) against two different leukemia cell lines (Jurkat acute T cell and THP-1 acute monocytic) were investigated. Our investigation included examining their activity in vivo in a zebrafish embryo model. Remarkably, compounds 4a and 4d were the most potent in suppressing cell proliferation, with an IC 50 value range of 4-6.5 µM. Flow cytometry analysis indicated that both compounds halted cell progression at the G2/M phase and induced apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses also showed that both compounds effectively induced apoptosis by upregulating the expression of proapoptotic factors while downregulating that of antiapoptotic factors. In vivo animal toxicity assays performed in zebrafish embryos indicated that compound 4d was more toxic than compound 4a , with compound 4d inducing multiple levels of teratogenic phenotypes in zebrafish embryos at a sublethal concentration. Moreover, both compounds perturbed the hematopoiesis process in developing zebrafish embryos. Collectively, our data suggest that compounds 4a and 4d have the potential to be used as antileukemic agents.

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a - n . The structure of the newly prepared compounds was proved by microanalysis, IR, 1 H-NMR, 13 C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC 50 value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2's active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.

A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.

Twenty new quinazolinone derivatives bearing a piperonyl moiety were designed and synthesized. The structures of the target compounds were in agreement with the microanalytical and spectral data. Compounds 4-10, 13, 14 and 17-27 were screened for their cytotoxic activity against HepG-2 and MCF-7 cancer cell lines. The target compounds showed IC 50 in the range of 2.46-36.85 µM and 3.87-88.93 µM for HepG-2 and MCF-7, respectively. The promising compounds 7, 19, 26 and 27 were selected to measure their EGFR inhibitory activity. The IC 50 values of the promising compounds were in the range of 146.9-1032.7 nM for EGFR in reference to Erlotinib (IC 50  = 96.6 nM). In further studies on compounds 7, 19, 26 and 27 using HepG-2 cell line, there was significant overexpression of p21 and downregulation of two members of IAPs protein family; Survivin and XIAP, relative to their controls. Annexin V-FITC and caspase-3 analyses have established a significant increase in early apoptosis. Moreover, the four selected compounds have impaired cell proliferation by cell cycle arrest at the G2/M phase compared to their respective control. Considering radiotherapy as the primary treatment for many types of solid tumors, the radiosensitizing abilities of compounds 7, 19, 26 and 27 were measured against HepG-2 and MCF-7 cell lines combined with a single dose of 8 Gy gamma radiation. Measurement of the IC 50 of the promising compounds after irradiation revealed their ability to sensitize the cells to the lethal effect of gamma irradiation (IC 50  = 1.56-4.32 µM and 3.06-5.93 µM for HepG-2 and MCF-7 cells, respectively). Molecular docking was performed to gain insights into the ligand-binding interactions of 7, 19, 26 and 27 inside the EGFR binding sites and revealed their essential interactions, explaining their good activity towards EGFR., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail and evaluation of their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio) acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with free radical scavenging activity (IC 50  = 28 µM) and in vivo median lethal dose (LD 50 ) of 500 mg/Kg. The possible radioprotective activity of compound 17 was evaluated in (7 Gy) irradiated mice. Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS, malondialdehyde (MDA) and NQO1 in liver tissues. Moreover, compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key amino acids as those of the co-crystallized ligand. This study identifies 17 as a novel antioxidant that protects against the harmful effect of radiation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A promising approach has been emerging to enhance dissolution of hydrophobicdrugsby encapsulation in mesoporous silica materials. Olanzapine is a practically insoluble antipsychotic drug which is subjected to excessive first pass effect and shows inadequate oral bioavailability. Therefore, mesoporous silica was used to improve bioavailability of olanzapine incorporated in nano-structured lipid carriers (NLCs). These systems were characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE) and differential scanning calorimetry (DSC) as well asits release profile. The optimized mesoporous NLC system displayed nano-spherical particles (120.56 nm), possessed high entrapment efficiency (88.46%) and the highest percentage of drug released after six hours (75.13%). The biological performance of the optimized system was assessed in comparison with the drug suspension in healthy albino rabbits. The optimized system showed significantly (P < 0.05) prolonged MRT (8.47 h), higher C max (22.12± 0.40 ng/ml) and T max (2.0 h) values compared to drug suspension. Physiologically based pharmacokinetic (PBPK) model was simulated and verified. All the predicted results were within 0.6 and 1-fold of the reported data. To set a conclusion, in vitro results as well as in vivo pharmacokinetic study and PBPK data showed an enhancement in bioavailability of the optimized NLCs system over the plain drug suspension. These results proved the potentiality of incorporating olanzapine in mesoporous NLC for a significant improvement in oral bioavailability of olanzapine.

Objective : To validate an Arabic version of the Danish Prostatic Symptom Score (DAN-PSS), a self-administered quality-of-life questionnaire. Patients and methods : The reliability of the Arabic DAN-PSS was assessed by determining the internal consistency (Cronbach's α coefficient) and by assessing the test-retest reliability (Kappa [κ] test). Inter-domain associations were examined using Spearman's correlation coefficient ( r ). The discrimination validity was evaluated using receiver operating characteristic (ROC) curves. The sensitivity to change of the questionnaire and its individual items was assessed before and after intervention using a paired t -test. Results : In all, 106 men (55 patients with BPH and 51 without BPH symptoms) were included. A high level of internal consistency amongst the three domains of the answered Arabic DAN-PSS questionnaire was observed (Cronbach's α > 0.70). Also, there was a good correlation between storage and voiding ( r = 0.75; P < 0.001) and post-micturition symptoms domains ( r = 0.51; P < 0.001). Voiding and post-micturition symptoms domains also had a good correlation ( r = 0.51; P < 0.001). The agreement between the test and retest scores had a κ value of 0.83 ( P < 0.001). The ROC curve had an area under the curve of 0.98. The sensitivity to change comparing patients with BPH who received medical or surgical intervention revealed Arabic DAN-PSS mean (SD) scores of 34.7 (17.7) and 17 (8.7) before and after the intervention, respectively ( P < 0.001). Conclusion : The Arabic DAN-PSS is a clear questionnaire, valid, reliable, and responsive that can be used for BPH associated with lower urinary tract symptoms assessment and follow-up in clinical practice and research in Arabic-speaking patients. Abbreviations : AUC: area under the curve; BPH: benign prostatic hyperplasia; CI: confidence interval; DAN-PSS: Danish Prostatic Symptom Score; DRE: digital rectal examination; ICIQ-MLUTS: International Consultation on Incontinence Male LUTS Questionnaire; ICS: international continence society; IPSS: international Prostatic Symptom Score; IPSS-Arb: Arabic version of the IPSS; LUTS: lower urinary tract symptoms; PSA: prostatic specific antigen; PSS: prostatic symptom score; QoL: quality of life; ROC: receiver operating characteristic; UTI: urinary tract infection., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

A library of iodoquinazolinones endowed with benzenesulfonamide moiety was designed and synthesized as human carbonic anhydrase (hCA) inhibitors. Compounds 4-17 showed generally poor activity against the cytosolic hCA I and hCA II isoforms. Contrarily they were more potent and showed a variable spectrum of selectivity against the tumor-specific isoforms hCA IX and hCA XII. The 4-iodophenyl derivative 12 and the 4-pyridinyl derivative 15 were the most active and selective in this series against hCA IX and hCA XII isoforms with K I of 18 and 9 nM, respectively. Compounds 12 and 15 were further screened for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines besides WI38 and MCF-10A normal cell lines to determine their selectivity towards cancer cells. Compound 12 was selective towards HepG-2 and HCT-116 cell lines but less selective towards MCF-7. While compound 15 showed higher selectivity towards HepG-2 than HCT-116 and MCF-7 cell lines. The ability of compounds 12 and 15 to sensitize the cells against gamma irradiation's effect proved their potential radiosensitizing activity. Molecular docking analysis was carried out to discover the possible binding mode of the compounds within the active site of isoform hCA IX and XII. Compounds 12 and 15 revealed the probable fundamental interactions explaining the good activity and selectivity towards the tumor-specific isoforms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The purpose of this study was to develop miconazole nitrate (MN) based solid lipid nano-carrier formulae for topical delivery to enhance its antifungal effectiveness. Miconazole nitrate loaded Solid lipid nanoparticles (MN-SLNs) were formulated using a high shear homogenization technique characterized by particle size, polydispersity index (PI), trapping efficiency (EE percent), drug loading (DL percent) and zeta potential (ZP) characteristics. Furthermore, the optimized formulae were investigated for in-vitro release, ex-vivo study, skin toxicity test, and antifungal activity. With a particle size range of 244.2 ± 27.2 nm to 493.6 ± 35.3 nm, the selected MN-SLNs were spherical shaped. A high EE product percentage ranging from 79.38 ± 2.35 percent to 95.92 ± 6.12 percent and Zeta potential ZP values ranging from-21.6 ± 7.05 mV to-31.4 ± 6.84 mV suggesting strong stability was achieved. A controlled release of MN from the SLNs up to 48 h was shown in-vitro release study. The ex-vivo study showed that the selected MN-SLN (F4) mixture exhibited higher MN flux in the skin than a 1% MN solution. Moreover, selected MN-SLN (F4) has demonstrated a higher zone of inhibition against Candida albicans than a simple drug solution. MN-SLN (F4) had the lowest toxicity value for the skin. Besides, the MN-SLNs (F4) substantially reported antifungal activity with the least histopathological improvements compared to MN-solution utilizing immune-suppressing albino rats with induced candidiasis fungal infection. It can be fulfilled that SLNs can be acquired as a promising carrier for topical delivery of poorly soluble MN., Competing Interests: Declaration of Interest Statement The author reports no conflicts of interest in this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4-18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro. Compound 15 had low toxicity in mice (LD 50  = 500 mg/kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In the present work, we report the design and synthesis of a set of iodinated quinazolinones carrying benzenesulfonamide moiety as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The target compounds showed promising inhibitory activity against the four examined human (h) CA isoforms; I, II, IX and XII. Compounds 4-18 displayed variable inhibition constants, ranging as follows: 7.6-782.8 nM for hCA I, 34.4-412.1 nM for hCA II, 29.1-2225.3 nM for hCA IX and 8.8-429.4 nM for hCA XII. Compound 9, the most potent against the tumor-specific CA IX/CA XII (K I  = 29.1 and 8.8 nM) gives the possibility to evaluate its cytotoxicity and selectivity in vitro against HepG-2, HCT-116 and MCF-7 cancer cell lines. Compound 9 showed significant cytotoxicity against the tumor cell lines (IC 50  = 1.78, 1.94 and 3.07 μM, respectively) and relatively lower toxicity against WI38 normal cell line. The radiosensitizing activity of compound 9 was evaluated and displayed an increase in the radiation-induced cell death in cancer cells after receiving a single dose of 8 Gy gamma radiation. Thus, radiation was able to enhance the antiproliferative activity of compound 9. Molecular docking of 9 into the active site of CA IX and XII revealed the key interactions that could explain its potent activity and selectivity towards these isoforms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The present work is designed to achieve efficient localised skin delivery of folic acid (FA)-loaded nanostructured lipid carriers (NLCs) to infer efficient treatment of skin photoageing conditions induced via excessive exposure to ultraviolet (UV) radiation. FA NLCs were prepared by high-speed homogenisation followed by ultrasonication. The obtained NLCs revealed high encapsulation efficiencies (89.42-99.26%) with nanometric particle sizes (27.06-85.36 nm) of monodisperse distribution (PDI = 0.137-0.442), zeta potential values >|27| mV, pseudoplastic rheological behaviour, good spreadability (2.25-3.30 cm) and promoted occlusive properties throughout 48 h. Optimised NLC formulations appeared as sphere-shaped particles using transmission electron microscopy, showed improved photostability of FA and prolonged in vitro release profile best fitted to Higuchi diffusion model. Ex vivo permeation and deposition of FA, employing Wistar rat skins, depicted enhanced permeability and existence of FA in skin layers after 6 h. Based on the obtained results, FA-loaded NLC formulations demonstrate a promising modality for anti-photoageing therapy.

The novelty of the present work looks in the synthesis of aqueous dispersed selenium nanoparticles (Se NPs) using gamma rays with the aid of various natural macromolecules such as citrus pectin (CP), sodium alginate (Alg), chitosan (CS) and aqueous extract of fermented fenugreek powder (AEFFP) using Pleurotus ostreatus for investigating their impact in vitro toward carcinoma cell. The synthesized Se NPs were characterized by XRD, UV-Vis., DLS, HRTEM, SEM, EDX and FTIR. Nucleation and growth mechanisms were also discussed. The factorial design was applied to examine the importance of multiple parameters on Se NPs production with a special focus on temperature and gamma rays influences. FTIR spectrum exhibited the existence of several functional groups in Se NPs-capping macromolecules. Results revealed that Se NPs' size was dramatically-influenced by the type of stabilizer, precursors concentration, pH and the absorbed gamma rays dose. The current research reported the promising antitumor application of Se NPs against Ehrlich Ascites Carcinoma (EAC) and human Colon Adenocarcinoma (CACO) in vitro. The proliferation of EAC was significantly-hindered by Se NPs-CS (38.0 μg/ml) at 60 kGy (IC 50  = 23.12%) and Se NPs-AEFFP (19.00 μg/ml) at 15 kGy (IC 50  = 7.21%). Also, Se NPs control the generation of CACO cells, IC 50 was recorded as 25.32% for Se NPs-CS (38.0 μg/ml) and 8.57% for Se NPs-AEFFP (19.00 μg/ml)., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

In this research, we examined the effect of rosuvastatin calcium-loaded nanoparticles on the hair growth-promoting activity on Albino rats. Nanoparticles were prepared using 2:1 weight ratio of drug to methyl-β-cyclodextrin with 10, 20, and 30% stabilizers (phospholipid, polyvinyl pyrrolidone K30, and Compritol 888 ATO) using nanospray dryer. Subsequently, the prepared nanoparticles were evaluated for their process yield, particle size, polydispersity index, zeta potential, and in vitro drug release as well as in vivo studies. The dried nanoparticles showed process yield values up to 84% with particle size values ranging from 218 to 6258 nm, polydispersity index values ranging from 0.32 to 0.99, and zeta potential values ranging from - 6.1 to - 11.9 mV. Combination of methyl-β-cyclodextrin with 10% polyvinyl pyrrolidone K30 accomplished nanoparticles with the lowest particle size (218 nm) and polydispersity index (0.32) values. These nanoparticles had suitable process yield value (70.5%) and were able to retard drug release. The hair growth-promoting activity for the selected nanoparticles revealed the highest hair length values in Albino rats after 14 days of the hair growth study compared with non-medicated nanoparticles, nanoparticles' physical mixture, rosuvastatin solution, and marketed minoxidil preparation groups as well as the control group. The immunohistochemistry images for both selected nanoparticles and marketed minoxidil groups showed a significant increase in the diameter of hair follicle and percent area fraction of cytokeratin 19 in the outer root sheath of hair follicle compared with other tested groups. Rosuvastatin nanoparticles prepared by nanospray drying technique could be a good competitor to minoxidil for hair growth-promoting activity. Graphical abstract.

In order to discover new antioxidants, fifteen novel quinazolinone derivatives bearing benzenesulfonamide moiety with variable heterocyclic tail, were synthesized and their structures were established on the basis of spectral data. All the synthesized compounds were screened for their antioxidant potential using DPPH assay in comparison to ascorbic acid. The N-(pyrazin-2-yl)-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide 16 was the most active scaffold in this series with greater scavenging activity than that of ascorbic acid. In vivo acute toxicity study of compound 16 indicates its relative safety with a median lethal dose of 200 mg/kg. The possible antioxidant and hepatoprotective activities of compound 16 were evaluated in irradiated mice. Compound 16 caused mitigation of gamma radiation-induced oxidative stress verified by the decline in MDA, ROS and NF-κB levels. Moreover, SOD and PON1 activities, as well as Zn 2+ levels, were improved in liver tissues. Furthermore, molecular docking of compound 16 inside the active site of SOD and PON1 demonstrated the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings support that compound 16 may represent a structural lead for developing new antioxidants and hepatoprotective agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose . To investigate the knowledge, attitude, and practice of surgeons toward introducing novel surgical techniques in Egypt, Palestine, and Vietnam. Summary Background Data . Despite the recent advances in modern surgical care and its role in advancing the quality and the length of lives, surgery in the developing world has stagnated or even regressed. Methods . A survey was undertaken among the surgeons in 9 hospitals belonging to the 3 countries. Questions were categorized into knowledge, attitude, and practice questions. Meta-analyses were performed to estimate the event rate and compare between knowledge and practice, senior and junior surgeons. Results . A total of 244 responses, with a response rate of 79.7%, were included in the analysis. Regarding knowledge and attitude, the results were satisfactory except that only 55.8% of surgeons appraised their level of education and 43.3% wanted to earn money from the novel procedure. There was a significant difference between knowledge and practice regarding getting informed consent from the patients ( P = .024), discussing the novelty of the procedure ( P < .001), discussing the alternative procedures ( P < .001), discussing the surgeons' experience and level of skills ( P < .001), discussing the risk of the new procedure ( P < .001), and monitoring the outcomes after the new procedure ( P < .001). Conclusions . Most surgeons have sufficient knowledge and are motivated regarding adopting novel surgical techniques in order to provide the best care for the patients. However, there was a gap between knowledge and practice. Training programs and evidence-based guidelines regarding the introduction of novel surgical techniques are needed to overcome these challenges.

Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5-18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC 50 in the range of 0.34-149.10 µM. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09-20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC 50 of the promising compounds were in the range of 247-793 nM for VEGFR-2 in reference to sunitinib (IC 50 320 nM), and 369-725 nM for EGFR in reference to erlotinib (IC 50 568 nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC 50 37 & 97 µM, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8 Gy of gamma radiation. IC 50 of 12 and 13 decreased from 1.91 & 0.51 µM to 0.79 & 0.43 µM, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pulmonary delivery of vasodilators is a promising alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). The aim of this study was to design and evaluate hydrogel microparticles as a carrier for sustained pulmonary delivery of sildenafil citrate. Spray dried hydrogel microparticles containing biodegradable sodium carboxymethyl cellulose, sodium alginate, and sodium hyaluronate polymers at variable concentrations were prepared. A design of experiment using the "Extreme Vertices Mixture" design was executed. The design was used to study the influence of polymer concentration and their interactions on the physicochemical properties of the formulations in terms of particle size, particle size distribution, product yield, entrapment efficiency, and in-vitro drug release. Selected formulations were also evaluated for swelling, biodegradation, moisture content, in-vitro aerodynamic performance, and cytotoxicity. In addition, a lung deposition and pharmacokinetic study was conducted in rats to study drug accumulation in lungs and blood after intratracheal administration of the spray dried inhalable hydrogel microparticles in comparison to orally administered Viagra®. The results demonstrated that formulated microparticles had a mean geometric particle size between 2 and 5 μm, entrapment efficiency of >80%, and yield ranging between 47 and 66% w/w. The in-vitro drug release profiles showed a sustained drug release of sildenafil citrate for over 24 h. The statistical design showed a significant influence of the microparticulate composition on the physicochemical properties. Furthermore, selected formulations were evaluated for their aerodynamic properties. The aerodynamic properties included fine particle fraction ranging between 24 and 30%, dose recovery percent of 68-8 5%, and average mass median aerodynamic diameter of 4.6-4.8 μm. The in-vivo pharmacokinetic study showed that inhaled spray dried hydrogel microparticles (M6) formulation had significantly higher lung/blood C max , AUC, extended half-life, and mean residence time in comparison to orally administered sildenafil citrate of the same dose. In conclusion, the formulated drug-loaded spray dried hydrogel microparticles showed promising in-vitro and in-vivo results for the pulmonary delivery of sildenafil citrate. The spray dried hydrogel microparticles formulation can be considered as a potential alternative of oral sildenafil citrate for treatment of PAH., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study we explored the role of rosuvastatin calcium in skin regeneration as statins play important role in the field of tissue engineering. Chitosan hydrochloride was crosslinked with different weight ratios of collagen, β-glycerolphosphate and carboxymethyl cellulose to produce scaffolds by lyophilization technique. Subsequently, the fabricated scaffolds were examined for their morphology, water absorption capacity, water retention, friability and in-vitro drug release as well as in-vivo studies. The results revealed porous 3-D structured scaffolds with maximum water absorption values-ranging between 396 and 2993%. Scaffolds containing carboxymethyl cellulose revealed highest water absorption-values. In-vitro drug release results showed gradual drug release for 60 h with mean dissolution time-values (MDT) between 13 and 21 h. Combination of chitosan, collagen, carboxymethyl cellulose in weight ratio of 40:30:30, respectively achieved gradual disintegration of the scaffold in a simulating medium to an open wound after 4 days. This selected scaffold loaded with rosuvastatin revealed increase proliferation of human dermal fibroblasts compared to placebo scaffold. After 30 days of implantation of selected medicated scaffold loaded with/without mesenchymal stem cells and placebo scaffolds to induced wounds in Albino rats, enhanced skin regeneration and absence of scar formation for drug loaded scaffolds were observed. The histopathological study showed the advantage of stem cells-loaded scaffolds through the normal redistribution of collagen in the epidermal layer. In conclusion, rosuvastatin calcium and stem cells loaded in the tested scaffolds proved their potential effect in enhancing skin healing and regeneration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Betamethasone dipropionate is a highly effective corticosteroid anti-inflammatory. However, the main drawback of its topical use is the limited skin penetration into deeper skin layers. Also, its systemic use has shown many side effects., Objective: The goal of this research was to formulate betamethasone dipropionate in nanostructured lipid carriers (NLC) formulae that contain oleic acid to aid its penetration to deeper skin layers and to aid absorption to local regions upon topical application., Methods: NLC formulae were prepared by high shear homogenization then sonication. Formulae were characterized for their particle size, size distribution, electric potential, occlusion factor, entrapment efficiency, drug loading, transmission electron microscopy, in vitro drug release, and ex vivo skin penetration. Compatibility of ingredients with drug was tested using differential scanning calorimetry. Formulae were shown to have appropriate characteristics. NLC formulae were superior to traditional topical formulation in drug release., Results: Upon testing ex vivo skin penetration, betamethasone dipropionate prepared in NLC formulae was shown to penetrate more efficiently into skin layers than when formulated as a traditional cream. NLC formulation that contained higher percentage of oleic acid showed higher penetration and higher amount of drug to pass through skin., Conclusion: In general, NLC with lower oleic acid percentage was shown to deliver betamethasone dipropionate more efficiently into deeper skin layers while that of a higher oleic acid percentage was shown to deliver the drug more efficiently into deeper skin layers and through the skin, transdermally., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC 50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC 50 0.009 and 0.021 µM for EGFR and HER2, respectively.

We report the synthesis and characterisation of a novel series of triazole benzenesulfonamide derivatives, which incorporate the general pharmacophore associated with carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesised compounds were tested in vitro against four human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I, hCA II, hCA IV and hCA IX. The obtained results showed that the tumour-associated hCA IX was the most sensitive to inhibition with the synthesised derivatives, with the triazolo-pyridine benzenesulfonamides 14, 16 and 17 being the most effective inhibitors. Some selected compounds were chosen for a single dose anti-proliferative activity testing against a panel of 57 human tumour cell lines and show some anti-proliferative activity ex vivo.

Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC 50 values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC 50 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC 50 of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC 50 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5-18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC 50 of all the compounds were in the range of 0.36-40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00-16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC 50 in the range of 0.64-1.81 µM for EGFR and 1.13-2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10-13b as most active anticancer agents with IC 50 equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 µM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC 50 values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC 50 by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Management of epilepsy requires brain delivery therapy, therefore, this study was aimed to prepare lamotrigine loaded poly-ɛ-(d,l-lactide-co-caprolactone) (PLCL) nanoparticles using spontaneous emulsification solvent diffusion method. Nanoparticles for brain delivery required to have a particle size <200 nm, polydispesity index <0.2 and a sustained drug release properties. For such aim different factors were considered in preparing the nanoparticles as PLCL monomers' ratio, type of organic solvent used to prepare the nanoparticles, amount of PLCL and Pluronic®F127 in the nanoparticles. Prepared nanoparticles were characterized for their shape, particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading capacity, process yield and in-vitro drug release pattern. The in-vivo investigation for brain delivery of selected nanoparticles delivered by intravenous route was investigated in rats and compared to that for oral tablet. The obtained nanoparticles were spherical in shape. The amount of surfactant and PLCL affected the properties of the obtained nanoparticles. Using a mixture of organic solvent in preparing the nanoparticles improved its properties. The nanoparticles prepared using PLCL with monomers' ratio of 25:75, had particle size value of 125 nm, polydispersity index value of 0.184, zeta potential value of -39 mV and encapsulation efficiency value of 99%, was selected to study their efficacy to deliver the drug to the brain. The tested nanoparticles showed higher values of T max , C max , AUC, and MRT in homogenized rat brain, compared to oral lamotrigine tablet, while the bioavailability of the oral tablet was higher in rat plasma compared to that for the nanoparticles. This reflects that brain was the main distribution site for tested nanoparticles, and plasma was the main distribution site for oral tablets. This confirms the goal of the selected formulation as brain delivery nanoparticles., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aqueous dispersed zinc nanoparticles (ZnNPs) were synthesized using natural polysaccherides (chitosan (CS), citrus pectin (CP) and alginate (Alg)) using aqueous fermented fenugreek powder (FFP) by Pleurotus ostreatus as reducing and stabilizing agent or using gamma irradiation. The synthesized ZnNPs are characterized by ultra violect spectroscopy (UV), Transmission electronmicroscopy (TEM), Dynamic light scattering (DLS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). XRD analysis of the ZnNPS confirmed the formation of metallic nanoparticles. The nucleation and growth mechanism of ZnNPs is also discussed. TEM showed that the average diameter of ZnNPs was in the range of 46nm. The size of nanoparticles is influenced by certain parameters such as the choice of stabilizer, pH during synthesis and absorbed dose. Evaluating the antioxidant and anticancer activities of ZnNPs was performed. The results indicating the ZnNPs synthesized by aqueous fermented fenugreek extract have high activity and the average size is 46nm. The results explored that ZnNPs show anticancer activity against Ehrlich Ascites Carcinoma (EAC) and human colon adenocarcinoma (CACO) and the IC 50% was 47.5μg/ml and 65μg/ml respectively. Also, ZnNPs had excellent bactericidal activity against gram positive and negative bacteria and yeast., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In an attempt for development of new antimicrobial agents, three series of quinoline derivatives bearing pyrazole moiety have been synthesized. The first series was synthesized through the synthesis of 4-(quinolin-2-yloxy)benzaldehyde and 4-(quinolin-2-yloxy)acetophenone and then treatment with ketone or aldehyde derivatives to afford the corresponding chalcones. Cyclization of the latter chalcones with hydrazine derivatives led to the formation of new pyrazoline derivatives. The second series was synthesized via the synthesis of 2-hydrazinylquinoline and then treatment with formylpyrazoles to afford the corresponding hydrazonyl pyrazole derivatives. The third series was synthesized through the treatment of 2-hydrazinylquinoline with ethoxyethylidene, dithioacetal and arylidene derivatives to afford the corresponding pyrazole derivatives. The synthesized compounds were evaluated for their expected antibacterial and antifungal activities; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Pyrazole derivative 13b showed better results when compared with the reference drugs as revealed from their MIC values (0.12-0.98 μg/mL). The pyrazole derivative 13b showed fourfold potency of gentamycin in inhibiting the growth of S. flexneri (MIC 0.12 μg/mL). Also, compound 13b showed fourfold potency of amphotericin B in inhibiting the growth of A. clavatus (MIC 0.49 μg/mL) and C. albicans (MIC 0.12 μg/mL), respectively. The same compound showed twofold potency of gentamycin in inhibiting the growth of P. vulgaris (MIC 0.98 μg/mL), equipotent to the ampicillin and amphotericin B in inhibiting the growth of S. epidermidis (MIC 0.49 μg/mL), A. fumigatus (MIC 0.98 μg/mL), respectively. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antibacterial and antifungal agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

An array of some new N-(substituted)-2-((4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)acetamide 5-19 were synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl)benzenesulfonamide 4, to be assessed for their cytotoxic activity against A549 lung cancer cell line and to determine their inhibitory effect on EGFR tyrosine kinase enzyme. Compounds 5-19 showed high activity towards A549 cell line with IC 50 values of 0.12-8.70 μM. Compounds 6, 12 and 18 were the most potent in this series. These compounds were further screened as dual inhibitors for EGFR/HER2 enzymes in comparison with erlotinib and were found to possess very potent activity. Compound 12 showed the highest activity with IC 50 values of 0.06 μM and 0.30 μM towards EGFR and HER2, respectively. Accordingly, the apoptotic effect of the most potent compounds 6, 12 and 18 was investigated and showed a marked increase in the level of caspases-3 by 6, 9 and 8 folds, respectively, compared to the control cells. Moreover, Molecular modeling was performed inside the active site of EGFR, keeping in mind their binding possibilities, bond lengths, angles and energy scores. It was found that the most active compounds demonstrated the best binding scores in the active site of EGFR, which may clarify their high inhibition profile., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)