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Defensive fortifications are one of the most important means used by the ruling authorities to defend and protect Islamic cities, and cities in Morocco retain a huge heritage of fortresses, castles, fences and Kasbah that the rulers of successive countries have taken care of for their rule. They have built military settlements or defensive fortifications in order to defend their properties and protect their cities From the raids of the countries attacking them, staving off the danger and ensuring living in security and stability, As countries do not live in safety unless they include a strong army in strong fortresses that protect them from raids and raids by aggressors, and with the fact that most of the countries that have successively governed these countries and their wars have had a great impact on building fences, towers, Kasbah, forts, and others Of the defense establishments, and the emergence of bronchoscopes began in the Morocco in the era of the Almohad rulers, Merinids and Saadians, but it is in the Alawite era, especially during the era of Molly Ismail, which took on a new character in fortification so it was used to monitor the tribes, and to control and secure trade routes in all Moroccan cities.The Kasbah in the countries of Morocco is a building fortified with strong walls, which the castle meets in the Arab Levant and its purpose of fortification, and it is considered the most important building in the city and represents the first nucleus from which the city’s construction begins, and it represents the administrative and residential center of the rulers with its various facilities, and the Moroccan reeds were built Using local materials available in the surrounding environment, including dust, which is mixed with other materials, constituting a technique used in the various buildings in the Morocco, which is the Tapia technique.The research problem is represented in the difficulty of restricting all Kasbah in Morocco through different periods of time, and the research aims to shed light on the Kasbah as a model for the military buildings in Morocco and to identify the building materials and architectural planning, and highlight the main objective of its establishment, which is to fortify the Moroccan cities from any external dangers.

A series of 1,2,4-triazolo[1,5- a ]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a - p with 3-phenyl-1,2,4-triazole-5-amine ( 5 ). The novel compounds were analyzed using several spectroscopic techniques, and their antimicrobial efficacies against six pathogens (Gram-negative, Gram-positive, and fungi) were tested. Most of the tested compounds exhibited significant antimicrobial activity compared to ciprofloxacin and fluconazole. Four compounds ( 9d , 9n , 9o , and 9p ) showed promising results. Their minimal inhibitory concentration (MIC) values were between 16 and 102 μM, similar to ciprofloxacin's 10-90 μM values. MIC values against the tested fungal species were between 15.50 and 26.30 μM, higher than fluconazole's 11.50-17.50 μM values. Compounds 9n and 9o , in particular, showed excellent bactericidal activity. Compounds 9n and 9o , the most effective antibacterial agents, were further evaluated for their inhibitory effects on bacterial DNA gyrase and DHFR enzymes as possible molecular targets. The results indicated that 9n and 9o demonstrated a similar level of activity against DNA gyrase and DHFR when compared to the reference drugs ciprofloxacin and trimethoprim. We conducted molecular docking to investigate the binding mechanism and evaluate the reactivity of the intriguing compounds. Compounds 9n and 9o demonstrated favorable binding interactions with the essential amino acids necessary for the inhibition of E. coli DNA gyrase and DHFR enzymes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

COX-2-selective drugs were withdrawn from the market just a few years after their development due to cardiovascular side effects. As a result, developing a selective COX-2 inhibitor as an anti-inflammatory agent with cardioprotective characteristics has become a prominent objective in medicinal chemistry. New 15 diaryl-1,2,4-triazolo[3,4- a ]pyrimidine hybrids 8a - o were synthesized and investigated in vitro as dual COX-2/sEH inhibitors. Compounds 8b , 8m , and 8o have the highest potency and selectivity as COX-2 inhibitors (IC 50 = 15.20, 11.60, and 10.50 μM, respectively; selectivity index (COX-1/COX-2) = 13, 20, and 25, respectively), compared to celecoxib (COX-2; IC 50 = 42 μM; SI = 8). The 5-LOX inhibitory activity of compounds 8b , 8m , and 8o was further examined in vitro . Compounds 8m and 8o , the most effective COX-2 selective inhibitors, demonstrated stronger 5-LOX inhibitory action than the reference quercetin, with IC 50 values of 2.90 and 3.05 μM, respectively. Additionally, compounds 8b , 8m , and 8o were the most potent dual COX-2/sEH inhibitors, with IC 50 values against sEH of 3.20, 2.95, and 2.20 nM, respectively, and were equivalent to AUDA (IC 50 = 1.2 nM). In vivo investigations also demonstrated that these compounds were the most efficacious as analgesic/anti-inflammatory derivatives with a high cardioprotective profile against cardiac biomarkers and inflammatory cytokines. The docking data analysis inquiry helped better understand the binding mechanisms of the most active hybrids within the COX-2 active site and supported their COX-2 selectivity. Compounds 8b , 8m , and 8o exhibited a similar orientation to rofecoxib and celecoxib, with a larger proclivity to enter the selectivity side pocket than the reference compounds., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The aim of this study is to evaluate the anti-HPV potential of a Moringa olifera Lam seed, Nigella sativa L. seed, and Musa Acuminata peel herbal mixture in the form of polymer film-forming systems. A clinical trial conducted in outpatient clinics showed that the most significant outcome was wart size and quantity. Compared to the placebo group, the intervention group's size and number of warts were considerably better according to the results. Chemical profiling assisted by LC-HRMS led to the dereplication of 49 metabolites. Furthermore, network pharmacology was established for the mixture of three plants; each plant was studied separately to find out the annotated target genes, and then, we combined all annotated genes of all plants and filtered the genes to specify the genes related to human papilloma virus. In a backward step, the 24 configured genes related to HPV were used to specify only 30 compounds involved in HPV infection based on target genes. CA2 and EGFR were the top identified genes with 16 and 12 edges followed by PTGS2, CA9, and MMP9 genes with 11 edges each. A molecular docking study for the top active identified compounds of each species was conducted in the top target HPV genes, CA2 and EGFR, to investigate the mode of interaction between these compounds and the targets' active sites.

Over the past decades, cancer has been a challenging domain for medicinal chemists as it is an international health concern. In association, small molecules such as 2-aminothiophenes and their derivatives showed significant antitumor activity through variable modes of action. Therefore, this article aims to review the advances regarding these core scaffolds over the past 10 years, where 2-aminothiophenes and their fused analogs are classified and discussed according to their biological activity and mode of action, in the interest of boosting new design pathways for medicinal chemists to develop targeted antitumor candidates., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Layered double hydroxides (LDH) are promising 2D nanomaterials being investigated for several engineering and biomedical applications. In this work, quinary Zr Al Fe Co Ni LDH and its Al Fe Co Ni LDH quaternary and Fe Co Ni LDH tertiary roots were prepared and characterized. All samples showed an aggregated, layered morphology with zero surface charge and approximately 300 nm of hydrodynamic size. BET surface area of Al Fe Co Ni LDH showed a remarkable value of 143.25 m 2 g -1 as opposed to 26.2 m 2 g -1 and 45.4 m 2 g -1 for Fe Co Ni LDH and Zr Al Fe Co Ni LDH, respectively. The antimicrobial activity of the prepared samples was assessed against the many pathogenic bacteria; Bacillus ( B. ) subtilis , Escherichia ( E. ) coli , Haemophilus ( H. ) influenza , Listeria ( L. ) monocytogenes , Staphylococcus ( S. ) aureus , and Streptococcus ( St. ) pneumonia , and six fungal species. Furthermore, anti-biofilm activity, growth curve assay, and effect of UV illumination were examined against various pathogenic microbes. Zr Al Fe Co Ni displayed remarkable antibacterial activity, as indicated by the lowest values of the minimum inhibitory concentrations (MIC) of 4-166.7 μg mL -1 . Results for fungal strains varied in terms of their susceptibilities for the different samples tested. Zn Al Fe Co Ni was able to inhibit the biofilm formation of S. aureus (96.09%), E. coli (98.32%), and Candida ( C. ) albicans (95.93%). This study shown that certain LDH categories, particularly Zr Al Fe Co Ni, may be promising antibacterial agents against variety of pathogenic microorganisms that cause serious infections., Competing Interests: None of the authors have a conflict of interest to disclose., (This journal is © The Royal Society of Chemistry.)

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC 50 ) values of 2.7-63 μM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC 50 of 2.0 and 0.9 μM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC 50  = 1.7 μM). Notably, 6c inhibited both kinases, with IC 50 values of 2.7 and 3.0 μM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases., 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 Ltd. All rights reserved.)

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a - j , 8a - j , 9a - c , and 10a - c . The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d , 8g , 8i , and 10c inhibited EGFR with IC 50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC 50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d , 8g , 8i , and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.

Some cyclooxygenase (COX)-2 selective medications were withdrawn from the market just a few years after their production due to cardiovascular side effects. In this study, a new series of pyrimidine/thiazole hybrids 7a-p was synthesized as selective COX-2/soluble epoxide hydrolase (sEH) inhibitors with analgesic and anti-inflammatory effects, and lower cardiotoxicity effects. The target compounds were synthesized and in vitro tested against COX-1, COX-2, and sEH enzymes. Hybrids 7j, 7k, and 7i showed the greatest COX-2-inhibitory activity and were discovered to be the most potent dual COX-2/sEH inhibitors. In vivo tests revealed that these hybrids were the most active analgesic/anti-inflammatory agents, with improved ulcerogenic and cardioprotective properties. Finally, the most active dual inhibitors were docked into COX-2/sEH active regions to explain their binding mechanisms., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Protein kinases have grown over the past few years as a crucial target for different cancer types. With the multifactorial nature of cancer, and the fast development of drug resistance for conventional chemotherapeutics, a strategy for designing multi-target agents was suggested to potentially increase drug efficacy, minimize side effects and retain the proper pharmacokinetic properties. Kinase inhibitors were used extensively in such strategy. Different kinase inhibitor agents which target EGFR, VEGFR, c-Met, CDK, PDK and other targets were merged into hybrids with conventional chemotherapeutics such as tubulin polymerization and topoisomerase inhibitors. Other hybrids were designed gathering kinase inhibitors with targeted cancer therapy such as HDAC, PARP, HSP 90 inhibitors. Nitric oxide donor molecules were also merged with kinase inhibitors for cancer therapy. The current review presents the hybrids designed in the past five years discussing their design principles, results and highlights their future perspectives., 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 © 2021 Elsevier Masson SAS. All rights reserved.)

DNA gyrase and topoisomerase IV (topo IV) inhibitors are among the most interesting antibacterial drug classes without antibacterial pipeline representative. Twenty-four new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids were developed and tested against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compounds 4c, 4e, 4f, and 5e displayed an IC 50 of 34, 26, 32, and 90 nM against E. coli DNA gyrase, respectively (novobiocin, IC 50  = 170 nM). The activities of 4c, 4e, 4f, and 5e on DNA gyrase from S. aureus were weaker than those on E. coli gyrase. Compound 4e showed IC 50 values (0.47 µM and 0.92 µM) against E. coli topo IV and S. aureus topo IV, respectively in comparison to novobiocin (IC 50  = 11, 27 µM, respectively). Antibacterial activity against Gram-positive and Gram-negative bacterial strains has been studied. Some compounds have demonstrated superior antibacterial activity to ciprofloxacin against some of the bacterial strain studied. The most active compounds in this study showed no cytotoxic effect with cell viability>86%. Finally, a molecular docking analysis was performed to investigate the binding mode and interactions of the most active compounds to the active site of DNA gyrase and topoisomerase IV (topo IV) enzymes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Quinolones are well known antibacterial chemotherapeutics. Furthermore, they were reported for other activities such as anticancer and urease inhibitory potential. Modification at C7 of quinolones can direct these compounds preferentially toward target molecules., Methods: Different derivatives of ciprofloxacin by functionalization at the piperazinyl N-4 position with arylidenehydrazinecarbonyl and saturated heterocyclic-carbonyl moieties have been synthesized and characterized using different spectral and analytical techniques. The synthesized compounds were evaluated for anticancer, antibacterial, and urease inhibitory activities., Results: Among the synthesized compounds derivatives 3f and 3g experienced a potent antiproliferative activity against the breast cancer BT-549 cell line, recording growth percentages of 28.68% and 6.18%, respectively. Additionally, compound 3g revealed a remarkable antitumor potential toward the colon cancer HCT-116 cells (growth percentage 14.76%). Activity of compounds 3f and 3g against BT-549 cells was comparable to doxorubicin (IC 50  = 1.84, 9.83, and 1.29 µM, respectively). Test compounds were less active than their parent drug, ciprofloxacin toward Klebsiella pneumoniae and Proteus mirabilis. However, derivative 4a showed activity better than chloramphenicol against Klebsiella pneumoniae (MIC = 100.64 and 217.08 µM, respectively). Meanwhile, many of the synthesized compounds revealed a urease inhibitory activity greater than their parent. Compound 3i was the most potent urease inhibitor with IC 50 of 58.92 µM, greater than ciprofloxacin and standard inhibitor, thiourea (IC 50  = 94.32 and 78.89 µM, respectively)., Conclusion: This study provided promising derivatives as lead compounds for development of anticancer agents against breast and colon cancers, and others for optimization of urease inhibitors.

A new series of pyrimidine-5-carbonitrile derivatives 8a-p carrying the 1,3-thiazole moiety has been designed and synthesized as novel anti-inflammatory EGFR inhibitors with cardiac and gastric safety profiles. 8a-p have been assessed for their inhibitory activity against COX-1/COX-2 activity. Compounds 8h, 8n, and 8p were found to be potent and selective COX-2 inhibitors (IC 50  = 1.03-1.71 μM) relative to celecoxib (IC 50  = 0.88 μM). The most potent COX-2 inhibitors have been further investigated for their in-vivo anti-inflammatory effect. Compounds 8h, 8n, and 8p showed anti-inflammatory activity up to 90%, 94% and 86% of meloxicam after 4 h interval. 8h, 8n, and 8p showed higher gastric safety profiles than meloxicam. A substantial reduction in serum concentrations of PGE 2 , TNF-α, IL-6, iNO and MDA and a significant induction of TAC was also observed. In vivo experiments on heart rate and blood pressure established the cardiovascular safety profile of 8h, 8n, and 8p. Anti-proliferative and wild-type EGFR inhibitory assays displayed similar results to selective COX-2 inhibition where compounds 8h, 8n, and 8p had a superior inhibition than other tested ones. Molecular docking study demonstrated that these compounds revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to enter the side pocket selectively. Also, they interacted with EGFR tyrosine kinase main amino acids similar to erlotinib with a strong binding energy score., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The JNKs are members of mitogen-activated protein kinases (MAPK) which regulate many physiological processes including inflammatory responses, macrophages, cell proliferation, differentiation, survival, and death. It is increasingly clear that the continuous activation of JNKs has a role in cancer development and progression. Therefore, JNKs represent attractive oncogenic targets for cancer therapy using small molecule kinase inhibitors. Studies showed that the two major JNK proteins JNK1 and JNK2 have opposite functions in different types of cancers, which need more specification in the design of JNK inhibitors. Some of ATP- competitive and ATP non-competitive inhibitors have been developed and widely used in vitro, but this type of inhibitors lack selectivity and inhibits phosphorylation of all JNK substrates and may lead to cellular toxicity. In this review, we summarized and discussed the strategies of JNK binding inhibitors and the role of JNK signaling in the pathogenesis of different solid and hematological malignancies.

Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC 50 0.041-0.081 μM, SI 139.74-321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3-48.3, 1 h; 58.4-60.5, 2 h; 70.8-83.2, 3 h; 78.9-89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI 50 ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI 50 level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC 50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC 50  = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of -9.80 to -11.25 kcal/mol compared to -12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e., 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 Inc. All rights reserved.)

New 1,3,4-thiadiazine-thiourea derivatives have been synthesized. All the synthesized compounds were examined for in vitro cytotoxic activity against Non-Small Cell Lung Cancer (NSCLC) cell line A549, using MTT bioassay. Compounds 5d, 5i, 5j showed the highest cytotoxic activity with IC 50 values of 0.27 ± 0.01, 0.30 ± 0.02, and 0.32 ± 0.012 μM respectively with sorafenib as reference (IC 50 3.85 ± 0.27 μM). These compounds were chosen for further investigations against various biological targets known to play roles in NSCLC specifically: vascular endothelial growth factor receptor 2 (VEGFR2), B-RAF and matrix metalloproteinase 9 (MMP9). Encouraging results were exhibited by the three compounds against the selected targets. Compound 5j was specially promising as it exhibited inhibitory activity of VEGFR2 close to sorafenib (IC 50 0.11 ± 0.01 μM), most potent B-RAF activity inhibition (IC 50 0.178 ± 0.004 μM) and MMP9 inhibition (IC 50 0.08 ± 0.004 μM). Moreover, cell cycle analysis of A549 cells treated with 5j exhibited cell cycle arrest at G2-M phase and pro-apoptotic activity as indicated by Annexin V-FITC staining. Also, it reflected antinvasive and antimigration properties to A549 cells. Additionally, docking study of 5j on VEGFR2, B-RAF and MMP9 revealed that it binds to the target enzymes in a similar way as the co-crystallized ligand. The three compounds exhibited significantly high selectivity to A549 cancer cells against the normal human fetal lung fibroblast cell line WI-38 with higher selectivity index compared to sorafenib (5d IC 50 136.76 ± 2.38 μM, SI = 506.52; 5i IC 50 89.20 ± 2.11 μM, SI = 297.33; 5j IC 50 79.60 ± 3.8 μM, SI = 248.75; sorafenib IC 50 30.32 ± 2.41 μM, SI = 7.88). In conclusion, compounds 5d, 5i and 5j, specially 5j are promising anticancer agents targeting important pathways in NSCLC and warrant further preclinical and clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/purpose of the Study: Worldwide and national efforts are directed against eradication of HCV. The introduction of direct-acting antivirals (DAAs) has changed dramatically the outcome of HCV treatment. In spite of the Food and Drug Administration approval of the oral drugs sofosbuvir (SOF) and ledipasvir (LED) for the treatment of HCV in adolescents more than or equal to 12 years old, sufficient real-world experience is still lacking. The aim of this study was to assess the safety and efficacy of the generic SOF/LED fixed-dose combination 400/90 (400 mg SOF + 90 mg LED) for the treatment of adolescents and children (9-12 years) with chronic hepatitis C (CHC)., Methods: In this prospective observational study, 100 cases of genotype 4 CHC were recruited consecutively from those fulfilling the inclusion and exclusion criteria. All cases received the generic fixed-dose combination SOF/LED (400/90), one tablet daily for 12 weeks. All clinical, laboratory, and virologic characteristics were evaluated at base line, and week (W) 2, 4, 8, and 12 of therapy and W12 post-treatment (SVR12)., Results: Recruited children (9-12) and adolescents weighed 28-83 and 31-90 kg, respectively. Eighty cases were naïve and 20 cases were pegylated interferon/ribavirin treatment-experienced. Very rapid virologic response (vRVR) at W2 was 96%, while at W4 response rate was 100% and maintained till the end of treatment and at W12 post-treatment (SVR12). All reported side effects were mild and did not lead to treatment termination and disappeared at W12 post-treatment., Conclusion: The generic SOF/LED fixed-dose combination is safe and effective in children, 9-12 years, and adolescents with vRVR rate of 96%, 100% EOT response and SVR12.

Different studies about the anticancer potential of several medically used antibacterial fluoroquinolones have been established. Fluoroquinolone derivatives, like some anti-cancer drugs, such as doxorubicin, can achieve antitumor activity via poisoning of type II human DNA topoisomerases. Interestingly, structural features required for the anticancer activity of quinolones have been determined. Most of the chemical modifications required to convert antibacterially acting fluoroquinolones into their anticancer analogs were at position 7 and the carboxylic group at position 3. This review highlights the antitumor potential of fluoroquinolones in general and summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. Moreover, the review gives a quick recap on metal ion chelates with fluoroquinolones and their substantial role in topoisomerase poisoning and antitumor potential improvement. Hence, it should be highly interesting for researchers attempting to design and synthesize novel anticancer fluoroquinolone candidates., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

Aim of the Study: Biliary atresia (BA) is a fibro-inflammatory cholangiopathy of intra- and extrahepatic biliary radicles. The standard-of-care treatment is surgical restoration of bile flow by Kasai hepatoportoenterostomy (HPE). We aimed to identify the predictors of short-term outcome of the Kasai operation three months postoperatively., Material and Methods: This retrospective study included 107 infants diagnosed with BA by intraoperative cholangiography. All underwent a Kasai operation. The surgical outcome was classified after 3 months post-operatively as successful (bilirubin ≤ 2 mg/dl) or failed (bilirubin > 2 mg/dl). The two groups were compared according to basic clinical, ultrasonographic and histopathological characteristics., Results: Of the studied patients 29 (27.1%) had a successful outcome while 78 (72.9%) had failed Kasai HPE. Of the preoperative characteristics, lower age and lower serum alkaline phosphatase (ALP) were significantly associated with successful surgical outcome ( p = 0.009 and < 0.0001, respectively). In addition, surgical type of BA affected the short-term outcome ( p = 0.017), while there was no statistically significant difference regarding the other studied parameters between groups. Age of 69.5 days or less was predictive of successful outcome with 74.4% specificity but with low sensitivity (58.6%), and ALP at a cutoff level of 532.5 U/l or less was predictive of successful outcome with 75.9% sensitivity and 74.4% specificity., Conclusions: Younger age at the time of surgery and lower ALP are good predictors for the short-term outcome of Kasai HPE with better performance of ALP. This may help to anticipate those who can benefit from surgical correction and those who should be given high priority for transplant referral., Competing Interests: Authors report no conflict of interest.

Although its economic, cultural and biological importance, many genes haven't been depicted, sequenced or analyzed to date for Camelus dromedarius. In the present paper, the full-length c-DNA of a novel CYP2J2 (GenBank accession number MH511989) was cloned from liver, heart, and kidney mRNA by RACE-PCR. The full-length c-DNA of the cloned CYP2J2 was sequenced and analyzed using bioinformatics methods. The full-length c-DNA sequence was 2135 bp with no introns. The open reading frame (ORF) had 1341 nucleotides which coded for a putative protein of 446 amino acids. The deduced protein is located in the endoplasmic reticulum. It has two transmembrane regions. The nucleotides and deduced amino acids sequences of the cloned CYP2J2 were 1400 nucleotides and 47 amino acids shorter than the predicted homolog respectively. This study is the first description of the putative CYP2J2 gene, which opens the way to a new investigation-so far-never accomplished in Camelus dromedarius., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC 50  = 56 nM) and 9n against MOLT-4 (IC 50  = 80 nM), more potent than monastrol (IC 50  = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Two polymorphisms, rs755622 and rs5844572, in the promoter region of the macrophage migration inhibitory factor (MIF) gene influence the basal and/or induced transcriptional activity and have been linked to several inflammatory and autoimmune diseases. The aim of this study was to investigate the association between these two polymorphisms and disease susceptibility in patients with biliary atresia (BA). Allele frequencies of rs755622 and rs5844572 were assessed in 60 Egyptian infants with a confirmed diagnosis of BA. DNA was extracted from archival material. For the rs755622, samples were tested using Taqman real-time PCR, and for the rs5844572, samples were tested using fluorescence-based genotyping. The allele frequency in the general population was assessed in 141 healthy adults from the same geographical location. No statistical differences were observed in the allele frequencies of either rs755622 or rs5844572 between BA patients and controls. The homozygous and heterozygous short repeats (5/5, or 5/X) of rs5844572 were observed more frequently (16/28, 57.1%) in BA patients with mild to moderate fibrosis compared with those with marked fibrosis (10/32, 31.3%). The difference was statistically significant (P  =  0.032). In conclusion, we observed no association between MIF rs755622 and rs5844572 polymorphisms and susceptibility to BA; however, the rs5844572 could be linked to the rate of progression of the disease and extent of fibrosis., (© 2017 John Wiley & Sons Ltd/University College London.)

A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives 13a-p were synthesized via aldol condensation of 3/4-nitroacetophenones with appropriately substituted aldehydes followed by cyclization of the formed chalcones with 4-methanesulfonylphenylhydrazine hydrochloride. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity and ulcerogenic liability. All compounds were more potent inhibitors for COX-2 than COX-1. While most compounds showed good anti-inflammatory activity, compounds 13d, 13f, 13k and 13o were the most potent derivatives (ED50 = 66.5, 73.4, 79.8 and 70.5 μmol/kg, respectively) in comparison with celecoxib (ED50 = 68.1 μmol/kg). Compounds 13d, 13f, 13k and 13o (ulcer index = 3.89, 4.86, 4.96 and 3.92, respectively) were 4-6 folds less ulcerogenic than aspirin (ulcer index = 22.75) and showed approximately ulceration effect similar to celecoxib (ulcer index = 3.35). In addition, molecular docking studies were performed for compounds 13d, 13f, 13k and 13o inside COX-2 active site which showed acceptable binding interactions (affinity in kcal/mol -2.1774, -6.9498) in comparison with celecoxib (affinity in kcal/mol -6.5330).

The epidemiology and public health significance of Cryptosporidium species and genotypes were investigated in Beni-Suef Governorate, Egypt. A total of 610 animal fecal samples (480 from cattle and 130 from buffaloes) beside 290 stool samples from humans were collected in the period between January and December 2014. Based on the microscopic examination, the overall estimated prevalence of Cryptosporidium spp. in cattle, buffaloes, and humans was 10.2, 12.3, and 19 %, respectively. The highest detection rates were in calves less than 2 months of age (17.1 %) and diarrheic animals (13.0 %). Likewise in humans, the highest prevalence of Cryptosporidium was in infants (31.3 %) and diarrheic individuals (21.1 %). The gender distribution in humans denoted that Cryptosporidium was reported more frequently in males (21.7 %) than females (14.5 %). Based on the molecular characterization of Cryptosporidium, Cryptosporidium oocyst wall protein (COWP) and gp60 genes were successfully amplified in 36 out of 50 samples subjected to genotyping. Restriction fragment length polymorphism (RFLP) analysis of the COWP fragments revealed that Cryptosporidium parvum was the only species detected in cattle (12 isolates) and buffaloes (4 isolates), while in humans, the detected species were Cryptosporidium hominis (15 isolates) and C. parvum (5 isolates). Sequence analysis of the gp60 gene identified the subtype IIdA20G1 within C. parvum isolated from both animals and humans. The common occurrence of zoonotic subtypes of C. parvum in cattle and buffaloes highlights the potential role of these animals as significant reservoirs of infection to humans. Also, the presence of C. hominis and C. parvum in humans indicates that both anthroponotic and zoonotic pathways are expected.

In continuation to our previous work, thiazolopyrimidines 2a-x were synthesized through intramolecular cyclization of 2-phenacylthio-dihydropyrimidine hydrobromides 1a-x using polyphosphoric acid. On the other hand, thiazolo[3,2-a]pyrimidine-3-one 3 was coupled with aryldiazonium salts or condensed with isatin to afford compounds 4a-c or 5, respectively. Chemical structure of the target compounds was substantiated by IR, FT-IR, (1)H-, (13)C and DEPT-(13)C NMR, MS as well as microanalyses. Moreover, the lipophilicity of the target compounds is expressed as Clog P. The antimicrobial screening of the test compounds 2a-x, 4a-c and 5 revealed moderate activity in comparison to reference drugs. Compounds 2a-c, 2e, 2o and 2v showed a gradual increase in their anti-inflammatory activity reaching its maximum at 5 h compared to indomethacin. Furthermore, the analgesic activity of compounds 2a-c, 2e, 2o and 2v revealed a maximum activity after 5 h of injection compared to aspirin and the LD50 of compounds 2e and 2v was determined.

Background: Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. Multiple viral infections in IBC tissues were found to be associated with disease pathogenesis., Objective: The aim of the present study was to correlate the incidence of viral DNA with breast cancer progression., Materials and Methods: Overall, 135 women diagnosed with breast cancer were enrolled in this study. Using polymerase chain reaction and sequencing assays, we determined the incidence of human papillomavirus types 16 and 18 (HPV-16 and -18), human cytomegalovirus (HCMV), Epstein-Barr virus, human herpes simplex virus type 1 and 2, and human herpes virus type 8 (HHV-8) in breast carcinoma tissue biopsies. We also assessed the expression of the cell proliferation marker Ki-67 by immunohistochemistry in association with the incidence of viral DNA., Results: HCMV and HPV-16 were the most detected viral DNAs in breast carcinoma tissues; however, the frequency of HCMV and HHV-8 DNA were significantly higher in IBC than non-IBC tissues. Moreover, the prevalence of multiple viral DNAs was higher in IBC than non-IBC tissues. The incidence of multiple viral DNAs positively correlates with tumor size and number of metastatic lymph nodes in both non-IBC and IBC patients. The expression of Ki-67 was found to be significantly higher in both non-IBC and IBC tissues in which multiple viral DNAs were detected., Conclusions: The incidence of multiple viral DNAs in IBC tissues was higher compared with non-IBC tissues. The present results suggest the possibility of a functional relationship between the presence of multiple viral DNAs and disease pathogenesis.

The schistosomal parasite plays a critical role in the development of malignant lesions in different organs. The pathogenesis of cancer is currently under intense investigation to identify reliable prognostic indices for disease detection. The objective of this paper is to evaluate certain biochemical parameters as diagnostic tools to efficiently differentiate between colonic carcinoma and colonic carcinoma associated with schistosomal infection among Egyptian patients. The parameters under investigation are interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-α), carcinoembryonic antigen (CEA) levels, tissue telomerase, pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G-6-PD) and lactate dehydrogenase (LDH) enzyme activities. The results revealed a significant elevation in the level of the tumour markers IL-2, TNF-α and CEA as well as the activities of LDH, telomerase and G-6-PD among non-bilharzial and bilharzial colonic cancer groups, with a more potent effect in bilharzial infection-associated colonic cancer. A significant inhibition in PK activity was recorded in the same manner as compared to normal tissues. The efficacy of this biomarker was also evaluated through detecting sensitivity, specificity, negative and positive predictive values. In conclusion, schistosomal colonic carcinoma patients displayed more drastic changes in all parameters under investigation. The combination of the selected parameters succeeded in serving as biomarkers to differentiate between the two malignant types.

Purpose: The purpose of this paper is to develop a model for improving health services provided by the pre-employment medical fitness check-up system affiliated to Egypt's Health Insurance Organization (HIO)., Design/methodology/approach: Operations research, notably system re-engineering, is used in six randomly selected centers and findings before and after re-engineering are compared. The re-engineering model follows a systems approach, focusing on three areas: structure, process and outcome. The model is based on six main components: electronic booking, standardized check-up processes, protected medical documents, advanced archiving through an electronic content management (ECM) system, infrastructure development, and capacity building. The model originates mainly from customer needs and expectations., Findings: The centers' monthly customer flow increased significantly after re-engineering. The mean time spent per customer cycle improved after re-engineering--18.3 +/- 5.5 minutes as compared to 48.8 +/- 14.5 minutes before. Appointment delay was also significantly decreased from an average 18 to 6.2 days. Both beneficiaries and service providers were significantly more satisfied with the services after re-engineering. The model proves that re-engineering program costs are exceeded by increased revenue., Research Limitations/implications: Re-engineering in this study involved multiple structure and process elements. The literature review did not reveal similar re-engineering healthcare packages. Therefore, each element was compared separately., Practical Implications: This model is highly recommended for improving service effectiveness and efficiency., Originality/value: This research is the first in Egypt to apply the re-engineering approach to public health systems. Developing user-friendly models for service improvement is an added value.

Work climate is indicative of how well the organization is realizing its full potential. An accurate assessment of work climate can identify the unnecessary obstacles to nurses interfering with their best performance. The present study aims to assess nurses' work climate at Alexandria Main University Hospital. The study sample included all nurses (N=400) who were working in inpatient medical and surgical units at the Alexandria Main University Hospital who were available at the time of data collection. A structured questionnaire was developed to assess nurses' perceptions regarding the dimensions of work climate. Data was collected by individual interview using the structured questionnaire. Results indicated that the highest percentages of nurses in medical and surgical units perceived that their work climate is characterized by good way of performance management, feeling of responsibility, warmth and supportive relationships, quality of communication, morale, organizational clarity and feeling of identity and belongness to the hospital. Nurses perceived that they are lacking work climate conducive to conflict resolution, participation in decision making, opportunity for training and development, fair rewards and recognition, calculated risks, sufficient resources, effective leadership and teamwork. There were no significant difference between nurses perceptions in medical and surgical units regarding all dimensions of work climate. The highest percentage of nurses in all units were satisfied only with the feeling of responsibility, way of performance management, and quality of communication. Conflict and identity were perceived as the most important areas that need improvement in the hospital. Based on the results recommendations were given to enhance work climate through designing compensation and recognition systems, and negotiate their requirements and accomplishment based on established standards and outcomes measures. Also, encouragement of and planning for participative decision making, teamwork, in-service training program and open communication are recommended to be present in the work units.

In the search for new antimicrobial compounds, several new sulfur bearing heterobicyclic moieties (4-11) have been synthesized by acylation and alkylation of acetamide, thioacetamide and semicarbazide derivatives. The structure of the products was deduced from elemental analyses as well as spectral data (IR, 1H NMR and MS). Significant antimicrobial activities were obtained for all new compounds especially against Fusarium oxysporum.

The pharmacological properties of a limited series of tetrahydro-isoquinoline [trimetoquinol (TMQ)] analogs for inhibition of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced aggregatory and secretory responses in platelets, and contraction of rat aorta in a concentration-dependent manner. R-(+)-TMQ was a competitive-type inhibitor of U46619-induced contractions of rat aorta. The relative inhibitory potency for TMQ analogs against U46619-induced effects was TMQ greater than N-methyl TMQ greater than or equal to erythro-alpha-methyl TMQ greater than threo-alpha-methyl TMQ greater than or equal to alpha-dimethyl TMQ. R-(+)-TMQ and the azoprostanoid analog (U51605) were potent antagonists of U46619 action in rat aorta with pA2 values of 5.97 and 5.70, respectively. Other experiments indicated that U51605 was a partial agonist and R-(+)-TMQ was an inhibitor of U51605-induced contractions of rat aorta (pKB = 5.94). R-(+)-TMQ also blocked prostaglandin E2-mediated responses in rat aorta (pA2 = 5.46) but was ineffective as an antagonist of prostaglandin F2 alpha and LTD4 responses in dog iris sphincter and guinea-pig trachea or lung parenchyma, respectively. The data indicate that 1) the TMQ analogs were antagonists of endoperoxide/thromboxane A2-mediated responses in rat aorta and human platelets involving a similar mechanism of action and 2) stereochemical requirements of these TMQ analogs for activation of beta adrenoceptors and antagonism of endoperoxide/thromboxane A2-mediated responses are different. It is concluded that selectivity for these two pharmacological properties of TMQ can be achieved by appropriate stereochemical modification of the tetrahydroisoquinoline nucleus.

Decrease in the solvation of polymer by inclusion of ethanol in the acetone casting solution resulted in greater permeability to urea of cast acrylate-methacrylate film. The greater permeability was accompanied particularly by a decrease in pore size and increase in pore number, despite the absence of change in pore area. A decrease in cohesiveness in the film was suggested by the decrease in tortuosity of the pores as seen by scanning electron microscopy; also, water uptake was increased when the film was cast from an ethanolic solution. The results support the view that, in practice, the composition of the solvent, by its effect on microstructure, can affect the function of the film cast from it.