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A study is done on an Iraqi building to estimate and show how the use ofover hang reduces the cooling load. The study shows how the effectiveness ofover hang is affected by the orientation and the area (height) of the windows.This study shows that limit width of over hang on south window reduces thecooling load by (9%), and when using the over hang on the east or westwindow we need a large width over hang to reduce the cooling load by thesame percentage. Also this study shows that using over hang and increasingthe area of south windows allow us to receive a wide range of solar radiationin winter and use it in heating and lighting and the cooling load does notincrease by the same percentage when using west or east windows. The resultsshow that the using of over hang in Iraq is important especially for southwindows.

Background: Virtual journal clubs (VJCs) are innovative technologies with the potential to foster collaboration, facilitate multilingual communication, improve cultural competencies, and expand global professional networks. This allowed participants to be exposed to critical appraisal of the articles. However, its long-term impact on competency development has been debated. This study aimed to investigate the impact of implementing VJCs on developing competencies for critical appraisal among postgraduate nursing students., Methods: A quasi-experimental (pretest/posttest one-group) research design was used with a convenience sample of 40 participants from the community health nursing department, Faculty of Nursing, Mansoura University, Egypt who agreed to participate. The participants received an online self-administered knowledge and attitude data collection tool through Google Forms. However, critical appraisal skills were evaluated by an observational checklist with a rubric through synchronized mode. Eleven VJC sessions were conducted for each participant. Descriptive analysis served as the primary method for analyzing participants' responses. Students' t-test and one-way analysis of variance (ANOVA) were used to measure differences between the pretest and post-test. The study also used a correlation test to assess the relationship of variables., Results: The findings indicated a highly statistically significant difference among the participants regarding knowledge, critical appraisal skills, and attitudes toward VJC before, immediately, and six months after VJC session implementation. In addition, a positive significant correlation with a highly statistically significant difference between the participants' total knowledge score levels, total practice score levels, and total attitude score levels in the immediate post and after six months of VJC session implementation (p < 0.001)., Conclusion: The findings indicate this intervention has the potential to enhance critical appraisal competencies among postgraduate students. Therefore, VJCs should be included regularly to enhance critical appraisal competencies in academic settings for continued professional development., (© 2024. The Author(s).)

Undecaprenyl Pyrophosphate Synthase (UPPS) is a vital target enzyme in the early stages of bacterial cell wall biosynthesis. UPPS inhibitors have antibacterial activity against resistant strains such as MRSA and VRE. In this study, we used several consecutive computer-based protocols to identify novel UPPS inhibitors. The 3D QSAR pharmacophore model generation (HypoGen algorithm) protocol was used to generate a valid predictive pharmacophore model using a set of UPPS inhibitors with known reported activity. The developed model consists of four pharmacophoric features: one hydrogen bond acceptor, two hydrophobic, and one aromatic ring. It had a correlation coefficient of 0.86 and a null cost difference of 191.39, reflecting its high predictive power. Hypo1 was proven to be statistically significant using Fischer's randomization at a 95% confidence level. The validated pharmacophore model was used for the virtual screening of several databases. The resulting hits were filtered using SMART and Lipinski filters. The hits were docked into the binding site of the UPPS protein, affording 70 hits with higher docking affinities than the reference compound (6TC, - 21.17 kcal/mol). The top five hits were selected through extensive docking analysis and visual inspection based on docking affinities, fit values, and key residue interactions with the UPPS receptor. Moreover, molecular dynamic simulations of the top hits were performed to confirm the stability of the protein-ligand complexes, yielding five promising novel UPPS inhibitors., (© 2024. The Author(s).)

Objectives: The purpose of this study was to evaluate possible factors that might be accompanied by high level of human monkey pox (HMPX) knowledge and to explain the relationship between HMPX knowledge and Beliefs regarding emerging viral infections., Study Design: A descriptive cross-sectional study was conducted for the implementation of this study., Methods: Study was conducted at two general hospitals in Mansoura City (Old General Hospital and International Hospital) El Dakahlia Governorate among 620 healthcare workers (HCWs) using a self-managed questionnaire for 1 week (1 to 7 January 2023). The questionnaire has items adapted from the previously published literature to assess HMPX knowledge and Beliefs regarding emerging viral infections., Results: The mean age of the study sample was 27.97 years and most of them were female (86.1%). Physicians and other HCWs (nurses, laboratory technicians, radiographer technicians, and pharmacists) had significantly different levels of knowledge of monkeypox for the majority of the questions. A higher belief was found among two items: viruses are biological weapons manufactured by the superpowers to take global control and the government is misleading the public about the cause of the virus., Conclusion: This study discovered lower levels of knowledge of HMPX among HCWs in Egypt. Beliefs about emerging viral infections were widespread, and future research should look into their potential negative impact on health behavior., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)-induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty-seven compounds were identified, with monoterpene hydrocarbons being abundant class. d-Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d-limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2-12.27, 1.79-5.91, and 235.05-585.28 μM Trolox eq/mg oil for 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic (ABTS), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo, citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d-limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of -6.17, -4.51, and -5.61 kcal/mol, respectively., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Background Workplace-based assessment (WBA) is a group of assessment approaches that assesses the trainees' performance through their observation and monitoring in real clinical settings and then provides them with constructive and relevant feedback. Many WBA tools are available, including the mini-clinical evaluation exercise (mini-CEX), direct observation of procedural skills (DOPS), case-based discussions, and multisource feedback (peers, seniors, and patients). A WBA can help medical students improve their clinical competencies and ensure that qualified physicians graduate. Methods This prospective study was done in the family medicine department at the Menoufia Faculty of Medicine in Egypt and passed through two phases. Phase I was introducing an orientation lecture for family medicine staff and a convenient sample of 21 family medicine postgraduates about WBA. Phase II was conducting a monthly mini-CEX and DOPS for the postgraduates. Finally, students' satisfaction with the WBA was assessed, and all collected data were analyzed via Statistical Package for Social Science (SPSS) version 23 (IBM Corp., Armonk, NY). Results A total of 105 feedback sheets were obtained. These feedback sheets were subdivided into 63 mini-CEX feedback sheets (21 sheets from each mini-CEX session for three sessions) and 42 DOPS feedback sheets (21 sheets from each DOPS session for two sessions), all of which were collected and analyzed. A significant improvement was detected in the mini-CEX and DOPS feedback scores of the postgraduates throughout the consecutive sessions (9.5 ± 2.7, 24.9 ± 2.5, 27.29 ± 1.5) (P < 0.001) for Mini-CEX and (6.1 ± 1.8 versus 9.0 ± 1.2) (P < 0.001) for DOPS. About 93% of the postgraduates recommended the application of WBA for their peers, and 86% of them requested to perform it again for other different clinical cases and procedures. Conclusion Workplace-based assessment in the form of Mini-CEX and DOPS revealed its ability to improve clinical knowledge and skills among family medicine postgraduates who became motivated to undergo it again in search of improving their clinical performance and reducing their stresses related to final summative and objective structured clinical examinations (OSCEs)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alkalash et al.)

Introduction: Pediatric immune thrombocytopenia (ITP) is a potentially life threating autoimmune disorder with different responses to therapy and different bleeding phenotypes in critical organs. The molecular basis for the variable response has not yet been fully elucidated. This study was designed to address the predictive value of regulatory B-cell (B reg ) count and interleukin-10 (IL-10) serum levels for acute ITP patients who progress to chronic phase. The present study included 80 children with acute ITP )38 males and 42 females (with median age of 8 years and 40 matched healthy controls. Assessment of B reg (CD19 + CD24 hi CD38 hi ) was carried out by a multicolor flowcytometry, however, IL-10 serum levels were evaluated by enzyme-linked immunosorbent assay. A significant reduction of B reg percentage and a significant increase in serum IL-10 levels were identified in children with acute ITP as compared with controls ( P <0.001 for both). Fourteen ITP patients passed to chronic phase, while 66 patients achieved remission within 6 months. The absolute B reg was significantly lower, while IL-10 was significantly higher in patients with acute ITP who progressed to chronic phase in comparison with acute ITP patients who achieved complete remission. Cox proportional hazards for ITP chronicity revealed that IL-10 OR was 2.46 (confidence interval: 1.42-4.27; P =0.001) and absolute B reg OR was 0.147 (confidence interval: 0.128-0.624; P =0.005) in the peripheral blood. Therefore, they could predict chronicity in ITP cases., Conclusion: Reduced B reg count and elevated IL-10 levels in patients with acute ITP at diagnosis can predict chronicity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Cysteine-based mesenchymal-epithelial transition (c-Met) is a receptor tyrosine kinase that plays a definitive role during cancer progression and was identified as a possible target for anti-angiogenesis drugs. In the present study, different protocols of computer-based drug design were performed. Construction of predictive pharmacophore model using HypoGen algorithm resulted in a validated model of four features of positive ionizable, hydrogen bond acceptor, hydrophobic, and ring aromatic features with a correlation coefficient of 0.87, a configuration cost of 14.95, and a cost difference of 357.92. The model revealed a promising predictive power and had >90% probability of representing true correlation with the activity data. The model was established using Fisher's validation test at the 95% confidence level and test set prediction (r = 0.96), furthermore, the model was validated by mapping of set of compounds undergoing clinical trials as class Ⅱ c-met inhibitors. The generated valid pharmacophore model was then anticipated for virtual screening of three data bases. Moreover, scaffold hopping using replace fragments protocol was implemented. Hits generated were filtered according to Lipinski's rule; 510 selected hits were anatomized and subjected to molecular docking studies into the crystal structure of c-Met kinase. The good correlation between docking scores and ligand pharmacophore mapping fit values provided a reliable foundation for designing new potentially active candidates that may target c-Met kinase. Eventually, eight hits were selected as potential leads. Subsequently, seven (Hits) have displayed a higher dock score and demonstrated key residue interactions with stable molecular dynamics simulation. Therefore, these c-Met kinase inhibitors may further serve as new chemical spaces in designing new compounds., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A series of thieno[2,3- d ]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC 50 =185 nM), potent EGFR inhibition (IC 50 =1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC 50 =19 nM) and (IC 50 =5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC 50 = 68 nM and VEGFR2 IC 50 = 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

Objective: Multiple myeloma is an incurable hematological malignancy. Currently, the use of proteasome inhibitors could be superior to chemotherapy-based regimen in the treatment of this disease. However, resistance to bortezomib combination therapy still occurs in some patients. So, this research work aims to assess CD69 and CD56 expression in these cases and their relation to the response to therapy., Materials and Methods: Immunophenotyping by 4-color multi-parameter flow cytometry was carried out on 98 multiple myeloma cases. Clonal plasma cells were gated by co-expression of CD38 with CD138 with low SSC, negative or dim CD45., Results: Double negative CD69 and CD56 (47.9%) multiple myeloma cases were associated with high serum β2 microglobulin, creatinine, calcium and low serum albumin. There was also a significant correlation between the absence of these markers with osteolytic lesions and unfavorable cytogenetic t (4;14) ( p  < 0.001). Moreover, there was a highly significant correlation between CD69- and CD56- with non-response to bortezomib combination therapy in multiple myeloma patients ( p  < 0.0001). Regression analysis for the prediction of non- response to treatment in these cases using different prognostic indicators revealed that high serum β2 microglobulin, unfavorable cytogenetic, advanced stage, and low expression of CD69 and CD56 were poor predictors of non-response., Conclusion: CD69 in association with CD56 could be an independent prognostic factor in multiple myeloma cases. It could be used in the routine laboratory assessment for refining stratification and timely therapeutic decision for highly cost therapy in developing countries.

Background: The Lambda-Mu-Sigma (LMS) and Z score methods are important for assessment of growth and nutritional status. In Egypt, there is a lack of this tool for monitoring growth in preschool children. Objective: To develop LMS and Z score growth references for assessment of growth and nutritional status for Egyptian children from birth up to 5 years. Methods: A total of 27,537 children [13,888 boys (50.4%) and 13,649 girls (49.6%)] from birth up to 5 years were included in a multistage cross sectional randomized study from different Egyptian geographic districts to create LMS and Z score references for weight, length/height, and body mass index corresponding to age in addition to weight for length/height. Healthy term infants and children, exclusive breast feeding for at least 4 months and not suffering from any chronic diseases were included in this study. Children with dysmorphic features, preterm infants, admitted in neonatal or pediatric intensive care units and having any chronic diseases (hematological, cardiac, hepatic, and renal) were excluded. In addition any health condition that affects child growth including nutritional disorders was also excluded. Un-paired t -test was calculated to compare the means of weight for age, length/height for age, weight for length/height, and BMI for-age z scores of the Egyptian and WHO reference values. Results: Through detailed tables and graphs, LMS and Z scores for weight for age, length/height for age, weight for length/height, and BMI for age of both sexes were represented. Our findings showed no statistically significant difference between reference charts of WHO and Egyptian Z score charts ( P > 0.05). Conclusion: This study provides the first reference for Egyptian children from birth up to 5 years based on Z score tool for assessment the growth and nutritional status in various clinical conditions and research, also allows comparison with references of other countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 El Shafie, El-Gendy, Allahony, Hegran, Omar, Samir, Kasemy, El-Bazzar, Abd El-Fattah, Abdel Monsef, Kairallah, Raafet, Baza, Salah, Galab, Alkalash, Salama, Farag and Bahbah.)

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC 50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC 50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC 50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC 50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC 50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC 50  = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC 50 values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p&#95;PVB might have promising activity as a PDE-5 inhibitor., 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 Ltd. All rights reserved.)

A series of novel 6,7-dihydro-5H-cyclopenta[d]pyrimidine derivatives was successfully designed, synthesized and evaluated as a new chemical scaffold with vascular endothelial growth factor receptor (VEGFR 2) inhibitory activity. Compounds 6c and 6b showed enzyme inhibition of 97% and 87% at 10 µM, respectively, and exhibited potent dose-related VEGFR 2 inhibition with IC 50 values of 0.85 µM and 2.26 µM, respectively. The design of the 6,7-dihydro-5H-cyclopenta[d]pyrimidine scaffold was implemented via consecutive molecular modelling protocols prior to the synthesis and biological evaluation of the derivatives. First, sorafenib was docked in the binding site of VEGFR 2 to study its binding orientation and affinity, followed by the generation of a valid 3D QSAR pharmacophore model for use in the virtual screening of different 3D databases. Structures with promising pharmacophore-based virtual screening results were refined using molecular docking studies in the binding site of VEGFR 2. A novel scaffold was designed by incorporating the results of the pharmacophore model generation and molecular docking studies. The new scaffold showed hydrophobic interactions with the kinase front pocket that may be attributed to increasing residence time in VEGFR 2, which is a key success factor for ligand optimization in drug discovery. Different derivatives of the novel scaffold were validated using docking studies and pharmacophore mapping, where they exhibited promising results as VEGFR 2 inhibitors to be synthesized and biologically evaluated. 6,7-dihydro-5H-cyclopenta[d]pyrimidine is a new scaffold that can be further optimized for the synthesis of promising VEGFR 2 inhibitors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495-9.05nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds 4d, 6f, 7e showed significant inhibition (IC50=1.76-2.38μM) in these mutant lines and significant Her2 enzyme inhibition (IC50=19.2-40.6nM) compared to lapatinib (60.1nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure-activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb-f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa-g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC50 ranging from 2.27 to 10.71μM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1-11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A novel series of 1,2,4-triazole derivatives were synthesized and confirmed with different spectroscopic techniques. The prepared compounds exhibited remarkable anti-inflammatory activity comparable to that of indomethacin and celecoxib after 3 h. The tested compounds exhibited very low incidence of gastric ulceration compared to indomethacin. Most of the newly developed compounds showed excellent selectivity towards human COX-2 with selectivity indices (COX-1 IC50/COX-2 IC50) ranged from 62.5 to 2127. Docking studies results revealed that the highly selective tested compounds 6h and 6j showed lower CDOCKER energies, which means that they require less energy for proper interaction with the enzyme. The additional H-bonds with the oxygen of the amide and/or H of NH of the amide with the amino acid residues may be responsible for the higher binding affinity of this group of compounds towards COX-2., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

4-Anilino-6-substituted-quinazolines were designed, synthesized and evaluated for EGFR-TK and tumor growth inhibitory activities. The target compounds were designed with enamine ester or urea moieties appended at the C-6 of quinazoline as additional hydrogen bond acceptor functions. Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity at 10 μM and the 6-ureido-anilinoquinazoline derivative 7a showed IC50 value of 0.061 μM. Moreover, six compounds were tested by National Cancer Institute (NCI), USA for their anti-proliferative activity at 10 μM in full NCI 60 cell panel. Compound 7a was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Non-Small Cell Lung Cancer EKVX (GI50 = 0.37 μM), NCI-H322M (GI50 = 0.36 μM), Renal Cancer A498 (GI50 = 0.46 μM), TK-10 (GI50 = 0.99 μM) and Breast Cancer MDA-MB-468 (GI50 = 1.096 μM) which are of high EGFR expression. Docking study was performed for the active compounds into ATP binding site of EGFR-TK which showed similar binding mode to gefitinib and additional binding with Cys-773 at the gatekeeper of EGFR-TK enzyme., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, we aimed to test the potential antidiabetic effect of phytol (250 mg/kg), the natural precursor of phytanic acid, a RXR ligand and/or pioglitazone (5 mg/kg) to diabetic insulin-resistant rats. Regarding the molecular docking simulation on PPARγ, phytanic acid, rather than phytol, showed a binding mode that mimics the crystal orientation of rosiglitazone and pioglitazone, forming H bonds with the same amino acids (S289, H 323, H 449 and Y 473), and the least energy level, which emphasizes their importance for PPARγ molecular recognition, activation, hence antidiabetic activity. In addition, docking on the RXRα/PPARγ heterodimer, revealed that phytanic acid has higher binding affinity and lesser energy score on RXRα, compared to the original ligand, retinoic acid. Phytanic acid binds by 3H bonds and shares retinoic acid in arginine (R 316). These results were further supported biochemically, where oral phytol and/or pioglitazone (5 mg/kg) improved significantly glucose homeostasis, lipid panel, raised serum adiponectin level and lowered TNF-α, reaching in most cases the effect of the 10 mg/kg pioglitazone. The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid.

A series of 2,5,7-trisubstituted pyrimido[4,5-d]pyrimidine cyclin-dependent kinase (CDK2) inhibitors is designed and synthesized. 6-Amino-2-thiouracil is reacted with an aldehyde and thiourea to prepare the pyrimido[4,5-d]-pyrimidines. Alkylation and amination of the latter ones give different amino derivatives. These compounds show potent and selective CDK inhibitory activities and inhibit in vitro cellular proliferation in cultured human tumor cells.

Several hybrid molecules of diphenylamine-2,4'-dicarboxamide with various azolidinones and related heterocyclic rings have been synthesized and explored as epidermal growth factor receptor (EGFR) kinase inhibitors. Most of them displayed promising in vitro tyrosine kinase inhibition as well as potent cellular antiproliferative activity in the EGFR over-expressing breast cancer cell line (MCF-7). Compounds 12b and 13b that exhibited the highest inhibition in the kinase assay (89, 81% inhibition at 10 μM, respectively), showed potent antiproliferative effect against MCF-7 tumor cell line (IC(50) 1.04, 0.91 μM respectively). Molecular docking studies revealed that these compounds can bind to ATP binding site of the EGFR kinase domain and were involved in H-bonding with Met 793, in analogy to the known EGFR tyrosine kinase inhibitors. Moreover, compounds 15a-c possessed profound antitumor activity (IC(50) 0.59-0.73 μM) and significant EGFR-TK inhibition, making them of particular interest. In summary, the newly synthesized compounds provide promising new lead for the future design and development of anticancer agents of potential EGFR-TK inhibitory activity.

A number of new furobenzopyranones and pyranobenzopyranones carrying an electron-withdrawing function at the position 3 are synthesized in order to obtain new photoreagents towards DNA. Our interest in this study is to investigate the effect of introduction of electron withdrawing function on the position 3 of the benzo-á-pyranone ring of linear furobenzo-á-pyranone (5,8-dimethoxypsoralen) or angular pyranobenzo-á-pyranone on the biological activity, by preparing 3-cyano, carboxylic acid, carboxylic acid ester, acid hydrazide, thiosemicarbazide, or mercaptotriazole derivatives. 5-acetyl-6-hydroxybenzofuran, and 8-acetyl-7-hydroxy-4-phenylbenzopyranone are the key starting compounds on which 3-cyano-4-methylfurobenzopyranone and 3-cyano-4-methyl pyranobenzopyranone moieties were built respectively. The photobiological activity of the newly synthesized compounds was evaluated. It looks most promising for enhancement of photoreactivity of compounds towards DNA, and a certain effect was observed in the dark determining the antimicrobial activity. Compounds 5, 6, 7, 13, 14 exhibit potential photoreactivity towards DNA, while 3-mercaptotriazole derivatives 7, 14 possess only photosensitizing activity. To investigate the antimicrobial data on structural basis, molecular modelling and docking studies of the tested compounds into the crystal structure of topoisomerase II DNA Gyrase B complexed with the natural inhibitor bearing the coumarin moiety clorobiocin (1kzn), using Molsoft ICM 3.4-8C program was performed in order to predict the affinity and orientation of the synthesized compounds at the active site. The ICM score values and hydrogen bonds formed with the surrounding amino acids show good agreement with predicted binding affinities obtained by molecular docking studies as verified by antimicrobial screening, where compounds 5, 6, 13 were the most active compounds against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli. Compound 13 has good affinity with the receptor and forms six hydrogen bonds with Asp-73, and two bonds with Thr-165, compound 6 has ICM score value -85.66 and forms one hydrogen bond with Asp-73, and three with Thr-165, and compound 5 has ICM score value -53 but forms one hydrogen bond with Asp-73, and four bonds with Thr-165 which may reveal the potent antimicrobial activity referred to the natural antimicrobial Clorobiocin which forms two hydrogen bonds with Asp-73 and three with Thr-165., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

8-Acetyl-7-hydroxy-4-phenyl-2H-benzopyran-2-one as starting material a number of 8-substituted derivatives (i.e., hydrazones 2a,b, imine 2c, chalcones 3, pyrazoles 4, 3-cyano-2-oxo-dihydropyridines 5, and/or 3-cyano-2-imino-dihydropyridines 6) were synthesized and assayed for their anti-inflammatory, analgesic and antipyretic activities. Compounds 3c, 4b and 4i showed significant anti-inflammatory, analgesic and antipyretic activities. In addition, 1, 3b, 4d, 4e, 5b, 6a, 6c, 6d, 6e showed anti-inflammatory activity, 2b, 4h, 5e exhibit analgesic activity, and 2b, 4h, 5e showed antipyretic effect. In addition, molecular modeling and docking of the tested compounds into cyclooxygenase II complexed with its bound inhibitor indomethacin (4COX) using molsoft icm 3.4-8C program was performed in order to predict the affinity and orientation of the synthesized compounds at the active site. Also, it was found that the active compounds 1, 4i, 6a-e interact with both Serine 530, and Tyrosine 385 amino acids which are the main amino acids involved in the mechanism of cyclooxygenase II inhibition. The synthesis of the pyrazole-containing new compounds 4 proved a successful hit; also, the 2-imino derivatives of 3-cyano-dihydropyridines were more successful than the 2-oxo derivatives. According to these results, we can conclude that compounds 1, 3c, 4b, 4i, and 6c appear to be the most interesting and seem potentially attractive as anti-inflammatory, analgesic, and antipyretic agents.

The synthesis and the photobiological activity of new tetrahydrobenzo- and benzofurobenzopyrone derivatives carrying at position 4 of benzopyrone ring of furobenzopyrone moiety a phenyl, or a methyl group with a linear structure or with various angular arrangements, are reported. The new compounds are characterized by having an additional cyclohexene or phenyl ring condensed at the 2, 3 double bond of the furan ring of furobenzopyrone nucleus. The syntheses were performed starting from the appropriate hydroxybenzopyrones on which the tetrahydrobenzofuran or benzofuran moiety was built, which look most promising for enhancement of photoreactivity of compounds toward DNA. All the synthesized compounds were screened for photosensitizing activity and some of them exhibited good activity also a certain effect was observed in the dark.

In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H-benzopyran-2-one) analogues. These derivatives include substituted azetidin-2-ones (beta-lactam) 3a-f, pyrrolidin-2-ones 4a-f, 2H-1,3,4-oxadiazoles 5a-f, and thiazolidin-4-ones 6a-f attached to 4-phenyl-2H-benzopyran-2-one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2-oxo-4-phenyl-2H-benzo[b]pyran-7-yl-oxyacetic acid hydrazides 2a-f. The new compounds were evaluated as DNA gyrase-B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4-8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram-positive and Gram-negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.

Two new series of 2H-1-benzopyran-2-one derivatives substituted at C-6 and/or C-7 with propanolamines, and/or piperazine propanol derivatives have been synthesized and assayed for the H(1)-histamine antagonist. Twelve of the 20 newly synthesized 4- substituted benzopyrones have shown potent antihistaminic H(1) activity. In addition, molecular modeling and docking of the tested compounds into high affinity histamine binding protein (HBP) and histamine N-methyltranseferase (HNMT) active site in complex with its bound inhibitor (diphenhydramine) was performed in order to predict the affinity and orientation of these compounds at the active sites. The ICM score values show good agreement with predicted binding affinities obtained by molecular docking studies as verified by pharmacological screening. The results showed similar orientation of the target compounds at HBP, and HNMT active sites compared with reported histamine H(1) antagonist. Also, it was concluded that in order for the compounds to be active, they must bind with both active sites of HNMT enzyme (two pockets) to inhibit it. Compounds 8c, 8i, 11g, 11i, and 11k; observe the maximum activities.