Insight on Some Newly Synthesized Trisubstituted Imidazolinones as VEGFR-2 Inhibitors.

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (3a, 3c, 3f, 3g, 3h, 3i, 3j, 6a, 6f, and 6i) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 µM, compared with Sorafenib and Sunitinib with IC50 values of 0.06 and 0.12 µM, respectively. The most promising candidate, 3j, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.

Utility of sulfachloropyridazine in the synthesis of novel anticancer agents as antiangiogenic and apoptotic inducers.

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 IC50 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.

Molecular docking approach for the design and synthesis of new pyrazolopyrimidine analogs of roscovitine as potential CDK2 inhibitors endowed with pronounced anticancer activity.

Cyclin-dependent kinase 2 (CDK2) is a vital protein for controlling cell cycle progression that is critically associated with various malignancies and its inhibition could offer a convenient therapeutic approach in designing anticancer remedies. Consequently, this study aimed to design and synthesize new CDK2 inhibitors featuring roscovitine as a template model. The purine ring of roscovitine was bioisosterically replaced with the pyrazolo[3,4-d]pyrimidine scaffold, in addition to some modifications in the side chains. A preliminary molecular docking study for the target chemotypes in the CDK2 binding domain revealed their ability to accomplish similar binding patterns and interactions to that of the lead compound roscovitine. Afterwards, synthesis of the new derivatives was accomplished. Then, the initial anticancer screening at a single dose by the NCI revealed that compounds 7a, 9c, 11c, 17a and 17b achieved the highest GI% values reaching up to 150 % indicating their remarkable activity. These derivatives were subsequently selected to undertake five-dose testing, where compounds 7a, 9c, 11c and 17a unveiled the most pronounced activity against almost the full panel with GI50 ranges; 1.41-28.2, 0.116-2.39, 0.578-60.6 and 1.75-42.4 µM, respectively and full panel GI50 (MG-MID); 8.24, 0.6, 2.46 and 6.84 µM, respectively. CDK2 inhibition assay presented compounds 7a and 9c as the most potent inhibitors with IC50 values of 0.262 and 0.281 µM, respectively which are nearly 2.4 folds higher than the reference ligand roscovitine (IC50 = 0.641 µM). Besides, flow cytometric analysis on the most susceptible and safe cell lines depicted that 7a caused cell cycle arrest at G1/S phase in renal cancer cell line (RXF393) while 9c led to cell growth arrest at S phase in breast cancer cell line (T-47D) along with pronounced apoptotic induction in the mentioned cell lines. These findings afforded new anticancer pyrazolo[3,4-d]pyrimidine, roscovitine analogs, acting via CDK2 inhibition.

How did the use of the social marketing approach in Egyptian communities succeed in improving breastfeeding practices and infants' growth?

INTRODUCTION: Improving breastfeeding practices does not always link to interventions relying only on improving nutrition awareness and education but needs cultural and behavioral insights . AIM: This study aimed to evaluate the changes in core breastfeeding indicators as a result of the use of social marketing (SM) approach for improving breastfeeding practices of Egyptian women and the physical growth of infants aged 6 to 12 months. The core breastfeeding indicators were: Early initiation of breastfeeding within one hour of birth, Predominant and exclusive breastfeeding to 6 months (EBF), Bottle feeding with formula, continued breastfeeding to 1 and 2 years, and responsiveness to cues of hunger and satiety. METHODS: A quasi-experimental longitudinal study with a posttest-only control design was done over 3 years in three phases; the first was in-depth interviews and formative research followed by health education and counseling interventions and ended by measuring the outcome. Motivating mothers' voluntary behaviors toward breastfeeding promotion "feeding your baby like a baby" was done using SM principles: product, price, place, and promotion. The interventions targeted 646 pregnant women in their last trimester and delivered mothers and 1454 women in their childbearing period. The statistical analysis was done by using SPSS program, version 26. RESULTS: Most mothers showed significantly increased awareness about the benefits of breastfeeding and became interested in breastfeeding their children outside the house using the breastfeeding cover (Gawn) (p < 0.05). Breastfeeding initiation, exclusive breastfeeding under 6 months, frequency of breastfeeding per day, and percentage of children who continued breastfeeding till 2 years, were significantly increased (from 30%, 23%, 56%, and 32% to 62%, 47.3%, 69%, and 43.5% respectively). The girls who recorded underweight results over boys during the first year of life were significantly improved (p < 0.01) after the intervention (from 52.1% to 18.8% respectively). At the same time, girls found to be obese before the intervention (15.6%) became no longer obese. CONCLUSIONS: Improvement for the majority of the key breastfeeding indicators and physical growth of infants indicates that raising a healthy generation should start by promoting breastfeeding practices that are respectable to societal norms.

Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors.

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 µM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.

Esophageal cancer: a twenty-four-year experience at a tertiary care center with an evaluation of the prognostic significance of the neutrophil-lymphocyte ratio.

BACKGROUND: A high neutrophil-lymphocyte ratio (NLR) may be associated with worse survival in esophageal cancer (EC). Our aims were to describe the demographic and clinical data of EC in a tertiary referral center in Lebanon and to determine the prognostic value of NLR. METHODS: A retrospective cohort study based on chart review of patients diagnosed with EC was conducted at the American University of Beirut Medical Center (AUBMC). The demographic characteristics, clinical presentation and outcomes were described and compared between squamous cell carcinomas (ESCC) and adenocarcinomas (EAC). Data about esophageal cancer incidence were obtained from the National Cancer Registry, the Ministry of Public Health and GLOBOCAN 2020. Cox regression analysis was performed to determine whether the NLR is an independent predictor of survival, using variables based on clinical knowledge and previously established data. RESULTS: 110 patients were diagnosed with EC, which was the least common among other gastrointestinal malignancies. Our follow up rates reached 86.4%. The median survival was 9 months (IQR 3-25.5.) and was comparable between ESCC (median of 7 months, IQR 2-25) and EAC (median of 9 months, IQR 3-26.3), p = 0.803. Advanced stage was associated with a worse prognosis (p = 0.037). The mean NLR(±SD) was 5.20 ± 6.8, with no significant difference between EAC and ESCC (4.5 ± 3.4 vs. 5.9 ± 9.2, p = 0.420) or between early or advanced stages (5.4 ± 8.1 vs. 4.7 ± 6.8, p = 0.732). The area under the curve for the NLR was 0.560 (95% CI: 0.374-0.746, p = 0.488). After adjusting for age, gender, TNM staging and grading, cox regression analysis showed that an increased NLR was a significant predictor of mortality, with an adjusted hazard ratio of 1.095 (p = 0.011). CONCLUSION: EC is quite uncommon in Lebanon despite a high prevalence of smoking and obesity. Advanced stage and high NLR were associated with a negative prognostic value.

Added value of 3D THRIVE (T1-weighted high-resolution isotropic volume examination) MRI pulse sequence in the detection of bony erosions of sacroiliac joints in patients of spondyloarthritis.

Purpose: Early depiction of bony erosions in sacroiliac (SI) joints increases the diagnostic accuracy of spondyloarthritis. The new 3D magnetic resonance imaging (MRI) sequence THRIVE (T1-weighted high-resolution isotropic volume examination) can depict cartilage erosions in sacroiliac joints. The aim of the study was to compare the diagnostic capacity of the new MRI sequence 3D THRIVE (T1-weighted high-resolution isotropic volume examination) with the routinely used T1 TSE pulse sequence in the depiction of structural erosions in sacroiliac joints by using MRI sequence zero echo time (zero ET) as a reference standard. Material and methods: Seventy five adult patients were included in this study. They underwent MRI sacroiliac joints examination using routine T1 TSE and STIR pulse sequences with the addition of the new 3D THRIVE and zero echo time (zero ET) sequences. Images of T1 TSE, 3D THRIVE, and zero ET sequences were evaluated by 2 radiolo-gists separately for the detection of sacroiliac joints erosions, then a comparison between T1 TSE and 3D THRIVE sequences was done using a CT-like image MRI sequence zero ET as a reference standard. Sensitivity, specificity, and accuracy for each sequence were calculated by the 2 readers. Results: Sensitivity, specificity, and accuracy of 3D THRIVE were higher than those of T1 TSE for reader 1 (sensitivity: 94.5% vs. 86.2%; specificity: 93.4% vs. 85.1%; and accuracy 95.2% vs. 88.5%) and for reader 2 (sensitivity: 93.3% vs. 79.9%; specificity: 94.7% vs. 86.2%; and accuracy 95.8% vs. 82.1%). Conclusions: Using CT-like image MRI sequence zero ET as the reference standard, 3D THRIVE pulse sequencing of the sacroiliac joints has much better diagnostic value in the depiction of bony erosions in patients suspected having spondyloarthritis as compared to the routinely used T1 TSE sequence.

Removal of chromium from tannery industry wastewater using iron-based electrocoagulation process: experimental; kinetics; isotherm and economical studies.

Chromium is a hazardous compound from industrial processes, known for its toxicity, mutagenicity, teratogenicity, and carcinogenicity. Chemical methods are efficient but cost-effective alternatives with reduced sludge are sought. Electro-coagulation, utilizing low-cost iron plate electrodes, was explored for factual tannery wastewater treatment in this manuscript. Operating parameters such as initial chromium concentration, voltage, electrode number, operating time, agitation speed and current density has been studied to evaluate the treatment effeciency. Under optimal conditions (15 V, 0.4 mA/cm2, 200 rpm, 330 ppm chromium, 8 iron electrodes with a total surface area of 0.1188 m2, 3 h), chromium elimination was 98.76%. Iron anode consumption, power use, and operating cost were 0.99 gm/L, 0.0143 kW-h/L, and 160 EGP/kg of chromium eliminated, respectively. Kinetics studies were pursued first-order reaction (97.99% correlation), and Langmuir isotherms exhibited strong conformity (Langmuir R2: 99.99%). A predictive correlation for chromium elimination (R2: 97.97%) was developed via statistical regression. At HARBY TANNERY factory in Egypt, industrial sewage treatment achieved a final chromium disposal rate of 98.8% under optimized conditions.

Exploring novel anticancer pyrazole benzenesulfonamides featuring tail approach strategy as carbonic anhydrase inhibitors.

This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e, its bioisosteric carboxylic acid as in compounds 5a-e and 8e, ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7, hydrazide derivative 10e, hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b, 5b, 5d, 5e, 6b, 9b, 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e, 9d, 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 µM), renal cancer cell line (786-0; TGI = 4.32 µM) and breast cancer cell line (HS 578 T; TGI = 5.43 µM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI50 (0.45, 0.89 and 1.18 µM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786-0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis.

Assessment of macronutrients dietary intake, central adiposity among pre- and postmenopausal Egyptian women with benign and malignant breast tumors.

BACKGROUND: Breast cancer (BC) is the second most frequent cancer in women and the second most common cancer worldwide. Lifestyle factors, like body weight, physical activity and diet, may be accompanying with higher BC risk. AIM: The assessment of macronutrients dietary intake; protein, fat, carbohydrates and their components of amino, fatty acids, and central obesity/adiposity among pre- and postmenopausal Egyptian women with benign and malignant breast tumors. METHODS: The current case control study included 222 women: 85 control, 54 benign and 83 breast cancer patients. Clinical, anthropocentric and biomedical examinations were performed. Dietary history and health attitude were done. RESULTS: The anthropometric parameters including waist circumference (WC) and the body mass index (BMI) of the benign and the women with malignant breast lesions showed the highest values when compared to the control (35.45 ± 15.58 km2 and 101.24 ± 15.01 cm, 31.39 ± 6.77 km2 and 98.85 ± 13.53 cm and 27.51 ± 7.10 km2 and 84.33 ± 13.78 cm). The biochemical parameters revealed high concentration of the total cholesterol (TC) (192.83 ± 41.54 mg/dl), low density lipoprotein-cholesterol (LDL-C) (117.88 ± 35.18 mg/dl) and the median insulin level 13.8 (10.2-24.1) µu/ml in the malignant patients with high significant difference compared to the control. The malignant patients had the highest daily caloric intake (795.84 ± 519.95 K calories) proteins (65.39 ± 28.77 g), total fats (69.09 ± 32.15 g) and carbohydrates (196.70 ± 85.35 g), when compared to the control. Data also revealed the high daily consumption of the different types of the fatty acids with high linoleic/linoleinic ratio among the malignant group (14.284 ± 6.25). Branched chain amino acids (BGAAs), sulphur amino acids (SAAs), conditional amino acids (CAAs) and aromatic amino acids (AAAs) proved to be the highest in this group. Correlation coefficient between the risk factors revealed either positive or negative weak correlation except that between serum LDL-C concentration and the amino acids (isoleucine, valine cysteine, tryptophan and tyrosine) and negative association with the protective polyunsaturated fatty acids. CONCLUSION: Participants with breast cancer had the greatest levels of body fatness and unhealthy feeding habits relative to their high calorie, protein, carbohydrate, and fat intake.

Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity.

Design and synthesis of three novel series of aryl enaminones (3a-f and 5a-c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a-c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.

Exploration of thiazolidine-2,4-diones as tyrosine kinase inhibitors: Design, synthesis, ADMET, docking, and antiproliferative evaluations.

As dual EGFR and VEGFR-2 inhibitors, 22 innovative thiazolidine-2,4-diones were modeled, constructed, and measured for their anticancer performance versus four human neoplasms HCT-116, MCF-7, A549, and HepG2. Molecular docking and MD simulation were performed to inspect the binding technique of the proffered congeners with the EGFR and VEGFR-2 receptors. Evidence realized thanks to the docking inquests was vastly consistent together with that detected through the biological screening. Structures 14a and 14g emerged as the most active compounds toward HCT116 (IC50 = 6.01 and 7.44 µM), MCF-7 (IC50 = 5.77 and 7.23 µM), A549 (IC50 = 5.35 and 5.47 µM) and HepG2 (IC50 = 3.55 and 3.85 µM) tumefaction cells. Compounds 14a and 14g exhibited higher events than sorafenib (IC50 = 5.05, 5.58, 4.04, and 4.00 µM) against HepG2 instead subordinate incidents concerning A549, MCF-7, and HCT116, parallelly. Nevertheless, these compounds signified weightier performance than erlotinib (IC50 = 13.91, 8.20, 5.49, 7.73, and µM), with respect to the four cell lines. Compounds having the best activity against the four cell lines, 12a-f, 13a-d, and 14a-g were chosen to appraise their in vitro VEGFR-2 and EGFRT790M inhibiting activities. The best results were for compounds 14a and 14g compared to sorafenib and erlotinib, respectively, with IC50 values of 0.74 and 0.78 µM and 0.12 and 0.14 µM, respectively. Moreover, 13d, 14a, and 14g showed an adequate in silico calculated ADMET profile. The current investigation presents novel candidates for future optimization to construct mightier and eclectic binary VEGFR-2/EGFRT790M restrainers with higher antitumor effects.

Antiproliferative, antiangiogenic and apoptotic effect of new hybrids of quinazoline-4(3H)-ones and sulfachloropyridazine.

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 IC50 = 66 ± 0.002, 108 ± 0.004 and 146 ± 0.006 nM, respectively. Compound 8f showed also moderate inhibition against PDGFR (IC50 = 180 ± 0.009 nM), EGFR (IC50 = 98 ± 0.004 nM), FGFR-1 (IC50 = 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.

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors.

The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide 7a-f, benzoic acid 8a-f or ethylbenzoate 9a-f moieties. The synthesised compounds were screened for their carbonic anhydrase inhibitory activity (CAI) against four isoforms hCA I, II, IX, and XII. Compounds 7a, 7b, 7c, and 7f exhibited a potent inhibitory activity towards hCAI (Kis = 58.20, 56.30, 33.00, and 43.00 nM), respectively compared to acetazolamide (AAZ) and SLC-0111 (Kis = 250.00 and 5080.00 nM). Compounds 7a, 7b, 7c, 7e, and 7f elicited selectivity over h CA II (Kis = 2.50, 2.10, 56.60,39.60 and 39.00 nM) respectively, relative to AAZ and SLC-0111(Kis = 12.10 and 960.00 nM). Also, compounds 7c, 7f, and 9e displayed selectivity against the tumour-associated isoform hCA IX (Kis = 31.20, 30.00 and 29.00 nM) respectively, compared to AAZ and SLC-0111 (Kis = 25.70 and 45.00 nM). Additionally, compounds 8a and 8f revealed a moderate to superior selectivity towards hCAXII (Kis = 17.00 and 11.00 nM) relative to AAZ and SLC-0111(Kis = 5.70 and 45.00 nM). Molecular docking and ADME prediction studies were performed on the most active compounds to shed light on their interaction with the hot spots of the active site of CA isoforms, in addition to prediction of their pharmacokinetic and physicochemical properties.

Design and synthesis of some new benzoylthioureido phenyl derivatives targeting carbonic anhydrase enzymes.

The present study aimed to develop potent carbonic anhydrase inhibitors (CAIs). The design of the target compounds was based on modifying the structure of the ureido-based carbonic anhydrase inhibitor SLC-0111. Six series of a substituted benzoylthioureido core were prepared featuring different zinc-binding groups; the conventional sulphamoyl group 4a-d and 12a-c, its bioisosteric carboxylic acid group 5a-d and 13a-c or the ethyl carboxylate group 6a-d and 14a-c as potential prodrugs. All compounds were assessed for their carbonic anhydrase (CA) inhibitory activity against a panel of four physiologically relevant human CA isoforms hCA I and hCA II, and hCA IX, and hCA XII. Compounds 4a, 4b, 4c, 4d, 5d, 12a, and 12c revealed significant inhibitory activity against hCA I that would highlight these compounds as promising drug candidates for the treatment of glaucoma.

Design, synthesis, in silico docking, ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFRT790M tyrosine kinase inhibitors.

Fourteen recent thiazolidine-2,4-diones bearing furan and/or thiophene heterocyclic rings have been designed, synthesized and assessed for their anticancer activities against four human tumor cell lines HepG2, A549, MCF-7 and HCT-116 targeting both VEGFR-2 and EGFR tyrosine kinases. Molecular design was carried out to investigate the binding mode of the proposed compounds with VEGFR-2 and EGFR receptors. HepG2 was the most susceptible cell line to the influence of our derivatives. Compounds 5g and 4g revealed the highest activities against HepG2 (IC50 = 3.86 and 6.22 µM), A549 (IC50 = 7.55 and 12.92 µM), MCF-7 (IC50 = 10.65 and 10.66 µM) and HCT116 (IC50 = 9.04 and 11.17 µM) tumor cell lines. Sorafenib (IC50 = 4.00, 4.04, 5.58 and 5.05 µM) and elotinib (IC50 = 7.73, 5.49, 8.20 and 13.91 µM) were used as reference standards. Furthermore, the most active cytotoxic compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were selected to assess their VEGFR-2 inhibitory effects. Derivatives 5g, 4g and 4f were observed to be the highest effective derivatives that inhibited VEGFR-2 at the submicromolar level (IC50 = 0.080, 0.083 and 0.095 µM respectively) in comparison to sorafenib (IC50 = 0.084 µM). As well, compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were additionally assessed for their inhibitory activities against mutant EGFRT790M. Compounds 5g and 4g could interfere with the EGFRT790M activity exhibiting stronger activities than elotinib with IC50 = 0.14 and 0.23 µM respectively. Finally, our derivatives 4g, 5f and 5g showed a good in silico calculated ADMET profile. The obtained results showed that our compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

A randomized controlled trial of two-doses of vaginal progesterone 400 vs. 200 mg for prevention of preterm labor in twin gestations.

OBJECTIVES: To compare between the effectiveness and safety of two different daily doses of vaginal progesterone (400 vs. 200 mg) in the prevention of preterm labor in twin pregnancy. METHODS: This is a prospective single-blinded randomized controlled trial conducted on 100 primi-gravida who had twin pregnancy and attended the antenatal clinic of a University hospital. They were equally and randomly allocated into two arms each containing 50 patients. Arm 1 received 400 mg and arm 2 received 200 mg vaginal progesterone daily at bed time starting from 14 weeks of pregnancy to 36 weeks. Transvaginal ultrasound was performed for assessment of the length of cervix at 14 and 22 weeks. RESULTS: Both arms of the current study were comparable regarding the cervical length at 14 and 22 weeks, mean gestational age at delivery, incidence of pre-term delivery, birth weight of the first twin. Second twin in addition to the average weight of both twins. No statistical significance differences between two arms regarding incidence of early neonatal death. NICU, mechanical ventilation, length of admission in NICU for the first twin. Second twin as well as both twins. CONCLUSIONS: Vaginal progesterone treatment with different doses was tolerable, but wasn't effective in the prevention of preterm labor in twin pregnancy.

The role of diffusion tensor imaging in idiopathic sensorineural hearing loss: is it significant?

PURPOSE: To assess the role of diffusion tensor imaging metrics in the evaluation of the microstructural integrity of the central auditory tract in patients with idiopathic sensorineural hearing loss (SNHL), and to compare these patients with healthy controls. MATERIAL AND METHODS: This prospective study, which was conducted upon 30 subjects (21 males, 9 females; age range from 16 to 65 years, mean age 45years) with SNHL proven by audiometric tests. Ten age- and sex-matched healthy volunteers were included as a control group. Patients (n = 30) and volunteers (n = 10) underwent conventional magnetic resonance imaging and diffusion tensor imaging of the brain. Both fractional anisotropy and mean diffusivity (MD) of 3 points along the acoustic tract (inferior colliculus, lateral lemniscus and superior olivary nucleus) were measured bilaterally in all patients and correlated with controls. RESULTS: Mean fractional anisotropy (FA) values were reduced bilaterally at the superior olivary nucleus and/or lateral lemniscus and more significantly at the inferior colliculus of subjects with SNHL in comparison to the volunteers. In patients of unilateral SNHL, similar results were obtained in the contralateral side when compared to controls with statistically significant difference at the 3 regions (p = 0.001). No significant changes were noticed in the MD parameters either in patient or control groups. CONCLUSIONS: The FA value was a valuable non-invasive biomarker in evaluating the subtle microstructural abnormalities of the central auditory tract in idiopathic SNHL and correlated well with hearing impairment.

Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs).

New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC50 = 43.25 nM). Furthermore, preliminary anti-proliferative activity screening of some selected compounds on 60 cancer cell lines was performed at the (NCI/USA). Compounds 8a-c displayed promising growth inhibitory activity (mean %GI; 73.74, 94.32 and 74.19, respectively). Additionally, they were further selected by the NCI for five-dose assay, exhibiting pronounced activity against almost the full panel (GI50 ranges; 0.181-5.19, 1.07-4.12 and 1.07-4.82 µM, respectively) and (Full panel GI50 (MG-MID); 2.838, 2.306 and 2.770 µM, respectively). Screening the synthesized compounds 8a-c for inhibition of CDK isoforms revealed that compound 8a exhibited nearly equal inhibition to all the tested CDK isoforms, while compound 8b inhibits CDK4/D1 preferentially than the other isoforms and compound 8c inhibits CDK1, CDK2 and CDK4 more than CDK7. Flow cytometry cell cycle assay of 8a-c on Non-small cell lung carcinoma (NSCL HOP-92) cell line revealed S phase arrest by 8a and G1/S phase arrest by 8b and 8c. Apoptotic induction in HOP-92 cell line was also observed upon treatment with compounds 8a-c. Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents.