Iodoquinazoline-derived VEGFR-2 and EGFRT790M dual inhibitors: Design, synthesis, molecular docking and anticancer evaluations.

Herein, we report the synthesis of a series of new fourteen iodoquinazoline derivatives 7a-c to 13a-e and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The new derivatives were designed according to the target receptors structural requirements. The compounds were evaluated for their cytotoxicity against HepG2, MCF-7, HCT116 and A549 cancer cell lines using MTT assay. Compound 13e showed the highest anticancer activities with IC50 = 5.70, 7.15, 5.76 and 6.50 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Compounds 7c, 9b and 13a-d exhibited very good anticancer effects against the tested cancer cell lines. The highly effective six derivatives 7c, 10, 13b, 13c, 13d and 13e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Our conclusion revealed that compounds 7c, 10, 13b, 13c, 13d and 13e possessed low toxicity against VERO normal cells with IC50 prolonging from 41.66 to 53.99 µM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Also, their ability to bind with both EGFR and VEGFR-2 receptors was examined by molecular modeling. Compounds 13e, 13d, 7c and 13c excellently inhibited VEGFR-2 activity with IC50 = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFRT790M activity with IC50 = 0.30, 0.35, 0.45 and 0.47 µM respectively. Finally, our derivatives 7b, 13d and 13e showed good in silico calculated ADMET profile.

Incompleteness and misclassification of maternal death recording: a systematic review and meta-analysis.

OBJECTIVE: To quantify the extent of incompleteness and misclassification of maternal and pregnancy related deaths, and to identify general and context-specific factors associated with incompleteness and/or misclassification of maternal death data. METHODS: We conducted a systematic review of incompleteness and/or misclassification of maternal and pregnancy-related deaths. We conducted a narrative synthesis to identify methods used to capture and classify maternal deaths, as well as general and context specific factors affecting the completeness and misclassification of maternal death recording. We conducted a meta-analysis of proportions to obtain estimates of incompleteness and misclassification of maternal death recording, overall and disaggregated by income and surveillance system types. FINDINGS: Of 2872 title-abstracts identified, 29 were eligible for inclusions in the qualitative synthesis, and 20 in the meta-analysis. Included studies relied principally on record linkage and review for identifying deaths, and on review of medical records and verbal autopsies to correctly classify cause of death. Deaths to women towards the extremes of the reproductive age range, those not classified by a medical examiner or a coroner, and those from minority ethnic groups in their setting were more likely misclassified or unrecorded. In the meta-analysis, we found maternal death recording to be incomplete by 34% (95% CI: 28-48), with 60% sensitivity (95% CI: 31-81.). Overall, we found maternal mortality was under-estimated by 39% (95% CI: 30-48) due to incompleteness and/or misclassification. Reporting of deaths away from the intrapartum, due to indirect causes or occurring at home were less complete than their counterparts. There was substantial between and within group variability across most results. CONCLUSION: Maternal deaths were under-estimated in almost all contexts, but the extent varied across settings. Countries should aim towards establishing Civil Registration and Vital Statistics systems where they are not instituted. Efforts to improve the completeness and accuracy of maternal cause of death recording, such as Confidential Enquiries into Maternal Deaths, are needed even where CRVS is considered to be well-functioning.

Genetic Characterization of Myf5 and POU1F1 Genes in Different Egyptian Local Rabbit Breeds and Their Association with Growth Traits.

Genetic characterization and its association with quantitative traits in local breeds are important tools for the genetic improvement and sustainable management of animal genetic resources. Myogenic regulatory factor 5 (MYf5) and POU class 1 homeobox 1 (POU1F1) are candidate genes which play important roles in growth and development of mammals. The present study aims to detect the genetic diversity of the MYf5 and POU1F1 genes in four local Egyptian rabbit breeds and their association with growth traits, using PCR-restriction enzyme (PCR-RFLP), PCR-single-strand conformational polymorphism (PCR-SSCP), and direct sequencing techniques. The results showed that MYF5 exon 1 was observed with two genotypes in Baladi Black (BB), Gabali (GB) and New Zealand White (NZW) breeds while APRI-line (APRI) presented one genotype. The genetic diversity of Myf5 exon 2 between breeds showed two genotypes in APRI compared to three in NZW and four genotypes in BB and GB breeds. The genetic diversity of the POU1F1 gene (intron 5 and partial cds) in different rabbit breeds was two genotypes in NZW and three genotypes in BB, GB, and APRI breeds with different frequencies for each genotype. Based on the statistically significant difference between genes genotypes and growth weight, the results suggested that the genotypes of Myf5 exon 2 (1 and 2) of the BB breed, Myf5 exon 2 genotype 2 of the APRI breed, and genotype 1 of Myf5 exon 1 and genotype 1 of POU1F1 of the NZW breed compared to genotypes for each gene can be considered candidate molecular markers associated with the improvement of growth traits in these breeds.

Design, synthesis, and docking of novel thiazolidine-2,4-dione multitarget scaffold as new approach for cancer treatment.

Novel thiazolidine-2,4-diones have been developed and estimated as conjoint inhibitors of EGFRT790M and VEGFR-2 against HCT-116, MCF-7, A549, and HepG2 cells. Compounds 6a, 6b, and 6c were known to be the dominant advantageous congeners against HCT116 (IC50 = 15.22, 8.65, and 8.80 µM), A549 (IC50 = 7.10, 6.55, and 8.11 µM), MCF-7 (IC50 = 14.56, 6.65, and 7.09 µM) and HepG2 (IC50 = 11.90, 5.35, and 5.60 µM) mass cell lines, correspondingly. Although compounds 6a, 6b, and 6c disclosed poorer effects than sorafenib (IC50 = 4.00, 4.04, 5.58, and 5.05 µM) against the tested cell sets, congeners 6b and 6c demonstrated higher actions than erlotinib (IC50 = 7.73, 5.49, 8.20, and 13.91 µM) against HCT116, MCF-7 and HepG2 cells, yet lesser performance on A549 cells. The hugely effective derivatives 4e-i and 6a-c were inspected versus VERO normal cell strains. Compounds 6b, 6c, 6a, and 4i were found to be the most effective derivatives, which suppressed VEGFR-2 by IC50 = 0.85, 0.90, 1.50, and 1.80 µM, respectively. Moreover, compounds 6b, 6a, 6c, and 6i could interfere with the EGFRT790M performing strongest effects with IC50 = 0.30, 0.35, 0.50, and 1.00 µM, respectively. What is more, 6a, 6b, and 6c represented satisfactory in silico computed ADMET profile.

Temporal trends in childhood cancer survival in Egypt, 2007 to 2017: A large retrospective study of 14 808 children with cancer from the Children's Cancer Hospital Egypt.

Childhood cancer is a priority in Egypt due to large numbers of children with cancer, suboptimal care and insufficient resources. It is difficult to evaluate progress in survival because of paucity of data in National Cancer Registry. In this study, we studied survival rates and trends in survival of the largest available cohort of children with cancer (n = 15 779, aged 0-18 years) from Egypt between 2007 and 2017, treated at Children's Cancer Hospital Egypt-(CCHE), representing 40% to 50% of all childhood cancers across Egypt. We estimated 5-year overall survival (OS) for 14 808 eligible patients using Kaplan-Meier method, and determined survival trends using Cox regression by single year of diagnosis and by diagnosis periods. We compared age-standardized rates to international benchmarks in England and the United States, identified cancers with inferior survival and provided recommendations for improvement. Five-year OS was 72.1% (95% CI 71.3-72.9) for all cancers combined, and survival trends increased significantly by single year of diagnosis (P < .001) and by calendar periods from 69.6% to 74.2% (P < .0001) between 2007-2012 and 2013-2017. Survival trends improved significantly for leukemias, lymphomas, CNS tumors, neuroblastoma, hepatoblastoma and Ewing Sarcoma. Survival was significantly lower by 9% and 11.2% (P < .001) than England and the United States, respectively. Significantly inferior survival was observed for the majority of cancers. Although survival trends are improving for childhood cancers in Egypt/CCHE, survival is still inferior in high-income countries. We provide evidence-based recommendations to improve survival in Egypt by reflecting on current obstacles in care, with further implications on practice and policy.

The rational design, synthesis, and antimicrobial investigation of 2-Amino-4-Methylthiazole analogues inhibitors of GlcN-6-P synthase.

A series of novel 2-Amino-4-Methylthiazole analogs were developed via three-step reaction encompassing hydrazine-1-carboximidamide motif to combat Gram-positive and Gram-negative bacterial and fungal infections. Noticeably, the thiazole-carboximidamide derivatives 4a-d displayed excellent antimicrobial activity and the most efficacious analogue 4d with MIC/MBC values of 0.5 and 4 µg/mL, compared to reference drugs with very low toxicity to mammalian cells, resulting in a prominent selectivity more than 100 folds. Microscopic investigation of 4d biphenyl analogue showed cell wall lysis and promote rapid bactericidal activity though disrupting the bacterial membrane. In addition, an interesting in vitro investigation against GlcN-6-P Synthase Inhibition was done which showed potency in the nanomolar range. Meanwhile, this is the first study deploying a biomimicking strategy to design potent thiazole-carboximidamides that targeting GlcN-6-P Synthase as antimicrobial agents. Importantly, Molecular modeling simulation was done for the most active 4d analogue to study the interaction of this analogue which showed good binding propensity to glucosamine binding site which support the in vitro data.

Porous Activated Carbon from Lignocellulosic Agricultural Waste for the Removal of Acetampirid Pesticide from Aqueous Solutions.

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

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta-analysis of randomized clinical trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of personalized genotype-guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter-individual response variability which could limit its efficacy. METHODS: Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype-guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random-effects model. RESULTS: We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype-guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35-1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype-guided group (RR 0.44; 95% CI: 0.28-0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27-1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23-1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13-1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43-1.06; P = 0.09). CONCLUSION: In patients undergoing stent implantation, MACE with genotype-guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials.

Restrictive versus liberal red blood cell transfusion for cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.

Patients undergoing cardiac surgery are among the most common recipients of allogeneic red blood cell (RBC) transfusions. However, whether restrictive RBC transfusion strategies for cardiac surgery achieve a similar clinical outcome in comparison with liberal strategies remains unclear. We searched electronic databases from inception to December 2017 for randomized controlled trials (RCTs). We calculated the risk ratios (RRs) and weighted-mean difference (MD) using a random-effects model. We included 9 RCTs with a total of 9005 patients. There was no significant difference in mortality between groups [RR 1.03; 95% confidence interval (CI) 0.74-1.45; P = 0.86]. In addition, there were no significant differences between groups in the clinical outcomes of infections (RR 1.09; 95% CI 0.94-1.26; P = 0.26), stroke (RR 0.98; 95% CI 0.72-1.35; P = 0.91), respiratory morbidity (RR 1.05; 95% CI 0.89-1.24; P = 0.58), renal morbidity (RR 1.02; 95% CI 0.94-1.09; P = 0.68), myocardial infarction (RR 1.00; 95% CI 0.80-1.24; P = 0.99), cardiac arrhythmia (RR 1.05; 95% CI 0.88-1.26; P = 0.56), gastrointestinal morbidity (RR 1.93; 95% CI 0.81-4.63; P = 0.14), or reoperation (RR 0.90; 95% CI 0.67-1.20; P = 0.46). There was a significant difference in the intensive care unit length of stay (h) (MD 4.29; 95% CI 2.19-6.39, P < 0.01) favoring the liberal group. However, there was no significant difference in the hospital length of stay (days) (MD 0.15; 95% CI - 0.18 to 0.48; P = 0.38). In conclusion, this meta-analysis showed that restrictive strategies for RBC transfusion are as safe as liberal strategies in patients undergoing cardiac surgery with regards to short-term clinical outcomes.

Clopidogrel and aspirin after ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis of randomized clinical trials.

Recurrent stroke is common immediately following a transient ischemic attack (TIA) or ischemic stroke. Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin may provide greater protection against subsequent stroke than monotherapy. Electronic databases were searched for randomized clinical trials (RCTs) comparing DAPT with monotherapy in ischemic stroke/TIA. Sixteen RCTs with a total of 29,032 patients were included. Compared with monotherapy, DAPT was associated with significantly lower rates of any stroke (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.72-0.89) and ischemic stroke (RR 0.75; 95% CI 0.66-0.85) during any follow-up period. Although significant increases in intracranial bleeding (RR 1.55; 95% CI 1.20-2.01) and major bleeding (RR 1.90; 95% CI 1.33-2.72) were associated with DAPT, especially with long-term follow-up, the number needed to harm was 258 and 113, respectively. Nevertheless, short-duration DAPT (≤ 1 month) started during the early acute ischemic phase was associated with less bleeding than longer DAPT and greater reduction of recurrent strokes compared with monotherapy. In contrast, long DAPT and DAPT started later after the index event (≥ 1 month) were associated with similar rates of any stroke and increased risks of bleeding compared with monotherapy. Other clinical outcomes were essentially similar between the two groups and included recurrent TIA (RR 0.88; 95% CI 0.72-1.07), myocardial infarction (RR 1.04; 95% CI 0.84-1.29), vascular death (RR 0.99; 95% CI 0.82-1.19), and any death (RR 1.12; 95% CI 0.88-1.42). Similar findings were observed in patients who presented with minor stroke/TIA. Conclusions: Among patients who presented with ischemic stroke/TIA, short-course clopidogrel plus aspirin immediately following the index event appears to be more effective than and as safe as monotherapy for secondary stroke prevention.

Design, synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents.

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.

Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials.

Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence, we conducted a study to evaluate the efficacy and safety of tenecteplase compared with alteplase in acute ischemic stroke. Electronic databases were searched for randomized clinical trials (RCTs) comparing tenecteplase with alteplase in acute ischemic stroke patients eligible for thrombolysis. We evaluated various efficacy and safety outcomes using random-effects models for both pairwise and Bayesian network meta-analyses along with meta-regression analyses. We included 5 RCTs with a total of 1585 patients. Compared with alteplase, tenecteplase treatment was associated with significantly greater complete recanalization (odd ratio [OR] 2.01; 95% confidence interval [CI] 1.04-3.87; p = 0.04) and early neurological improvement (OR 1.43; 95% CI 1.01-2.03; p = 0.05). There were no differences between the two thrombolytics in terms of excellent recovery (modified Rankin Scale [mRS] 0-1; OR 1.17; 95% CI 0.95-1.44; p = 0.13), functional independence (mRS 0-2; OR 1.24; 95% CI 0.78-1.98), poor recovery (mRS 4-6; OR 0.78; 95% CI 0.49-1.25; p = 0.31), complete/partial recanalization (OR 1.51; 95% CI 0.70-3.26; p = 0.30), any intracerebral hemorrhage (OR 0.81; 95% CI 0.56-1.17; p = 0.26), symptomatic intracerebral hemorrhage (OR 0.98; 95% CI 0.52-1.83; p = 0.94), or mortality (OR 0.83; 95% CI 0.54-1.26; p = 0.38). In network meta-analysis, there were better efficacy and imaging-based outcomes with tenecteplase 0.25 mg/kg without increased risk of safety outcomes. Our results demonstrate that in acute ischemic stroke, thrombolysis with tenecteplase is at least as effective and safe as alteplase.

Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a systematic review and meta-analysis of randomized clinical trials.

Dual antiplatelet therapy with aspirin and clopidogrel are recommended as adjuncts to fibrinolytic-treated patients with ST-elevation myocardial infarction (STEMI). However, the role of switching to ticagrelor within 24 h of fibrinolytics compared with clopidogrel continuation in this setting is uncertain. Hence, we conducted a comprehensive search of electronic databases for all randomized clinical trials (RCTs) that evaluated the safety and efficacy of ticagrelor versus clopidogrel after fibrinolytic therapy in patients with STEMI. A random-effects model was used to calculate the risk ratios (RRs) and 95% confidence intervals (CIs). A total of 5 RCTs that evaluated the efficacy of ticagrelor post-fibrinolysis were identified. We included 3 RCTs with 3999 total patients for our meta-analysis. The results showed similar short-term clinical outcomes between ticagrelor and clopidogrel with regard to rates of Bleeding Academic Research Consortium (BARC) type ≥ 2 bleeding (RR 0.94; 95% CI 0.56-1.60; P = 0.83), major adverse cardiovascular events (RR 0.87; 95% CI 0.49-1.52; P = 0.62), mortality (RR 0.92; 95% CI 0.53-1.59; P = 0.77), myocardial infarction (RR 0.76; 95% CI 0.43-1.36; P = 0.36), and stroke (RR 0.93; 95% CI 0.50-1.73; P = 0.82). Our results demonstrate that in STEMI patients treated with fibrinolytic therapy, switching to ticagrelor was associated with similar bleeding and ischemic outcomes compared with clopidogrel continuation.

Design, Synthesis, Cytotoxic Evaluation and Molecular Docking of New Fluoroquinazolinones as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects.

A series of new fluoroquinazolinone 6⁻8 and 10a⁻g derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds 6 (IC50 = 0.35 ± 0.01 µM), 10f (IC50 = 0.71 ± 0.01 µM), 10d (IC50 = 0.89 ± 0.02 µM) and 10a (IC50 = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC50 = 0.97 ± 0.02 µM) against MCF-7. Compounds 10e (IC50 = 0.28 ± 0.02 µM), 10d (IC50 = 0.38 ± 0.01 µM), 7 (IC50 = 0.94 ± 0.07 µM) and 10c (IC50 = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC50 = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated.

Quinazolinone-Amino Acid Hybrids as Dual Inhibitors of EGFR Kinase and Tubulin Polymerization.

Some fluoroquinazolinones (A⁻H) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA-MBA-231. New derivative G (IC50 = 0.44 ± 0.01 µM) showed antitumor activity, better than that of the reference drug erlotinib (IC50 = 1.14 ± 0.04 µM) against MCF-7. New derivative E (IC50 = 0.43 ± 0.02 µM) showed higher activity than the reference drug erlotinib (IC50 = 2.55 ± 0.19 µM) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening.

Design, Synthesis, Antimicrobial Evaluation and Molecular Modeling Study of 1,2,4-Triazole-Based 4-Thiazolidinones.

A series of 3-(2H-1,2,4-triazol-5-yl)-1,3-thiazolidin-4-one derivatives (7c-l) was designed and synthesized. Their structures have been elucidated based on analytical and spectral data. They were evaluated for their antibacterial and antifungal activities. Compound 7h showed the highest activity against all tested strains, except P. vulgaris, with MIC 8 µg/mL and 4 µg/mL against S. aureus and C. albicans, respectively. Furthermore, Compounds 7c, 7h, and 7j demonstrated moderate anti-mycobacterium activity. The binding mode of the synthesized thiazolidinones to bacterial MurB enzyme was also studied. Good interactions between the docked compounds to the MurB active site were observed primarily with Asn83, Arg310, Arg188 and Ser82 amino acid residues.

Structural similarity between ß(3)-peptides synthesized from ß(3)-homo-amino acids and aspartic acid monomers.

Formation of stable secondary structures by oligomers that mimic natural peptides is a key asset for enhanced biological response. Here we show that oligomeric ß(3)-hexapeptides synthesized from L-aspartic acid monomers (ß(3)-peptides 1, 5a, and 6) or homologated ß(3)-amino acids (ß(3)-peptide 2), fold into similar stable 14-helical secondary structures in solution, except that the former form right-handed 14-helix and the later form left-handed 14-helix. ß(3)-Peptides from L-Asp monomers contain an additional amide bond in the side chains that provides opportunities for more hydrogen bonding. However, based on the NMR solution structures, we found that ß(3)-peptide from L-Asp monomers (1) and from homologated amino acids (2) form similar structures with no additional side-chain interactions. These results suggest that the ß(3)-peptides derived from L-Asp are promising peptide-mimetics that can be readily synthesized using L-Asp monomers as well as the right-handed 14-helical conformation of these ß(3)-peptides (such as 1 and 6) may prove beneficial in the design of mimics for right-handed α-helix of α-peptides.

Detection of immune effects of the Mannheimia haemolytica gamma irradiated vaccine in sheep.

Exposure to gamma rays from cobalt 60 (Co60) can induce a complete inactivation of Mannheimia haemolytica. The inactivated bacterial pathogen is a potential vaccine candidate for immunization of ruminants such as sheep. The subcutaneous administration of irradiated vaccine in a two-dose regimen (4.0 × 109 colony forming unit (CFU) per dose) results in no mortality in any of the vaccinated sheep during immunization and after subsequent challenge of the live bacteria of the same strain of M. haemolytica. A significant rise in serum IgG titer, detected through ELISA, is observed after the passage of two weeks from the inoculation of the first dose whereas, the peak of the mean serum antibody titer occurred after two weeks of booster dose. The vaccination does not bring significant change to the IFN-γ levels in serum. The bacterial challenge of the vaccinated sheep does not induce a further seroconversion relative to serum antibody titer. In conclusion, the vaccinated sheep are protected by the elevated IgG titer and increased levels of IL-4 (Th-2 response) compared to the non-vaccinated sheep. Radiation technology can provide the opportunity for mass production of immunologically safe vaccines against animal and zoonotic diseases. Ethics Approval by the National Research Center Ethics Committee (Trial Registration Number (TRN) no 13,602,023, 13/5/2023) was obtained.

Gamma Irradiated Pasteurella multocida Vaccine induces strong humoral immunity and protects rabbits from disease.

Pasteurella multocida is affecting a multitude of animals and severely affects livestock production. Existing vaccines are mostly chemically inactivated and do not lead to wide protection. Irradiated vaccines are enjoying a renaissance and the concept of "replication defficient but metabolically active" vaccines was recently evaluated in several vaccine trials. P. multocida was isolated from the nasal swab, blood, and lung swab samples from infected rabbits. Gamma irradiation of P. multocida for inhibition of replication was evaluated at an optimized irradiation dose of 10 Kgy established. Four groups of rabbits were (mock) vaccinated with a commercial P. multocida vaccine and three irradiated formulations as liquid, lyophilized formulations with added Trehalose and lyophilized-Trehalose with an "activation" culturing the irradiated bacteria for 24 in broth. Evaluation of humoral immune response by ELISA showed that all three irradiated vaccines produced an effective, protective, and continued IgG serum level after vaccination and bacterial challenge. The IFN-γ expression is maintained at a normal level, within each individual group however, the lyophilized trehalose irradiated vaccine showed peak mean of IFN-γ titer at one week after booster dose (day 21) which was statistically significant. Cumulatively, the results of this study show that gamma-irradiated P. multocida vaccines are safe and protect rabbits against disease. Moreover, Rabbits' immunization with the three irradiated formulations avoided adverse side effects as compared to commercial polyvalent vaccine, the body weight gain for the irradiated vaccine groups indicates less stress compared to the commercial polyvalent vaccine.