Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and molecular dynamic simulations.

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a-5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a-5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein-ligand complexes.

Novel hydrazone-isatin derivatives as potential EGFR inhibitors: Synthesis and in vitro pharmacological profiling.

Merging isatin and arylhydrazone moieties constitutes an efficient strategy to access new potential anticancer derivatives. Consequently, 14 hydrazone-isatin derivatives were synthesized and evaluated for their antiproliferative activity against the NCI-60 cancer cell line panel. A kinase assay demonstrated that compound VIIIb inhibited the epidermal growth factor receptor (EGFR), which was confirmed by docking studies, molecular dynamics, and binding free energy calculations. Further characterizations showed that this compound possesses drug-likeness properties, showed a significant decrease of the cell population in the G2/M phase and led to a significant increase in early and late apoptosis, comparable to erlotinib. Also, VIIIb increased the expression of caspase-3 and Bax and decreased the expression of Bcl-2, confirming its potential as a new proapoptotic compound.

An overview of the use of bacteriophages in the poultry industry: Successes, challenges, and possibilities for overcoming breakdowns.

The primary contaminants in poultry are Salmonella enterica, Campylobacter jejuni, Escherichia coli, and Staphylococcus aureus. Their pathogenicity together with the widespread of these bacteria, contributes to many economic losses and poses a threat to public health. With the increasing prevalence of bacterial pathogens being resistant to most conventional antibiotics, scientists have rekindled interest in using bacteriophages as antimicrobial agents. Bacteriophage treatments have also been investigated as an alternative to antibiotics in the poultry industry. Bacteriophages' high specificity may allow them only to target a specific bacterial pathogen in the infected animal. However, a tailor-made sophisticated cocktail of different bacteriophages could broaden their antibacterial activity in typical situations with multiple clinical strains infections. Bacteriophages may not only be used in terms of reducing bacterial contamination in animals but also, under industrial conditions, they can be used as safe disinfectants to reduce contamination on food-contact surfaces or poultry carcasses. Nevertheless, bacteriophage therapies have not been developed sufficiently for widespread use. Problems with resistance, safety, specificity, and long-term stability must be addressed in particular. This review highlights the benefits, challenges, and current limitations of bacteriophage applications in the poultry industry.

3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design EGFR inhibitors.

The overexpression of EGFR has been recognized as the driver mechanism in the development of several human malignancies and the clinical use of EGFR inhibitors currently constitutes the standard of care for a wide range of malignancies, including colorectal cancer. However, the clinical efficacy of EGFR targeted inhibitors is limited by the development of intrinsic or acquired resistance, requiring the discovery of new compounds with different structural characteristics from those already developed. In this context, we explored the replacement of the aminoquinazoline pharmacophore of several FDA-approved EGFR inhibitors by its bioisosteric hydrazinothiazole moiety. A series of 14 new compounds were designed, synthesized, and evaluated as potential EGFR inhibitors. Compound 5i was active against 12 different cell lines in the NCI-60 cell line panel and showed an IC50 of 6.9 ± 0.013 µM against HCT-116 cells, with no significant toxicity against normal human fibroblasts (WI-38). Further studies showed that this compound showed submicromolar activity against EGFR and was able to induce tumor cell cycle arrest and cell apoptosis. Additionally, docking experiments, molecular dynamics and binding free energy calculations were performed and confirmed the potential of 2-hydrazino-2,3-dihydrothiazole derivatives as new EGFR inhibitors.

In vitro evaluation of sodium butyrate on the growth of three Salmonella serovars derived from pigs at a mild acidic pH value.

Foodborne zoonotic diseases can be transferred into the food chain at the stage of livestock farming. As an emerging public health challenge, practicable reduction measures in porcine health management for Salmonella are constantly being investigated. This in vitro study aimed to determine the influence of six different sodium butyrate (SB) concentrations (0, 5, 10, 20, 40, and 80 mM) on the growth of three different Salmonella enterica serovars at a constant pH value of 6.0, corresponding to conditions in the pig's hindgut. S. Derby and S. Typhimurium, isolated from a pig farm, and S. Typhimurium DSM 19587, which served as control, were used. Broth microdilution assay was applied to record Salmonella growth in the presence of different SB-concentrations over six different incubation periods (0, 1, 2, 4, 6, and 24 h). Results were quantified in the log colony-forming units (log10 CFU/mL). For 1 h incubation, the addition of SB showed no significant differences in the range of initial Salmonella dose of about 5.7 log10 between concentrations (0-80 mM, 5.26 ± 0.10-5.60 ± 0.07 log10, p > 0.05). After 6 h, for SB addition, the range of Salmonella counts was significantly lower compared to no addition of SB (5-80 mM, p < 0.05), 6.78 ± 0.84-7.90 ± 0.10 log10 for 5 mM, and 7.53 ± 0.04-8.71 ± 0.22 log10 for 0 mM. Moreover, for SB concentrations of 40 and 80 mM, no difference in the range of Salmonella counts over 6 h was obtained (5.23 ± 0.11-5.38 ± 0.05 log10, p > 0.05), and minor Salmonella growth was recorded at the earliest after 24 h incubation. Growth rates for varying SB concentrations and incubation times were confirmed in a similar manner for the three serovars. Obtained results suggest that increasing SB concentrations suppress Salmonella growth for concentrations of 5-20 mM over a 6 h incubation period and for 40 and 80 mM over a 24 h incubation period. When transferring these in vitro findings to the porcine organism, it may be assumed that Salmonella reduction can be achieved by increased butyrate content in the chyme of the large intestine.

Influence of Using Perforated Plastic Flooring Beneath the Waterline on Growth Performance, Litter Quality, and Footpad Health of Broiler Chickens: A Field Study.

The aim of this study was to evaluate the effect of slatted flooring beneath waterlines in broiler barns on litter quality and, subsequently, footpad health. The hypothesis tested was that installing slatted flooring underneath waterlines helps to improve litter quality and thus reduces footpad diseases, enhancing animal welfare as a result. Five experimental runs with two groups were conducted. Each run was defined as one fattening period of 32 days and consisted of 15,000 broiler Ross 308 of both sexes. Every barn was divided into three areas (drinkers, feeders, and comfort area) for weekly sampling. No influence on growth performance was noted. The slatted flooring influenced the litter quality by preventing the litter in the experimental group (EG = 690 ± 167 g/kg DM) from becoming moisture until day 14 of the fattening period compared to the control group (CON = 636 ± 198 g/kg DM). The footpad health was also influenced by using slatted flooring, with lower camera-based footpad scores in the EG (8.80) compared to CON (22.0) at the slaughterhouse (p = 0.0258). Installing slatted flooring beneath the waterline reduced the moisture of the litter compared to the control barn in the first two weeks of age and showed a positive effect on the footpad health of the broilers at the end of fattening, which indicates an improvement in animal welfare.

Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers.

A novel series of 2-thioacetamide linked benzoxazole-benzamide conjugates 1-15 was designed as potential inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The prepared compounds were evaluated for their potential antitumor activity and their corresponding selective cytotoxicity was estimated using normal human fibroblast (WI-38) cells. Compounds 1, 9-12 and 15 showed good selectivity and displayed excellent cytotoxic activity against both HCT-116 and MCF-7 cancer cell lines compared to sorafenib, used as a reference compound. Furthermore, compounds 1 and 11 showed potent VEGFR-2 inhibitory activity. The cell cycle progression assay showed that 1 and 11 induced cell cycle arrest at G2/M phase, with a concomitant increase in the pre-G1 cell population. Further pharmacological studies showed that 1 and 11 induced apoptosis and inhibited the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in both cell lines. Therefore, compounds 1 and 11 might serve as promising candidates for future anticancer therapy development.

Lipid Nanocarriers Overlaid with Chitosan for Brain Delivery of Berberine via the Nasal Route.

This research aimed to design, optimize, and evaluate berberine-laden nanostructured lipid carriers overlaid with chitosan (BER-CTS-NLCs) for efficient brain delivery via the intranasal route. The nanostructured lipid carriers containing berberine (BER-NLCs) were formulated via hot homogenization and ultrasonication strategy and optimized for the influence of a variety of causal variables, including the amount of glycerol monostearate (solid lipid), poloxamer 407 (surfactant) concentration, and oleic acid (liquid lipid) amount, on size of the particles, entrapment, and the total drug release after 24 h. The optimal BER-NLCs formulation was then coated with chitosan. Their diameter, in vitro release, surface charge, morphology, ex vivo permeability, pH, histological, and in vivo (pharmacokinetics and brain uptake) parameters were estimated. BER-CTS-NLCs had a size of 180.9 ± 4.3 nm, sustained-release properties, positive surface charge of 36.8 mV, and augmented ex-vivo permeation via nasal mucosa. The histopathological assessment revealed that the BER-CTS-NLCs system is safe for nasal delivery. Pharmacokinetic and brain accumulation experiments showed that animals treated intranasally with BER-CTS-NLCs had substantially greater drug levels in the brain. The ratios of BER brain/blood levels at 30 min, AUCbrain/AUCblood, drug transport percentage, and drug targeting efficiency for BER-CTS-NLCs (IN) were higher compared to BER solution (IN), suggesting enhanced brain targeting. The optimized nanoparticulate system is speculated to be a successful approach for boosting the effect of BER in treating CNS diseases, such as Alzheimer's disease, through intranasal therapy.

Utilization of Polymeric Micelles as a Lucrative Platform for Efficient Brain Deposition of Olanzapine as an Antischizophrenic Drug via Intranasal Delivery.

Schizophrenia is a mental disorder characterized by alterations in cognition, behavior and emotions. Oral olanzapine (OZ) administration is extensively metabolized (~up to 40% of the administrated dose). In addition, OZ is a P-glycoproteins substrate that impairs the blood-brain barrier (BBB) permeability. To direct OZ to the brain and to minimize its systemic side effects, the nasal pathway is recommended. OZ-loaded polymeric micelles nano-carriers were developed using suitable biodegradable excipients. The developed micelles were physicochemically investigated to assess their appropriateness for intranasal delivery and the potential of these carriers for OZ brain targeting. The selected formula will be examined in vivo for improving the anti-schizophrenic effects on a schizophrenia rat model. The binary mixture of P123/P407 has a low CMC (0.001326% w/v), which helps in maintaining the formed micelles' stability upon dilution. The combination effect of P123, P407 and TPGS led to a decrease in micelle size, ranging between 37.5-47.55 nm and an increase in the EE% (ranging between 68.22-86.84%). The selected OZ-PM shows great stability expressed by a suitable negative charge zeta potential value (-15.11 ± 1.35 mV) and scattered non-aggregated spherical particles with a particle size range of 30-40 nm. OZ-PM maintains sustained drug release at the application site with no nasal cytotoxicity. In vivo administration of the selected OZ-PM formula reveals improved CNS targeting and anti-schizophrenia-related deficits after OZ nasal administration. Therefore, OZ-PM provided safe direct nose-to-brain transport of OZ after nasal administration with an efficient anti-schizophrenic effect.

Development of a loop-mediated isothermal amplification (LAMP) assay for molecular identification of Trueperella abortisuis isolated from pigs.

The first description of Trueperella (T.) abortisuis was presented in Japan in 2009 by Azuma and colleagues. In the current study, eight T. abortisuis strains were identified by a newly developed loop-mediated isothermal amplification (LAMP) assay based on the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) encoding gene gap. Two T. abortisuis strains were obtained from prepuce of a seven-month-old boar and pooled foetal stomach contents in the United Kingdom, while the other six T. abortisuis strains were recovered from aborted foetal material of six pigs from a single farm in Germany. The developed LAMP assay showed an analytical sensitivity of 22 pg µL-1T. abortisuis DNA. T. abortisuis DSM 19515T and field strain T. abortisuis P504054/19/1 were directly detectable in artificially contaminated vaginal swabs up to concentrations of 980 CFU and 770 CFU per swab, respectively. There was no cross reactivity with control strains representing six species of genus Trueperella and six species of the closely related genus Arcanobacterium and Schaalia (Actinomyces) hyovaginalis. Further field research is required to determine the usefulness of the designed LAMP assay for identifying T. abortisuis isolated from pigs of various origins and from test samples directly obtained at farm level.

Assessment of Nasal-Brain-Targeting Efficiency of New Developed Mucoadhesive Emulsomes Encapsulating an Anti-Migraine Drug for Effective Treatment of One of the Major Psychiatric Disorders Symptoms.

Migraine is one of the major symptoms of many psychiatric and mental disorders like depression and anxiety. Eletriptan Hydrobromide (EH) is a well-tolerated drug in migraine treatment, but suffers from low oral bioavailability and low brain targeting after oral delivery. New nasal mucoadhesive EH-emulsomes development could be a new means to direct the drug from the nose-to-brain to achieve rapid onset of action and high drug concentration in the brain for acute migraine treatment. Eletriptan mucoadhesive emulsomes formulations were prepared using thin-film hydration method and 23 full factorial design was adopted to study different formulation factors' effect on the emulsomes characters. The emulsomes were characterized for entrapment efficiency (EE%), zeta potential (ZP), particle size (PS), morphology, and ex-vivo permeation through the nasal mucosa. The selected formula was evaluated in mice for its in-vivo bio-distribution in comparison with EH intranasal and intravenous solutions. Drug targeting efficacy (DTE%) and nose-to-brain direct transport percentage (DTP%) were calculated. The optimization formulation showed a nanoparticle size of 177.01 nm, EE 79.44%, and ZP = 32.12 ± 3.28 mV. In addition, in-vitro permeability studies revealed enhanced drug permeability with suitable mean residence time up to 120 ± 13 min. EH-emulsomes were stable under different storage conditions for three months. In vivo examination and pharmacokinetic drug targeting parameters revealed EH transport to the CNS after EH nanoparticle nasal administration. Histopathology study showed no ciliotoxic effect on the nasal mucosa. From the results, it can be confirmed that the emulsomes formulation of EH proved safe direct nose-to-brain transport of EH after nasal administration of EH emulsomes.

Identification of Trueperella bernardiae isolated from peking ducks (Anas platyrhynchos domesticus) by phenotypical and genotypical investigations and by a newly developed loop-mediated isothermal amplification (LAMP) assay.

Trueperella (T.) bernardiae is a well-known bacterial pathogen in infections of humans, rarely in animals. In the present study, five T. bernardiae isolates, isolated from five Peking ducks of four different farms, were identified by phenotypic properties, by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis, and genotypically by sequencing the 16S ribosomal RNA (rRNA) gene, the superoxide dismutase A encoding gene sodA, and the glyceraldehyde-3-phosphate dehydrogenase encoding gene gap. In addition, the T. bernardiae isolates could be identified with a newly developed loop-mediated isothermal amplification (LAMP) assay based on the gyrase encoding housekeeping gene gyrA. All these tests clearly identified the T. bernardiae isolates to the species level. However, the detection of the specific gene gyrA with the newly designed LAMP assay appeared with a high sensitivity and specificity, and could help to identify this bacterial species in human and animal infections in future. The importance of the T. bernardiae isolates for the clinical condition of the ducks and for the problems at farm level remains unclear.

Nitrogen output in the urban environment using a vegetarian canine diet.

Pet owners are increasingly concerned about the links between health status, animal welfare, environmental impacts, climate change and consumption of animal products. Accordingly, many owners are increasingly interested in vegetarian diets for themselves and their companion animals. However, such diets should be investigated nutritionally regards digestibility as well as on fecal quality and nitrogen output. In light of this trend, six Beagle dogs were included in a cross-over experimental design and offered a vegetarian diet containing wheat gluten (8.81%), rice protein (8.81%) and sunflower oil (6.84%) or an meat-based diet containing poultry meal (19.5%) and poultry fat (5.23%). The dogs received extruded complete diets for 12 days (adaptation and collection period, each 6 days). The dogs fed both diets showed a high and identical palatability (scoring of food intake) of the experimental diets. No significant differences occurred regarding digestibility of organic matter, crude protein and crude fat between vegetarian and meat-based diets. However, dogs fed the meat-based diet had higher (p < 0.05) nitrogen-free extract digestibility (89.5%) compared to those fed the vegetarian diet (88.6%). The amount of nitrogen excreted in feces (g)/kg BW0.75 was slightly, but not significantly, higher for dogs fed the vegetarian diet compared to those fed the meat-based diet (0.88 vs 0.79). The fecal consistency scores were considered to be within an acceptable range (well formed and firm). The mass of the feces between both groups were similar (62.9 g wet feces/100 g dry matter food) for vegetarian and meat-based diets. Additionally, the fecal dry matter content was comparable between both groups (29.0% and 29.6% for vegetarian and meat-based diets, respectively). In conclusion, the results of this study appear to indicate that virtually the only significant difference between the two diets was lower nitrogen-free extract digestibility in the vegetarian diet. However, the vegetarian diet did not result in a significant difference in amount of nitrogen excreted in feces.

Combined Loop-Mediated Isothermal Amplification Assays for Rapid Detection and One-Step Differentiation of Campylobacter jejuni and Campylobacter coli in Meat Products.

A loop-mediated isothermal amplification (LAMP) assay system was established, allowing rplD gene-based simultaneous detection of Campylobacter jejuni and Campylobacter coli in enriched meat products. Additionally, one-step differentiation of target species on agar plates was enabled by cdtC gene- and gyrA gene-based duplex LAMP. Both the rplD and cdtC-gyrA LAMP assays amplified the target sequences in all 62 C. jejuni and 27 C. coli strains used for determining inclusivity and revealed 100% exclusivity toward 85 tested non-target species. Throughout the entire experiments, C. jejuni and C. coli strains were 100% distinguishable by melting curves of cdtC and gyrA LAMP products. After 24-h enrichment, the rplD LAMP assay reliably detected initial inoculation levels of 10-100 CFU/g in artificially contaminated minced meat. Investigation of naturally contaminated meat samples revealed a diagnostic accuracy of 95% toward real-time PCR and 94.1% toward the standard culture method applying the 24-h incubation period. Diagnostic sensitivity and specificity, and positive and negative predictive values were 89.8, 100, 100, and 91.2%, respectively, when measured against real-time PCR, and 89.6, 98.1, 97.7, and 91.2%, respectively, when measured against the standard culture method. After 48-h enrichment, the detection limit of the rplD LAMP assay improved to initial inoculation levels of 1-10 CFU/g in artificially contaminated minced meat. Applying the 48-h incubation period on naturally contaminated meat samples resulted in 100% concordant results between rplD LAMP, real-time PCR, and the standard culture method. The established LAMP assay system was proved to be suitable for rapid meat sample screening. Furthermore, it constitutes a promising tool for investigating other Campylobacter sources and could therefore make a valuable contribution to protect consumers from foodborne illness.

Discovery of pyridine- sulfonamide hybrids as a new scaffold for the development of potential VEGFR-2 inhibitors and apoptosis inducers.

New sulfonamide derivatives have been synthesized and tested as antitumor agents. All newly synthesized compounds were tested in vitro against 60 lines of human cancer cells. Compound VIIb shows broad-spectrum activity with a mean inhibition value of 91.67% against all cell lines. It exhibited potent anticancer activity with GI50 values of 1.06-8.92 µM relative to most of the tested cancer cell lines. Compound VIIb has been tested for enzyme inhibition activity toward vascular endothelial growth factor receptor 2, where VEGFR-2 was potently inhibited at a lower IC50 value of 3.6 µM, compared with sorafenib (IC50 = 4.8 µM). Hybrid VIIb was also able to induce cell cycle disturbance and apoptosis in Renal UO-31 cells, as shown by DNA flow cytometry and Annexin V-FITC/PI assays. It has also revealed lower Bcl-2 protein expression anti-apoptotic levels and higher BAX, p53, and caspases 3 expression levels.

Mitigating the Spread and Translocation of Salmonella Enteritidis in Experimentally Infected Broilers under the Influence of Different Flooring Housing Systems and Feed Particle Sizes.

This study aimed to evaluate the influences of different flooring designs and feed particle sizes on the spread of Salmonella (S.) in broiler chickens. Birds (n = 480) were allocated to four different housing systems (fully littered with and without floor heating, partially and fully slatted flooring with sand bath) and two dietary treatments (finely and coarsely ground diets) in 24 boxes. Two broilers per box were experimentally infected with S. Enteritidis (8.00 log10 CFU/bird) at d 17. Salmonella prevalence in caecal contents and the liver was highest in broilers housed on fully slatted floor until d 36/37 (88.1% and 91.5%, respectively), and lowest in litter flooring (caecal content 64.4%) and litter flooring with floor heating (liver 61.7%). In turn, broilers on littered flooring expressed the lowest Salmonella counts in caecal content at d 36/37 (2.21 ± 1.75 log10 CFU/g), partial slatted flooring the highest (3.76 ± 1.46 log10 CFU/g). The mean Salmonella count in the caecal content was significantly lower for birds fed a coarsely ground diet (0.96 and 1.94 log10 CFU/g) than a finely ground diet (5.07 and 3.34 log10 CFU/g) at d 23 and d 36/37, respectively (p < 0.0001). Slatted flooring with a sand bath did not show advantages in terms of Salmonella reduction, whereas the coarsely ground diet markedly reduced the spread of Salmonella.

Development of isatin-thiazolo[3,2-a]benzimidazole hybrids as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological and molecular dynamics investigations.

In the current medical era, human health is experiencing numerous challenges, particularly the human malignancies. Therefore, the therapeutic arsenal for these malignancies is to be inexorably enhanced with new treatments that target tumor cells in a selective manner. In this regard, the present work aims at developing a new set of small molecules featuring the privileged isatin scaffold conjugated with a thiazolo[3,2-a]benzimidazole (TBI) motif through a cleavable hydrazide linker (7a-e and 10a-i) as potential anticancer CDK2 inhibitors. The large tricyclic TBI motif is anticipated to achieve a plethora of hydrophobic interactions within the CDK2 binding site. The growth of the two examined cell lines was significantly inhibited by most the prepared hybrids with IC50 ranges; (2.60 ± 1.47-20.90 ± 1.17 µM, against MDA-MB-231) and (1.27 ± 0.06-16.83 ± 0.95 µM, against MCF-7). In particular, hybrids 7a, 7d and 10a displayed potent dual activity against the examined cell lines, and thus selected for further investigations. They exerted a significance alteration in the cell cycle progression, in addition to an apoptosis induction within both MDA-MB-231 and MCF-7 cells. Furthermore, 7a, 7d and 10a displayed potent CDK2 inhibitory action (IC50 = 96.46 ± 5.3, 26.24 ± 1.4 and 42.95 ± 2.3 nM, respectively). The docking simulations unveiled, as expected, the ability of the TBI ring to well-accommodate and establish several hydrophobic interactions within a hydrophobic pocket in the CDK2 binding site. Also, the docking simulations highlighted the significance of incorporation of the hydrazide linker and isatin unsubstituted (NH) functionality in the H-bonding interactions. Interestingly, the most potent CDK2 inhibitor 7d achieved the best binding score (-11.2 Kcal/mole) and formed the most stable complex with CDK2 enzyme (RMSD = 1.24 Å) in a 100 ns MD simulation. In addition, the MM-PBSA calculations ascribed the lowest binding free energy to the 7d-CDK2 complex (-323.69 ± 15.17 kJ/mol). This could be attributed to an incorporation of the 5-OCH3 group that was engaged in an extra hydrogen bonding with key THR14 amino acid residue. Finally, these results suggested hybrid 7d as a good candidate for further optimization as promising breast cancer antitumor agent and CDK2 inhibitor.

Novel piperazine-chalcone hybrids and related pyrazoline analogues targeting VEGFR-2 kinase; design, synthesis, molecular docking studies, and anticancer evaluation.

New piperazine-chalcone hybrids and related pyrazoline derivatives have been designed and synthesised as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The National Cancer Institute (NCI) has selected six compounds to evaluate their antiproliferative activity in vitro against 60 human cancer cells lines. Preliminary screening of the examined compounds indicated promising anticancer activity against number of cell lines. The enzyme inhibitory activity against VEGFR-2 was evaluated and IC50 of the tested compounds ranged from 0.57 µM to 1.48 µM. The most potent derivatives Vd and Ve were subjected to further investigations. A cell cycle analysis showed that both compounds mainly arrest HCT-116 cell cycle in the G2/M phase. Annexin V-FITC apoptosis assay showed that Vd and Ve induced an approximately 18.7-fold and 21.2-fold total increase in apoptosis compared to the control. Additionally, molecular docking study was performed against VEGFR (PDB ID: 4ASD) using MOE 2015.10 software and Sorafenib as a reference ligand.

Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies.

Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor receptor (EGFR) inhibition showed that compounds IXn, IXg, IXb and IXl exhibited excellent inhibitory effect (IC50 = 0.65, 0.75, 0.82 and 0.84 µM, respectively) compared to Erlotinib (IC50 = 0.95 µM). The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compounds IXg and IXn due to their significant EGFR inhibition. Flow cytometeric analysis indicated that compounds IXg and IXn result in increased cell numbers in phase G2/M, suggesting cell cycle arrest in phase G2/M in UO-31cells. Furthermore, real time PCR assay illustrated that compounds IXg and IXn elevated Bax/Bcl2 ratio which confirmed the mechanistic pathway of them. Moreover, the apoptotic induction of UO-31 renal cancer cells was enhanced effectively through activation of caspase-3 by compounds IXg and IXn. On the other hand, molecular docking study was performed to investigate binding mode of interaction of compounds with EGFR-PK in the active site with the aim of rationalizing its promising inhibitory activity. Finally, based on the aforementioned findings, compounds IXg and IXn could be considered as effective apoptosis modulators and promising leads for future development of new anti-renal cancer agents.

Synthesis and Biological Evaluation of New Pyridothienopyrimidine Derivatives as Antibacterial Agents and Escherichia coli Topoisomerase II Inhibitors.

The growing resistance of bacteria to many antibiotics that have been in use for several decades has generated the need to discover new antibacterial agents with structural features qualifying them to overcome the resistance mechanisms. Thus, novel pyridothienopyrimidine derivatives (2a,b-a,b) were synthesized by a series of various reactions, starting with 3-aminothieno[2,3-b]pyridine-2-carboxamides (1a,b). Condensation of compounds 1a,b with cyclohexanone gave 1'H-spiro[cyclohexane-1,2'-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin]-4'(3'H)-ones (2a,b), which in turn were utilized to afford the target 4-substituted derivatives (3a,b-8a,b). In vitro antibacterial activity evaluations of all the new compounds (2a,b-8a,b) were performed against six strains of Gram-negative and Gram-positive bacteria. The target compounds showed significant antibacterial activity, especially against Gram-negative strains. Moreover, the compounds (2a,b; 3a,b; 4a,b; and 5a,b) that exhibited potent activity against Escherichia coli were selected to screen their inhibitory activity against Escherichia coli topoisomerase II (DNA gyrase and topoisomerase IV) enzymes. Compounds 4a and 4b showed potent dual inhibition of the two enzymes with IC50 values of 3.44 µΜ and 5.77 µΜ against DNA gyrase and 14.46 µΜ and 14.89 µΜ against topoisomerase IV, respectively. In addition, docking studies were carried out to give insight into the binding mode of the tested compounds within the E. coli DNA gyrase B active site compared with novobiocin.