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A series of N‐arylpyrimido[4,5‐b]quinolines 3a–e and 2‐aryl‐2,3‐dihydropyrimido[4,5‐b]quinoline‐4(1H)‐ones 5a–e was designed and synthesized as potential anticancer agents against breast cancer. Compounds 3e, 5a, 5b, 5d, and 5e showed promising activity against the MCF‐7 cell line. Among them, compound 5b was the most active with IC50 of 1.67 μM. Compound 5b promoted apoptosis and induced cell cycle arrest at S phase. 5b increased the level of pro‐apoptotic proteins p53, Bax, and caspase‐7 and inhibited the anti‐apoptotic protein Bcl‐2. Furthermore, all the synthesized compounds were docked into the crystal structure of HER2 (PBD: 3 pp0). Compounds 3e, 5a, 5b, 5d, and 5e showed good energy scores and binding modes. Finally, Compound 5b was evaluated on the HER2 assay and revealed good inhibition with IC50 of 0.073 μM. [ABSTRACT FROM AUTHOR]

Background: Reducing pre- and in-hospital delays plays an important role in increasing the rate of intravenous thrombolysis (IVT) in patients with acute ischemic stroke. In Egypt, the IVT rate has increased steadily but is still far away from an ideal rate. Aim: The study aimed to investigate the factors associated with pre- and in-hospital delays of IVT among patients with acute ischemic stroke coming from urban and rural communities. Methods: This prospective, multicenter, observational cohort study was conducted from January 2018 to January 2019. Patients with acute ischemic stroke, who did not receive IVT, were included in the study. Patients were recruited from three large university stroke centers in Egypt, Assiut (south of Egypt), Tanta (north of Egypt), both serving urban and rural patients, and the University Hospital in Cairo (capital city), only serving an urban community. All participants underwent the National Institutes of Health Stroke Scale and full neurological assessment, urgent laboratory investigations, and computed tomography or magnetic resonance imaging to confirm the stroke diagnosis. The patients were subjected to a structured questionnaire that was designed to determine the parameters and time metrics for the pre- and in-hospital delays among patients from rural and urban regions. Results: A total of 618 patients were included in the study, of which 364 patients (58.9%) lived in rural regions and 254 (41.1%) in urban regions. General demographic characteristics were similar between both groups. Approximately 73.3% of patients who arrived within the therapeutic time window were urban patients. The time from symptom onset till hospital arrival (onset to door time, ODT) was significantly longer among rural patients (738 ± 690min) than urban patients (360 ± 342min). Delayed onset to alarm time (OAT), initial misdiagnosis, and presentation to non-stroke-ready hospitals were the most common causes of pre-hospital delay and were significantly higher in rural patients. For patients arriving within the time window, the most common causes of in-hospital delays were prolonged laboratory investigations and imaging duration. Conclusion: The limited availability of stroke-ready hospitals in rural Egypt leads to delays in stroke management, with subsequent treatment inequality of rural patients with acute stroke. [ABSTRACT FROM AUTHOR]

Novel halogenated phenoxychalcones 2a-f and their corresponding N-acetylpyrazolines 3a-f were synthesised and evaluated for their anticancer activities against breast cancer cell line (MCF-7) and normal breast cell line (MCF-10a), compared with staurosporine. All compounds showed moderate to good cytotoxic activity when compared to control. Compound 2c was the most active, with IC50 = 1.52 µM and selectivity index = 15.24. Also, chalcone 2f showed significant cytotoxic activity with IC50 = 1.87 µM and selectivity index = 11.03. Compound 2c decreased both total mitogen activated protein kinase (p38a MAPK) and phosphorylated enzyme in MCF-7 cells, suggesting its ability to decrease cell proliferation and survival. It also showed the ability to induce ROS in MCF-7 treated cells. Compound 2c exhibited apoptotic behaviour in MCF-7 cells due to cell accumulation in G2/M phase and elevation in late apoptosis 57.78-fold more than control. Docking studies showed that compounds 2c and 2f interact with p38alpha MAPK active sites. [ABSTRACT FROM AUTHOR]

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a–g), benzyl piperidine (4i), and aryl aminothiazoles (5a–e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model. [ABSTRACT FROM AUTHOR]

Z-configurated isomers are kinetically preferred molecules. Compounds with Z-configuration are contained in many natural products, biologically active compounds and as synthons for organic synthesis. Two series of new thiazole-based analogs were synthesized from appropriate starting materials hydrazinecarbothioamide derivatives (Z)-2a,b to be evaluated for their inhibitory activity towards VEGFR-2. The prepared thiazole compounds 3a-5b were screened for their cytotoxic potency against the MDA-MB-231 breast cancer cell line and their percentage inhibition against VEGFR-2. Compound 4d exhibited good VEGFR-2 inhibitory activity. A DNA flow cytometry analysis was conducted, and compound 4d demonstrated cell cycle arrest at the G1 and G2/M phases of the cell cycle profile and an apoptosis-inducing effect by increasing the percentage of pre-G1 phase. Compound 4d was further evaluated for its apoptosis-inducing effect by studying the effect on mitochondrial membrane potential (MMP) and p53 activation. It was found to boost the level of p53 and reduce the level of MMP compared with the untreated control cells. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS) has shown promising results in alleviating different types of pain. The present study compares the efficacy of three sessions of anodal tDCS applied over primary motor area (M1) or the left dorsolateral prefrontal cortex (DLPFC) or sham on reducing pain and the total opioid consumption in postoperative spine surgery patients. Materials: Sixty‐seven out of 75 eligible patients for postoperative spine surgery were randomly allocated into one of the three experimental groups. Group A received anodal tDCS applied over M1 cortex, group B over left DLPF cortex (2 mA, 20 min) and group C received sham tDCS, all for 3 consecutive postoperative days. Patients were evaluated using a visual analogue scale (VAS) and adynamic visual analogue scale (DVAS) at baseline, and on each of the treatment days. The total morphine consumption over the 3 postoperative days was assessed. Results: Two‐way repeated measures ANOVA showed no statistically significant difference in resting VAS between the three groups. However, there was significant pain improvement (P < 0.001) in DVAS in both active groups (group A and B) compared to the sham group (group C) in the postoperative period, with no significant difference between the active groups. Morphine consumption was significantly reduced in both active groups compared with the sham group, but there was no difference in consumption between the active groups. Conclusion: There was a significant postoperative reduction in morphine consumption and DVAS scores after three sessions of active tDCS. Significance: tDCS is a promising tool for alleviating pain in the field of postoperative spine surgery. [ABSTRACT FROM AUTHOR]

Background: The exact mechanism of cognitive impairment in PD is not known. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for cognitive impairment and to treat the motor symptoms in Parkinson's disease (PD) where its effects seem additive to those of dopaminergic medications. Objective: In this pilot study we investigated whether repeated sessions of rTMS have an effect on measures of cognitive impairment in patients with PD dementia. Methods: 33 patients with PD dementia were randomly assigned sham or real rTMS (2000 pulses; 20 Hz; 90% RMT; 10 trains of 10 s with 25 s between each train) over the hand area of each motor cortex (5 min between hemispheres) for 10 days (5 days/week) followed by 5 booster sessions every month for 3 months. Assessments included the Unified Parkinson's Disease Rating Scale part III (UPDRS), Montreal Cognitive Assessment (MoCA); Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR); Memory and Executive Screening (MES) and Instrumental activity of Daily Living (IADL). Event related potentials (P300) and cortical excitability were measured before treatment and after the last session. Results: There were no significant differences in the effects of rTMS between groups. Although rTMS improved motor function in the active group it had only a minor effect on two of the dementia rating scores (the MMSE and MoCA) but not the others (CDR and MES). There was also a reduction in the latency of the P300 in the active group. Conclusions: rTMS over M1 is useful for motor function and may have a small positive effect on cognition. However, better approaches for the latter are necessary, may be require multisite rTMS to target both motor and frontal cortical region. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A new series of diamide derivatives have been synthesized. • The newly synthesized compounds were evaluated for their anticancer activity. • Cell cycle analysis were done for the most active compounds. • Active compounds were tested for tubulin polymerization inhibitory activity. • P53, Bax, Bcl-2 and caspase-3/7 assays were carried out for the most active compounds. Abstract A new series of diamide functional compounds has been designed, synthesized and confirmed by spectroscopic methods and elemental analyses. All the synthesized compounds were evaluated for their antiproliferative activity on HepG2 cell line. Compounds 3k and 3l were proved to have potent anticancer activity equipotent or more potent than reference compound Combretastatin A-4. The results of DNA flow cytometry analysis demonstrated cell cycle arrest at G2/M phase. The extent of apoptosis induced by 3k and 3l was also determined. Moreover, the compounds produced a significant reduction in cellular microtubules for microtubule loss and potently inhibited the binding of [3H]colchicine to tubulin. Compounds 3k and 3l were proved to upregulate expression of proteins triggering apoptosis, such as p53, Bax, and decreased Bcl-2 overexpression as well as increased the expression of effector caspase- 3/7. [ABSTRACT FROM AUTHOR]

Background: Epidemiology continues to be an important research tool in the study of epilepsy and related disorders, providing a better understanding of the frequency, causes, and natural history of the disorder. Objective: To estimate the prevalence of epilepsy in Al-Quseir, Red Sea Governorate, Egypt, and its magnitude of treatment gap. Methods: The study was part of a door-to-door study, including every door, to screen all inhabitants in Al-Quseir (33,818 inhabitants) by three specialists of neurology and 15 female social workers (for demographic data collection) using a standardized screening questionnaire. All suspected cases were subjected to detailed history, clinical examination, and electroencephalogram. Neuroimaging studies and estimation of serum drug level were done in select cases if needed. Results: The study revealed that the lifetime prevalence rate of epilepsy in Al-Quseir is 5.5/1,000, with the highest peak during early childhood, while that of active epilepsy is 3.3/1,000 population. The annual incidence rate is 48/100,000, and the age-specific incidence rate has a U-shaped pattern with two peaks of incidence in early infancy and elderly life. Localizationrelated epilepsy is the most frequently encountered type (58.8%). The treatment gap of epilepsy in Al-Quseir is 83.8%. Conclusion: The lifetime prevalence of epilepsy in Al-Quseir city, Red Sea Governorate, was 5.5/1000. [ABSTRACT FROM AUTHOR]

Background Bell's palsy (BP) is one of the most common causes of acute-onset unilateral facial weakness. Through this study we aimed to estimate the incidence of BP in Al-Quseir City, Red Sea Governorate, Egypt. Patients and methods A project was undertaken to assess the epidemiology of major neurological disorders. A total of 33 285 eligible patients were screened through a door-to-door survey (every door) by three specialists in neurology and 15 social workers. All patients were subjected to detailed history taking and a meticulous neurological examination by means of a specific questionnaire designed for this study. Results Within 1 year, 27 patients were diagnosed with BP. This yielded an incidence rate of 98.9/100 000 population (aged 9 years and older). The incidence was higher in the male population than in the female population (116.4 and 81.2/100 000, respectively). Age-specific incidence of BP showed that its peak was between the ages of 18 and 60 years. About 78% of patients with BP recovered completely within 6 months after onset. There was no significant difference between male and female patients. Conclusion The incidence rate for BP was 98.9/100 000 among those aged 9 years and older. Most affected cases were older than 18 and less than 60 years. [ABSTRACT FROM AUTHOR]

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC50 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G2/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer. [ABSTRACT FROM AUTHOR]

• New thiazolidinone, thiazinone and dithiazepinone-benzenesulfonamides as cytotoxic agents. • Effect of 5a-d on MCF-7 and HepG2 cell cycle phase distribution. • Caspase 8 and 9 levels determination in MCF-7 and HepG2 after test agents' treatment. • In vivo biodistribution study of radioiodinated-5c. A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC 50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b , 5c and 5e , were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model. [ABSTRACT FROM AUTHOR]

• Novel azole derivatives were designed, synthesized and screened for their antitumor activity over HepG2 cells. • The cytotoxic screening showed that, triazole 25 exhibited higher activity by 4.75-fold than sorafenib. • Compounds 25 and 29 displayed a dual VEGFR-2 and β-tubulin polymerization inhibition and induced apoptosis by increasing sub-G 1 phase. • The pro-apoptotic activity for compounds 25 and 29 were due to up-regulation of P53, Fas/Fas-ligand and BAX/BCL-2 ratio. Novel azole derivatives 3 – 30 were designed, synthesized, and screened for their antitumor activity on HepG2 cell line. The cytotoxicity screening demonstrated that imidazolone 8 and triazoles 25 and 29 exhibited more potent cytotoxic activities by 1.21-, 4.75-, and 1.8-fold compared to Sorafenib (SOR). Furthermore, vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme inhibition assay declared that compounds 25 and 29 had inhibitory activity at the nanomolar concentration. Moreover, the tested compounds exhibited good β-tubulin (TUB) polymerization inhibition percentages. In addition, DNA flow cytometry analysis over HepG2 cells indicated that triazoles 25 and 29 demonstrated arrest at G 1 and G 2 /M phase of the cell cycle and induced apoptotic activity by increasing sub-G 1 phase. Finally, mechanistic studies of the proapoptotic activities of compounds 8 , 10 , 11 , 25 , and 29 indicated that they induced upregulation of P53, Fas/Fas-ligand, and BAX/BCL-2 ratio expression that resulted in increasing the active caspase 3/7 percentages and trigger apoptosis. [ABSTRACT FROM AUTHOR]

A new series of indolyl 1,2,4-triazole scaffolds was designed, synthesised, and biologically evaluated for their inhibitory activity against both CDK4 and CDK6. The results ranged from 0.049 μM to 3.031 μM on CDK4 and from 0.075 μM to 1.11 μM on CDK6 when compared to staurosporine, with IC 50 values of 1.027 and 0.402 μM, respectively. Moreover, all compounds were tested for their cytotoxicity against two breast cancer cell lines, MCF-7 and MDA-MB-231. All of the synthesised compounds showed promising anti-proliferative activity, with two compounds Vf (IC 50 = 2.91 and 1.914 μM, respectively) and Vg (IC 50 = 0.891 and 3.479 μM, respectively) having potent cytotoxic activity in comparison to the reference staurosporine (IC 50 = 3.144 and 4.385 μM, respectively). Vf and Vg were also found to significantly induce apoptosis to 45.33% and 37.26% (control = 1.91%) where Vf arrested the cell cycle at the S phase while Vg arrested the cycle at the G 0 /G 1 phase. The binding mode and interactions of all compounds were studied and found to mimic those of the FDA approved CDK4/6 inhibitor palbociclib that was used as a reference throughout the study., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

A novel series of pyrimidine-5-carbonitrile derivatives was designed, synthesized, then evaluated for their cytotoxic activity as novel anti-cancer with dual EGFR WT /COX-2 inhibitors. Two compounds 4e and 4f disclosed the highest activity against all NCI60 panel cell lines. They were most potent against Colo 205 (IC 50 = 1.66, and 1.83 μM), Sequentially. The most potent two compounds disturbed cell cycle of Colo-205 cells by blocking the G1 phase, coupled with increased annexin-Vstained cells which indicated the increasing in percentage of apoptosis. In addition, 4e and 4f increase the concentration of caspase-3 by 10, and 8-fold compared to control, respectively. Moreover, the two candidate compounds were screened for cytotoxicity on normal epithelial colon cells; fortunately, they were found to be safe. Molecular docking study displayed that these compounds bound to the active site as EGFR WT /COX-2 inhibitors. Furthermore, 3D pharmacophore mapping disclosed many shared features between the most potent candidates 4e and 4f and the standard EGFR WT /COX-2 inhibitors; erlotinib, and celecoxib, respectively. Finally, the physicochemical parameter was calculated for the most potent novel anticancer candidates and the SwissAdme parameter showed that the newly synthesized compounds have good drug-likeness properties., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Alzheimer's Disease (AD) is a multifactorial incurable neurodegenerative disorder. It is characterized by a decline of cholinergic function in parallel with β-amyloid fibril deposition. Such an imbalance causes severe loss in memory and cognition, leading to behavioral disturbances, depression, and ultimately death. During the last decades, only a few approved drugs were launched onto the market with indications for treating initial and moderate stages of AD. To date, cholinesterase inhibitors (ChEI) are the mainstay line of treatment to ameliorate AD symptoms. Tacrine and Donepezil are the most commonly prescribed anti-dementia drugs, given their potent inhibitory effects. Therefore, many trials have focused on both drugs' structures to synthesize new anti-dementia agents. This paper discusses recent trends of new AD-treating anti-dementia agents focusing on Tacrine and Donepezil analogs and multifunctional hybrid ligands., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Antimicrobial resistance is an aggravating global issue therefore it has been under extensive research in an attempt to reduce the number of antibiotics that are constantly reported as obsolete jeopardizing the lives of millions worldwide. Thiazoles possess a reputation as one of the most diverse biologically active nuclei, and phenylthiazoles are no less exceptional with an assorted array of biological activities such as anthelmintic, insecticidal, antimicrobial, antibacterial, and antifungal activity. Recently phenyl thiazoles came under the spotlight as a scaffold having strong potential as an anti-MRSA lead compound. It is a prominent pharmacophore in designing and synthesizing new compounds with antibacterial activity against multidrug-resistant bacteria such as MRSA, which is categorized as a serious threat pathogen, that exhibited concomitant resistance to most of the first-line antibiotics. MRSA has been associated with soft tissue and skin infections resulting in high death rates, rapid dissemination, and loss of millions of dollars of additional health care costs. In this brief review, we have focused on the advances of phenylthiazole derivatives as potential anti-MRSA from 2014 to 2021. The review encompasses the effect on biological activity due to combining this molecule with various synthetic pharmacophores. The physicochemical aspects were correlated with the pharmacokinetic properties of the reviewed compounds to reach a structure-activity relationship profile. Lead optimization of phenyl thiazole derivatives has additionally been outlined where the lipophilicity of the compounds was balanced with the metabolic stability and oral solubility to aid the researchers in medicinal chemistry, design, and synthesizing effective anti- MRSA phenylthiazoles in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)