SYNTHESIS, ANTITUMOR ACTIVITY, PHARMACOPHORE MODELING AND QSAR STUDIES OF NOVEL PYRAZOLES AND PYRAZOLO [1, 5-A] PYRIMIDINES AGAINST BREAST ADENOCARCINOMA MCF-7 CELL LINE

Objective: The present work aimed to synthesize New series of pyrazoles 3 and pyrazolo[1,5-a]pyrimidines 5, 7, 9 in order to evaluate their antiproliferative activity against human breast adenocarcinoma MCF-7cell line and study the cell cycle progression of the most active compounds. In addition, Pharmacophore modeling and QSAR Studies of these new compounds were done.Methods: The diazonium salt of 4-aminoacetophenone 1 was coupled with malononitrile in ethanol using sodium acetate affords 2-[(4-acetylphenyl)diazenyl] malononitrile Cycloaddition of hydrazine hydrate, in molar ratios 1:1 or 1:2, on compound 2, furnished 3,5-diaminopyrazolederivatives 3a and 3b respectively. Moreover, new pyrazolo[1,5-a]pyrimidine derivatives 5a-f were obtained upon cyclocondensation of 3a, b with different chalcones 4a-c in EtOH/piperidine,while compounds 7a-f were prepared via cycloaddition of 3a, b with various arylidene malononitriles 6a-c in the same reaction condition. Finally, treatment of 3a, b with ethyl 2-cyano-3-ethoxyacrylate 8a or 2-(ethoxymethylene)malononitrile 8b in EtOH/TEA yielded the novel pyrazolo[1,5-a]pyrimidine derivatives 9a, b respectively. These target compounds were screened for their cytotoxic activity against MCF-7 (human breast Cell Line) followed by study cell cycle of 7a. Finally, Pharmacophore modeling and QSAR Studies was carried out.Results: The pyrazolopyrimidine 7a was the most active compound (IC50 = 3.25 µM), whereas, some of the tested compounds exploited moderate growth inhibitory activity. Its effect was further studied on cell cycle progression; results showed that compound 7a induced cell cycle arrest at S-phase verifying this compound as a promising selective anticancer agent.Conclusion: Compound 7a was found to be the most active member against MCF-7 breast cancer (IC50= 3.25 μM), Further biological assessment of 7a using flow-cytometric analysis, revealed that it induced cell cycle arrest at S phase.Keywords: Pyrazole, Pyrazolo[1,5-a]pyrimidine, MCF-7 breast cancer cell line, Cell cycle profile, 3D pharmacophore,1 QSAR stud

Synthesis of Chromen-2-one, Pyrano[3,4-c]chromene and Pyridino[3,4-c]chromene Derivatives as Potent Antimicrobial Agents

In an attempt for development of new antimicrobial agents; new series of chromen-2-one, pyrano[3,4-c]chromene and pyridino[3,4-c]chromene derivatives bearing a diazo moiety were synthesized. Chromen-2-one derivatives were synthesized via treatment of 5-(aryldiazo) salicylaldehyde with different type of active methylene derivatives. Pyrano[3,4-c]chromene and pyridino[3,4-c]chromene derivatives were synthesized via treatment of chromen-2-one derivatives with another active methylene derivatives. The synthesized compounds were evaluated for their expected antimicrobial activity; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. This work is licensed under a Creative Commons Attribution 4.0 International License

Consolidating probiotic with dandelion, coriander and date palm seeds extracts against mercury neurotoxicity and for maintaining normal testosterone levels in male rats

Objective: Heavy metals are major elements polluting our universe. The inhalation, ingestion or even contacting human body with these elements results in huge health problems. The most common pollutant in our surrounding is mercury. Therefore, the present study aimed to elucidating the protective ability of hot water extracts of dandelion (DA), coriander (CO), date palm seeds (DS), probiotic supernatant (PS) and their combined mixture against mercury-induced neurotoxicity and altered testosterone levels in male rats. Methods: Fifty six male rats were randomly allotted into seven groups (n = 8 rats/group). Group1 (negative control; NC) animals were fed on the basal diet only, group2 (positive controls; PC) animals were fed on the basal diet and given an aqueous solution of mercuric chloride (25 ppm mercuric) in drinking water. Animals of the antioxidant-treated groups (3–7) were fed on the basal diet and given an aqueous solution of mercuric chloride (25 ppm mercuric) in drinking water together with the herbal antioxidant extracts and probiotics (25 ml/rat/day) throughout the experimental period. Where, group3 (Hg/CO) given coriander extract, group4 (Hg/DA) given dandelion extract, group5 (Hg/DS) given date palm seeds extract, group6 (Hg/PS) given probiotic supernatant, and group7 (Hg/Mix) given mixture of equal quantities of probiotic supernatant together with the three herbal extracts. The treatment lasted for 6 weeks, animals were sacrificed and blood samples were collected. Blood testosterone, enzyme activity and histopathological sections were performed. Results: The obtained data exhibited that mercury intoxication revealed increases of lactic dehydrogenase and decreases of glutathione-s-transferase and testosterone. Light microscopic investigations of the brain cortex and cerebellum were suggestive of multiple foci of inflammation, cellular infiltration, gliosis and degeneration. Moreover, decreased glial fibrillary acidic protein (GFAP)-immunoreactivity and potential astrocyte toxicity both reflected impaired neuro-protective function of astrocytes necessary for maintaining the brain structure and function. Conclusion: Administration of the herbal extracts and their mixture with probiotics enhance the body defense and contain protective factor against mercury neurotoxicity and for maintaining normal testosterone levels in male rats. Also, treatment restored the normal control levels of biochemical attributes and histological architecture. Keywords: Mercury toxicity, Dandelion, Coriander, Date seeds, Probiotics, GFAP, Histology, Brain, Rat

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially