Gehan M. Kamel

Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: Design, synthesis and evaluation as potential anti-inflammatory agents

Novel series of celecoxib analogs endowed with benzofuran moiety 3a-e and 9a-d were synthesized and evaluated for COX-1/COX-2 inhibitory activity in vitro. The most potent and selective COX-2 inhibitors - compounds 3c, 3d, 3e, 9c and 9d - were assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivatives 3c and 3e exhibited the highest anti-inflammatory activity, that is equipotent to celecoxib. Furthermore, the tested compounds proved to have better gastric safety profile compared to celecoxib. In particular, compound 3e demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug. Finally, molecular docking simulation of the new compounds in COX-2 active site and drug likeness studies showed good agreement with the obtained pharmaco-biological results.

Isolation of biologically active constituents from Moringa peregrina (Forssk.) Fiori. (family: Moringaceae) growing in Egypt

Background: Moringa peregrina is a wild plant that grown in the eastern desert mountains in Egypt. Although, this plant is native to Egypt, no details studies were traced on its chemical composition and biological activity. Materials and Methods: The different fractions of the ethanolic extract of the dried aerial parts of the plants were subjected to fractionation and purification on various silica and sephadex columns for the isolation of the major compounds which were tested for there anticancer activity. The aqueous and ethanolic extract as well as its different fractions were tested for antihyperglycemic effect on Streptozitocin-induced diabetes in rats. Results: Investigation of the different fractions of the ethanolic extract of the aerial parts of M. peregrina yielded lupeol acetate (1), β-amyrin (2), α-amyrin (3), β-sitosterol (4), β-sitosterol-3-O-glucoside (5), apigenin (6), rhamnetin (7), neochlorogenic acid (10), rhamnetin-3-O-rutinoside (12), and 6-methoxy-acacetin-8-C-β-glucoside (13) which were isolated for the first time from the plant. Compound (13) was isolated for the first time from genus Moringa. In addition, quercetin (8), chryseriol-7-O-rhamnoside (9) and quercetin-3-O-rutinoside (11) were also isolated. Identification has been established by spectral data (UV, MS, IR, 1H, 1H -1H COSY, and 13C-NMR). The major isolated compounds were found to have valuable cytotoxic activities against breast (MCF 7) and colon (HCT 116) cancer cell lines and their activities were comparable to the reference drug doxorubicin. On the other hand, the aqueous and ethanolic extracts as well as the n-hexane fraction were found to have potent antihyperglycemic effect on Streptozitocin-induced diabetes in rats. Conclusion: The Egyptian plant M. peregrina is rich in biologically active ingredients which showed potent cytotoxic activity and also its ethanolic extraxt exert a significant antihyperglycemic effect.

Hepatoprotective effect of methanol extracts of Zingiber officinale and Cichorium intybus.

The present work was carried out to investigate the hepatoprotective effect of ginger, chicory and their mixture against carbon tetrachloride intoxication in rats. Carbon tetrachloride treatment significantly elevated the alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma glutamyltransferase activities and the serum triglycerides and cholesterol concentration as compared to control group. It also increased RBCs counts and Hb concentration, total or differential leucocytes counts. However it decreased platelet counts, platelet distribution width, mean platelet volume, platelet larger cell ratio. Methanol extract of ginger (250 and 500 mg/kg) and chicory (250 and 500 mg/kg) given alone or mixed (1:1 wt/wt) significantly restored the carbon tetrachloride-induced alterations in the biochemical and cellular constituents of blood. No toxic symptoms were reported in doses up to 5 g/kg. Alkaloids and/or nitrogenous bases, carbohydrates and/or glycosides, tannins, flavonoids, saponins and unsaturated sterols and/or triterpenes are the main active constituents of their methanol extract. The hepatoprotective effect of ginger and chicory was also confirmed by the histopathological examination of liver tissue.

Pharmacokinetic and tissue distribution of doxycycline in broiler chickens pretreated with either: Diclazuril or halofuginone

Following IV injection of doxycycline in a dose of 20 mg kg(-1) b.wt., its serum concentration was best fitted in two-compartment open model in chickens fed either on control or on anticoccidials-containing rations. Diclazuril and halofuginone resulted in a significant short distribution half-life (t(½α)) (7.17±0.39 and 11.88±1.05 min, respectively) and increased total body clearance (Cl(tot)) 0.37±0.024 and 0.295±0.034 L/kg/h, respectively. Following oral dosing the tested drug absorbed with t(½ab) of 41.38±1.6, 17.48±0.86 and 41.83±1.8 min, respectively and their C(max) values (3.18±0.18, 5.425±0.48 and 0.986±0.037 μg/ml) were attained at 2.07±0.097, 1.403±0.074 and 2.55±0.106 h. For doxycycline alone and in presence of diclazuril and halofuginone, respectively. Systemic bioavailability was 22.64±3.46, 86.74±9.23 and 22.38±3.09%, respectively. Following IM injection t(½ab) were 9.096±1.34 for doxycycline alone, 16.24±2.21 and 15.6±1.7 min in the presence of diclazuril and halofuginone, respectively. C(max) was 3.10±0.28, 4.63±0.57 and 0.55±0.07 μg/ml reached at 0.8±0.083, 1.13±0.126 and 1.21±0.105 h. For the antibiotic alone, and in presence of either diclazuril and halofuginone, respectively. Systemic bioavailability was 22.41±3.86, 88.97±12.9 and 12.31±0.99% in chickens fed on anticoccidial-free, diclazuril- and halofuginone-containing rations, respectively. Both the tested anticoccidials induced higher doxycycline tissue residues in all tested tissue samples.

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1,3,5-triarylpyrazoline and 1,5-diarylpyrazole derivatives as selective COX-2 inhibitors.

Two new series of 1,3,5-triarylpyrazolines 10a-m and 1,5-diarylpyrazoles 14a-d were synthesized. All prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 10k was the most COX-2 selective compound (S.I.=5.91) and the most potent anti-inflammatory derivative (ED50=99μmol/kg) which is approximately five folds more potent than ibuprofen (ED50=499μmol/kg) and had half potency of celecoxib (ED50=47μmol/kg). All compounds were less ulcerogenic (Ulcer Indexes=1.20-5.00) than ibuprofen (Ulcer Index=20.25) and comparable to celecoxib (Ulcer Index=2.90).

Synthesis, cyclooxygenase inhibition, and anti-inflammatory evaluation of novel diarylheterocycles with a central pyrazole, pyrazoline, or pyridine ring

Five groups of diarylheterocycles with a central pyrazole ring (12a–d), pyrazoline ring (14a–d), or pyridine ring (15a–d, 16a–d and 17a–d) were synthesized and evaluated in vitro for COX-1/COX-2 inhibitory activity and in vivo for anti-inflammatory activity. All compounds that possessed anti-inflammatory activity were assessed for their ulcerogenic liability in comparison with ibuprofen and celecoxib. The pyrazole derivative 12b and the pyrazoline derivative 14b were the least ulcerogenic compounds with relative ulcerogenicities to celecoxib 0.85 and 0.90 respectively.Graphical Abstract

Synthesis and anti-inflammatory evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing an aminosulphonyl pharmacophore

A novel series of 2-pyrazoline derivatives 13a–l was synthesized via aldol condensation of 4-substituted acetophenones with appropriately substituted aldehydes followed by cyclization of the formed chalcones with 4-hydrazinobenzenesulfonamide hydrochloride. The chemical structures of the target pyrazoline derivatives were proved by means of IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses data. All the synthesized compounds were evaluated for their cyclooxygenase selectivity, anti-inflammatory and ulcerogenic liability. While compounds 13e, 13h and 13i showed moderate COX-2 selectivity in vitro and good anti-inflammatory activity in vivo, compound 13i showed the highest anti-inflammatory activity that is very close in potency to the reference drug (celecoxib) with better gastric profile than celecoxib.

Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: Histopathological and docking studies

A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72.72-54.54%) and perfect ED50 values (ED50 = 0.044-0.104 mmol/kg) relative to celecoxib (ED50 = 0.032 mmol/kg). To explore the most active compounds, ulcerogenic effect on stomach in comparison with indomethacin and celecoxib in addition to histopathological investigations were performed. Compound 5f showed better gastric profile (UI = 2.33) than celecoxib (UI = 3.00). Also, 5f caused 50% increase in thermal pain threshold close to reference drug indomethacin (53.13%). Docking study of all the target compounds into COX-2 and 5-LOX active sites was performed to rational their anti-inflammatory activities.

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1,5-diarylpyrazole derivatives

Abstract A new series of 1,5-diarylpyrazoles 10a–l was designed and synthesized for evaluation as COX inhibitors and as anti-inflammatory agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 10e was the most COX-2 selective compound (S.I. = 10.67) and the most potent anti-inflammatory derivative (ED50 = 46 μmol/kg) which is approximately 11-folds more potent than ibuprofen (ED50 = 499 μmol/kg) and had 2/3 potency of celecoxib (ED50 = 31 μmol/kg). All compounds were less ulcerogenic (ulcer indexes = 1.20–4.61) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.90).

Effect of butylated hydroxyl toluene on the immune response of Rift Valley fever vaccine in a murine model

Abstract The present study was planned to examine the effect of butylated hydroxy toluene (BHT) on the immune response of Rift Valley fever vaccine (RVFV) in Swiss mice. Animals were divided into four equal groups. The first group was kept as negative control. The 2nd group was orally administrated with the acceptable daily intake (ADI) of BHT 0.3 mg/kg b.wt. daily for 21 days and the 3rd group were vaccinated only by inactivated RVFV at a dose of 0.2 ml I/P two times. The 4th group was orally administrated BHT as in the 2nd group and vaccinated by inactivated RVFV as in the 4th group. Blood samples were collected from all groups two weeks from booster vaccination. The cellular immunity was determined by leucocytic indices and the neutrophil‐lymphocyte ratio (NLR) whereas, humoral immunity was evaluated with IgG antibodies titer using enzyme‐linked immune‐sorbent assay (ELISA) test, serum neutralization test (SNT) and challenge test. BHT induced leucopenia, neutrophilia and marked lymphocytopenia in both non‐vaccinated and vaccinated mice. Moreover, BHT significantly decreased the efficiency of vaccination by inducing 70% cytopathic effect (CPE) in the infected cell cultures and increasing the ED50 value of RVFV vaccine. The present study indicates that BHT possesses a potential for decreasing both cellular and humoral mediated mechanisms. HighlightsButylated hydroxy toluene (BHT) is a food preservative widely used even in infant’s milk to prevent the oxidation of lipids.BHT had many sources other than foodstuffs that exaggerated the exposure risks.The routine childhood vaccinations are essential to life and the immune responses may affect with the consumed food preservative.BHT had an immunosuppressive activity with an increased risk of infection as antibody concentrations are below the level of durable protection.