Kamal Eldin H. ElTahir

Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study.

New arylhydrazone derivatives and a series of 1,5-diphenyl pyrazoles were designed and synthesized from 1-(4-chlorophenyl)-4,4,4-trifuorobutane-1,3-dione 1. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw oedema model. Moreover, they were tested for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Some of the new compounds (2f, 6a and 6d) showed a reasonable in vitro COX-2 inhibitory activity, with IC₅₀ value of 0.45 μM and selectivity index of 111.1. A virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Docking study of the synthesized compounds 2f, 6a and 6d into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Part 2

New pyrazole and pyrazoline derivatives have been synthesized and their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. Among the tested compounds, N-((5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)-3,5-bis(trifluoromethyl)aniline 8d exhibit optimal COX-2 inhibitory potency (IC(50)=0.26 lM) and selectivity (SI)=>192.3] comparable with reference drug celecoxib (IC(50) value of 0.28 lM and selectivity index of 178.57). Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using carrageenan-induced rat paw edema model. Molecular modeling was conducted to study the ability of the active compounds to bind into the active site of COX-2 which revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis, analgesic and anti-inflammatory evaluation of some novel quinazoline derivatives

Two series of some new 2,4,6-trisubstituted-quinazoline derivatives were prepared and screened for their analgesic, anti-inflammatory activity and acute toxicity. Four compounds were more potent analgesic agents than the reference drug Indomethacin and thirteen compounds showed significant anti-inflammatory activity. Seven compounds showed combined ability to inhibit both pain and inflammation. Compounds tested for acute toxicity showed no toxic symptoms or mortality rates 24 h post-administration implying their good safety margin.

Synthesis, anti-inflammatory activity and COX-1/COX-2 inhibition of novel substituted cyclic imides. Part 1: Molecular docking study.

A group of cyclic imides (1-13) was designed for evaluation as selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model. Compounds 5b, 6b, 11b, 11c, 12b and 12c were proved to be potent COX-2 inhibitors with IC50 range of 0.1-1.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 5b as a highly potent (IC50=0.1 μM), and an extremely selective [COX-2 (SI)=400] comparable to celecoxib [COX-2 (SI)>333.3], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=104 mg/kg) relative to diclofenac (ED50=114 mg/kg). A Virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Molecular modeling (docking) study showed that the CH3O substituents of 5b inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such group underwent a H-bonding interaction with His90 (2.43, 2.83 Å), Arg513 (2.89 Å) and Tyr355 (3.34 Å). Docking study of the synthesized compound 5b into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis and anticonvulsant evaluation of some new 2,3,8-trisubstituted-4(3H)-quinazoline derivatives.

A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine) induced seizures and compared with the standard drugs methaqualone and sodium valproate. Compounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.

The Black Seed Nigella sativa Linnaeus - A Mine for Multi Cures: A Plea for Urgent Clinical Evaluation of its Volatile Oil

Abstract This review almost covers what is actually known to date about the black seed and its constituents. It is clear that most of the potent and fruitful activity resides in its volatile oil and a protein component. However, the volatile oil suffers the drawback of the bronhoconstricting effect of thymoquinone. However, the latter can be easily removed from the oil to obtain a dethymoquinoneated oil that has already been shown to possess the major characteristics of the whole oil. At this moment there are a lot of experimental data that hopefully, may stimulate the beginning of the era of pilot clinical studies to evaluate the clinical potential of the volatile oil, some of the protein fractions and the dethymoquinoneated volatile oil. It is hoped that this plea will have a rapid response.

Design and synthesis of novel 7-aminoquinazoline derivatives: Antitumor and anticonvulsant activities

A novel series of 7-substituted-4(3H)-quinazolinone were designed, synthesized and evaluated for their antitumor and anticonvulsant activity. Compound 7 revealed broad-spectrum antitumor effectiveness toward numerous cell lines that belong to different tumor subpanels, whereas compounds 9 and 18 possess selective activity toward leukemia cell lines. Additionally, compounds 3, 15, 16, 18, 19 and 20 showed advanced anticonvulsant activity as well as lower neurotoxicity than reference drugs. The achieved results proved that the distinctive compounds could be valuable as a model for future devise, acclimatization and investigation to construct more active analogues.

Prevention of Experimentally-induced Gastric Ulcers in Rats by an Ethanolic Extract of "Parsley" Petroselinum crispum

An ethanolic extract of Parsley, Petroselinum crispum (Mill.) Nym.ex A.W. Hill (Umbelliferae), was tested for its ability to inhibit gastric secretion and to protect gastric mucosa against the injuries caused by pyloric ligation, hypothermic restraint stress, indomethacin and cytodestructive agents (80% ethanol, 0.2 M NaOH and 25% NaCl) in rats. The extract in doses of 1 and 2 g/kg body weight had a significant antiulcerogenic activity on the models used. Besides, ethanol-induced depleted gastric wall mucus and non-protein sulfhydryl contents were replenished by pretreatment with Parsley extract. Acute toxicity tests showed a large margin of safety for the extract. The phytochemical screening of Parsley leaves revealed the presence of tannins, flavonoids, sterols and/or triterpenes.

Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1 μM), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4 mg/kg) relative to diclofenac (ED50=114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95 Å), Phe(518)(2.82 Å) and Arg(513)(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Gastric antiulcer, antisecretory and cytoprotective properties of celery (Apium graveolens) in rats

In the present investigation, an ethanol extract of celery [Apium graveolens L. (Apiaceae/Umbelliferae)], at doses of 250 and 500 mg/kg body weight, was evaluated for antigastric ulcer activity using various experimental gastric ulcer models in rats. Ulcers were induced by indomethacin, cytodestructive agents (80% ethanol, 0.2 M NaOH and 25% NaCl) and cold restraint stress. Gastric secretory studies were undertaken by using pylorus ligation (Shay rat model). In addition to gastric wall mucus (GWM), non-protein sulfhydryl (NP-SH) and malondialdehyde (MDA) were also estimated in gastric tissues after 80% ethanol treatment. Pretreatment of celery extract produced dose-dependent reduction in all experimentally induced gastric lesions. Ethanol (80%) decreased the levels of GWM, NP-SH and increase in MDA concentration in gastric tissue. Celery extract showed the ability to significantly replenish the ethanol-induced depleted levels of GWM and gastric mucosal NP-SH. The gastric mucosal MDA level was also significantly lowered in extract pretreated rats. The celery extract showed stomach protection against the models used for ulcerogenesis. Results were further confirmed by using histopathological assessment. The phytochemical screening showed the presence of various chemical constituents such as flavonoids, tannins, volatile oils, alkaloids, sterols and/or triterpenes. Acute toxicity test revealed no deleterious or toxic symptoms or mortality over a period of 14 days. However, the LD50 was found to be 7.55 g/kg, and showed a large margin of safety. The results suggest that Apium graveolens extract significantly protects the gastric mucosa and suppresses the basal gastric secretion in rats, possibly through its antioxidant potential.