Gamal El-Din A.A. Abuo-Rahma

Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities

Substituted carboxylic acid hydrazides 1a-d reacted with ethenetetracarbonitril 2 in dimethyl formamide with the formation of diacylhydrazines 4a-d and 5-amino-1-substituted pyrazole-3,3,4-tricarbonitriles 5a-d. On the other hand, 1a-d reacted with diethyl (E)-2,3-dicyanobutenedioate 3 to give oxadiazole derivatives 10a-d and pyrazolone derivatives 11a-d, respectively. The prepared compounds 4a-d, 5a-d and 11a-d were evaluated each for antidepressant activity using tail suspension behavioral despair test and anticonvulsant activity against PTZ induced seizures in mice. Compounds 4a and 4b induced markedly antidepressant activity compared to imipramine, and their activities as antidepressant nearly equal twice the activity of imipramine at 10 mg kg(-1) dose level. On the other hand, compounds 11b, 11a and 11d exhibited remarkable protective effect against clonic seizures induced by i.p. injection of PTZ at a dose level of 20 mg kg(-1). The results of anticonvulsant activity are nearly close to phenobarbital sodium at a dose level of 30 mg kg(-1) and more potent than phenytoin sodium at a dose level of 30 mg kg(-1).

Design, synthesis, antibacterial activity and physicochemical parameters of novel N-4-piperazinyl derivatives of norfloxacin

We report herein the synthesis of some N-Mannich bases in addition to different N-4 substituents of norfloxacin. The antibacterial activities of the newly synthesized compounds were evaluated and correlated with their physicochemical properties. Results revealed that some of the tested compounds exhibited better inhibitory activities than the reference antibiotic norfloxacin against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia and Staphylococcus aureus strains. Correlation results showed that there is no single physicochemical parameter that can determine the effect of N-4 piperazinyl group on the activity of these fluoroquinolones, where lipophilicity, molecular mass and electronic factors may influence the activity.

Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: Synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity

A group of novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids was prepared. One-dose anticancer test results indicated that compounds 3a and 3g exhibited the highest ability to inhibit the proliferation of different cancer cell lines. Compound 3a exhibited a broad-spectrum of anti-tumor activity without pronounced selectivity while compound 3g revealed high selectivity toward the leukemia subpanel with selectivity ratio of 6.71 at GI₅₀ level. Moreover, compounds 3e and 3j have shown remarkable topo II inhibitory activity compared to etoposide at 100 μM and 20 μM concentrations. Compounds 3e and 3j exhibited comparably potent topo I inhibitory activity at 20 μM concentration compared to camptothecin. Compounds 3e and 3j exhibited strong topo II inhibitory activities compared to topo I at 20 μM concentration. Studying of the solubility and partition coefficient revealed higher lipophilicity of the hybrids 3a-j compared to the parent ciprofloxacin.

Design, synthesis and hypolipidemic activity of novel 2-(naphthalen-2-yloxy)propionic acid derivatives as desmethyl fibrate analogs.

A series of 2-(naphthalen-2-yloxy)propionic acid derivatives were prepared. The hypolipidemic activity of the new compounds as well as the intermediate acid 2 was evaluated in the high cholesterol diet (HCD) fed hyperlipidemic rat model. Interestingly, the S-alkylated mercaptotriazole 8b and the 1,3,4-oxadiazole 9 produced striking reduction of serum levels of total cholesterol (TC), triglycerides (TGs) and low-density lipoproteins (LDLs) and elevation of serum high-density lipoproteins (HDLs) being more active than the reference gemfibrozil. In addition, the 1,2,4-triazole 7a, the hydroxypyrazoline 10 and the pyrazolone derivative 11 exhibited good hypolipidemic activity on different lipid parameters.

Design, synthesis and biological investigation of certain pyrazole-3-carboxylic acid derivatives as novel carriers for nitric oxide

Some novel pyrazole-NO hybrid molecules 5a-e, 6, 8 and 10 were prepared through binding of the pyrazole-3-carboxylic acid derivatives with nitric oxide donor moiety like oxime or nitrate ester. The prepared compounds were evaluated for nitric oxide release, antibacterial and anti-inflammatory activities. The organic nitrate 10 exhibited the highest percentage of NO release using Griess diazotization method. Some of the prepared compounds exhibited remarkable antibacterial activity against Escherichia coli C-600, Pseudomonas aeruginosa, Bacillus subitilis and Staphylococcus aureus NCTC 6571 compared to ciprofloxacin. Most of the tested compounds showed significant anti-inflammatory activity compared to indomethacine using carrageenan induced paw edema method. In general, structural modification of compound 2 either to nitrate ester or oxime hybrids showed better anti-inflammatory with less ulcerogenic liability than their corresponding starting intermediates.

1,2,4-Triazole/oxime hybrids as new strategy for nitric oxide donors: Synthesis, anti-inflammatory, ulceroginicity and antiproliferative activities.

A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity and antiproliferative activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their ketone intermediates and indomethacin. The NO-donating oximes 7i and 7k achieved remarkable cell growth inhibition activity against most of the tested cell lines. Compound 7k was found to be with high selectivity against CNS subpanel with selectivity ratio of 11.99 at GI₅₀ level.

New nitric oxide donating 1,2,4-triazole/oxime hybrids: synthesis, investigation of anti-inflammatory, ulceroginic liability and antiproliferative activities.

A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their intermediate ketones and indomethacin. The NO-donating oxime 6i revealed significant activity against renal cancer A498 cell lines with 50.52 cell growth inhibition.

Design, synthesis and anticancer activity of nitric oxide donating/chalcone hybrids

A group of nitric oxide (NO) donating chalcone derivatives was prepared by binding amino chalcones with different NO-donating moieties including; nitrate esters, oximes and furoxans. Screening of the anticancer activity of the target compounds revealed that the selected NO-donating compounds exhibited from mild to strong cytotoxic activity. The NO/chalcone hybrids 3a and 3b exhibited remarkable activity against different types of cancer cell lines especially against the colon and melanoma cancer cell lines. The nitrate ester 3a exhibited moderate selectivity toward colon cancer subpanel with selectivity ratio of 5.87 at TGI level.

Synthesis, anti-inflammatory activity and ulcerogenic liability of novel nitric oxide donating/chalcone hybrids.

A group of novel nitric oxide (NO) donating chalcone derivatives was prepared by binding various amino chalcones with different NO donating moieties including; nitrate ester, oximes and furoxans. Most of the prepared compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared with indomethacin. The prepared compounds exhibited more protection than indomethacin in regard to gastric toxicity. Histopathological investigation confirmed the beneficial effects of the NO releasing compounds in reducing ulcer formation. The incorporation of the NO-donating group into the parent chalcone derivatives caused a moderate increase in the anti-inflammatory activity with a marked decrease in gastric ulcerations compared to their parent chalcone derivatives.

Thieno[2,3-d]pyrimidines in the Synthesis of Antitumor and Antioxidant Agents

Dimethyl acetylenedicarboxylate, ethyl propiolate, and E‐dibenzoylethylene react with thienopyrimidines (cyclo‐pentyl, ‐hexyl, and ‐heptyl) derivatives to form thiazolo[3,2‐a]thieno‐[2,3‐d]pyrimidin‐2‐ylidene) acetates, thieno[2,3‐d]pyrimidin‐2‐ylthioacrylates, and thieno[2′,3′:4,5]pyrimido[2,1‐b][1,3]thiazin‐6‐ones, respectively. Reactions proceed via cyclization and thio‐addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep‐G2 cells with IC50 < 20 μM.