الفهرس 
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Abstract
The present thesis deals with the design and synthesis of a new hybrids of xanthine and chalcone derivatives and evaluating of their anti-inflammatory,ulcerogenicity, inhibitory activity against COX-1 and COX-2 enzymes, their binding mode to the enzymes and anticancer activities. The thesis includes four main parts; introduction, scope of investigation, results & discussion and the experimental one.1- Introduction The introductory chapter consists of four parts; the first one gave a general idea about the synthetic procedures used for the preparation of xanthine derivatives. The second part of introduction involves a brief look about biological activities of xanthine derivatives including anti-asthmatic, antibacterial, antidiabetic, lipid-lowering,vasorelaxtion, anti-inflammatory, analgesic and anti-cancer activities. The third part involves synthetic procedures for preparation of cahlcones. The fourth part involves an overview about the biological activities of chalcones including antibacterial, antifungal, anticonvulsant, antioxidant, anti-inflammatory and anti-cancer activities. 2- Scope of investigation This section outlines the main goals and the rational of this work, including the synthesis of target compounds, biological evaluation of novel xanthine-chalcone hybrids, indicating the idea of discovering novel and potent anti-inflammatory agents. The ability of the prepared compounds to induce gastric toxicity has been alsoevaluated. Inhibitory activity against COX-2 and COX-1 enzymes and their binding mode to the enzymes were predicted using docking studies. Moreover, the prepared compounds were evaluated for in vitro cytotoxic properties on different cancer cell lines.3- Results and discussion This chapter deals with discussion of the results obtained and it is subdivided into two main categories:A- The first part:Chemistry section, which includes description of the methods used for synthesis of the intermediates and the final target compounds via the alkylation of 1,3,8 trisubstituted and 1,8-disubstituted xanthine derivatives with 2-bromo-N-(4-(3-arylacryloyl)-phenyl) acetamides derivatives to give compounds 9-28. Structures of the final compounds were confirmed by different spectroscopic technique including; 1HNMR, 13C NMR as well as elemental analysis B- The second part:Biology which is subdivided into six parts:I. Evaluation of the anti-inflammatory activity:Twenty prepared compounds 9-28 were evaluated as anti-inflammatory compounds using carrageenan-induced paw edema in rats using indomethacin as areference drug. The results revealed that most of synthesized xanthine-chalcone hybrids induced significant anti-inflammatory activity compared to indomethacin. II. Evaluation of the ulcerogenicity:Most of the synthesized compounds exhibited safer ulcerogenic liability relative to indomethacin.III. Histopathology: Histopathological investigation of the ulcerative regions of the synthesized compounds in order to assess the ulcerogenicity of the synthesized compounds on thegastric mucosa. Stomach sections of the ulcers for the control and the treated groups were stained by standard hematoxylin and eosin stain. The produced slides were subjected to microscopical examination and pictures were picked for these slides. Avery low incidence of gastric ulceration was induced by the tested compounds where acontinuous mucosal layer was observed with the absence of capillary inflammatorycells and the ulcerative damage of the gastric mucosa was markedly decreased which was proved by the very low ulcer index.IV. Evaluation of cyclooxygenase inhibitory activity: Compounds 9, 11, 12, 22 and 25 were evaluated for their ability to inhibit COX-1 and COX-2 enzymatic activity, IC50 values of test compounds was determined and compared to that of reference molecules celecoxib and indomethacin; In vitro COX-1/COX-2 inhibition studies showed that the most potent COX inhibitors in this series
were 9 and 22.V. Docking studies:Compounds 9, 11, 12, 22 and 25 were docked into the active site of COX-1 and COX-2 enzymes by using MOE software program. Docking studies in COX-1 showed that the oxygen of amide carbonyl group of most of synthesized hybrids could form hydrogen bonding with with Arg 120. Furthermore, hydrogen bonds were observed between His 90 and C=O of compound 22 in COX-2 active site.VI. Evaluation of the anticancer activity:Compounds 9-11 and 13-18 were selected by National Cancer Institute (NCI)according to the protocol of the Drug Evaluation Branch of the National Cancer Institute, USA, for in vitro anticancer screening. The human tumor cell lines were derived from nine different cancer types. Results for each compound were reported as
the growth inhibition percent of the treated cells which are evaluated spectrophotometrically and compared to that of the untreated control cells. Most of the tested compounds exhibited moderate antiproliferative activity against most of the cell lines. Moreover, compound 18 showed remarkable antiproliferative activity against most of the cell lines.