الفهرس 
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Abstract
This thesis discusses synthesis of some new mercaptobenzimidazolyl acetohydrazide derivatives incorporating acetohydrazones (5a-l, 6a-l, 7a-l), 1,3-dioxoisoindolines (8a-c), 1,2,4-triazole (9), 1,2,4-triazolo[3,4-b]1,3,4- thiadiazines (10a-c) and hydrazones of 1,2,4-triazole (11a-f) derivatives with biological investigation for their in vitro COX-1 and COX-2 inhibitory activities and in vivo anti-inflammatory activity. In part, it includes also, structural elucidation of the newly synthesized compounds. Thus, it is prefaced by a brief account about different therapeutic targets for benzimidazoles as anti-inflammatory and analgesic candidates. Also a short discussion of anti-inflammatory activity of acetohydrazones, 1,3- dioxoisoindolines, 1,2,4-triazoles and 1,2,4-triazolo[3,4-b]1,3,4-thiadiazines. The scope of investigation declared design and synthesis of our benzimidazole targets; Figure 4, and Schemes 1-3. Accordingly, it involves synthesis of 50 new compounds (1 new key intermediate and 49 target compounds). This work required synthesis of key acetohydrazide intermediates 4a-c; which were prepared according to reported procedures. Purity of newly synthesized compounds was checked by TLC, elemental microanalyses and the elucidation of their structures was confirmed by IR, 1H-NMR, and some representatives by APT 13C-NMR and mass spectrometry. Tables 5-15 and Figures 5-25. In vivo anti-inflammatory activity of 49 compounds (5a-l, 6a-l, 7a-l; 8ac; 9; 10a-c and 11a-f) was evaluated in rats using carrageenan paw edema method and indomethacin as a reference drug. The study revealed that compounds 6j, 7f, 8b, 10b-c, 11a, and 11e-f had superior anti-inflammatory activity compared to indomethacin (100.66% - 154.21%) at the same time interval, Table 19 and Figures 27-30. Moreover, compounds which showed the highest in vivo antiinflammatory activity (6h, 7a, 7c, 7f-h, 7k, 10b-c and 11f) were tested for their in vitro anti-inflammatory activity against ovine COX-1 and human recombinant COX-2 enzymes. Compounds 7a, 7g and 7k exhibited higher activity towards COX-1 than diclofenac sodium (IC50 = 3.41, 2.98, 2.51 vs. 3.90 μmole respectively), Figure 31. Additionally, compounds 7c, 7g, 7k, 10c and 11f revealed superior inhibitory profiles against human recombinant COX-2 enzyme as evidenced by their IC50 values (IC50 = 0.33, 0.39, 0.49, 0.28 and 0.32 μmole respectively), when compared with indomethacin and diclofenac sodium (IC50 = 0.49 and 0.80 μmole respectively), Figure 32. Additionally, this study proved that all test compounds were selective inhibitors for COX-2 enzyme (SI = 5.07 - 29.35) exceeding indomethacin and diclofenac sodium (SI = 0.08 and 4.87 respectively). Compounds (6h, 7c, 10c, 11f) showed the highest selectivity to COX-2 enzyme (SI = 16.11 - 29.35). Moreover, compound 10c was the most potent COX-2 inhibitor (IC50 = 0.28 μmole) among the test compounds with approximate selectivity ratio of 29.35, that was higher than indomethacin and diclofenac sodium, which makes it a good lead-candidate for further optimization. Finally, molecular docking study of the target compounds was investigated and the study suggested a good affinity for most of the synthesized compounds towards COX-2 active site. This work was published in Der Pharma Chemica entitled ”Synthesis, Molecular Modeling Study and Anti-inflammatory Activity of Novel Benzimidazole Derivatives with Promising Cyclooxygenase Inhibitory Properties” vol. 8, issue 17, 2016, pp. 213-231.