Document Details
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Document Type |
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Thesis |
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Document Title |
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QUINAZOLINONES AND QUINAZOLINE THIONES AS POTENTIAL PHOSPHODIESTERASE 7 INHIBITORS ANTI-INFLAMMATORY AGENTS الكينازولينونات والكينازولينثايونات كمثبطات لانزيم الفوسفات ثنائى الاستريز7 كمضادات محتملة للالتهابات |
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Subject |
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Faculty of Science |
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Document Language |
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Arabic |
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Abstract |
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Literature revealed the importance of quinazolinones and their thio isosteres as Phosphodiesterase 7 inhibitors and Anti-inflammatory agents. There is a continuous need for new anti-inflammatory agents with high selectivity and minimal undesirable side effects. In the present work, forty-five novel quinazoline derivatives in five different classes were prepared namely, Dihydroisoindoloquinazolin-5,11-diones 127a-j, Quinazolin-2,4-diones 143a-h, Quinazolin-2,4-dithiones 144a-f, 1,2-disubstituted quinazolin-4(1H)-ones 155a-i and 2-thioquinazolin-4-ones(thiones) 165, 167 and 168. The target compounds were synthesized adopting several routes. One-pot ultrasound promoted multicomponent reaction of substituted isatoic anhydrides 17a, b, 2-formylbenzoic acid 27 and different amines 126a-e was used to prepare 3-substituted 6-aryldihydroisoindolo[2,1-a]quinazoline-5,11-diones 127a-j. Ultrasound promoted one-pot synthesis of 3-aryl quinazoline-2,4(1H,3H)-diones 143a-h was achieved through reaction of substituted isatoicanhydrides 17a-c and different amines 126a-e. Thionation of 3-arylquinazoline-2,4(1H,3H)-diones 143a-h using lawesson`s reagent afforded 3-arylquinazoline-2,4(1H,3H)-dithiones 144a-f. Intermediates 1,2-disubstituted-2,3-dihydroquinazolin-4(1H)-ones 154a-l were prepared from condensation reaction of N-substituted anthranilamides 153a, b with different aldehydes. These intermediates were oxidized using potassium permanganate to acquire 1,2-disubstituted quinazolin-4(1H)-ones 155a-l. The cyclocondensation and molecular cyclization of thiourea with anthranilic acid derivatives 164a-c was used to prepare 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones 165a-c which were S-alkylated using benzyl bromide in DMF in presence of potassium carbonate to afford disubstituted 2-benzylthio quinazolin-4(3H)-ones 167a-c. Compounds 167a-c were thionated using lawesson`s reagent to obtain disubstituted 2-benzylthio quinazoline-4(3H)-thiones 168a-c. The structures of the newly synthesized compounds were confirmed through microanalysis, IR, 1H NMR, 13C NMR and mass spectrometry. Molecular docking was performed for the proposed compounds 127-168, to evaluate their recognition profiles at the PDE7A1 binding-pocket. Twenty compounds fitted perfectly at the enzyme binding site and were capable of binding in an inhibitory mode. These compounds are 127b, c, d, h, I , 143b, c, d, g, 144a, c, 155b, d, e, g, h, i, and 165a-c. These compounds formed the proper interactions with the conserved amino acids at the pocket of the enzyme and showed high affinity to bind with PDE7A1 enzyme at its binding site. Compounds 127i and 143d showed the highest enzyme recognition compared to reference compound BRL50481.Twenty-eight compounds 127a-j, 143a-g, 144a, d, 155b, d, e, g-i and 165a-c were screened for in vitro inhibitory activity of recombinant PDE7 enzyme. All the compounds showed good inhibitory activity at micromolar level compared to BRL50481. Among the tested compounds, five compounds 127c, 127f, 127i, 143d and 143e showed highest inhibitory activity of recombinant PDE7 enzyme and were further screened for their PDE7A inhibitory activity against Jurkat, Clone E6-1 cell line. The compounds showed moderate inhibitory activity compared to rofluimilast in the cell line study. It is recommended that the compounds be subjected for in vivo analysis as anti-inflammatory agents in autoimmune disease and other chronic inflammations to examine their activity as well as their bioavailability. |
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Supervisor |
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Prof. Tariq R. Sobahi |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1440 AH
2019 AD |
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Co-Supervisor |
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Prof. Magdy M. Gineinah |
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Added Date |
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Thursday, May 16, 2019 |
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Researchers
| شيرين محمد الفقي | El Feky, Sherin Mohammed | Researcher | Doctorate | |
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