الفهرس 
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Abstract
The present thesis deals with the synthesis of different series of novel quinoline derivatives. The synthesized compounds were evaluated for their anti-cancer and anti-inflammatory activities.
The thesis includes four main chapters; introduction, scope of investigation, results and discussion, and experimental one.
The introduction deals with different synthetic methodologies for preparation of quinoline, 1,2,4-triazole, and chalcone derivatives. Also, it includes a summary for various biological activities of these derivatives, such as anti-cancer, anti-inflammatory, anti-bacterial, antimalarial, antifungal, and antiviral activities. Moreover, it involves an overview on nitric oxide (NO) as an important biological mediator, which is involved in the inflammatory response as well as tumor growth.
Scope of investigation chapter outlines the rationale and the main goals of this thesis including the incorporation of quinoline and 1,2,4-triazole rings with chalcone, amide, or oxime moieties in one compact structure in order to investigate the possible synergistic anti-cancer and anti-inflammatory activities.
The third chapter entitled “results and discussion” discusses and describes the obtained results and is divided into three parts. The first part discusses the results obtained from the synthesis of different quinoline-chalcone hybrids 7,8, 9a-j, quinoline-amide derivatives 11a-i and 12 a-j, oximes 15a-d and 17a-d. The structures of the prepared compounds have been confirmed by their melting points and different spectral methods including; IR, 1H NMR, 13C NMR and HRMS methods of analysis. The second part of this chapter is biology and subdivided into five sections. The first section is concerned with screening of the anti-cancer activity of the synthesized compounds. Compounds 7,8, 9a-j, 11a-i, 12 a-i, 15a-d and 17a-d have been selected by the National Cancer Institute (NCI) according to the protocol of the Drug Evaluation Branch of the National Cancer Institute, Bethesda, USA. In-vitro anti-cancer screening for the synthesized compounds was carried out against 60 cell lines of different nine cancer cell types including; leukemia, melanoma, ovarian, renal, CNS, prostate, lung, colon, and breast cancers. Compound 7b exhibited the most promising anti-cancer activity among all of the tested compounds. It showed remarkable inhibitory activity against leukemia (K-562, MOLT-4, and SR), colon (HCT-15 and SW-620), ovarian (OVCAR-8), and breast (MCF7) cancer cell lines with percent growth inhibition in the range of 72.37-94.60%. Moreover, compound 7b lead to complete cell death against colon (HCT-116), melanoma (LOX IMVI), and ovarian (IGROV1) cancer cell lines.
The second section investigates the antiproliferative activity of compounds 7a-f, 8a-f, and 9a-f on four different cancer cell lines, pancreatic cancer cell line (Panc-1), breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and epithelial cancer cell line (A-549). Compound 7b showed the highest activity among all tested compounds against cancer cell growth with average IC50 of 3.325 µM. Compounds 7g-j, 8g-j, and 9g-j were tested against cervical (Hela), fibrosarcoma (HT-1080), and colon (HT-29) cancer cell lines. Only compounds 9h and 9j elicited anti-cancer activity against these cell lines with IC50 = 2.5 -10.0 µM. Compounds 14a-d, 15a-d, 16a-d, and 17a-d showed no activity against the tested cell lines
The third section is concerned with rationalization of the cytotoxic activity of the most active compounds (7a, 7b, 9a, 9b, and 9d) via assessment of their ability to inhibit EGFR and BRAFV600E. Compounds 7a, 7b, 9a, 9b, and 9d exhibited remarkable inhibition of EGFR with IC50 values of 1.3-4.8 µM and good inhibition of BRAFV600E with IC50 values of 1.1-6.9 μM. This section also involves
The fourth section involves cell cycle and apoptosis analyses of compound 7b on Panc-1 cells. The results revealed that compound 7b caused significant apoptosis and cell cycle arrest of Panc-1 cells at G2/M phase.
The fifth section is concerned with measuring the inhibitory activity of compounds 11a-i and 12a-j on both bovine COX-1 and COX-2 subtypes using celecoxib as reference drug. Using colorimetric enzyme immunoassay (EIA) kit. The eight highest active compounds 11e-11i, 12b, 12e and 12f exhibited good inhibitory activity against COX-2 and were more potent inhibitors of COX-2 with IC50 values of 7.25-34.45 nM than COX-1 with IC50 values of 207.68-441.46 nM, the selectivity indices (SI) of 12.82-44.89. In all cases the measured activity was higher than that of celecoxib (SI = 8.05).
The third part of this chapter is concerned with a molecular docking study to evaluate the binding modes, orientations and interactions of compounds 7a, 7b, 9a, 9b, and 9d into the ATP binding sites of EGFR and BRAFV600E using AutoDock 4.2. The molecular docking analyses revealed that the new compounds adopted binding conformations into the active site of EGFR and BRAFV600E. The results of the docking study revealed that the new compounds 7a, 7b, 9a, 9b, and 9d exhibited higher binding affinities (Gb = -9.94 to -11.43 kcal/mol) toward EGFR compared to erlotinib (Gb = -7.39 kcal/mol). Additionally, the tested five compounds have high binding affinities (Gb = -9.11 to -9.94 kcal/mol) towards BRAFV600E, which were comparable to that of vemurafenib (Gb = -9.89 kcal/mol). Compound 7b exhibited the highest binding free energy (Gb = -11.43 kcal/mol) toward EGFR compared to -7.39 kcal/mol for erlotinib. Compound 9d displayed the highest binding free energy (Gb = of -9.94 kcal/mol) toward BRAFV600E compared to -9.89 kcal/mol for vemurafenib.
Compounds 11e, 11f, 11i, 12e, and 12f which showed the highest selectivity for COX-2, were docked into the active sites of COX-1, COX-2, and 5-LOX. The new compounds exhibited binding free energies (Gb) in the range of -7.34 to -9.65 kcal/mol for COX-1. On the other hand, the results of the docking study of the tested compounds revealed significantly higher binding free energies (Gb) in the range of -8.77 to -11.29 kcal/mol for COX-2 compared to COX-1, which is in agreement with the selectivity indices of these compounds toward COX-2.
The fourth chapter is the experimental one. This chapter is subdivided into three parts. The first part illustrates the general procedures for synthesis of the designed compounds and different spectroscopic data for these compounds. Sixty-five novel final compounds were synthesized and named as follows:
2-(4-Phenyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7a).
2-(4-Allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7b).
2-(5-(2-(4-Chlorophenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7c).
2-(4-Allyl-5-(2-(4-chlorophenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7d).
2-(5-(2-(4-Methoxyphenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7e).
2-(4-Allyl-5-(2-(4-methoxyphenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7f).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7g).
2-(4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7h).
2-(5-(2-(4-(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7i).
2-(4-Allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-chlorophenyl)acryloyl)phenyl)acetamide (7j).
2-(4-Phenyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8a).
2-(4-Allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8b).
2-(5-(2-(4-Chlorophenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8c).
2-(4-Allyl-5-(2-(4-chlorophenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8d).
2-(5-(2-(4-Methoxyphenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8e).
2-(4-Allyl-5-(2-(4-methoxyphenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8f).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8g).
2-(4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8h).
2-(5-(2-(4-(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8i).
2-(4-Allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(4-methoxyphenyl)acryloyl)phenyl)acetamide (8j).
2-(4-Phenyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9a).
2-(4-Allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9b).
2-(5-(2-(4-Chlorophenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9c).
2-(4-Allyl-5-(2-(4-chlorophenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9d).
2-(5-(2-(4-Methoxyphenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9e).
2-(4-Allyl-5-(2-(4-methoxyphenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9f).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9g).
2-(4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9h).
2-(5-(2-(4-(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)acetamide (9i).
2-(4-Allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl) acetamide (9j).
2-(4-Phenyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-chloro phenyl)acetamide (11a).
2-(4-Allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-chloro phenyl)acetamide (11b).
2-(5-(2-(4-Chlorophenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11c).
2-(4-Allyl-5-(2-(4-chlorophenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11d).
2-(5-(2-(4-Methoxyphenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11e).
2-(4-Allyl-5-(2-(4-methoxyphenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11f).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11g).
2-(4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11h).
2-(5-(2-(4-(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-chlorophenyl)acetamide (11i).
2-(4-Phenyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl) acetamide (12a).
2-(4-Allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl) acetamide (12b).
2-(5-(2-(4-Chlorophenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12c).
2-(4-Allyl-5-(2-(4-chlorophenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12d).
2-(5-(2-(4-Methoxyphenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12e).
2-(4-Allyl-5-(2-(4-methoxyphenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12f).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12g).
2-(4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12h).
2-(5-(2-(4-(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12i).
2-(4-Allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-methoxyphenyl)acetamide (12j).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-acetylphenyl)acetamide (14a).
2-(4-allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-acetylphenyl)acetamide (14b).
2-(5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N-(4-acetylphenyl)acetamide (14c).
2-(4-allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-(4-acetylphenyl)acetamide (14d).
N-(4-(1-(Hydroxyimino)ethyl)phenyl)-2-((5-(2-(4(methylsulfonyl) phenyl) quinoline-4-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)acetamide (15a).
2-((4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-(1-(hydroxyimino)ethyl)phenyl)acetamide (15b).
N-(4-(1-(hydroxyimino)ethyl)phenyl)-2-((5-(2-(4(aminosulfonyl) phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)acetamide (15c).
2-((4-Allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-(1-(hydroxyimino)ethyl)phenyl)acetamide (15d).
2-(5-(2-(4-(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-1-phenylethanone (16a).
2-(4-Allyl-5-(2-(4-(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-1-phenylethanone (16b).
2-(5-(2-(4-(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-1-phenylethanone (16c).
2-(4-Allyl-5-(2-(4-(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-ylthio)-1-phenylethanone (16d).
2-((5-(2-(4(Methylsulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)-1-phenylethan-1-one oxime (17a).
2-((4-Allyl-5-(2-(4(methylsulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)-1-phenylethan-1-one oxime (17b).
2-((5-(2-(4(Aminosulfonyl)phenyl)quinolin-4-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)-1-phenylethan-1-one oxime (17c).
2-((4-Allyl-5-(2-(4(aminosulfonyl)phenyl)quinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)-1-phenylethan-1-one oxime (17d).
The second part outlines the detailed procedures used for the biological evaluation experiments. It describes the procedures of the anti-cancer activity at the national institute of cancer (NCI), MTT assay, antiproliferative, cell apoptosis assays. It also describes in vitro COX-1/2, 5-LOX, EGFR, BRAF kinase inhibition assays.
The third part includes the method used for establishing docking studies of the new compounds into the active site of EGFR, BRAFV600E, COX-1, COX-2, and 5-LOX using AutoDock 4.2 programme.