الفهرس 
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Abstract
1. Abstract:
The parent ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl)propanoate (3) was used for obtaining forty seven novel compounds. The starting material for their corresponding mono, dipeptides, and hydrazones was produced by chemoselective N-alkylation via addition reaction of ethyl acrylate to 4-benzylphthalazin-1(2H)-one (2) in presence of anhydrous potassium carbonate to give ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl)propanoate (3). The ester 3 was hydrazinolyzed to give the corresponding hydrazide 3-(4-benzyl-1-oxophthalazin-2(1H)-yl)propanehydrazide (5), which converted to the corresponding azide 6. The azide 6 was coupled with amines and/or amino acid ester hydrochloride to afford several amides 7a-g, and esters 8a-c respectively, then a Series of hydrazinolyzed reactions occurred on esters 8a-c to give corresponding hydrazides 9a-c. The hydrazides 9a-c under azide coupling method were coupled with amines and/or amino acid ester hydrochloride to give several dipeptides. On the other hand, the hydrazides 9a-c were also condensed with several aldehydes to produce hydrazone derivatives 12a-l. All synthesized compounds were tested against some cell lines such as HCT-116, HepG-2, and A549. It was found that, some compounds such as 9c, 11b, and 12c exhibited Interestingly potent cytotoxicity with IC50 values of 1.58, 0.32 and 0.64 μM respectively compared to Sorafenib (IC50=2.93 μM). Compound 11b exhibited potent vascular endothelial growth factor receptor VEGFR2 inhibition by 95.2% with an IC50 value 17.8 μM compared to Sorafenib (94.7% and IC50 of 32.1 μM). For apoptosis activity, 11b-treatment induced apoptosis in HCT-116 cells by 21.7-fold, arresting the cell proliferation at S-phase. Finally, it formed a good binding affinity towards VEGFR2 protein with a binding energy of -10.66 Kcal/mol, and it formed binding interactions with the key interactive amino acids. On the other hand, other classes of compounds such as 10i, 10l and 12k were investigated against HepG-2 cell lines and showed that Compared to Erlotinib, which had an IC50 value of 1.88 μM, compound 12k showed strong cytotoxicity against HepG-2 cancer cells at a concentration of 0.14 μM. In contrast to Erlotinib (92.6% and IC50 of 79.4 μM), Compounds 12k showed strong epidermal growth factor receptor EGFR inhibition by 98.2% with an IC50 value of 47.1 μM. In terms of apoptotic activity, 12k -treatment increased expression of genes involved in cell death, including P53, Bax, PUMA, and caspases. Finally, it exhibited strong binding affinity with the key amino acids with a binding energy of -27.21 Kcal/mol towards the EGFR protein. Hence, compound 12k was worthy of studying as a target-oriented anti-liver agent with a good selectivity profile. The rest of our synthesized compounds such as 10f, 11f, 12e, and 11e were tested against the lung cancer cells line A549 and they unfortunately showed non promising activity with IC50 values of 38.6, 33.2, 48.9, and 64.5 μM respectively compared to Doxorubicin, which had IC50 value of 1.88 μM. The antibacterial activity was tested for these compounds, and interestingly they showed that, the compounds 10f, 11e, and 12e demonstrated antibacterial activity against gram-positive bacteria, compound 12e exhibited potent antibacterial activity with an inhibition zone of 23.5 and 34.6 mm against Staphylococcus aureus, and Bacillus subtilis respectively. compound 10h exhibited activity against Escherichia coli with an inhibition zone of 31 mm, compared with ciprofloxacin, which showed an inhibition zone of 18 mm. compound 11e demonstrated activity against Salmonella typhimurium with an inhibition zone of 16.7 mm, which proved the potent antibacterial activity to our newly synthesized compounds.
2. Scheme of work:
Synthesis of ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl)propanoate (3) and their corresponding acid 4 & hydrazide 5.
Synthesis of 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-alkyl-propanamide 7a-g by methods (A) & (B).
Synthesis of methyl (3-[4-benzyl-1-oxophthalazin-2(1H)-yl) propanoyl amino] alkanoates 8a-c by methods (A)&(B).
Synthesis of Hydrazides 9a-c from Corresponding esters 8a-c.
Synthesis of N-substituted-3-(4-benzyl-1-oxophthalazin-2(1H)-yl)-2-oxoethyl) propanamides 10a-l.
Synthesis of Dipeptides 11a-i from Corresponding Hydrazides 9a-c.
Synthesis of some hydrazone derivatives 12a-l.