الفهرس 
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Abstract
According to American Cancer Society (ACS) statistics, cancer is the third most lethal disease following cardiovascular diseases, infectious diseases, and parasites. Cancer treatment tend to be one of the most important fields of scientific research.
Targeted therapy is a cancer treatment that uses drugs to target specific genes and proteins that are involved in the growth and survival of cancer cells; tyrosine kinase inhibitors (TKIs) are a type of targeted therapy. The formation of new blood vessels (angiogenesis) is one of the hallmarks well known in the carcinogenesis cycle. Vascular endothelial receptor-2 growth factor (VEGFR-2) plays a significant role in angiogenesis of cancer. Angiogenesis is greatly inhibited by targeting VEGFR which leads to tumor cell death. MYT1 (Membrane-associated tyrosine and threonine-specific cdc2-inhibitory kinase) is one of WEE kinase family that regulate and control cell cycle through phosphorylation of Cdk1/Cyclin B complex at G2/M transition which essential to entry into mitotic phase. Consequently, inhibition of MYT1 is promising target for synergistic action with convential cancer therapy to target cancer cell over non-cancerous cells.
In this study, quinazoline and quinoline derivatives were developed and synthesized as targeted inhibitors of VEGFR-2 and MYT1 kinases. The design centered on the scaffold hopping, redesign approach and analysis of previous SAR studies to approved lead compounds and in clinical studies ones;
Synthesis of the designed compounds was then achieved, and various spectral and microanalytical data validated their structures.
This study involved the synthesis of the following commercially unavailable reported intermediates:
1) 1-(4-Nitrophenyl)-3-phenylurea (Ia)
2) 1-(3-Fluorophenyl)-3-(4-nitrophenyl)urea (Ib)
3) 1-(4-Fluorophenyl)-3-(4-nitrophenyl)urea (Ic)
4) 1-(3-Methoxyphenyl)-3-(4-nitrophenyl)urea (Id)
5) 1-(4-Methoxyphenyl)-3-(4-nitrophenyl)urea (Ie)
6) 1-(4-Chlorophenyl)-3-(4-nitrophenyl)urea (If)
7) 1-(4-Nitrophenyl)-3-(3-(trifluoromethyl)phenyl)urea (Ig)
8) 1-(3,4-Dichlorophenyl)-3-(4-nitrophenyl)urea (Ih)
9) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-nitrophenyl)urea (Ii)
10) 1-(4-Aminophenyl)-3-phenylurea (IIa)
11) 1-(4-Aminophenyl)-3-(4-fluorophenyl)urea (IIb)
12) 1-(4-Aminophenyl)-3-(4-fluorophenyl)urea (IIc)
13) 1-(4-Aminophenyl)-3-(3-methoxyphenyl)urea (IId)
14) 1-(4-Aminophenyl)-3-(4-methoxyphenyl)urea (IIe)
15) 1-(4-Aminophenyl)-3-(4-chlorophenyl)urea (IIf)
16) 1-(4-Aminophenyl)-3-(3-(trifluoromethyl)phenyl)urea (IIg)
17) 1-(4-Aminophenyl)-3-(3,4-dichlorophenyl)urea (IIh)
18) 1-(4-Aminophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (IIi)
19) 1-(3-Chlorophenyl)-3-(4-nitrophenyl)urea (IIIa)
20) 1-(4-Nitrophenyl)-3-(m-tolyl)urea (IIIb)
21) 1-(4-Aminophenyl)-3-(3-chlorophenyl)urea (IVa)
22) 1-(4-Aminophenyl)-3-(m-tolyl)urea (IVb)
23) 1-(4-hydroxyphenyl)-3-phenylurea (Va)
24) 1-(4-Hydroxyphenyl)-3-(m-tolyl)urea (Vb)
25) 1-(4-Hydroxyphenyl)-3-(3-methoxyphenyl)urea (Vc)
26) 1-(3-Chloro-4-methylphenyl)-3-(4-hydroxyphenyl)urea (Vd)
27) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (Ve)
28) Ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate (VII)
29) Ethyl 4-chloroquinazoline-2-carboxylate (VIII)
30) 2-Oxo-1,2-dihydroquinoline-4-carboxylic acid (XIII)
31) 2-Chloroquinoline-4-carbonyl chloride (XV)
Also, it comprised the following new intermediates:
1) 1-(2-Fluoro-4-hydroxyphenyl)-3-(m-tolyl)urea (VIa)
2) 1-(2-fluoro-4-hydroxyphenyl)-3-(3-methoxyphenyl)urea (VIb)
Also, the study involved the synthesis and the characterization of the following new-targeted compounds:
1) Ethyl 4-((4-(3-phenylureido)phenyl)amino)quinazoline-2-carboxylate (IXa)
2) Ethyl 4-((4-(3-(3-fluorophenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXb)
3) Ethyl 4-((4-(3-(4-fluorophenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXc)
4) Ethyl 4-((4-(3-(m-tolyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXd)
5) Ethyl 4-((4-(3-(3-methoxyphenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXe)
6) Ethyl 4-((4-(3-(4-methoxyphenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXf)
7) Ethyl 4-((4-(3-(4-chlorophenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXg)
8) Ethyl 4-((4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXh)
9) Ethyl 4-((4-(3-(3,4-dichlorophenyl)ureido)phenyl)amino)quinazoline-2-carboxylate (IXi)
10) Ethyl 4-((4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)amino) quinazoline-2-carboxylate (IXj)
11) N-Methyl-4-((4-(3-phenylureido)phenyl)amino)quinazoline-2-carboxamide (Xa)
12) 4-((4-(3-(3-Fluorophenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xb)
13) 4-((4-(3-(4-Fluorophenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xc)
14) N-Methyl-4-((4-(3-(m-tolyl)ureido)phenyl)amino)quinazoline-2-carboxamide (Xd)
15) 4-((4-(3-(3-Methoxyphenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xe)
16) 4-((4-(3-(4-Methoxyphenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xf)
17) 4-((4-(3-(4-Chlorophenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xg)
18) N-Methyl-4-((4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)amino) quinazoline-2-carboxamide (Xh)
19) 4-((4-(3-(3,4-Dichlorophenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xi)
20) 4-((4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)amino)-N-methylquinazoline-2-carboxamide (Xj)
21) Ethyl 4-(4-(3-phenylureido)phenoxy)quinazoline-2-carboxylate (XIa)
22) Ethyl 4-(4-(3-(m-tolyl)ureido)phenoxy)quinazoline-2-carboxylate (XIb)
23) Ethyl 4-(4-(3-(3-methoxyphenyl)ureido)phenoxy)quinazoline-2-carboxylate (XIc)
24) Ethyl 4-(4-(3-(3-chloro-4-methylphenyl)ureido)phenoxy)quinazoline-2-carboxylate (XId)
25) Ethyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy) quinazoline-2-carboxylate (XIe)
26) Ethyl 4-(3-fluoro-4-(3-(m-tolyl)ureido)phenoxy)quinazoline-2-carboxylate (XIIa)
27) Ethyl..4-(3-fluoro-4-(3-(3-methoxyphenyl)ureido)phenoxy)quinazoline-2- carboxylate (XIIb)
28) 2-Oxo-N-(4-(3-phenylureido)phenyl)-1,2-dihydroquinoline-4-carboxamide (XIVa)
29) N-(4-(3-(3-Fluorophenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (XIVb)
30) N-(4-(3-(4-Fluorophenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (XIVc)
31) 2-Oxo-N-(4-(3-(m-tolyl)ureido)phenyl)-1,2-dihydroquinoline-4-carboxamide (XIVd)
32) N-(4-(3-(3-Methoxyphenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (XIVe)
33) N-(4-(3-(4-Methoxyphenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (XIVf)
34) N-(4-(3-(4-Chlorophenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-
carboxamide (XIVg)
35) 2-Oxo-N-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1,2-dihydroquinoline-4-carboxamide (XIVh)
36) N-(4-(3-(3,4-Dichlorophenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (XIVi)
37) N-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (XIVj)
38) 2-Chloro-N-(4-(3-phenylureido)phenyl)quinoline-4-carboxamide (XVIa)
39) 2-Chloro-N-(4-(3-(3-fluorophenyl)ureido)phenyl)quinoline-4-carboxamide (XVIb)
40) 2-Chloro-N-(4-(3-(4-fluorophenyl)ureido)phenyl)quinoline-4-carboxamide (XVIc)
41) 2-Chloro-N-(4-(3-(m-tolyl)ureido)phenyl)quinoline-4-carboxamide (XVId)
42) 2-Chloro-N-(4-(3-(3-methoxyphenyl)ureido)phenyl)quinoline-4-carboxamide(XVIe)
43) 2-Chloro-N-(4-(3-(4-methoxyphenyl)ureido)phenyl)quinoline-4-carboxamide (XVIf)
44) 2-Chloro-N-(4-(3-(4-chlorophenyl)ureido)phenyl)quinoline-4-carboxamide (XVIg)
45) 2-Chloro-N-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)quinoline-4-carboxamide (XVIh)
46) 2-chloro-N-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)quinoline-4-carboxamide(XVIi)
47) 2-Chloro-N-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)quinoline-4-carboxamide (XVIj)
The enzymatic assay was performed at Thermo Fischer Scientific, USA.The enzymatic activity of the synthesized compounds was assessed against VEGFR-2 and MYT1 kinases at 10 μM concentration. Some of the synthesized compounds showed potent VEGFR-2 inhibitory potency in particular IXd, Xd, Xe, Xh, Xi, Xj, XIc, XIIa, XIIb. The NH-linked urea based derivatives highlighted that incorporating a carboxamide moiety at position 2 of quinazoline scaffold, replacing the ester functionality, resulted in marked increase in enzymatic potency (Xa-j vs. IXa-j), which is probably attributed to the extra H-bond with Cys919 that is suggested to be crucial for potent VEGFR-2 inhibition. Thus, five quinazoline-2-carboxamide derivatives (Xd, Xe, Xh, Xi and Xj) exhibited potent nanomolar VEGFR-2 inhibition with IC50 values of 12.1, 40.3, 15.5, 13.1 and 57.4 nM, respectively, superior to that of sorafenib (IC50 78.9 nM).
Compound (XVIg) showed moderate inhibitory activity on MYT1 kinase at 10 μM concentration. This compound may be a gleam of hope to design and develop more selective MYT1 inhibitors in the future perspective.
Twenty three of fourty seven of the targeted compounds have been selected by the National Cancer Institute (NCI), namely (IXa, IXb, IXc, IXd, IXe, IXf, IXh, IXg, Xc, Xe, Xg, Xh, Xi, Xj, XIa, XIb, XIVa, XIVc, XIVg, XIVj,XVIa, XVIc, XVIj). Compound (XVIc), showed the highest cell growth inhibition with mean growth inhibition percent of 38.55%. It exhibited good anti-proliferative activity against several NCI cell panel. Using Discovery Studio 2.5 software, molecular docking study was finally attempted to investigate the binding mode of the targeted compounds and interpret their variable inhibitory behavior. The same software was also used to perform computer aided ADMET study.