الفهرس 
Rationale and design
ChemistryOnly 14 pages are availabe for public view
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Abstract
In this thesis a new series of tri-substituted pyrazole derivatives was designed as anticancer agents and synthesized, starting by the formylation of semicarbazone via
Vilsmeier-Haack reaction to give 3-(4-Bromophenyl)-1H-pyrazole-4-carbaldehyde
36 which was the precursor of compounds I-XIX. All the structures were confirmed
by analytical and spectral measurements in addition to a single crystal X-ray study
performed on compound VII confirming our proposed molecular structure. The new
chemical entities were screened for their anti-cancer activity on various human cancer
cell lines namely: hepatocellular carcinoma HepG2, breast cancer MCF7, lung
carcinoma A549, prostatic cancer PC3 and colon carcinoma HCT116 at the National
Research Centre (NRC, Egypt). Most of the synthesized compounds showed
remarkable activity on the tested cell lines, especially compounds VId, VII and IX.
The molecular modeling study was used to explain the synthesized compounds’
mechanism of action as potential B-Raf kinase inhibitors.
The presented thesis comprises the following chapters:
1- Introduction:
It contains a survey covering the definition of cancer, its risk factors and etiology.
This section also explains cancer therapeutic strategies, with a focus on protein
kinases and a review on the B-Raf kinase inhibitory activity of pyrazole derivatives.
2- Rationale and design:
In this section a series of novel tri-substituted pyrazole derivatives was designed as
potential B-Raf kinase inhibitors. Our design was based on the bioisosteric
modifications of the reference compound after exploring the key interactions with the
binding site. The different routes adopted for the preparation of the target compounds
are outlined in schemes (1-3).3- Results and Discussion:
This part contains the results and their theoretical discussions.
3.1. Chemistry:
Different methods of preparation used in the synthesis of the intermediate and final
compounds were explained, in addition to their physical and spectroscopic
elucidation.
3.2. Single crystal X-ray study:
from the X‐ray diffraction data, the positions of individual atoms, the distances
between atoms, bond angles, molecular conformations and absolute configurations
were determined with high precision for compound VII. The data also provide
intermolecular, intramolecular and packing interactions between molecules in the
solid state.
3.3. Biological evaluation:
The twenty five synthesized compounds were tested against five cancer cell lines,
hepatocellular carcinoma HepG2, breast cancer MCF7, lung carcinoma A549,
prostatic cancer PC3 and colon carcinoma HCT116 at the National Research Centre
(NRC), Egypt. A number of the compounds showed significant anti-cancer activity.
3.4. Molecular modeling:
The design was based on molecular modeling simulation using C-Docker protocol of
discovery studio software v2.5.
4- Conclusion:
This part contains summary of the most significant results in the thesis.5- Experimental:
This section explains in detail the methodologies and techniques used in this
thesis.
5.1. Chemistry:
This part describes the practical procedures involved in the synthesis of the new
chemical compounds with record of their physical and spectral properties.
The chemistry part includes synthesis of the following:
Reported starting material:
3-(4-Bromophenyl)-1H-pyrazole-4-carbaldehyde (36)
New intermediates:
3-(4-Bromophenyl)-1-ethyl-1H-pyrazole-4-carbaldehyde (I)
(E)-3-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-
one (VII)
2-((3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4yl)methylene)malononitrile (XIII)
New targeted compounds:
2-Amino-4-(3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-1,6-dihydro-6-
oxopyrimidine-5-carbonitrile (II)
5-((3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)methylene)-3-phenyl-2-
thioxoimidazolidin-4-one (IIIa)
5-((3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)methylene)-3-(4-fluorophenyl)-2-
thioxoimidazolidin-4-one (IIIb)5-((3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)methylene)-3-(4-methoxyphenyl)-2-
thioxoimidazolidin-4-one (IIIc)
5-((3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)methylene)pyrimidine-
2,4,6(1H,3H,5H)-trione (IV)
5-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-2H-1,2,4-triazol-3(4H)-one (Va)
5-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-2H-1,2,4-triazole-3(4H)-thione (Vb)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-1,2-dihydro-2-oxo-6-(thiophen-2-
yl)pyridine-3-carbonitrile (VIa)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-6-(furan-2-yl)-1,2-dihydro-2-
oxopyridine-3-carbonitrile (VIb)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-1,2-dihydro-2-oxo-6-(1H-pyrrol-2-
yl)pyridine-3-carbonitrile (VIc)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-1,2-dihydro-2-oxo-6-(pyridin-2-
yl)pyridine-3-carbonitrile (VId)
6-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-4-(4-chlorophenyl)pyrimidine-
2(1H)-thione (VIII)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-6-(4-chlorophenyl)pyrimidin-2-
amine (IX)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-6-(4-chlorophenyl)-1,2-dihydro-2-
oxopyridine-3-carbonitrile (X)
1-(5-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-3-(4-chlorophenyl)-4,5-
dihydropyrazol-1-yl)ethanone (XI)
4-(3-(4-Bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-6-(4-chlorophenyl)-2-hydroxy-4Hpyran-3-carbonitrile (XII)
1,6-Diamino-4-[3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (XIV)2,7-Diamino-4-(3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-4H-chromene-3-
carbonitrile (XV)
7-Amino-5-(3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydro-2,4-
dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (XVI)
2-Amino-4-(3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-5,6,7,8-
tetrahydroquinoline-3-carbonitrile (XVII)
2-Amino-4-(3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-7-hydroxy-4H-chromene-
3-carbonitrile (XVIII)
5-Acetyl-2-amino-4-(3-(4-bromophenyl)-1-ethyl-1H-pyrazol-4-yl)-6-methyl-4Hpyran-3-carbonitrile (XIX)
5.2. Single crystal X-ray study:
This part contains an explanation of the procedure used in the X-ray study of
compound VII.
5.3. Biological evaluation:
Procedure of the in-vitro anti-cancer screening was thoroughly discussed in this part.
5.4. Molecular docking study:
This section contains the procedure of molecular modeling simulation using CDocker protocol of discovery studio software v2.5.
6- References:
The thesis contains 159 references, some of which are recent, recorded for the
literature survey of this research.