TY  - BOOK
AU  - El-Ansary,Dina Yousry Mohamed Kamel
AU  - George,Riham François
AU  - Kandeel,Manal Mostafa Hassan
AU  - El Kerdawy,Ahmed Mahmoud Mahmoud
TI  - Design, synthesis and antitumor activity of some novel pyrazoline derivatives
U1  - 615.7 22
KW  - Synthesis
KW  - Pyrazoline
N1  -  supervision of Ass. Prof. Dr. Riham François George, Prof. Dr. Manal Mostafa Hassan Kandeel,  Dr. Ahmed Mahmoud Mahmoud El Kerdawy; Thesis (M.Sc)-Cairo university, Faculty of pharmacy, 2020; Includes bibliographical references
N2  -  Cancer is the second cause of death after cardiac diseases worldwide. It is
continuing to act as the main health problem in both developing and developed
countries. Therefore, there is an incessant need to search for new anticancer
agents that inhibit new targets leading to more effectiveness and less side
effects compared to the conventional chemotherapy.
 Literature review showed that pyrazoline derivatives display a therapeutic
activity as anticancer agents against breast, colon, lung, liver, cervical cancer
by different mechanisms of action through acting on variable targets.
 Accordingly, the present study is concerned with the synthesis of some
derivatives belonging to the 1,3,5-trisubstituted pyrazolines IIa-c, IIIa-c, IVaf, VIa-c, VIIa-f, VIIIa-f, IXa,b. This is achieved via the intermediates
(1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one (Ia), (1E,4E)-1,5-Bis(4-chlorophenyl) penta-1,4-dien-3-one (Ib), (1E,4E)-1,5-Bis(4-methoxyphenyl)penta1,4-dien-3-one (Ic), (2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one (Va), (2E,4E)
-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-one (Vb) and (2E,4E)-1-(4-
Methoxyphenyl)-5-phenylpenta-2,4-dien-1-one (Vc).
 The newly synthesized compounds were evaluated for their in vitro
cytotoxicity against human breast cancer cell line (MCF-7) in addition to
normal fibroblast cell (WI38) using staurosporine and erlotinib as reference
standards. Compounds eliciting superior anticancer activity were screened for
their EGFR inhibitory activity and were compared to erlotinib. Moreover,
Molecular docking simulations were performed on compounds revealing
significant EGFR inhibitory activity to investigate their binding mode in the
active site of the enzyme.
The thesis consists of the following parts:
1. Introduction
 This part includes a brief introduction on cancer and the different
anticancer agents based on their mode of action. Also, it presents a literature
review concerning the different biological activities of pyrazoline containing
compounds.
2. Aim of the work
 This part explains the chemical and the pharmacological basis upon which
the synthesis of our target compounds was designed aiming to obtain new
anticancer hits acting as EGFR inhibitors.
v
3. Theoretical Discussion
 This part includes the synthetic pathways for the synthesis of the target
compounds using 3 Schemes. Also, it deals with the discussion of various
experimental methods and conditions of the reactions adopted for the synthesis
of six intermediate compounds and twenty-nine final compounds as well as a
summarized data concerning the analytical methods for the verification of the
obtained compounds structures.
4. Experimental
 This part deals with the practical procedures for the synthesis of the
intermediates and the final compounds. Moreover, their physical property,
elemental analyses and spectral data are presented.
Known Intermediates: (6 compounds)
1- (1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one (Ia)
2- (1E,4E)-1,5-Bis(4-chlorophenyl)penta-1,4-dien-3-one (Ib)
3- (1E,4E)-1,5-Bis(4-methoxyphenyl)penta-1,4-dien-3-one (Ic)
4- (2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one (Va)
5- (2E,4E)-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-one (Vb)
6- (2E,4E)-1-(4-Methoxyphenyl)-5-phenylpenta-2,4-dien-1- one (Vc)
Known final compounds: (14 compounds)
1- (E)-1-(5-Phenyl-3-styryl-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one
(IIa)
2- (E)-1-[5-(4-Chlorophenyl)-3-(4-chlorostyryl)-4,5-dihydro-1Hpyrazol-1-yl]ethan-1-one (IIb)
3- (E)-1-[5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazol-1-yl]ethan-1-one (IIc)
4- (E)-5-Phenyl-3-styryl-4,5-dihydro-1H-pyrazole-1-carboxamide (IIIa)
5- (E)-1,5-Diphenyl-3-styryl-4,5-dihydro-1H-pyrazole (IVa)
6- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-1-phenyl-4,5-dihydro-1Hpyrazole (IVb)
7- (E)-5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-1-phenyl-4,5-dihydro1H-pyrazole (IVc)
8- (E)-1-(4-Methoxyphenyl)-5-phenyl-3-styryl-4,5-dihydro-1H-pyrazole
(IVd)
9- (E)-1,5-Bis(4-methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazole (IVf)
10- (E)-1-(3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one
(VIa)
vi
11- (E)-1-[3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazol-1-
yl]ethan-1-one (VIb)
12- (E)-1-[3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazol-1-
yl]ethan-1-one (VIc)
13- (E)-1,3-Diphenyl-5-styryl-4,5-dihydro-1H-pyrazole (VIIIa)
14- (E)-3-(4-Methoxyphenyl)-1-phenyl-5-styryl-4,5-dihydro-1Hpyrazole (VIIIc)
New final compounds: (15 compounds)
1- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-4,5-dihydro-1H-pyrazole1-carboxamide (IIIb)
2- (E)-5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazole-1-carboxamide (IIIc)
3- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-1-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazole (IVe)
4- (E)-3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazole-1-carboxamide
(VIIa)
5- (E)-3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-
carboxamide (VIIb)
6- (E)-3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-
carboxamide (VIIc)
7- (E)-3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazole-1-carbothioamide
(VIId)
8- (E)-3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-
carbothioamide (VIIe)
9- (E)-3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-
carbothioamide (VIIf)
10- (E)-3-(4-Chlorophenyl)-1-phenyl-5-styryl-4,5-dihydro-1H-pyrazole
(VIIIb)
11- (E)-1-(4-Methoxyphenyl)-3-phenyl-5-styryl-4,5-dihydro-1H-pyrazole
(VIIId)
12- (E)-1-[(2E,4E)-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-
ylidene)-2-(4-methoxyphenyl]hydrazine (VIIIe)
13- (E)-1-(4-Methoxyphenyl)-2-[(2E,4E)-1-(4-methoxyphenyl)-5-
phenylpenta-2,4-dien-1-ylidene]hydrazine (VIIIf)
14- N'-[(1E,4E)-1,5-Diphenylpenta-1,4-dien-3-ylidene]benzohydrazide
(IXa)
15- N'-[(1E,4E)-1,5-Bis(4-chlorophenyl)penta-1,4-dien-3-
ylidene]benzohydrazide (IXb)
vii
5. Biological evaluation
 This part includes the cytotoxic activity of the prepared compounds against
MCF-7 (breast cancer) cell line in addition to normal fibroblast cell line
(WI38) using staurosporine and erlotinib as reference standards. The results
revealed that the synthesized compounds showed a significant anticancer
activity (IC50= 3.79 - 10.59 µM) compared to staurosporine (IC50= 10.61 µM).
Furthermore, five of the tested compounds elicited superior cytotoxic activity
were evaluated for their EGFR inhibitory activity using erlotinib as a reference
drug. The results indicated that compounds IIIc, VIc, VIId and VIIId
exhibited significant EGFR inhibitory activity at sub-micromolar level (IC50=
0.33, 0.46, 0.33 and 0.343 µM), respectively, compared to erlotinib (IC50= 0.23
µM).
6. Molecular docking:
 This part involves the results of molecular docking of compounds IIIc,
VIc, VIId, VIIIb and VIIId that were tested for EGFR inhibitory activity in
order to validate the obtained results and study their binding mode to the active
site of the enzyme in comparison to erlotinib as a reference standard.
7. References:
 This part includes 118 references covering the period from 1946 to 2019.
8. Arabic summary
UR  - http://repository.fue.edu.eg/xmlui/handle/123456789/5781
ER  -