الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
The prevalence of monoterpenoids (thymol) and heterocyclic moieties as biologically activ molecules highlighted the importance of these heterocyclic ring systems in medicinal>chemistry and stimulated the need for elegant and effective ways to make use of these
heterocyclic functions.
Terpenoids and their derivatives containing compounds have a long history of application as
pharmaceutical agents having antimicrobial, antimalarial, insecticidal, antioxidant, antiinflammatory,
anticancer and antiseptic activities.
This motivated our interest in the present investigation to design and synthesize new
compounds comprising thymol and heterocyclic moieties.
All the new compounds were tested
for their anti-inflammatory and also tested to be screened for their anticancer activity.
The work done in the present thesis can be classified as follows.
Chapter 1: Introduction:
This chapter presented a brief literature survey on some biological activities of thymol
isolated or combined derivative compounds exhibiting anti-inflammatory activities as well as
anticancer activities.
<Chapter 2:Research objectives:
<This chapter demonstrated the rationale upon which the synthesis of the new dual acting antiinflammatory
and anticancer compounds was designed.
<Chapter 3:Discussion:
<This section presented the theories upon which new compounds were synthesized based on
methods previously reported in the literature.
The structures of the new synthesized
compounds were confirmed by analytical and spectral data.
Discussion contained the following 3 Schemes:
<Scheme 1:
This Scheme outlined the synthesis of the starting material 2-Hydroxy-3-isopropyl-6-
methylbenzaldehyde (2) from the thymol where was allowed to react with magnesium
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methoxide, Mg(OCH3)2 then with Paraformaldehyde.
Compound 2 was then reacted with
thiosemicarbazides 3a-g (which werer prepared by the reaction of appropriate amine with CS2
and TEA, then with CH3I, finally with hydrazine hydrate to obtain compounds 3a-g to give the
corresponding thiosemicarbazones, 2-(2-hydroxy-3-isopropyl-6-methylbenzylidene)-N-substitutedhydrazine-
1-carbothioamide (4a-g). On the other hand, cyclization of the compounds 4ag
by treating them with appropriate phenacyl bromides to obtain 2-((2-Hydroxy-3-isopropyl-6-
methylbenzylidene)hydrazono)-3,4-disubstituted-2,3-dihydrothiazole (6a-l). Further more,compounds 4a-c were treated with chloroacetone to give 2-((2-Hydroxy-3-isopropyl-6-
methylbenzylidene)hydrazono)-4-methyl-3-substituted-2,3-dihyrothiazole (7a-c).
Scheme 2:
Scheme 2 discussed the reaction of compounds 4a-g with each of chloroacetic acid, α-
chlorophenylacetic acid and maleic anhydride to give the corresponding compounds 2-((2-
hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-3-substitutedthiazolidin-4-one (8a-e), 2-
((2-hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-5-phenyl-3-substitutedthiazolidin-4-
one (9a-e) and 2-(2-((2-hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-4-oxo-3-
substituted thiazolidin-5-yl)acetic acid (10a-g) respectively.
Scheme 3:Scheme 3 illustrated the synthesis of pyrazoles, starting from Methyl4-hydroxy-2-oxo-4-(4-
substitutedphenyl)but-3-enoate (13a-c) which were reacted with hydrazine hydrate to give 3-
(Substituted phenyl)-1H-pyrazole-5-carbohydrazide (14a-c).
The acid hydrazides 14a-c were
condensed with the compound 2 to obtain N’-(2-hydroxy-3-isopropyl-6-methylbenzylidene)-
3-(substitutedphenyl)-1H-pyrazole-5- carbohydrazide (15a-c).
This Scheme also showed the reaction of (Substituted phenyl)hydrazine hydrochloride (17a-c)
with Sodium4-methoxy-3,4-dioxo-1-(substitutedphenyl)but-1-en-1-olate (12a -c) to give the
ester of pyrazoles, Methyl5-(4-substitutedphenyl)-1-(4-substituted phenyl)-1H-pyrazole-3-
carboxylate (18a-i).
These esters 18a-i were treated with hydrazine hydrate to obtain the
corresponding acid hydrazides, 5-(4-Substituted phenyl)-1-(4-substitutedphenyl)-1Hpyrazole-3-carbohydrazide (19a-i). Finally the acid hydrazides were reacted with compound
2 to give the pyrazoles 5-(4-substituted phenyl)-1-(4-substitutedphenyl)-N’-(2-hydroxy-3-
isopropyl-6-methylbenzylidene)-1H-pyrazole-3-carbohydrazide (20a-i).
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Chapter 4:
Experimental:
<This section described the detailed experimental procedures adopted for the synthesis of
intermediates and final compounds. The structures of the synthesized compounds were
confirmed by elemental analyses, I.R., 1H-NMR spectra for all compounds as well as 13CNMR
and mass spectra for some representative compounds.
The prepared compounds in this section were listed as follow:
Scheme 1: It illustrated the synthesis of the following compounds:
2-Hydroxy-3-isopropyl-6-methylbenzaldehyde 2
2-(2-Hydroxy-3-isopropyl-6-methylbenzylidene)-N-substitutedhydrazine-1-
carbothioamide 4a-g
2-((2-Hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-3,4-disubstituted -
2,3-dihydrothiazole 6a-l
2-((2-Hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-4-methyl-3-
substituted-2,3-dihyrothiazole 7a-c
Scheme 2: It described the synthesis of the following compounds:
2-((2-Hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-3-
substitutedthiazolidin-4-one 8a-e
2-((2-Hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-5-phenyl-3-
substitutedthiazolidin-4-one 9a-e
2-(2-((2-Hydroxy-3-isopropyl-6-methylbenzylidene)hydrazono)-4-oxo-3-
substitutedthiazolidin-5-yl)acetic acid 10a-g
Scheme 3: It showed the synthesis of the following compounds:
Sodium-4-methoxy-3,4-dioxo-1-(substitutedphenyl)but-1-en-1-olate 12a-c
Methyl-4-hydroxy-2-oxo-4-(4-substitutedphenyl)but-3-enoate 13a-c
3-(Substituted phenyl)-1H-pyrazole-5-carbohydrazide 14a-c
N’-(2-Hydroxy-3-isopropyl-6-methylbenzylidene)-3-(substitutedphenyl)-1Hpyrazole-
5-carbohydrazide 15a-c
(Substituted phenyl)hydrazine hydrochloride 17a-c
Methyl5-(4-substitutedphenyl)-1-(4-substitutedphenyl)-1H-pyrazole-3-
carboxylate 18a-i
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5-(4-Substitutedphenyl)-1-(4-substitutedphenyl)-1H-pyrazole-3-carbohydrazide
19a-i
5-(4-Substitutedphenyl)-1-(4-substitutedphenyl)-N’-(2-hydroxy-3-isopropyl-6-
methylbenzylidene)-1H-pyrazole-3-carbohydrazide 20a-i
Chapter 5:
Biological screening:
-Anti-inflammatory screening:
Compounds 4a-g, 6a-l, 7a-c, 10a-g, 15a-c and 20a-i were subjected to in vitro antiinflammatory
assay (The compounds (6b, 6d, 6e, 6f (best one), 10b, 10d and 20g) showed
dual inhibitory activities against COX-2 and 5-LOX, larger than that of Celecoxib and
Quercetin against these enzymes respectively), they were tested in vivo except
thiosemicarbazones 4a-e which showed low activity, where the in vivo anti-inflammatory
activity screening (table 2) showed that 27 compounds (6a-f, 6i-l, 7a, 7c, 10a, 10c, 10f, 10g,
15a-c, 20a and 20c-20i) have higher % inhibition than Celecoxib. 18 compounds (6a-c, 6e-f,
6i-j, 10a, 10f-g, 15a-c, 20c-e, 20g and 20i) from these 27 compounds showed higher %
inhibition than that of Diclofenac sodium.
Five compounds (6b, 6j, 10g, 15a and 20i)
exhibited double % inhibition exhibited by Celecoxib, and the higher one was compound 15a
with % inhibition 81.93 comparing with 36.37 and 52.37 of Celecoxib and Diclofenac
sodium respectively.
Gross observation of the isolated rat stomachs showed a normal stomach texture for the
tested compounds as well as the references Celecoxib and Diclofenac, while for compounds
(6c-e, 6g, 7a, 7c, 10d, 15c, 20a, 20c-f, 20h and 20i) variable degrees of hyperemia were
observed Figure 17.
Gross examination revealed that compounds (6a-b, 6f, 6h-l, 7b, 10a-c, 10e-g, 15a-b, 20b
and 20g) showed superior gastrointestinal safety profile (no ulceration) as the references
Celecoxib and Diclofenac sodium in the population of fasted rats.
Anticancer screening:
The in vitro inhibition assay against PIM-1 and PIM-2 kinases explained that the compounds
(9e, 10d, 10e and 10g) have inhibition against PIM-1 kinase less than that of Staurosporinee,
while 9c showed 1.7 times the activity of Staurosporinee towards this enzyme.
<The same compounds were tested against PIM-2 kinase, where compound 9c showed
1.1times the inhibition activity of Staurosporinee, and compounds 9e, 10d exhibited about
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87%, 69% of the activity of the reference, while 10g displayed half the activity of the
reference (Staurosporinee).
All the compounds (9e, 10d, 10e and 10g) have SI (3.938, 7.388, 2.349 and 2.143
respectively) more than that of Staurosporinee (2.029) except compound 9c with less SI
(1.288).
The higher one, 10d with SI (7.388) which is approximately 3.5times that of
Staurosporinee, then 9e with SI (3.938) which is twice that of Staurosporinee, while the SI of
the rest were nearly the same or little more than that of Staurosporinee.
This indicates that
10d, 9e have larger selectivity toward PIM-2 kinase. The higher SI ratio, the theoretically
more effective and safe compound would be during in vivo assay.<from above, the compound 9c showed more inhibition activity against PIM-1, PIM-2 kinases
than that of the reference Staurosporinee, while the compound 10d have higher SI.
- Molecular modeling
The results of docking of compounds into COX-1, COX-2 and 5-LOX showed high scores
for synthesized pyrazole compounds, while the selected compounds (9c, 9e, 10d, 10e and
10g) were docked toward PIM-1 and PIM-2 kinases independently, which showed high
scores comparing to Staurosporinee which was reference to in vitro screening.
<Chapter 7:<>References:In this section, 154 references were used for planning and accomplishing the work done.
These references have been listed in the order of their appearance in the text.