الفهرس 
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Abstract
Title: Synthesis of indole derivatives as indomethacin analogues.
Keywords: Indomethacin; Indole derivatives; Cyclooxygenase; Anti-inflammatory activity; Ulcerogenicity.
In the present work, design and synthesis of several substituted indole derivatives IVa-h, Va-d, Xa-f and XIa-f have been discussed. Reaction of the starting materials Ia-c with butyrophenone II afforded the substituted indole derivatives IIIa-b, which underwent N-acylation or N-alkylation to achieve new compounds IVa-h and Va-d, respectively. Also, the starting compound indole VI was reacted via Vilsmeier reaction to produce indole-3-carbaldhyde VII, which underwent N-acylation or N-alkylation to achieve compounds VIIIa-b and IXa-b, respectively. Then, compounds VIIIa-b and IXa-b were reacted with compounds Ib-d via Schiff`s base reaction to give the finally synthesized compounds Xa-f and XIa-f. The rational for these compounds was discussed. characterization of the chemical structures of the new compounds was done using spectral and elemental analyses. The newly synthesized compounds were evaluated for their in vivo and in- vitro activities compared to suitable reference standards. Finally, docking studies were performed for certain compounds to strengthen our rational.
This thesis consists of the following parts:
1- Introduction:
In this section, a literature review about inflammation, anti-inflammatory targets, various biological and pharmacological activities of indole nucleus and certain synthetic approaches for indole derivatives was presented.
2- Aim of the work:
It included the research objectives and the major aims that directed the theoretical and practical work.
3- Discussion:
In this part, various experimental methods and conditions of reactions adopted for the preparation of the designed compounds were discussed. In addition, it dealt with the confirmation of the newly synthesized compounds by different methods including microanalytical data, infrared, mass, 1H NMR and 13C NMR spectra.
4- Expermintal:
This part presented the practical procedures used for the synthesis of the reported and new intermediates as well as new final compounds. Also, it summarized their spectral and microanalytical data.
Synthesis of the following compounds was found to be essential for our study.
Reported intermediates:
1. 3-ethyl-2-phenyl-1H-indole (IIIa).
2. 1H-indole-3-carbaldehyde (VII).
3. 1-benzoyl-1H-indole-3-carbaldehyde (VIIIa).
4. 1-(4-chlorobenzoyl)-1H-indole-3-carbaldehyde (VIIIb).
5. 1-benzyl-1H-indole-3-carbaldehyde (IXa).
6. 1-(4-chlorobenzyl)-1H-indole-3-carbaldehyde (IXb).
Newly synthesized intermediates:
1. 3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indole (IIIb)
Reported final compounds:
2. 1-benzyl-3-ethyl-2-phenyl-1H-indole (Va)
Newly synthesized final compounds:
Include 23 new compounds classified into four series.
A. The first series included:
• (3-ethyl-2-phenyl-1H-indol-1-yl)(phenyl)methanone (IVa)
• (3-ethyl-2-phenyl-1H-indol-1-yl)(4-fluorophenyl)methanone (IVb)
• (3-ethyl-2-phenyl-1H-indol-1-yl)(4-methoxyphenyl)methanone (IVc)
• (4-chlorophenyl)(3-ethyl-2-phenyl-1H-indol-1-yl)methanone (IVd)
• (3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indol-1-yl)(phenyl)methanone (IVe).
• (3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indol-1-yl)(4-fluorophenyl)methanone (IVf).
• (3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indol-1-yl)(4-methoxyphenyl)methanone (IVg)
• (4-chlorophenyl)(3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indol-1-yl)methanone (IVh)
B. The second series included:
• 1-(4-chlorobenzyl)-3-ethyl-2-phenyl-1H-indole (Vb)
• 1-benzyl-3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indole (Vc).
• 1-(4-chlorobenzyl)-3-ethyl-5-(methylsulfonyl)-2-phenyl-1H-indole (Vd).
C. The third series included:
• phenyl(3-((2-(p-tolyl)hydrazono)methyl)-1H-indol-1-yl)methanone (Xa).
• (3-((2-(4-(methylsulfonyl)phenyl)hydrazono)methyl)-1H-indol-1-yl)(phenyl)methanone (Xb).
• 4-(2-((1-benzoyl-1H-indol-3-yl)methylene)hydrazinyl)- benzenesulfonamide (Xc).
• (4-chlorophenyl)(3-((2-(p-tolyl)hydrazono)methyl)-1H-indol-1-yl)methanone (Xd).
• (4-chlorophenyl)(3-((2-(4-(methylsulfonyl)phenyl)hydrazono)methyl)-1H-indol-1-yl)methanone (Xe).
• 4-(2-((1-(4-chlorobenzoyl)-1H-indol-3-yl)methylene)hydrazinyl)- benzenesulfonamide (Xf).
D. The fourth series included:
1. 1-benzyl-3-((2-(p-tolyl)hydrazono)methyl)-1H-indole (XIa).
2. 1-benzyl-3-((2-(4-(methylsulfonyl)phenyl)hydrazono)methyl)-1H-indole (XIb).
3. 4-(2-((1-benzyl-1H-indol-3-yl)methylene)hydrazinyl)- benzenesulfonamide (XIc).
4. 1-(4-chlorobenzyl)-3-((2-(p-tolyl)hydrazono)methyl)-1H-indole (XId).
5. 1-(4-chlorobenzyl)-3-((2-(4-(methylsulfonyl)phenyl)hydrazono)- methyl)-1H-indole (XIe).
6. 4-(2-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)hydrazinyl)- benzenesulfonamide (XIf).
5- Biological screening:
It included techniques used for in vivo and in vitro pharmacological evaluation o;f the finally synthesized compounds. Also, all results of biological evaluation of finally synthesized compounds were listed in tables and illustrated with charts in comparison to suitable standard references.
It included 2 sections:
• In vitro screening:
The ability of the new compounds to inhibit Cox-1 and Cox-2 activities was determined using COX Colorimetric Inhibitor Screening Kit. All finally synthesized compounds were tested for their COX-inhibitory activity and all of them showed better selectivity towards COX-2 than COX-1.
• In vivo screening:
1. Anti-inflammatory screening:
The anti-inflammatory activity of the new compounds was evaluated using ”rat paw carrageenan edema” method. All compounds showed moderate to high anti-inflammatory activities compared to the standard indomethacin. Also, ED50 value was evaluated for the most active compounds relative to indomethacin.
2. Ulcerogenic liability:
Ulcer index was calculated for the most potent active compounds compared to indomethacin and celecoxib. All compounds were less ulcerogenic than indomethacin and comparable to celecoxib.
These results proved the safety gastric profile of the newly synthesized compounds.
5- Molecular Docking
6- References:
This part included 180 references covering the period 1883-2016.
7- Arabic summary.