الفهرس 
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Abstract
The Thesis Is Prefaced By A Comprehensive Literature Survey On Anti-Inflammatory Drugs With Fewer Side Effects And Cardiac Toxicity. The Present Work Shows The Design And Synthesis Of Some Diaryl Pyrazole, Triaryl Pyrazole, And Triaryl Pyrazoline Derivatives Va-D, Via-E, Xia-G, XII, XIII, XIV, Xva-C And Xixa-H. The Chemical Structures Of The Newly Synthesized Compounds Were characterized Using Spectral And Elemental Analyses. These Compounds Were Estimated For Their In Vitro Coxs, LOX, And Seh Inhibitory Assay Relative To Celecoxib, Zileuton And AUDA. In Addition To, In Vivo Anti-Inflammatory/Analgesic Activities Compared To Celecoxib With The Calculation Of ED50 Values And Ulcer Index Of The Most Potent Compounds Via,B,D, Xib,C,F, Xvb,C, And Xixd Was Evaluated. Finally, Docking Studies Were Performed For Certain Compounds.
This Thesis Consists Of The Following Parts:
• Introduction:
In This Part Presented A Literature Review About The Biological View Of Inflammation And Different Drugs Used In Its Treatment.
• Aim Of The Work:
It Involved The Research Objectives And The Major Aims That Guided The Theoretical And Practical Work.
• Discussion:
This Section Showed Several Experimental Methods That Could Be Used For The Preparation Of The Designed Compounds. Also, It Contracts With The Approval Of The Newly Synthesized Compounds By Different Methods Including Microanalytical Data, Infrared, Mass, 1H NMR And 13C NMR Spectra.
• Experimental:
This Part Explains The Practical Procedures Used For The Preparation Of Newly Synthesized Compounds. Also, It Contains Their Spectral And Elemental Micro-Analytical Data.
The Following Compounds Are Prepared
Reported Compounds
• 4-Methanesulfonylphenylhydrazine Hydrochlorid (I).
• 1-(1-(4-Chlorophenyl)Ethylidene)-2-(4-(Methylsulfonyl)Phenyl)Hydrazine (III).
• 3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carbaldehyde (IV).
• 1-(3-Nitrophenyl)-3-Phenylprop-2-En-1-One (Ixa).
• 3-(4-Chlorophenyl)-1-(3-Nitrophenyl)Prop-2-En-1-One (Ixb).
• 3-(4-Fluorophenyl)-1-(3-Nitrophenyl)Prop-2-En-1-One (Ixc).
• 1-(3-Nitrophenyl)-3-(P-Tolyl)Prop-2-En-1-One (Ixd).
• 3-(4-Methoxyphenyl)-1-(3-Nitrophenyl)Prop-2-En-1-One (Ixe).
• 3-(2-Chlorophenyl)-1-(3-Nitrophenyl)Prop-2-En-1-One (Ixf).
• 3-(Furan-2-Yl)-1-(3-Nitrophenyl)Prop-2-En-1-One (Ixg).
• P-Sulfamoylphenylhydrazine Hydrocloride (X).
• 1-(4-Nitrophenyl)Butane-1,3-Dione (Xviiia).
• 1-(3-Nitrophenyl)Butane-1,3-Dione (Xviiib).
• 1-(4-Aminophenyl)Butane-1,3-Dione (Xviiic).
• 1-(3,4-Dimethoxyphenyl)Butane-1,3-Dione (Xviiid).
New Intermediate Compounds:
• 3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carboxylic Acid (XII).
• Methyl 3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carboxylate (XIII).
• 3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carbohydrazide (XIV).
Newly Synthesized Compounds:
• N-((3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)Methylene)Aniline (Va).
• N-((3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)Methylene)-4-Methoxyaniline (Vb).
• N-((3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)Methylene)-4-Methylaniline (Vc).
• 4-Chloro-N-((3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)Methylene)Aniline (Vd).
• 1-(4-Chlorophenyl)-3-(3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)Prop-2-En-1-One (Via).
• 3-(3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)-1-(4-Nitrophenyl)Prop-2-En-1-One (Vib).
• 3-(3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)-1-(4-Hydroxyphenyl)Prop-2-En-1-One (Vic).
• 3-(3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)-1-(3,4-Dimethoxyphenyl)Prop-2-En-1-One (Vid).
• 3-(3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazol-4-Yl)-1-P-Tolylprop-2-En-1-One (Vie).
• 4-(3-(3-Nitrophenyl)-5-Phenyl-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xia).
• 4-(5-(4-Chlorophenyl)-3-(3-Nitrophenyl)-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xib).
• 4-(5-(4-Fluorophenyl)-3-(3-Nitrophenyl)-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xic).
• 4-(3-(3-Nitrophenyl)-5-P-Tolyl-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xid).
• 4-(5-(4-Methoxyphenyl)-3-(3-Nitrophenyl)-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xie).
• 4-(5-(2-Chlorophenyl)-3-(3-Nitrophenyl)-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xif).
• 4-(5-(Furan-2-Yl)-3-(3-Nitrophenyl)-4,5-Dihydro-1H-Pyrazol-1-Yl) Benzenesulfonamide (Xig).
• N-Benzylidene-3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carbohydrazide (Xva).
• N-(4-Chlorobenzylidene)-3-(4-Chlorophenyl)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carbohydrazide (Xvb).
• 3-(4-Chlorophenyl)-N-(4-Methylbenzylidene)-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole-4-Carbohydrazide (Xvc).
• 3-Methyl-1-(Methylsulfonyl)Phenyl)-5-(4-Nitrophenyl)-1H-Pyrazole (Xixa).
• 3-Methyl-1-(Methylsulfonyl)Phenyl)-5-(3-Nitrophenyl)-1H-Pyrazole (Xixb).
• 5-(4-Aminophenyl)-3-Methyl-1-(Methylsulfonyl)Phenyl)-1H-Pyrazole (Xixc).
• 5-(3,4-Dimethoxyphenyl)-3-Methyl-1-(4-(Methylsulfonyl)Phenyl)-1H-Pyrazole (Xixd).
• 4-(3-Methyl-5-(4-Nitrophenyl)-1H-Pyrazole-1-Yl)Benzenesulfonamide (Xixe).
• 4-(3-Methyl-5-(3-Nitrophenyl)-1H-Pyrazole-1-Yl)Benzenesulfonamide (Xixf).
• 4-(5-(4-Aminophenyl)-3-Methyl-1H-Pyrazole-1-Yl)Benzenesulfonamide (Xixg).
• 4-(5-(3,4-Dimethoxyphenyl)-3-Methyl-1H-Pyrazole-1-Yl)Benzensulfonamide (Xixh).
5- Biological Screening:
This Part Contained The Methods And The Results Used For In Vivo And In Vitro Pharmacological Estimation Of The Newly Synthesized Compounds. It Included:
A) In Vitro Inhibition Of COX-2:
All Final Compounds Were Estimated For Their In Vitro Inhibition Of Both COX-1 And COX-2 Activities Was Determined Using Enzyme Immunoassay Kits from Cayman Chemical Company. Lastly, The New Compounds Were Estimated For Their COX Inhibitory Activity where They Indicated Better selectivity Towards COX-2 Than COX-1.
B) In Vitro Lipoxygenase (5-LOX) Inhibition Assay:
The Most Active Compounds (Vib,D And Xib,C) Were Estimated For Their Ability To Inhibit Lipoxygenase Enzyme Using The LOX Enzyme Assay Kit. Concerning 5-LOX Inhibitory Activity, Compounds Vid And Xic Were The Most Active As 5-LOX Inhibitors With (IC50 1.33 And 0.79 Mm, Respectively) Compared That Of Standard Drug, Zileuton (IC50 = 0.61 Μm).
C) In Vitro Seh IC50 Assay:
Compounds Vd, Via, Vib, Vid, Xib, Xic, Xif, Xvb, Xvc, Xixd, And Xixe Were Estimated For Their Ability To Inhibit Activity Against Seh Using Seh IC50 Assay. All The Compounds Showed Moderate Inhibitory Activity Against Seh With IC50 Range (38.16-275.2) µg/Ml Compared To AUDA (IC50 = 24.39 µg/Ml) As A Reference Inhibitor Of Seh Except Two Compounds Vid And Xif Which Elicited Good Seh Inhibition With IC50 Of 43.71 And 38.16 µg/Ml, Respectively.
D) In Vivo Anti-Inflammatory Study:
The Anti-Inflammatory Activity Of Target Compounds Va-D, Via-E, Xia-G, XII, XIII, XIV, Xva-C, Xixa-H Were Evaluated Using Carrageenan-Induced Foot Paw Edema Method In Rats Using Reference Drug Celecoxib. The Tested Compounds Va-D, Via-E, Xia-G, XII, XIII, XIV, Xva-C, Xixa-H Indicated Significantly Anti-Inflammatory Activities Different For Moderate To Potent And Increased With The Time. Also, ED50 Value Was Evaluated For The Most Active Compounds Relative To Celecoxib.
E) Ulcerogenic Liability Study:
The Most Potent Final Compounds Via, Vib, Vid, Xib, Xic, Xif, Xvb, Xvc, And Xixd Were Expected For Their Gastric Ulcerogenic Potential In Rats. The Ulcerogenic Effect Was Compared With Celecoxib (Selective COX-2 Inhibitor Drug) And Aspirin (Classical NSAID). All Compounds Were Less Ulcerogenic Than Aspirin And Compounds Xib And Xic Were Less Ulcerogenic Than Celecoxib. The Results Proved The Safety Gastric Profile Of The Newly Synthesized Compounds.
F) Analgesic Activity:
The Most Potent Final Compounds Via, Vib, Vid, Xib, Xic, Xif, Xvb, Xvc And Xixd Were Estimated For Hot Plate Latency Test. Analgesic Effect Was Compared With Celecoxib. The Results Revealed Moderate To High Analgesic Activities For The Tested Compounds Compared To The Standard Celecoxib.
G) Cardiovascular Evaluation:
The Cardiovascular Estimation Of The Most Potent Compounds Vd, Vid, Xif, And Xvb Were Tested Through Inhibition Of Both COX-2 And Seh Isoenzymes, where The Estimated Compounds Showed A Good Protective Ability Against The COX-2 Inhibitors Associated With Cardiovascular Disorders.
6- Molecular Docking:
Molecular Modeling Studies Were Performed Using Molecular Operating Environment (MOE) Version 2008 Software. The Most Active In Vivo Compounds Were Docked Into Both COX-2 And Seh Iso-Enzymes To Rationalize The Biological Results.
7- References:
This Part Included 213 References Covering The Period 1927-2021
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8- Arabic Summary.