الفهرس 
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Abstract
Synthesis and Investigation of Certain Pyrazole-3-Carboxylic Acid Derivatives as Novel Carriers for Nitric Oxide
The thesis begins with an introduction displaying a summarized literature about synthesis and chemical behavior of pyrazole-3-carboxylic acid. Also, displaying a detailed study about the biological importance of nitric oxide. In addition, a detailed literatures about the different NO donor moieties and their metabolism to release NO.
The present investigation is concerned with the synthesis of pyrazolee3-carboxylic acid derivatives as amides Ia-g or ester IV which considered as intermediates for the synthesis of the ~orresponding oximes IIb-f& III or nitrate ester V & VII , respectively being NO donors.
The key intermediate chalcone 74 was prepared by the reaction of benzaldehyde with acetophenone in ethanol at aco using NaOH as a base. Bromination of chalcone 74 in ice bath afforded the dibromo derivative 75 which was converted to dibenzoylmethane 76 by refluxing it with sodium methoxide in methanol.
Furthermore, reaction of compound 76 with oxalyl chloride at room temperature afforded the furan2,3-dione derivative 1 which upon reaction with benzaldehyde phenylhydrazone 2a the key intermediate pyrazolecarboxylic acid 3 was produced. The resulting acid 3 was converted to pyrazole-3-carboxylic acid chloride 11 by refluxing with thionyl chloride in steam bath. The reaction of the acid chloride 11 with aromatic amines or 2-
bromoethanol afforded the corresponding pyrazole-3-carboxamides and the ester IV intennediates, respectively.
The oximes IIb-f & III were prepared by refluxing pyrazolecarboxamide derivatives Ib-Ig with hydroxylamine hydrochloride for 4-30hr in ethanol using pyridine or TEA as a base. The same reaction using amide Ig afforded the oxime III in a time of less than 4hr. The nitrate esters V & VII were synthesized by the reaction of the intermediates IV & VI \vith AgN03 (4 equivalents) in acetonitrile.
• 4-Benzoyl-N-( 4-chlorophenyl)-1 ,5-diphenyl-lH-pyrazole-3-carboxamide Ib
• 4-Benzoyl -N-( 4-methoxyphenyl)-1 ,,5carboxamide Id
• (4-Benzoyl-l ,5-diphenyl-lH-pyrazol-3-yl)( 4-(2-chloro acetyl)piperazinnl-yl)methanone (VI)
The following new final compounds were prepared:
• N-( 4-Chlorophenyl)-4-[ a(hydroxyimino) (phenyl)methyl]-1 ,5IH-pyrazole-3-carboxamide lIb
• 4-((Hydroxyimino )(phenyl)methyl)-l ,53-carboxamide lIe
• 4-((Hydroxyimino )(phenyl)methyl)-N-( 4-methoxyphenyl)-1 ,5IH-pyrazole-3-carboxamide lId
• 4-[4-((Hydroxyimino )(phenyl)methyl)-l ,5carboxamido] benzoic acid lIe
• 4-((Hydroxyimino )(phenyl)methyl)-l ,5-diphenyl-N-( 4ylsulfamoyl)phenyl)-IH-pyrazole-3-carboxamide IIf
• 4-Benzoyl-N-( 4-( l-(hydroxyimino )et~yl)phenyl)-1 ,5pyrazole-3-carboxamide III
• 2-(Nitrooxy)ethyl 4-benzoyl-l ,5-diphenyl-l H-pyrazole-3-carboxylate V
• (4-Benzoyl-l ,5-diphenyl-lH-pyrazol-3-yl)( 4-(2-nitroxy acetyl) piperazinnl-yl)methanone (VII)
The purity of the target compounds was checked by TLC and their structural formula were confirmed by elemental analyses as well as IR, IHNMR and MS spectral data.
The compounds IIb-IIf, III, V & VII were screened for their NO release ability after 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 min. The nitrate derivatives V & VII exhibited the highest percentage of NO release than the
oxime derivatives.
Furthermore, the compounds Ib, Id-g, lIb, IId-f, III, IV & V were evaluated for their antibacterial activity. The results revealed that the tested compounds showed marked inhibitory activity against the used G-ve bacteria. The most active compound which showed the lowest MIC value is the oxime lId.
On the other hand, results showed that most of NO donating compounds possessed antibacterial activity greater than the corresponding intermediates.
In addition, the antiinflammatory activity of the prepared compounds 3, Ia-g, IIb-f, III, IV, V & VII were evaluated by determination of their inhibitory effect on carrageenan induced rat paw edema according to the reported method using indomethacin as a reference at a dose 100 mg/kg. Results showed that all the tested compounds exhibited significant activity relative to the control group. The NO containing compounds showed higher anti-inflammatory activity than their corresponding intermediates.
The stomachs of the rats ·used in the antiinflammatory activity screening were examined for ulceration to determine the VI and PI.
Histopathological examination was carried out for the ulcerative regions. Results showed that the control group exhibited no lesions while most of the intermediates showed ulcers with higher severity compared with the corresponding oximes or nitrate esters.