الفهرس 
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Abstract
The present study was focused on the design and synthesis of two series of novel pyrazole derivatives; i) pyrazole linked 3-cyano-2-oxopyridines and ii) pyrazole appended 3,5-disubstituted-1,2,4-oxadiazoles derivatives and investigating their anti-inflammatory activities. The thesis consisted of four main sections: introduction, aim of the work, results & discussion and experimental sections in addition to references and summary.
1- Introduction
The background on inflammation, inflammatory mediators, and anti-inflammatory agents is presented in the first section. In addition, this section discusses the biological activity of 1,3,4-trisubstituted pyrazole, 1,2,4-oxadiazole, pyrazolo[3,4-d]pyrimidine, and cyanopyridine scaffolds as anti-inflammatory drugs.
Aim of the work
This section outlined the research’s goals and objectives, which included synthesis of the target compounds and biological evaluation of the synthesized compounds’ anti-inflammatory activity, as well as studies of the mechanism of anti-inflammatory activity induced by some of the designed compounds.
2- Results and discussion
This section is subdivided into three main parts:
A-The first part
Chemistry section, provided a discussion of the various methods utilized to synthesize the intermediates and the target molecules. It also showed how diverse spectroscopic techniques, such as IR, 1H-NMR, 13C-NMR, and elemental analysis, helped to reveal the structural details of these compounds.
In this work we reported the synthesis of the following compounds:
Forty reported compounds 1, 3a-f, 4a-f, 5a-f, 9a-h, 10a-h, 11, 13a,b and 14a,b.
Three new intermediates 2 and 16a,b.
Novel thirty final compounds 6a-f, 8a-h, 17a-h and 18a-h.
B-The second part
Biology section, this section is subdivided into four parts:
I. Inhibitory activity of NO production
We investigated the potential inhibitory effect of all the newly synthesized target compounds on the over-production of NO from LPS-stimulated macrophages. Results revealed that compounds 6b, 6e 8c, 17e-g, 18c, 18e-g proved to the most potent NO inhibitors. Furthuremore, compounds 6a, 6d, 6f, 8b, 8d, 8e, 8g, 8h, 17a, 17c, 17d, 17h, 18b, 18d, 18h displayed moderate NO inhibition activity. Moreover, compounds 6c, 8a, 8f, 17b, 18a were the least NO inhibitor activity.
II. In vitro COX-1/COX-2 inhibition assay
The obtained results revealed that among the targeted derivatives, compounds 6e, 6f, 8e. 17b, 18a and 18b proved to be the most potent COX-2 inhibitor and more selective against COX2 than reference drug celecoxib. Notably, compounds 6a, 6d, 8f and 8h came next with good COX2 inhibitory activity more than COX-1. While compounds 6e, 8g, 8h, 17d, 17h, and 18d exhibited strong inhibition against COX-1. On the other hand, compounds 6c, 8a, 17a and 18h were moderate inhibitor of COX-1 and very weak or inactive inhibitor of COX-2.
III. In vitro 5-LOX inhibition assay
All synthesized compounds 6a-f, 8a-h, 17a-h and 18a-h were assessed for their in vitro 5-LOX inhibitory activity. The attained results revealed that compounds 6e, 8c, 17e-g, 18e and 18f proved to be the strongest 5-LOX inhibitors. Remarkably, compounds 6a, 8e, 17c, 17d, 18b and 18h exhibited moderate inhibitory activity. Finally, compounds 6c, 8b, 17c and 18a displayed weak activity as 5-LOX inhibitor.
B-The third part
Molecular Docking, in this section, the results attained from molecular docking of the selected compounds in each series 8e and 18c with the target COX-2 and 8c and 18f with the target 5-LOX, which showed good fitting on COX-2 and 5-LOX enzymes and agreed with the obtained inhibitory activity results.
4- Experimental
This section explained how the various procedures were carried out in detail. It is divided into three sections:
I. The first Part
Chemistry section, this section covered the various processes for synthesizing the targeted derivatives 1, 2, 4a-f, 5a-f, 6a-f, 8a-h, 9a-h, 10a-h, 11, 13a,b, 14a,b, 16a,b, 17a-h and 18a-h. This section also included all detailed spectroscopic and analytical data of the synthesized compounds.
II. The second part
Biology section, this part summarized the procedures used to investigate the anti-inflammatory activity of the synthesized compounds 6a-f, 8a-h, 17a-h and 18a-h at Confirmatory diagnostic unit, VACSERA, Egypt, Inhibitory activity of NO production, In vitro COX-1/COX-2 inhibition assay and In vitro 5-LOX inhibition assay.
III. The third part
Molecular docking, this section defines the methodology and software used for the molecular modeling of the selected compounds to investigate their binding mode with the with the target COX-2 enzyme (PDB ID: 3LN1) and 5-LOX enzyme (PDB ID: 6N2W) using Discovery Studio software package.
One article has been published:
Mamdouh F. A. Mohamed, Marwa A. Aziz and Gamal El-Din A. Abuo-Rahma. Ultrasound-assisted green synthesis of 2,4-thiazolidinedione and di-aryl substituted pyrazolyl thiazolidinediones catalyzed by β-alanine. International Journal of Pharmaceutical Sciences and Drug analysis, 2021; 1(1): 18025.