Synthesis of some pyridazine derivatives of pharmacological interest /
تشييد بعض مركبات البيريدازين ذات اهميه دوائية
by Sara Yahia Ewieda Awad ; Supervision Prof. Dr. Eman Mohamed Ahmed, Prof. Dr. Rasha Ahmed Mahmoud, Dr. Marwa Sobhy Ahmed.
- 131 pages : illustrations ; 25 cm. + CD.
Thesis (Ph.D)-Cairo University, 2024.
Bibliography: pages 117-131.
The present thesis comprises four chapters. The first chapter is a general introduction which consists of three parts. The first part is a brief literature survey on the synthesis of pyridazine derivatives. The second part is about pyridazine derivatives as commercialized or under clinical trials drugs. The third part deals with cyclooxygenase-2 inhibitory activity of some reported pyridazine derivatives. The second chapter outlines the aim of the study, the rational behind the synthesis of the novel target compounds, and the schemes (1-3) that were designed for their preparation. Scheme 1 includes the synthesis of 4,5-dihydropyridazinone derivatives IIa–d via the reaction of appropriate oxohexenoic acid derivatives Ia–d with hydrazine hydrate. Condensation of compounds IIa–d with the appropriate aldehyde in ethanolic KOH for 3 h produced the target pyridazinone derivatives IIIa–f. In Scheme 2 the pyridazinones IIIa,b, or d were reacted with 4-methoxyphenylpiperazine and formalin using absolute ethanol to get the target compounds IVa–c. Reaction of compounds IIIa, b, or d with phosphorous oxychloride produced the corresponding 3-chloro derivatives Va–c. Finally, the reaction of pyridazines Vb and Vc with the proper aromatic amine using absolute ethanol and anhydrous K2CO3 produced the required derivatives VIa–c. Scheme 3 displays the synthesis of the target compounds VIIa–d via the reaction of compounds IIIa, b, d or f with ethyl bromoacetate. Compound VIIa or VIIc reacted with hydrazine hydrate to yield the pyridazinone derivatives VIIIa or VIIIb, respectively. N-Acylhydrazone derivatives IXa–f were produced by reacting the appropriate aromatic aldehyde with the pyridazinone derivatives VIIIa and VIIIb. The third chapter consists of three parts, the first part outlines the theoretical discussion of the experimental work used to prepare the newly synthesized compounds, along with an explanation of their spectral data and elemental analyses. Additionally, the second part, outlines the discussion of the results of the in vitro COX-1 and COX-2 inhibition assays of all the newly synthesized compounds, in vivo anti-inflammatory assay, histopathological study of the most potent and selective COX-2 inhibitor VIb, and the in vitro anti-inflammatory assay of compounds IXa and IXf. Moreover, there was a brief explanation of the relationship between structure and activity. In addition, the discussion of the molecular docking of the most potent compounds was covered. The experimental section of this thesis is covered in the fourth chapter, which also includes the physical characteristics, spectral data, and elemental analyses of the produced compounds, as well as the specific methods utilized for the synthesis of the target and intermediate compounds. Additionally, it covers the procedure for the in vitro COX-1 and COX-2 inhibitory assays of every compound that has been synthesized. The procedures of the in vivo and the in vitro anti-inflammatory assays, as well as the molecular docking steps for the compounds with the highest COX-2 inhibition. تحتوي الرسالة علي أربعة فصول. الفصل الأول يعد بمثابة مقدمة ويتضمن عرض مختصر عن التقنيات المختلفه لتشييد البيريدازين و النشاط المثبط لانزيم السيكلواوكسيجيناز-٢ للمركبات التي تحتوي على البيريدازين. الفصل الثاني يوضح الهدف من البحث و عرض الأسس العلميه التي بني عليها تصميم المركبات المستهدفه و عرض الخطط التي توضح الطرق العلميه التي صممت للحصول علي هذه المركبات. الفصل الثالث يتكون من المناقشه النظرية لكل من الجزء العملي ونتائج الفحوصات الحيويه للمركبات المشيدة حديثا بالأضافه الي مناقشة نتائج النمذجة الجزيئية. الفصل الرابع يحتوي علي الجزء العملي للرسالة. ويشمل الأجراءات العملية المتبعة لتشييد المركبات المستهدفة و المركبات الوسيطة بالاضافه الي الخصائص الفيزيائية وتحاليل العناصر. يوضح هذا الجزء ايضا الخطوات المتبعة للفحص المختبري لقدرة جميع المركبات الجديدة علي تثبيط انزيم السيكلواوكسيجيناز-١و انزيم السيكلواوكسيجيناز-٢. كما يتناول الطرق العمليه لاختبار التـأثير المضاد للألتهابات في الحيوانات و في المختبر بالأضافه الي التحليل النسيجي المرضي للنسيج الذي تعرض للمركبات الأكثر فعالية وتحديدا مثبطات انزيم السيكلواوكسيجيناز-٢ مع شرح الخطوات المتبعة في النمذجة الجزئية.