Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Organic Chemistry

This thesis comprises five chapters. The first chapter is an introduction, which highlights the pharmacological importance of some thieno[3,2-d]pyrimidine derivatives, and briefly reviews the different synthetic strategies used for their synthesis. Further, it touches on the role of p38Ü mitogen activated protein kinase (MAPK) in inflammation, its tertiary structure, and its inhibition using small molecule inhibitors. The second chapter demonstrates the aim of this work along with proposed Schemes detailing the pathways used for the synthesis of the starting materials, intermediates, and the new target compounds. Scheme 1 illustrates the synthesis of the intermediate compounds IIIa-c and IVa-k. Nitration of p-toluidine and p-anisidine using urea nitrate afforded the corresponding 3-nitro derivatives Ib, c. The latter compounds, along with the commercially available 3-nitroaniline (Ia), were reacted with benzoyl chloride to afford the corresponding benzamides IIa-c, which were subsequently subjected to iron-catalyzed reduction reaction to give the benzamides IIIa-c. Reaction of the latter as well as some commercially available substituted anilines, with chloroacetyl chloride afforded 2-chloro-N-(substituted phenyl)acetamides IVa-k.Scheme 2 describes the synthesis of the tetrasubstituted thiophenes VIIa-g, VIII and IXa-k starting with bis(methylsulphanyl)methylenemalononitrile (V), which was reacted with phenylpiperazine and Na2S·9H2O to give the thioamide derivative VI. The latter was subjected to S-alkylation followed by Thorpe-Ziegler cyclization using commercially available phenacyl bromides, ethyl chloroacetate, and 2-chloroacetamides IVa-k to afford VIIa-g, VIII, and IXa-k, respectively

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