Synthesis, Structural Elucidation, DNA-PK, PI3K and Antiplatelet Activity of 2-Morpholino-Substituted Chromeno-, Benzo- and Naphtho- 1,3-Oxazin-4-ones

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Pharmacy & Applied Science, College of Science, Health and Engineering, La Trobe University, Bendigo.

This thesis has been divided up into nine chapters relating to key areas of synthesis and the biological evaluations. Chapter 1 provides an introduction to chromen-2-ones, benzoxain-4-ones and naphtho-1,3- oxazines in addition to the structurally similar chromen-4-ones. This gives an overview of their development via various synthetic approaches and discusses the key areas relating to their biological activity. Overall this information is then utilised to give a context for the investigation and to justify its place in the scientific literature. Chapter 2 discusses the synthesis of a series chromene-2-one carboxylic acids as well as several bromo- substituted salicylic acids and naphthoic acids. Chapter 3 discusses the synthesis of a series of 2-thioxo-chromeno-1,3-oxazines from chromene2-one carboxylic acids and PPh3(SCN)2. Additionally, the preparation of several novel bromo-2- thioxo-1,3-benzoxazin-4-ones and bromo-naphtho-1,3-oxazines are discussed. Furthermore, this chapter also serves to further examine PPh3(SCN)2 as a reagent for the synthesis of 2-thioxo-1,3- oxazine compounds. Chapters 4 and 5 present the reaction details of the thioxo-1,3-oxazine compounds with morpholine and the subsequent reactions to produce 7- and 7,8-O-subsituted derivatives. The main highlight of Chapter 4 is the development of a one-pot in situ procedure for the reaction of thioxo-1,3-oxazine compounds with morpholine via their intermediary 2-methylsulfanyl analogues. Chapter 6 discusses the development of a general procedure for the Suzuki coupling reaction of arylboronic acids with bromo-substituted 2-morpholino benzo- and naphtho- 1,3-oxazines. These compounds are important analogues of the chromen-4-one compounds that inhibit DNA-PK, PI3K and platelet aggregation. Chapter 7 presents the DNA-PK, PI3K, antiplatelet and antibacterial biological assays results for the newly synthesized compounds. The observed biological activity for the 8-substiuted targets was exceptionally comparable to the chromen-4-one inhibitors. While the 6-aryl-1,3-benzoxazin- XIII 4-ones, 6-, 8- and 10-aryl-naphtho-1,3-oxazines displayed low inhibition activity against DNAPK and PI3K. All of the chromeno compounds tested failed to inhibit in vitro bacterial proliferation. Chapter 8 concludes this investigation by summarising the main points and presenting possible future investigations arising from this work. Chapter 9 presents the experimental details of all synthesized compounds in addition to the general procedures that were developed for both their synthesis and biological evaluations.