Synthesis, identification, DNA-PK, anti-platelet and anti-bacterial activity of 2-amino-benzo- and naphth-1,3-oxazin-4-one

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Pharmacy and Applied Science & School of Molecular Sciences, Faculty of Science, Technology and Engineering, La Trobe University, Bendigo.

This thesis investigates synthetic strategies towards substituted 2-thioxo-1,3- benzoxazines. The biological significance of new 2-amino-[5, 6, 7 and 8]-O-substituted1,3-benzoxazines and 2-amino-8-methyl-7-O-substituted-1,3-benzoxazines is investigated. The reaction of 2-thio-1,3-benzoxazine with benzyl amine is also examined. In addition synthesis and the biological activity for a number of new angular morpholino-(substituted)-naphth-oxazines, linear morpholino-(substituted)-naphthoxazines, linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3- oxazines. The O-substituents were the 2yl- and 3yl-methyl pyridine as well as (4- methylpiperazin-1-yl)ethoxy. Furthermore the synthesis of 2-methyl-thioxo-1,3-benzoxazines is established and the biological implications for new 2-(pyridin-3-ylamino)-4H-(substituted-benz[e]-1,3- oxazin-4-one and 2-(N-Substituted-(pyridin-3-ylmethyl)amino)-substituted-1,3- benzoxazines is accomplished. The X-ray crystallography was used to confirm that the 2-N-substituted structures were formed rather than 3-N-substituted analogue. Homology modeling was used to build a 3D model of DNA-PK based on the X-ray structure of PI3K. Docking of selected synthesized compounds within the binding pocket and SAR analyses of the poses were performed and results agreed well with observed activity. Biological assays were performed, and many of the 5, 6, 7 and 8-O-substituted-2- amino-1,3-benzoxazines and 2-amino-substituted-1,3-naphth-oxazines were evaluated for their anti-platelet and DNA-PK activity with promising results. Several of the assayed compounds showed potent inhibition of collagen induced platelet aggregation and DNA-PK inhibition. The antimicrobial evaluation of the benzyl thio urea and some of the dione benzyl urea compounds prepared herein is also presented.