Synthesis, antiplatelet and antimicrobial activity of new substituted-1,3-oxazine, 2- hydroxy- substituted-benzyl-thiourea and ureas

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

The thesis investigates the synthesis, anti-microbial and anti-platelet activity relating to 1,3-oxazines. While providing a past and present overview of the biological importance of 1,3-oxazines, the thesis is also intended to provide the rationale for synthesis of the new 1,3-oxazines compounds. Discuses previous methods of 1,3-benzoxazine synthesis as well as providing a generalized method for the synthesis of new 1,3-oxazines from newly prepared 2- hydroxy-substituted-carboxylic acids. Generalized procedures for the synthesis of 2- amino-1,3-oxazine derivatives from 1,3-oxazine derivatives were further optimised with their reaction schemes and reaction mechanisms presented. In the thesis the successful synthesis of a number of important 7,8-O and 7-N substituted2-amino-1,3-benzoxazines as well as a number of substituted-bis-morholino-1,3-oxazines has been achieved. The reaction of a variety of thio-1,3-oxazine with benzylamine were also examined. The thesis also covers the second sub-group of interest, methylthio-1,3-oxazines. The general method was developed for the synthesis of methylthio-oxazines. Further reaction of 7-N-Acetyl-2-methylthio-1,3-benzoxazines with benzylamine, 2-amio pyridine, 3- aminopyridine, 4-amino pyridine and L-Leucine methyl ester were carried out with varying degrees of success. Finally the synthesis of some 4-substituted-N-benzyl-2- (benzyloxy)benzamides was investigated with benzyl bromide, starting from 7-Nsubstituted, 1,3-oxazine, 2,4-di-ones. Many of the 7, 8-O and 7-N-substituted-2-amino-1,3-benzoxazines were evaluated for their anti-platelet activity with promising results, as several compounds assayed showed potent inhibition of collagen induced platelet aggregation. Also a range of different 1,3- oxazine structural functionality was investigated for antimicrobial activity. The results indicated that a number of substituted-(benzylcarbamothioyl)-hydroxy-benzamides assayed inhibited the growth of certain bacteria and fungi.