Year
2004
Degree Name
Doctor of Philosophy (PhD)
Department
Department of Chemistry - Faculty of Science
Recommended Citation
Yepuri, Nageshwar R, The design and synthesis of novel anti-malarial agents, PhD thesis, Department of Chemistry, University of Wollongong, 2004. http://ro.uow.edu.au/theses/247
Abstract
A new convergent methodology has been developed for the synthesis of the anti-malarial lead compound ADAM (24). A series of 41 derivatives were successfully synthesized, 35 of which were new compounds; all of which related to ADAM (24). All the synthesized derivatives were screened against in vitro Plasmodium falciparum K1, of which 11 showed significant activity in the low micromolar range, including compound (46) (IC50 0.3 ?g/ml), (80) (0.7 ?g/ml). and (88) (1.4 ?g/ml). A preliminary structure activity relationship analysis study was performed, which suggested that while 4,6-diaminopyrimidine analogs are inactive, if one of the two amines are alkylated then anti-malarial activity is returned. In order to generate a more thorough analysis, more compounds need to be synthesized by modifying the side chain. The SAR study also suggests that the heteroatom nitrogens in the pyrimidine ring are required for anti-malarial activity. The entire range of derivatives based on 5-benzoyl-4,6-dichloropyrimidine are inactive. The replacement of the phenyl substituent with an isopropyl group resulted in good anti-malarial activity but less than the parent compound. Novel synthetic dimerising methodology mediated by thallium(III) trifluoroacetate has been developed for the synthesis of biindoles. The methodology included the development of 2,2- and 2,7-biindoles, and 2,7,7,7-triindole. A series of 41 new indole derivatives were synthesized and screened for anti-malarial activity, of which three showed significant anti-malarial activity. During this study, the dimerisation of indole mediated by triflic anhydride was demonstrated for the first time. There are two other interesting synthetic results were observed, the triflic anhydride-mediated bi-pyrroloindole formation and the formation of the 1,2-dihydropyridineindole. Most compounds synthesized here were further tested in a series of additional biological assays, and a number of them showed activity against HIV reverse transcriptase, integrase, tuberculosis, anti-fungal and anti-cancer. In particular, the biaryl derivatives showed moderate activity against tuberculosis and fungal, which may be able to investigate further. A couple of biaryl compounds also showed significant anti-cancer activity. [Note: this abstract contained scientific formulae that would not come across on this form. Please see the 01Front files abstract for the full details.]
Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.