Oxazolopyridines towards the treatment of Human African sleeping sickness

by B Almohaywi

Institution: University of Tasmania
Year: 2014
Keywords: oxazolopyridine; Trypanosoma brucei; Human African Trypanosomiasis; Monash Institute of Pharmaceutical Science (MIPs)
Record ID: 1059625
Full text PDF: http://eprints.utas.edu.au/20839/1/front-Almohaywi-thesis.pdf



This thesis describes the synthesis and structure activity relationship (SAR) of oxazolopyridine and related analogues against Trypanosoma brucei, the causative agent of Human African Trypanosomiasis, a neglected, fatal parasitic disease that is a major cause of death and disability affecting many sub-Saharan African countries. Collaborators at Monash Institute of Pharmaceutical Science (MIPs), and ESKITIS institute found eight compounds as potential candidates via high throughput screening (HTS) of a large library of compounds against the disease. Amongst the compounds screened, an oxazolo[4,5-b]pyridine compound was of particular interest. In collaboration with MIPS, this work aimed to modify certain regions of the lead compounds and to develop a SAR against T. brucei, aiming for the synthesis of better analogues of the lead compound, as discussed in Chapter 2 and Chapter 3. A number of compounds have been made through modification around the central phenyl ring and the heterocyclic oxazolopyridine core. Modification at the central phenyl ring revealed the intolerance of that position for substitution, while the best compounds remained either the lead compound itself or its analogues, with the chlorine being replaced by either a hydrogen or substituting the 2-furyl amide for its 3-furyl counterpart. Modification of the heterocyclic core has resulted in a number of active compounds. We suggested that the modification and substitutions on oxazolopyridine core is more favourable for better activity. In addition to the anti-trypanosomal activities, these compounds are similar to heterocyclic amine derivatives found in cooked meat and fish, which has the potential to cause cancer. This has prompted us to investigate the potential for DNA damage activity of these compounds and the amine precursors, as discussed in Chapter 4.