Structure-based Drug Design, Synthesis, and Optimization of Broad Range Anti-schistosomal Agents




Tarpley, Reid Samuel

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Schistosomiasis is a major human parasitic disease afflicting more than 250 million people, historically treated with chemotherapies praziquantel or oxamniquine. Since oxamniquine is species-specific, killing Schistosoma mansoni but not other schistosome species (S. haematobium or S. japonicum) and evidence for drug resistant strains is growing, research efforts have focused on identifying novel approaches. Guided by data from X-ray crystallographic studies, in silico modeling, and Schistosoma worm killing assays on oxamniquine, our structure-based drug design approach produced a robust structure-activity relationship (SAR) program that identified several new lead compounds with effective worm killing. These studies culminated in the discovery of compound 37, which demonstrated broad-species activity in killing S. mansoni (57%), S. haematobium (95%) and S. japonicum (100%). Extensive SAR studies have been carried out around multiple structural moieties of our lead compounds, thus providing insight for guiding for further optimization.

Based on this work, this thesis is organized into three chapters; 1) SAR studies on oxamniquine cores with decreased rigidity and sidechain diversification, 2) studying impact of steric, electronic and hydrogen-bonding aspects of the benzyl alchol pro-drug moiety, and 3) design and synthesis of novel core structures.


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Oxamniquine, S. haematobium, S. japonicum, S. mansoni, Schistosomiasis, structure based drug design