UC Santa Cruz

Leishmaniasis is a deadly neglected tropical disease caused by protozoan infection of immune cells. Implicated in more than 60,000 annual deaths across 98 countries, it confers a global burden second only to that of malaria among parasitic diseases. Among the most widely used treatments for leishmaniasis is a class of drugs known as the pentavalent antimonials, which contain the heavy element antimony (Sb). Despite having been in clinical use for more than seventy years, the molecular composition of these clinically effective but highly toxic drugs is unknown, with the prevailing literature indicating that they consist of intractable mixtures of compounds.This thesis will begin with a series of vignettes that underscores the importance of structural understanding in the context of medicinally employed inorganic compounds. It will then proceed to describe our efforts to circumvent the lack of structural understanding as it pertains to the pentavalent antimonial drug stibogluconate through the development of a nanoparticle delivery framework. The outcome of this work served as the motivation for our subsequent research into the elucidation of the structure of the drug. This research was informed primarily by multidimensional and heteronuclear (1H, 13C, 121Sb) NMR spectroscopic experiments performed on derivatized analogues of stibogluconate as well as on stibogluconate that was synthesized in the laboratory. The work presented herein indicates the presence of a single predominant species in solution; offers insights into the connectivity of the ligand to the Sb center; demonstrates the equilibrium nature of the synthetic reaction; and explores the thermodynamics of that equilibrium.