Discovery And Development Of Drugs For Neglected Diseases Chagas Disease Human African Trypanosomiasis And Leishmaniasis PDF Download

Neglected tropical diseases (NTDs) are a global burden affecting the lives of over 1 billion people worldwide. Current chemotherapeutics suffer from a slew of undesirable properties, necessitating new drugs. Target repurposing can greatly accelerate the drug discovery process and avoid much of the financial load, indispensable requirements for NTD drug discovery. This practice has been applied to repurposing known inhibitors of human protein tyrosine kinases for three NTDs: African sleeping sickness, Chagas disease, and leishmaniasis. The first project outlined in this dissertation describes the development and target identification of NEU-321, a ligand efficient inhibitor of Trypanosoma cruzi cytochrome P450 lanosterol 14alpha-demethylase. The second project involves the ongoing optimization of analogs of the repurposed anticancer drug lapatinib against Trypanosoma brucei, T. cruzi, and Leishmania. Scaffold variations of lapatinib has identified key motifs for activity and differentiated leads for the NTDs caused by these protozoan parasites. Enhancement of the physicochemical properties has led to new, more drug-like leads, one of which has shown efficacy in a mouse model of bloodstream T. brucei infection. The third project details our efforts repurposing a larger group of known kinase inhibitors with greater structural diversity. From this campaign was identified NEU-1053, a compound that showed no structural similarity to any other within the screening panel. While highly potent, this compound is not predicted to be brain penetrant, a necessary property to treat late stage African sleeping sickness. This chapter entails our efforts identify important structural parameters for activity, and to improve the predicted brain penetration.