Optimization of Quinazolines for Inhibition of Trypanosoma brucei Proliferation.

A large population of people remain at risk of contracting human African trypanosomiasis (HAT), which has significant health implications and leads to death. To prepare for future epidemics and provide alternative therapies in case of resistance to current treatment options for HAT, there is a need to continue developing novel therapeutics. Previously, we reported the repurposing and reoptimization of human kinase inhibitor, Lapatinib, toward inhibiting Trypanosoma brucei proliferation. These efforts improved the selectivity and potency; however, the physicochemical properties of derivatives such as 2 remained unsatisfactory. As such, here we report the further structural optimization of 2 to improve ADME properties and retain antitrypanosomal potency. Modifications at the 4- and 6-positions of the quinazoline core were systematically investigated to assess ADME properties and T. brucei inhibition. Combining the best substituents for antitrypanosomal potency and aqueous solubility led to the identification of compounds with significantly improved potency and metabolic stability.