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Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC 50 )) was established, as part of the lead selection process. Increasing the sp 3 carbon content of 1 resulted in 10e (0.19 μM EC 50 against T. brucei and 990 μM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC 50 : 0.013 μM; aqueous solubility: 880 μM; and CEC 50 : 0.18 μM). Compound 22a reduced parasitemia 10 9 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.

journal of medicinal chemistry

Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development