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

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 (CEC50)) was established, as part
of the lead selection process. Increasing the sp3 carbon
content of 1 resulted in 10e (0.19 μM
EC50 against T. brucei and
990 μM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine
(EC50: 0.013 μM; aqueous solubility: 880 μM;
and CEC50: 0.18 μM). Compound 22a reduced
parasitemia 109 fold in trypanosome-infected mice; it is
an advanced lead for HAT drug development.