Improvement of Aqueous Solubility of Lapatinib-derived Analogs: Identification of a Quinolinimine as a Lead for Human African Trypanosomiasis Drug Development.

Research paper by Kelly Ann KA Bachovchin, Amrita A Sharma, Seema S Bag, Dana M DM Klug, Katherine M KM Schneider, Baljinder B Singh, Hitesh B HB Jalani, Melissa M Buskes, Naimee N Mehta, Scott S Tanghe, Jeremiah D JD Momper, Richard J RJ Sciotti, Ana A Rodriguez, Kojo K Mensa-Wilmot, Michael P MP Pollastri, et al.

Indexed on: 20 Dec '18Published on: 20 Dec '18Published in: Journal of Medicinal Chemistry


Lapatinib, an approved EGFR 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 anti-trypanosome 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.