Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 2, Pages 665-687Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01365
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Funding
- National Institutes of Health [R01A1082577, R56AI099476, R01AI124046, R21AI127594]
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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 (CEC50)) was established, as part of the lead selection process. Increasing the sp(3) carbon content of 1 resulted in 10e (0.19 mu M EC50 against T. brucei and 990 mu M aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC50: 0.013 mu M; aqueous solubility: 880 mu M; and CEC50: 0.18 mu M). Compound 22a reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.
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