The compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against T. brucei cultures. With an eye towards using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, improve the physicochemical properties and improve the selectivity profile over human kinases. In this work we have developed structure-activity relationships (SAR) for analogs of 1 and have prepared analogs of 1 with improved solubility properties and good predicted central nervous system exposure. In that way, we have identified 4e, 9, 16e and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases.