Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT)

We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei. Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC ₅₀ = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense) with excellent selectivity for parasite cells relative to mammalian cell lines (EC₅₀ > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t_1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.