Fig 1.
Structures of NEU-1183, -1184, and -1185.
Table 1.
Targeted values, cluster average, and individual values for the physicochemical properties of interest of NEU-1183, NEU-1184 and NEU-1185.
Data from original HTS [13]. nd = no data.
Fig 2.
General structure of analogs presented in Table 2 as well as structures of NEU-1184, -5456, and -5459.
Table 2.
Potency, LLE, and toxicity data for substituted-core analogs.
Fig 3.
General scheme for synthesis of sulfonamide replacements and construction of substituted isatin core.
Reagents and reaction conditions: a) Aryl halide, hydrazine monohydrate; 120°C, 12 h (52–86%). b) Isatin, methanol; RT, 12 h (10–100%). c) 4-Bromoisatin, boronic acid pinacol ester, K2CO3, Pd(PPh3)4; 100°C, 12 h (66%).
Fig 4.
T. b. brucei activity of hesperadin and synthetic scheme for synthesis of NEU-4893.
Reagents and reaction conditions: a) Piperidine, TEA, AcOH, NaHB(OAc)3, DCM; RT, 12 h (85%). b) Boc-NH-NH2, NaOtBu, Pd2(dba)3, XPhos, dioxane; μw, 150°C, 2 h (74%). c) 4M HCl in dioxane; RT, 3 h (74%). d) NaOtBu, isatin, MeOH; RT-50°C, 48 h (28%).
Fig 5.
General structure of analogs presented in Table 3.
Table 3.
Potency, LLE, and toxicity data for sulfonamide replacement analogs.
Table 4.
ADME profile of NEU-4893.
Fig 6.
a) Peripheral blood levels of NEU-4391 after IP administration at 10 mg/kg. b) Blood and brain levels at 0. 0.5, and 4 h. Female NMRI mice (n = 3). 1% DMSO:99%, 20% Captisol in water. Individual values for each time point are represented in the plot. Concentrations after 1 h in Fig 6A were below the lower limit of quantitation.