Table 3. Physicochemical Properties and Antimycobacterial and Antiparasitic Activities of 34a–pg.
| compound |
solubility
(μM)b |
antimycobacterial
MIC90 (μg/mL)c |
antiparasitic
IC50 (μM) (pIC50 ± SE) |
cell viability CC50 (μM) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| code | R1 | link | R2 | mol. weight | ALogPa | H2O | PBS | acetate, pH 4.5 | HCl, pH 1 | Mtb normoxia | Mtb hypoxia | T. b. bruceid | T. cruzie | HEK293f |
| 34a | Ph | para | Ph | 346 | 2.50 | <1 | <1 | <1 | <1 | 16 | 79% I at 32 μg/mL | 53–55% I at 7.9 μM | 4.65 (5.3 ± 0.003) | >100 |
| 34b | 4-OCF3-Ph | 430 | 4.62 | <1 | <1 | <1 | <1 | 32 | >32 | 0.045 (7.4 ± 0.003) | 0.043 (7.4 ± 0.007) | >100 | ||
| 34c | 4-CH3-Ph | 360 | 2.97 | <1 | <1 | <1 | <1 | 6 (4–8) | 32 | 0.074 (7.13 ± 0.0003) | 0.077 (7.1 ± 0.013) | >50 | ||
| 34d | 3-OCF3-Ph | 430 | 4.62 | <1 | <1 | <1 | <1 | 2 (1–8) | 32 | 0.110 (7.0 ± 0.009) | 0.065 (7.2 ± 0.015) | >100 | ||
| 34e | Pyridin-3-yl | 347 | 1.35 | 3.9 ± 0.67 | 3.2 ± 1.0 | 19 ± 1.4 | >200 | 0.5 | 8 | 0.042 (7.4 ± 0.003) | 0.10 (7.0 ± 0.004) | >92 | ||
| 34f | pyridin-3-yl | Ph | 347 | 1.78 | <1 | <1 | <1 | 18 ± 0.3 | 32 | >32 | 0.067 (7.2 ± 0.003) | 0.073 (7.1 ± 0.005) | >50 | |
| 34g | 4-OCF3-Ph | 431 | 3.90 | <1 | <1 | <1 | <1 | 32 | >32 | 0.026 (7.6 ± 0.003) | 0.16 (6.8 ± 0.016) | >50 | ||
| 34h | 4-CH3-Ph | 361 | 2.26 | <1 | <1 | <1 | 7.8 ± 0.4 | 8 | 81% I at 32 μg/mL | 0.008 (8.1 ± 0.002) | 0.066 (7.2 ± 0.001) | >50 | ||
| 34i | 3-OCF3-Ph | 431 | 3.90 | <1 | <1 | <1 | <1 | 4 (2–16) | >32 | 0.021 (7.7 ± 0.0005) | 0.088 (7.0 ± 0.046) | >50 | ||
| 34j | pyridin-2-yl | 4-OCF3-Ph | 431 | 3.68 | <1 | <1 | <1 | 3.7 ± 0.69 | 0.0625 (0.0625–0.125) | 84% I at 8–32 μg/mL | 0.002 (8.6 ± 0.0001) | 0.016 (7.8 ± 0.0002) | >74 | |
| 34k | pyridin-3-yl | meta | 4-OCF3-Ph | 431 | 3.47 | <1 | <1 | <1 | 16 ± 0.5 | 0.25 (0.25–1) | 85% I at 4–32 μg/mL | 0.028 (7.6 ± 0.005) | 0.43 (6.4 ± 0.019) | >100 |
| 34l | 4-CH3-Ph | 361 | 1.84 | <1 | <1 | <1 | 27 ± 14 | 0.0625 (0.0625–0.125) | 84% I at 8–32 μg/mL | 0.067 (7.2 ± 0.018) | 0.12 (6.9 ± 0.002) | >94 | ||
| 34m | 3-OCF3-Ph | 431 | 3.47 | <1 | <1 | <1 | 6.6 ± 0.3 | 2 (0.125–4) | 84% I at 32 μg/mL | 0.093 (7.0 ± 0.024) | 0.23 (6.6 ± 0.014) | >100 | ||
| 34n | Ph | para | thiazol-2-yl | 353 | 1.36 | <1 | <1 | <1 | <1 | >32 | >32 | 0.53 (6.3 ± 0.051) | 0.21 (6.7 ± 0.005) | >50 |
| 34o | thiazol-5-yl | Ph | 353 | 1.44 | <1 | <1 | <1 | <1 | 0.5 (0.5–1) | >32 | 0.045 (7.3 ± 0.001) | 0.051 (7.3 ± 0.003) | >50 | |
| 34p | Ph | para | piperidinyl | 353 | 2.06 | 3.8 ± 0.5 | <1 | 2.7 ± 0.05 | >200 | 1.5 (1–2) | 8 | 39–67% I at 73.3 μM | 82–83% I at 36.6 μM | >100 |
ALogP values were calculated using Pipeline Pilot (Accelrys, version 9.1.0.13).
Solubility in water, PBS (pH 7.4), acetate buffer (pH 4.5), and 0.1 M HCl (pH 1 ) were determined by LC-UV (254 nm).
H37RV, Mtb-O2 primary screen at 32 μg/mL n = 2, Mtb-hypoxia primary screen at 32 μg/mL n = 2, MIC-normoxia/hypoxia of active compounds n = 3–4. For compounds that gave varied MIC in different replicates (n = 3–6), a median value was reported with the MIC range indicated in parentheses. Isoniazid control Mtb-normoxia MIC = 0.04 μg/mL, Mtb-hypoxia MIC > 5 μg/mL.
Control pentamidine IC50 = 0.002 μM, diminazene aceturate IC50 = 0.062 μM, puromycin IC50 = 0.05 μM, n = 2.
Control nifurtimox IC50 = 1.4 μM, benznidazole IC50 = 5.2 μM, puromycin IC50 = 2.5 μM, posaconazole IC50 = 0.04 μM, n = 2.
ATCC CRL-1573, CC50n = 3. Additional cytotoxicity data are detailed in the Supporting Information, Table S2.
For compounds that did not completely inhibit growth at the concentration tested, the percentage inhibition (% I) is given.