Figure 1.
Known nitroaromatic antimicrobial drugs and nitrofurans explored in this study.
Figure 2.
Synthesis of pentacyclic nitrofurans.
Reagents and conditions: a) MsCl, Et3N, CH2Cl2, RT, 2 h, 94%; b) substituted phenol, nBu4NCl, H2O, 100°C, 12 h, 86–90%; c) TFA, CH2Cl2, RT, 1 h, 92–95%; d) aryl bromide, 2-(di-tert-butylphosphino)biphenyl, NaOtBu, Pd(OAc)2, toluene, 100°C, 3 h, 50–70%; e) 8, Et3N, CHCl3, RT, 3 h, 50–68%.
Table 1.
In vitro antitubercular and in vitro metabolic profile.
Table 2.
Susceptibility of non-tuberculosis mycobacteria.
Table 3.
In vivo pharmacokinetic parameters.
Figure 3.
Murine model of acute tuberculosis infection.
Log10 reduction provided by compound 9a in lungs (black bars) and spleen (grey bars) after 9 days of daily oral administration of 300 mg/kg was determined by calculating the difference between bacillary loads in organs from the untreated group and 9a dissolved in (1) 0.5% methylcellulose in DI-H2O (2) 30% captisol in DI-H2O (3) 10% vitamin E TPGS in DI-H2O (4) 0.5% Tween 80 in DI-H2O (5) 20% cyclodextrin in DI-H2O or (6) cold PEG (50∶35∶15 H2O:PEG300:PG). Error bars indicate SEM within treatment groups of 5–7 mice per group.
Table 4.
In vitro Interactions with Antitubercular Drugs.
Table 5.
MIC and MBCs for select nitrofurans and controls.
Figure 4.
Nutrient starvation model of nonreplicating persisters.
The viability of mid-log phase (black bars) or nutrient-starved (gray bars) after exposure to DMSO carrier (1% v/v), 1 µg/mL of isoniazid (INH), or 1 µg/mL of 9a. Averaged results and SEM from two biologically independent experiments are presented.
Table 6.
In vitro activity against NRP bacteria grown under hypoxic conditions.
Table 7.
Mechanism of activation and primary resistance.
Table 8.
Cross Resistance Profiles for Compounds 9a Resistant Clones.