Figure 1.
General three step synthesis of IPAs and the chemical structure of ND-09759, N-(4-(4-chlorophenoxy)benzyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide.
Reagents: (a) 1,2-Dimethoxyethane, reflux, 48 h.; (b) 1. LiOH, Ethanol, 2. HCl, 56 h.; (c) EDCI, DMAP, (4-(4-chlorophenoxy)phenyl)methanamine, CH3CN, 16 h.
Figure 2.
Maximum Tolerated Dose and Pharmacokinetics of ND-09759 in mice.
(A) Mouse survival curves from maximum tolerated dose study. All mice (n = 5) received one dose daily 6 times weekly for 4 weeks. 80% aqueous propylene glycol, (vehicle control). (B) Mean serum concentration of ND-09759 at different times post-treatment (±standard deviations) in Balb/c mice (n = 5) after a single oral dose (30 mg/kg).
Figure 3.
Lung (A) and spleen (B) weight of M. tuberculosis-infected Balb/c mice (n = 5) treated with ND-09759 alone or in combination with INH or RMP.
Mock, 80% aqueous propylene glycol, (vehicle control), Bars represents means ±standard deviation. **, P<0.05 compared to no treatment group.
Figure 4.
Mycobacterial counts in the lungs and spleens of M. tuberculosis-infected Balb/c mice after treatment with ND-09759 or combination regimens.
Balb/c mice (n = 5) were infected with M. tuberculosis H37Rv by aerosol challenge and then treated by oral gavage with 80% aqueous propylene glycol (solid cycle, vehicle control), ND-09759 (cycle), ND-09759 plus INH (solid square), ND-09759 plus RMP (solid triangle), INH (square) and RMP (triangle), respectively, as described in Materials and Methods. The results show the log10 CFU in the lung (A and C) and spleen (B and D). C and D, Mycobacterial counts after the completion of chemotherapy and each open cycle represents an individual mouse. ***, p<0.05 compared to no treatment group; **, P<0.05 between ND-09759 alone and ND-09759+ INH or RMP.
Figure 5.
Lung histopathology in drug-treated and untreated infected mice.
(A) Images are shown for TB-infected Balb/c mice treated with 80% aqueous propylene glycol (mock), ND-09759 alone, ND-09759 plus INH or RMP, or with INH or RMP alone. The left and right panels show low power (original magnification 50X) and high power (original magnification 400X) of H&E-stained lung sections, respectively. Sections are representative of lung sections from 5 mice per group and from one of two independent experiments. (B) Quantitative scoring of histopathology. Bars represent means ±standard deviation.
Figure 6.
Acid-fast staining of lung sections from M. tuberculosis-infected Balb/c mice (n = 5) following treatment with 80% aqueous propylene glycol (vehicle control) or chemotherapy with drugs as indicated.
Magnification (630X). Acid fast bacilli indicated by arrows.