Article Figures & Data
Figures
- FIG 1
Structures of BTZ043, PBTZ169, and PyrBTZ derivatives and their respective MICs against M. tuberculosis H37Rv.
- FIG 2
Synthetic routes for the synthesis of pyrrole-BTZs. Step a, NaHS, NH4Cl, ethanol; step b, (i) 2,5-dimethoxytetrahydrofuran, acetic acid, reflux; (ii) NaOH; step c, 2,5-hexanedione, p-toluenesulfonic acid, toluene, reflux.
- FIG 3
Comparative inhibition of DPA synthesis. Decaprenylphosphoryl-β-d-ribose epimerization by M. tuberculosis H37Ra cells was inhibited by PyrBTZ01 (200 μg/ml), PyrBTZ02 (200 μg/ml), and BTZ043 (25 μg/ml). The ratios of the intensities of the DPA and DPR bands (quantified in ImageJ) are also shown.
- FIG 4
Molecular docking of pyrrole-BTZs in the DprE1 active site. Superposition of the M. tuberculosis DprE1 crystal structure with BTZ043 (A) or PBTZ169 (B) and the modeled structures of docked PyrBTZ01 (blue carbons) (C) and docked PyrBTZ02 (red carbons) (D) show an induced-fit complex. Cocrystallized DprE1 with PBTZ169 (PDB accession no. 4NCR) (yellow carbons) was used as the template. Residues important for the interactions are shown as sticks. FAD, flavin adenine dinucleotide.
- FIG 5
PK profiles in plasma following oral administration of PyrBTZ01 (50 mg/kg) or BTZ043 (25 mg/kg) to BALB/c mice. Data for BTZ043 in the plot were reported previously (3).
Tables
- TABLE 1
MIC99 values for PyrBTZ01 and PyrBTZ02 against wild-type and BTZ-resistant mycobacterial strains
Strain Amino acid at position 387 MIC99 (μg/ml) PyrBTZ01 PyrBTZ02 BTZ043 M. tuberculosis H37Rv Cys 0.16 0.16 0.001 M. tuberculosis NTB1 Ser 100 >100 10 M. tuberculosis ss18b Cys >100 >100 >10 M. smegmatis mc2155 Cysa 0.78 0.39 0.004 M. smegmatis MN47 Glya >100 >100 4 M. smegmatis MN84 Sera >100 >100 >16 M. bovis BCG Cys 0.39 0.2 0.003 M. bovis BCG BN2 Ser 25 >100 >16 ↵a The active site cysteine in M. smegmatis DprE1 is Cys394.
- TABLE 2
IC50 values measured for PyrBTZ01, PyrBTZ02, and BTZ043 against wild-type and BTZ-resistant M. tuberculosis DprE1
Compound IC50 (μM) Wild-type C387G C387S PyrBTZ01 1.61 11.4 4.00 PyrBTZ02 7.34 >40 27.7 BTZ043 0.00425 0.0395 0.0108 - TABLE 3
Cytotoxicity (TD50) and selectivity index values
Cell line PyrBTZ01 PyrBTZ02 BTZ043 TD50 (μg/ml) SI TD50 (μg/ml) SI TD50 (μg/ml) SI HepG2 47 294 94 588 19 19,000 Huh7 50 313 81 506 16 16,000 A549 51 319 >100 >625 34 34,000 THP1 46 288 97 606 77 77,000 - TABLE 4
Metabolic stability of PyrBTZ01 and PyrBTZ02 in the presence of mouse and human microsomes
Compound CLint (μl/min/mg protein) Mouse microsomes Human microsomes Carbamazepine 2.10 0.60 PyrBTZ01 22.7 12.2 PyrBTZ02 16.2 22.3 BTZ043 16.5 4.20 PBTZ169 36.7 20.8
Supplemental material
- Supplemental file 1 -
Supplemental material describing the synthetic route for PyrBTZ.
PDF, 209K
- Supplemental file 1 -
