Table 2.

Comparison of selection profiles, in vitro assay potencies, and SPR-binding constants for InhA inhibitors

CompoundSeriesProfile classInhA NAD+ assay IC50, µMInhA NADH assay IC50, µMInhA NAD+ SPR Kd, µMInhA NADH SPR Kd, µMInhA Apo SPR Kd, µM
111110.389 ± 0.0070.168 (n = 1)NTNTNT
10a1020.038 ± 0.0060.198 ± 0.0090.26 ± 0.125 ± 1.2012.4 ± 1.41
121220.682 ± 0.2076.838 ± 0.175NTNTNT
2a*1–330.060 ± 0.0040.057 ± 0.00646.7 ± 11.60.094 ± 0.06>100
131330.791 ± 0.0080.609 ± 0.114NTNTNT
8a*8 and 93NT0.130 ± 0.00649 ± 2.900.055 ± 0.03>100
6a*6 and 73NT5.917 ± 1.22>10036.8 ± 3.25>100
4a*4 and 53NT0.297 ± 0.053>1000.25 ± 0.11>100
1a*1–33NT0.065 ± 0.00813.4 ± 4.300.34 ± 0.22>100
14143NT5.568 ± 0.777>1006.3>100
  • Profile classes: 1, enriched only in the presence of apo InhA; 2, enriched only in the presence of the InhA:NAD+ complex; 3, enriched only in the presence of the InhA:NADH complex but not in presence of small molecule. NT, not tested. Chemical structures for compounds 11–14 are given in Fig. S1.

  • * WT InhA cocrystal structures reported herein.