Article Figures & Data
Figures
- FIG. 1.
Structure of TLM (A) and the corresponding 3D Unity constraints (B) used to search for related compounds in the NCI database.
- FIG. 2.
General synthesis of 1,2-dithiole-3-thiones and 1,2-dithiole-3-ones. R4 and R5 are shown in Table 1. R was generally either a methyl or ethyl group. LDA, lithium diisopropylamide.
- FIG. 3.
Effect of preincubation time with compound 5 (squares) or compound 3 (circles) on residual activity of saFabH.
- FIG. 4.
Effect of added substrate on residual activity of saFabH inhibited with compounds 3 and 5.
- FIG. 5.
Decrease in intrinsic fluorescence of ecFabH with addition of compounds 3 (A) and 11 (B) and restoration of fluorescence of ecFabH after removal of unbound inhibitor (C).
Tables
- TABLE 1.
1,2-Dithiole-3-(thi)one compounds tested as FabH inhibitors in this studya
↵ a Compounds 1 to 4 were identified and obtained from NCI during the initial screening process. Compound 5 was identified in a second search and obtained from NCI. The remaining compounds were synthesized. Compounds 1, 3, and 5 have previously been referred to as HR19, HR12 (RWJ-3981), and HR45, respectively (4, 26, 53).
b For compound 1, R1 = R2 = phenyl. For compound 2, R1 = R2 = CH2CH2Ph.
- TABLE 3.
IC50 values of 1,2-dithiole-3-(thi)one inhibitors for saFabH
Inhibitor IC50 (μM)a Preincubation No preincubation 3 0.983 ± 0.041 1.92 ± 0.17 (2) 5 0.156 ± 0.010 2.25 ± 0.18 (14) 6 0.109 ± 0.028 3.19 ± 0.43 (30) 7 26.0 ± 4.9 31.0 ± 5.1 8 22.4 ± 4.6 22.0 ± 2.8 9 50.5 ± 11.8 51.9 ± 9.3 10 35.2 ± 3.0 32.2 ± 3.9 11 102 ± 11 ND 12 15.68 ± 0.54 30.0 ± 4.6 (2) 13 9.3 ± 1.5 29.2 ± 2.1 (3) 14 >100 >100 15 >100 >100 ↵ a Assays for IC50 values were conducted with a 15-min preincubation or without preincubation. For values obtained without preincubation, the fold differences from values obtained with preincubation are shown in parentheses. ND, not determined.
- TABLE 4.
MIC determination for 1,2-dithiole-3-ones against E. coli K-12 (ATCC 10798) and S. aureusa
Strain MIC (μg/ml) of inhibitor for indicated strain Compound 1 Compound 3 Compound 5 TLM E. coli K-12 100 4.0 1 140 S. aureus RN 450 35 8.7 25 300 S. aureus N315 17.5 8.7 25 300 ↵ a Some of these data were reported previously (29).
