Table 1. 5-substituted orotate derivatives designed in this study.
| Inhibitor | 5-substituent | TcDHODH (μM) | HsDHODH (μM) | SI | Co-crystalb | |||
|---|---|---|---|---|---|---|---|---|
| IC50 | Kiapp | IC50 | Kiapp | (Fold)a | Resolution (Å) | PDBc | ||
| OROd | H | 112 ± 21 | 5.51 | n.d.e | n.d. | n.d. | 1.64 | 2E6A |
| 1 | 2,2‐dimethylpentane | > 400 | > 19.7 | n.d. | n.d. | n.d. | 1.85 | 3W1Q |
| 2 | propylbenzene | 62.4 ± 16.9 | 3.07 | > 5,000 | > 2,500 | > 814 | 1.58 | 3W1R |
| 3 | 1-propyl-3-(trifluoromethyl)benzene | 12.5 ± 0.8 | 0.62 | 284 ± 50 | 142 | 231 | 1.68 | 3W1T |
| 4 | 2-propylnaphthalene | 4.51 ± 0.09 | 0.22 | 46.1 ± 17.2 | 23.1 | 104 | 1.67 | 3W7H |
| 5 | 1-propylnaphthalene | 15.5 ± 0.8 | 0.76 | 434 ± 41 | 217 | 284 | 1.55 | 3W72 |
| 6 | 1-methoxy-6-propylnaphthalene | 2.24 ± 0.42 | 0.110 | 20.6 ± 3.1 | 10.3 | 93.6 | 1.75 | 3W7C |
| 7 | 2-methoxy-6-propylnaphthalene | 2.89 ± 0.07 | 0.14 | 46.2 ± 3.2 | 23.1 | 163 | 1.97 | 3W3O |
| 8 | 2-methoxy-7-propylnaphthalene | 5.90 ± 0.19 | 0.29 | 13.3 ± 0.5 | 6.65 | 22.8 | 1.82 | 4JDB |
| 9 | 6-propylnaphthalene-1-carboxylic acid | 0.67 ± 0.06 | 0.03 | > 5,000 | >2,500 | > 75,760 | 2.63 | 3W6Y |
| 10 | 6-propylnaphthalene-2-carboxylic acid | 0.50 ± 0.03 | 0.02 | 1,785 ± 1,773 | 893 | 37,210 | 1.58 | 3W7J |
| 11 | 1-methyl-4-propylbenzene | 8.68 ± 0.68 | 0.427 | 5.77 ± 0.66 | 2.88 | 6.75 | 1.85 | 3W1U |
| 12 | 1-tert-butyl-4-propylbenzene | 22.4 ± 2.1 | 1.10 | 16.8 ± 1.4 | 8.40 | 7.64 | 1.98 | 3W22 |
| 13 | 1-phenoxy-4-propylbenzene | 22.6 ± 1.5 | 1.11 | 16.6 ± 1.8 | 8.30 | 7.48 | 2.60 | 3W70 |
| 14 | 4-propyl-1,1'-biphenyl | 16.0 ± 1.9 | 0.79 | 0.97 ± 0.18 | 0.48 | 0.61 | 1.68 | 3W71 |
a, selectivity index calculated from the ratio of HsDHODH Kiapp / TcDHODH Kiapp values.
b, information from co-crystal structures of 5-substituents with TcDHODH.
c, Protein Data Bank identification code
d, orotate