Table 5. Validation of Moiety Exchanges Predicted to Improve GN Activity by Screening In VitroE. coli MIC Data and Permeation-Proxy Data Curated from ChEMBL for Every Added or Removed “Main Moiety” and Its “Opposite Moiety” Counterparta.
| main moiety | +/– | exchange moiety | ΔpMIC ± std | pMIC Repeats | inactive → active | GP → GN (repeats) |
|---|---|---|---|---|---|---|
| primary amine | addition | ether | 0.83 ± 0.61 | 225 | 50 | 28 (179) |
| primary amine | addition | carbonyl | 1.07 ± 0.71 | 655 | 283 | 122 (396) |
| primary amine | addition | secondary amine | 0.49 ± 0.63 | 2267 | 60 | 32 (2049) |
| lactone | removal | secondary amine | 1.40 ± 0.15 | 5 | 0 | 0 (3) |
| lactone | removal | tertiary amine | 0.78 ± 0.32 | 71 | 0 | 0 (39) |
| ester (carboxylate ester) | removal | secondary amine | 0.81 ± 0.45 | 21 | 2 | 0 (13) |
| ester (carboxylate ester) | removal | carboxamide | 1.23 ± 0.51 | 28 | 27 | 25 (26) |
| ester (carboxylate ester) | removal | ether | 0.55 ± 0.62 | 26 | 3 | 1 (13) |
| ester (carboxylate ester) | removal | primary amine | 0.89 ± 0.45 | 36 | 12 | 1 (25) |
| ester (carboxylate ester) | removal | tertiary amine | 0.74 ± 0.35 | 106 | 5 | 4 (51) |
| carbonyl | removal | aryl chloride | 0.67 ± 0.68 | 48 | 16 | 2 (16) |
| nitrile | removal | ether | 0.33 ± 0.55 | 77 | 6 | 5 (34) |
| carboxamide | removal | thiophene | 0.27 ± 0.27 | 8 | 0 | 0 (1) |
| carboxamide | removal | carboxylic acid | 0.59 ± 0.33 | 42 | 25 | 5 (11) |
| carboxamide | removal | aryl chloride | 0.42 ± 0.61 | 5 | 1 | 1 (2) |
| thiophene | addition | nitrile | –0.04 ± 0.89 | 9 | 3 | 3 (4) |
| thiophene | addition | secondary amine | –0.23 ± 1.09 | 31 | 4 | 1 (8) |
| thiophene | addition | aniline | 0.42 ± 0.69 | 16 | 5 | 3 (6) |
| thiophene | addition | carbonyl | 0.74 ± 0.40 | 39 | 4 | 2 (15) |
| tertiary carboxamide | removal | thiophene | 0.37 ± 0.26 | 5 | 0 | 0 (1) |
| tertiary carboxamide | removal | secondary carboxamide | 0.5 ± 0.35 | 35 | 6 | 1 (13) |
| aryl chloride | addition | nitrile | 0.16 ± 0.48 | 53 | 8 | 2 (9) |
| aryl chloride | addition | tertiary amine | 0.39 ± 0.65 | 52 | 16 | 2 (4) |
| aryl chloride | addition | aryl fluoride | 0.02 ± 0.50 | 291 | 17 | 5 (49) |
| secondary amine | addition | tertiary amine | 0.43 ± 0.68 | 1066 | 142 | 85 (755) |
| secondary amine | addition | ether | 0.70 ± 0.51 | 203 | 53 | 37 (150) |
| secondary amine | addition | nitrile | 1.19 ± 1.03 | 62 | 26 | 14 (35) |
| tertiary amine | removal | aryl chloride | 0.39 ± 0.65 | 52 | 16 | 2 (4) |
| tertiary amine | removal | alkanol | 0.45 ± 0.51 | 236 | 31 | 18 (99) |
| α,β-unsaturated carbonyl | removal | thiophene | 1.04 ± 0.21 | 11 | 0 | 0 (6) |
| α,β-unsaturated carbonyl | removal | secondary amine | 1.24 ± 0.69 | 25 | 4 | 0 (2) |
| α,β-unsaturated carbonyl | removal | aryl chloride | 1.20 ± 0.74 | 7 | 3 | 0 (2) |
| aryl fluoride | addition | nitrile | 0.17 ± 0.60 | 64 | 1 | 0 (16) |
| aryl fluoride | addition | tertiary amine | 0.79 ± 0.64 | 56 | 21 | 2 (17) |
| aryl fluoride | addition | alkanol | 0.33 ± 0.69 | 81 | 14 | 2 (23) |
a
As defined in Table 4, identical matched pairs were identified in the ChEMBL datasets. “pMIC repeats” denotes the number of identified pairs, “ΔpMIC” the average change in experimental pMIC, and “inactive → active”, the number of times the change in pMIC changed the core molecule from GN-inactive (pMIC < 5) to GN-active (pMIC > 5) in ChEMBL dataset 1. “GP → GN” displays the number of times a core molecule is altered from GN-inactive to GN-active in the subset, ChEMBL dataset 2, with the number of repeats for the respective pairs in this dataset shown in parentheses. The full distributions of the change in pMIC for every transform are shown in the Supporting Information, Figure S3.