Extended Data Table 2.
Structure–activity relationship study of the bicyclic azetidine series
| |||||||
|---|---|---|---|---|---|---|---|
|
PfDd2 EC50(µM) |
PfcPheRS IC50(µM) |
R1 | R2 | R3 | R4 | n | |
| BRD8805 | 0.003 | 0.033 | -NMe2 | -Ph | -H |
|
1 |
| BRD7929 | 0.009 | 0.023 | - | - | - |
|
1 |
| BRD1095 | 0.010 | 0.046 | -NH2 | - | - | - | 1 |
| BRD3444 | 0.011 | 0.033 | -OH | - | - | - | 1 |
| BRD3316 | 0.022 | 0.029 | -O(CH2)2CO2H | - | - | - | 1 |
| BRD4716 | 0.024 | 0.086 | -NM/Pr | - | - | - | 1 |
| BRD2132 | 0.048 | 0.179 | -NMe(CH2)2F | - | - | - | 1 |
| BRD0185 | 0.087 | 0.097 | -OH | - | - | - | 2 |
| BRD8493 | 0.116 | 0.162 |
|
- | - | - | 1 |
| BRD6479 | 0.158 | 0.233 |
|
- | - | - | 1 |
| BRC4873 | 0.261 | 0.221 | -OH | -2-CNPh | - | - | 1 |
| BRD9599 | 0.850 | 0.366 | - | -Ph | - | - | 0 |
| BRD2936 | 1.87 | 29.4 | - | - | -CH2OH | - | 1 |
| 3RD5349 | 8.32 | 30.9 | - | - | -H |
|
1 |
| BRD5774 | 12.2 | 23.4 | - |
|
- |
|
1 |
| BHD8260 | 19.5 | 34.6 | - | -Ph | - |
|
1 |
The structures of 16 bicyclic azetidine analogues with varying potency against asexual blood-stage parasites (Dd2), along with their corresponding inhibition of the P. falciparum PheRS activity in a biochemical assay. Aminoacylation inhibition activities were characterized using purified recombinant PheRS in which a range of inhibitor concentrations was used to determine IC50 values. The biochemically derived IC50 values correlate extremely well (r2 = 0.89) with the EC50 determined usingthe blood-stage parasite growth-inhibition assay (see Fig. 3d).