TABLE 1.
Comparisons of inhibitor efficacies of pyrimethamine analogs against WT and C59R S108N double-mutant PfDHFR-TS, determined by bacterial complementation (IC50), in vitro parasite culture assay (IC50), and PfDHFR enzyme (Ki) inhibition screening methodsa
| Compound tested | Inhibition of wild type
|
Inhibition of mutant (C59R S108N)
|
||||
|---|---|---|---|---|---|---|
| IC50 (μM) for E. coli | IC50 (μM) for TM4* | Ki (nM) for PfDHFR* | IC50 (μM) for E. coli | IC50 (μM) for K1* | Ki (nM) for PfDHFR* | |
| Pyr (P1) | 0.02 ± 0.004 | 0.08 ± 0.01 | 0.6 ± 0.2 | >50 | 30.9 ± 8.4 | 53.9 ± 6.5 |
| P30 | 0.08 ± 0.02 | 0.4 ± 0.1 | 0.8 ± 0.1 | 1.51 ± 0.45 | 1.3 ± 0.5 | 1.4 ± 0.0 |
| P38 | 0.27 ± 0.06 | 2.4 ± 1.1 | 1.9 ± 0.5 | 12.48 ± 2.56 | 4.8 ± 0.7 | 3.1 ± 0.3 |
| P20 | 0.12 ± 0.04 | 0.7 ± 0.24 | 2.3 ± 0.3 | 7.88 ± 1.67 | 3.3 ± 0.4 | 8.7 ± 0.2 |
| P34 | 0.22 ± 0.04 | 3.7 ± 0.8 | 7.0 ± 1.0 | >50 | 17.4 ± 3.1 | 534.5 ± 65.2 |
| P36 | ND | 7.4 ± 2.6 | 10.9 ± 1.5 | 39.69 ± 8.41 | 30.8 ± 6.5 | 36.7 ± 4.3 |
| P64 | 3.19 ± 0.80 | 13.9 ± 1.9 | 4.5 ± 0.3 | >50 | >50 | 14.2 ± 2.0 |