Table 1.
Comparison of the in vitro susceptibility of Plasmodium knowlesi (A1-H.1) and Plasmodium falciparum (3D7) exposed to established and investigational antimalarial agents for one complete life cycle.
| Compound | EC50 values (nM) |
Fold difference (Pk/Pf) | p-valuea | |
|---|---|---|---|---|
|
P. knowlesi (A1-H.1) 27 h exposure |
P. falciparum (3D7) 48 h exposure |
|||
| P. knowlesi EC50 > 3 × P. falciparum EC50 | ||||
| Cipargamin (KAE609) | 6.1 ± 0.5 | 0.89 ± 0.08 | 6.83 | <0.0001 |
| SJ733 | 386 ± 34 | 64.3 ± 4.3 | 6.00 | <0.0001 |
| PA21A092 | 63.8 ± 7.6 | 10.2 ± 1.4 | 6.25 | 0.0002 |
| AN13762 | 2762 ± 296 | 41.3 ± 3.8 | 66.88 | <0.0001 |
| Pentamidine | 331 ± 20 | 99 ± 4 | 3.34 | 0.0003 |
| Cladosporin | 411 ± 134 | 133 ± 10 | 3.09 | 0.0831 |
| P. knowlesi EC50 < 1/3 × P. falciparum EC50 | ||||
| KAF156 | 1.7 ± 0.16 | 7.9 ± 0.12 | 0.22 | <0.0001 |
| Halofantrine | 0.92 ± 0.25 | 3.60 ± 0.40 | 0.31 | 0.0174 |
| NMT MMV884705 | 46.2 ± 16 | 206 ± 44 | 0.22 | 0.0266 |
| P. knowlesi EC50 ≈ P. falciparum EC50 | ||||
| New Isoquine | 15.9 ± 2.4 | 11.4 ± 2.38 | 1.39 | 0.2474 |
| Bisquinoline | 2.2 ± 1.40 | 2.3 ± 0.94 | 0.97 | 0.9715 |
| AQ-13 | 11.4 ± 2.82 | 5.1 ± 1.15 | 2.23 | 0.1091 |
| Quinidine | 38.4 ± 10.5 | 52.9 ± 10.7 | 0.73 | 0.3704 |
| Naphthoquine | 117 ± 83 | 111 ± 23 | 1.05 | 0.5544 |
| Methylene Blue | 5.38 ± 1.8 | 3.31 ± 0.7 | 1.63 | 0.3543 |
| MMV253 | 13.0 ± 1.9 | 7.4 ± 1.5 | 1.76 | 0.0810 |
| MMV048 | 17.2 ± 0.9 | 29.5 ± 2.5 | 0.58 | 0.0103 |
| Cyclohexamide | 117 ± 40 | 188 ± 35 | 0.62 | 0.2544 |
| Benzylquine | 31.53 ± 10.88 | 22.05 ± 2.02 | 1.43 | 0.3469 |
| WR194965 | 282 ± 111 | 539 ± 236 | 0.52 | 0.3633 |
| BIX-01294 | 22.6 ± 4.4 | 21.2 ± 4.1 | 1.07 | 0.8207 |
| Sitamaquine | 112 ± 25 | 72 ± 15 | 1.56 | 0.2350 |
| Methotrexate | 1991 ± 125 | 693 ± 48 | 2.87 | 0.0006 |
| MK-4815 | 47.6 ± 6 | 127 ± 16 | 0.37 | 0.0100 |
| MMV688558 | 17.5 ± 2.0 | 42.4 ± 1.6 | 0.41 | 0.0006 |
| Endoperoxides | ||||
| Dihydroartemisinin | 2.35 ± 0.23 | 5.16 ± 0.62 | 0.46 | 0.0017 |
| Artemisinin | 7.39 ± 1.87 | 11.00 ± 1.32 | 0.67 | 0.1667 |
| Artemisone | 0.47 ± 0.14 | 0.72 ± 0.15 | 0.65 | 0.2701 |
| Artesunate | 10.30 ± 1.9 | 8.28 ± 1.05 | 1.24 | 0.3552 |
| Artemether | 4.56 ± 0.55 | 6.93 ± 0.73 | 0.66 | 0.0413 |
| Arterolane (OZ277) | 2.27 ± 0.42 | 4.03 ± 0.59 | 0.56 | 0.0407 |
| Artefenomel (OZ439) | 4.76 ± 0.40 | 4.82 ± 0.62 | 0.99 | 0.9350 |
| Deoxyartemisinin | >10,000 | >10,000 | N.D. | N.D. |
| Delayed death compounds (multiple life cycle exposure)b | ||||
| Trans-mirincamycin | 2.49 ± 0.56 | 4.89 ± 1.17 | 0.51 | 0.1124 |
| Cis-mirincamycin | 2.51 ± 0.64 | 4.61 ± 1.01 | 0.54 | 0.1296 |
EC50 values report the mean ± SEM from at least 3 experiments, and some up to seven repeats, each performed in duplicate.
a
p values are calculated by comparing EC50 values for P. falciparum versus P. knowlesi using Student's two-tailed unpaired t-test.
b
Asynchronised parasites were exposed to these compounds for 68 h (P. knowlesi) or 120 h (P. falciparum).