Fig. 3.

Rational design of selective inhibitors targeting PfHT1. (A) Potency against P. falciparum (3D7 and Dd2 strains) and cytotoxicity in HEK293T₁₇. PfHT1 inhibitors showed equal potency to quinine-resistant strain, Dd2, as well as 3D7. All EC₅₀ and CC₅₀ values are an average of two or three biological replicates. The entire dataset is in SI Appendix, Table S2. C3361 is shown as a reference compound reported in ref. 20. (B) The generic chemical structures of TH-PF01, TH-PF02, and TH-PF03 containing a sugar moiety, a substituted heteroaromatic tail, and a flexible linker. The predicted ClogP values calculated by ChemDraw for each compound were 4.01, 3.79, and 2.06. (C) TH-PF01, TH-PF02, and TH-PF03 demonstrated robust parasite growth inhibitory activities, selectivity, and cytotoxicity. The IC₅₀ values were determined by proteoliposome-based counterflow assay. The blood-stage P. falciparum (3D7 and Dd2) and mammalian cells (HEK293T₁₇ and HepG2) were incubated with the compounds for 72 h, and the cell growth was quantified with SYBR Green I and Cell Titer Glo correspondingly. The data are representative of three bioreplicates and shown as average ± SD of three technical replicates.