DOS compounds exhibit stereoselective inhibition of Pb-Luc exoerythrocytic-stage
parasite growth. (a) Representative compounds and activity profiles
with activity against P. berghei in
HepG2 cells. Stereocenters (Cn) are listed below the corresponding chemical structure. Pb-Luc
exoerythrocytic-stage activity was measured for each of the eight
possible stereoisomers (SRR, SSR, SRS, SSS, RRR, RSR, RRS, and RSS) of each compound. Three of the eight possible stereoisomers of
BRD9781 have exoerythrocytic-stage activity, two with potent activity
(SRR and SSS, IC50 <
0.1 μM) and another with moderate activity (RSS, IC50 < 1 μM). One stereoisomer of BRD0326 (SSS) is active (IC50 < 1 μM). Two stereoisomers
of BRD47390 have significant exoerythrocytic-stage activity (SSR, IC50 < 0.1 μM; SRS, IC50 < 0.1 μM). (b) Compounds were tested in
dose in the P. berghei/HepG2 assay,
a Dd2 erythrocytic-stage assay, and in a mammalian cell cytotoxicity
assay. Compounds from three scaffold libraries are shown. Compounds
were tested twice in the exoerythrocytic-stage assay; values from
the second assay are shown in parentheses.