Fig. 1.

Structures of PQ and OH-PQm and their activity against P. falciparum liver stages and gametocytes. a Structures of compounds used in this study. b, f Dose dependent reduction in exoerythrocytic forms (EEFs) numbers at day 3.5 post infection with NF54 sporozoites in YEM (poor metaboliser, black line) and NON (extensive metaboliser, dashed blue line) hepatocyte lots. b Primaquine (PQ). c 5-hydroxy-primaquine (5-HPQ). d 5-quinoneimine (PQQI). e 5,6-dihydroxy-primaquine (5,6-DPQ). f 6-hydroxy-5-quinoneimine (6OHPQQI). Viability is expressed as mean percentage of vehicle control ± S.D. of two independent experiments performed in triplicates. For each drug, IC₅₀ values are reported for the poor metaboliser, YEM, and extensive metaboliser, NON, hepatocyte lots. g Coupled in vitro metabolism-GC-LUC assay. PQ and PQ metabolites (30 μM) were reacted with (blue squares) or without (red circles human liver microsomes (HLM) prior to dilution to 10 μM (nominal parental compound concentration) in a GC-LUC assay with mature gametocytes. Viability was measured after 72 h and expressed as mean percentage of control (no drug) viability ± S.D. (n = 3, each in triplicate). h as in g, but with (blue squares) or without (red circles) CYP2D6 (n = 2, 5 total replicates). For paroxetine inhibition, CYP2D6 was pre-incubated with 10 μM paroxetine for 15 min prior to compounds (black triangles, n = 2, 4 total replicates); i as in g, but without (red circles) or with (blue squares) recombinant human CPR, or with huCPR in the presence of 10 mM sodium pyruvate (brown diamonds) with huCPR in the absence of NAPD⁺ (black triangles). NoNADP⁺ n = 1 in duplicate; all other huCPR conditions n = 4 in duplicate