Effect of Stereochemistry on the Antiplasmodial Activity and Metabolomic Profile of Novel Tadalafil Analogues

Analogues of tadalafil, an FDA-approved inhibitor of human phosphodiesterase 5, have been reported to block the growth of human Plasmodium falciparum in vitro. Herein, we synthesized and evaluated 56 tadalafil analogues prepared as pure diastereomers. Some of the analogues showed potent antiplasmodial activity at nanomolar concentrations with selectivity indices >20–250 in vitro. Compound 33 was the most potent analogue, with an IC₅₀ of 80 nM against cultured parasites and an IC₅₀ > 20 μM on HeLa cells, resulting in a selectivity index >250. Several compounds were tested for potential inhibition of synthetic malaria pigment (β-hematin) formation and PfIspD (2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase); it is possible that compounds 2 and 4 act by disrupting hemozoin formation whereas none of the tested analogues acted as PfIspD inhibitors. Metabolomic profiling revealed that some analogues strongly affect hemoglobin catabolism yet principal component analysis grouped them separately, suggesting differences in their antiplasmodial mechanisms of action.