PR002795 (Project)

Description:Analogues of tadalafil, an FDA-approved inhibitor of human phosphodiesterase 5 have been reported to block Plasmodium falciparum growth in vitro. In this study, we synthesized 56 new tadalafil analogues with specific stereochemistry; some of the novel analogues showed potent antiplasmodial activity at nanomolar concentrations and high selectivity in vitro. Compound 33 demonstrated the highest potency, with an IC50 of 80 nM against cultured parasites and an IC50 > 20 µM on human HeLa cells, resulting in a selectivity index >250. Most active compounds showed stereospecific activity favoring the cis isomer with a 6R, 12aR configuration. We demonstrate that conformational and spatial orientation play a more critical role than lipophilicity in determining the activity of these compounds. Metabolomic profiling revealed that several tadalafil analogues strongly affect hemoglobin catabolism; yet principal component analysis (PCA) grouped them separately, suggesting subtle differences in their antiplasmodial mechanisms. Further work will be needed to elucidate their precise mode of action, and future structural optimization will be necessary towards development of tadalafil analogues as antimalarial treatments.