Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C₂ symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K_i, 1.93 ± 0.29 µM for Plm II; K_i, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K_i, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC₅₀, 2.27 ± 0.95 µM for 10f; IC₅₀, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC₅₀ value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.