Identification of a Novel 1,3,4-Thiadiazole-Based Scaffold as a Plasmepsin V Inhibitor

Abstract

The growing resistance to existing antimalarial drugs, along with the expanding distribution of mosquito vectors transmitting Plasmodium species, underscores the urgent need for new therapeutic agents. Plasmepsins (PMs), a family of aspartic proteases in Plasmodium, among which plasmepsin V (PMV) is the most structurally distinct enzyme compared to other Plasmodium and human aspartic proteases, allowing for the achievement of selectivity against nontarget proteases. The current literature demonstrates that depletion of PMV leads to the immediate cessation of parasite growth after its invasion into red blood cells, establishing PMV as a compelling target for drug discovery. Here, we performed grating-coupled interferometry (GCI) and fluorescence resonance energy transfer (FRET) enzymatic assay screening of a fragment library to identify novel nonpeptidomimetic PMV inhibitors. A 1,3,4-thiadiazole-based compound 11b (LE = 0.45) was identified as a promising hit and subjected to a preliminary structure–activity relationship (SAR) exploration. A total of more than 30 hit analogues were synthesized or obtained commercially and evaluated. A structure–activity relationship exploration led to compounds 11ad and 11ae with IC50 (PvPMV) values of 22.0 and 20.7 μM, respectively. The resulting SAR proved largely flat, with modifications failing to break the sub-10 μM potency threshold. This plateau suggests that the current 1,3,4-thiadiazole core may be approaching its potency ceiling. Although these compounds display suboptimal inhibitory potency, they map out the structural boundaries of this novel nonpeptidomimetic chemotype against PMV.