Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome

Plasmodium falciparum subtilisin-like
serine protease 1 (PfSUB1) is essential for egress of invasive merozoite
forms of the parasite, rendering PfSUB1 an attractive antimalarial
target. Here, we report studies aimed to improve drug-like properties
of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity
and selectivity over human proteasome (H20S). Structure–activity
relationship investigations revealed that lipophilic P3 amino acid side chains as well as N-capping groups
were well tolerated in retaining PfSUB1 inhibitory potency. At the
P1 position, replacing the methyl group with a carboxyethyl
substituent led to boralactone PfSUB1 inhibitors with remarkably improved
selectivity over H20S. Combining lipophilic end-capping groups with
the boralactone reduced the selectivity over H20S. However, compound 4c still showed >60-fold selectivity versus H20S and low
nanomolar
PfSUB1 inhibitory potency. Importantly, this compound inhibited the
growth of a genetically modified P. falciparum line expressing reduced levels of PfSUB1 13-fold more efficiently
compared to a wild-type parasite line.