Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor

The Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is an essential enzyme required for parasite egress from host red blood cells and represents a promising target for antimalarial drugs. Peptidic boronic acids are potent reported PfSUB1 inhibitors, however their drug-likeness is limited by their pronounced peptidic character. Based on molecular docking studies using peptidic boronic acids, we designed a series of partially depeptidized PfSUB1 inhibitors by replacing the P1-P2 dipeptide fragment with a 3-aminomethylphenylboronic acid core. Structure-activity relationship (SAR) investigations targeting interaction with active-site residue Lys138 revealed that introducing a meta-carboxylate group (compound 3a) markedly enhanced inhibitory activity, yielding a low-nanomolar PfSUB1 inhibitor (IC50= 10.2 nM). Bioisosteric replacement of the carboxylic acid demonstrated that an N-acylsulfonamide group (compound 4k) retained high enzymatic potency (IC50= 13.5 nM)). In cellular assays against blood-stage P. falciparum (3D7 strain), the leading depeptidized boronic acids exhibited growth inhibition with values in the low-micromolar range suggesting that further structural modifications are needed to enhance membrane permeability across host and parasite membranes to reach exonemes prior to egress. Overall, this study validates the P1-P2 depeptidization of boronic acid scaffolds and provides key SAR insights for the rational design of non-peptidic PfSUB1-targeted antimalarials.