Substrate derived peptidic α-ketoamides as inhibitors of the malarial protease PfSUB1

Peptidic alpha-ketoamides have been developed as inhibitors of the malarial protease PfSUB1. The design of inhibitors was based on the best known endogenous PfSUB1 substrate sequence, leading to compounds with low micromolar to submicromolar inhibitory activity. SAR studies were performed indicating the requirement of an aspartate mimicking the P-1' substituent and optimal P-1-P-4 length of the non-prime part. The importance of each of the P-1-P-4 amino acid side chains was investigated, revealing crucial interactions and size limitations. (C) 2014 Elsevier Ltd. All rights reserved.