Highlights of Medicinal Chemistry Optimization Strategies in Peptidomimetic Antimalarial Drug Discovery

Progress in the fight against malaria appears to have stalled, as reflected by the nearly unchanged mortality figures reported in 2022 and 2023–600,000 and 597,000 deaths, respectively. In addition to reports of resistance to artemisinin-combination therapies (ACTs) in South-East Asia, resistance to ACTs has now been confirmed in Africa. Therefore, new drugs are urgently needed. In this perspective, we summarize different medicinal chemistry strategies employed to address various liabilities in hit antimalarial peptidomimetics. These include an increase in Log P; macrocyclization; chemically reducing amide bonds within peptide backbones; modifying natural amino acid residues; and rigidification. We also propose aggressive integration of drug metabolism and pharmacokinetics (DMPK) profiling; a careful choice of drug targets; and incorporation of more phenotypic-based approaches in hit identification. We believe this perspective is an important repository of medicinal chemistry strategies, and a useful resource for peptidomimetic antimalarial drug discovery.