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.