Structure-Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Artemisinin resistance necessitates novel antimalarial drug targets.
• The Plasmodium proteasome is a validated target for antimalarial drug development.
• Previous studies identified a selective Plasmodium falciparum proteasome inhibitor.

Purpose of the Study:

• To optimize a series of macrocyclic proteasome inhibitors for antimalarial activity.
• To identify novel compounds with improved drug-like properties, including permeability and metabolic stability.
• To further investigate structure-activity relationships (SAR) of biphenyl ether-tethered macrocycles.

Main Methods:

• Structure-activity relationship (SAR) studies were performed on macrocyclic scaffolds.
• Extensive modifications were made to the P1, P3, and P5 groups and peptide backbone.
• Compound efficacy, selectivity, solubility, permeability, and metabolic stability were evaluated.

Main Results:

• Compound TDI-8414 was identified, exhibiting nanomolar antiparasitic activity.
• TDI-8414 demonstrated high selectivity for the Plasmodium proteasome over human proteasomes.
• The compound showed improved solubility, PAMPA permeability, and metabolic stability in human and mouse systems.
• No toxicity was observed in HepG2 cells.

Conclusions:

• TDI-8414 represents a promising lead compound for antimalarial drug development targeting the Plasmodium proteasome.
• Optimization of the macrocyclic scaffold yielded a compound with potent activity and favorable pharmacokinetic properties.
• The findings support the targeting of the Plasmodium proteasome as a viable strategy against drug-resistant malaria strains.