Histidinal-Based Potent Antimalarial Agents.

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health threat, necessitating the development of new antimalarial drugs.
• Targeting essential parasite proteases, such as falcipain-2/3, is a promising strategy for antimalarial drug development.

Purpose of the Study:

• To synthesize and evaluate novel peptide-histidinal conjugated drug scaffolds.
• To assess the antimalarial activity of these compounds against the human malaria parasite.
• To investigate the mechanism of action and drug-likeness of the most potent inhibitors.

Main Methods:

• Synthesis of peptide-histidinal conjugated scaffolds with diverse substitutions.
• In vitro antimalarial activity testing to determine EC50 values.
• Structure-based docking studies against falcipain-2/3 proteases (PDB:2GHU, PDB:3BWK).
• In silico ADME (Absorption, Distribution, Metabolism, and Excretion) profiling.
• Phenotypic assays to confirm inhibition of hemoglobin degradation.

Main Results:

• Compounds 8g, 8h, and 15 demonstrated potent antimalarial activity with EC50 values in the nanomolar range (∼0.018–0.069 μM).
• Docking studies indicated strong, substrate-like interactions of these compounds with the falcipain-2/3 active sites.
• In silico ADME studies suggested favorable drug-like properties with minimal violations.
• Compound 8g and its biotinylated derivative effectively inhibited hemoglobin degradation in the parasite food vacuole.

Conclusions:

• Peptide-histidinal conjugated scaffolds are effective inhibitors of falcipain-2/3 proteases.
• The identified potent inhibitors exhibit promising antimalarial activity and favorable pharmacokinetic profiles.
• These compounds represent valuable lead structures for the development of next-generation antimalarial drugs.