Repositioning Salirasib as a new antimalarial agent

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health threat, primarily caused by Plasmodium falciparum.
• Salirasib, an S-farnesyl thiosalicylate, targets isoprenylcysteine carboxyl methyltransferase (ICMT), a validated cancer target.
• High homology exists between human and Plasmodium ICMT, suggesting potential for drug repurposing.

Purpose of the Study:

• To explore the repurposing of Salirasib and its derivatives as antimalarial agents.
• To synthesize and evaluate S-substituted thiosalicylic acid derivatives for antiplasmodial activity.
• To assess the in vitro toxicity and therapeutic index of novel compounds against Plasmodium falciparum.

Main Methods:

• Synthesis of S-substituted thiosalicylic acid derivatives, incorporating 1,2,3-triazole or direct alkylation.
• In vitro antiplasmodial activity assays using nanoluciferase-transfected Plasmodium falciparum.
• Cytotoxicity evaluation in Vero cells to determine therapeutic indices.

Main Results:

• Several synthesized analogs demonstrated activity at low micromolar concentrations against Plasmodium falciparum.
• Salirasib itself exhibited antiplasmodial effects.
• The most potent compound featured an S-farnesyl group and a phytyl-substituted 1,2,3-triazole moiety.
• A methyl-naphthyl substituted compound showed favorable physicochemical properties and activity.
• Active analogs displayed low cytotoxicity in eukaryotic cells, indicating good therapeutic potential.

Conclusions:

• S-substituted thiosalicylic acid derivatives, including Salirasib, show promise as starting points for new antimalarial drug development.
• The identified compounds possess favorable activity and safety profiles, warranting further investigation.
• Drug repurposing of cancer therapeutics offers a viable strategy for addressing malaria.