Design, synthesis, and biological evaluation of multiple targeting antimalarials

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health threat, exacerbated by increasing drug resistance.
• Current antimalarial drug development predominantly focuses on single-target inhibitors, necessitating new strategies.
• Multi-targeting inhibitors are crucial for overcoming resistance in malaria treatment.

Purpose of the Study:

• To design and identify a novel multi-targeting antimalarial molecule.
• To overcome the challenge of drug resistance in *Plasmodium falciparum*.
• To explore structure-based drug design targeting the parasite's mitochondrial respiratory chain.

Main Methods:

• Structure-based drug design targeting the mitochondrial respiratory chain of *Plasmodium falciparum*.
• Identification of a potent molecule, RYL-581, binding to multiple protein sites.
• In vitro and in vivo evaluation of RYL-581's efficacy, solubility, and activity.

Main Results:

• RYL-581 identified as a potent molecule binding simultaneously to multiple sites (allosteric site of type II NADH dehydrogenase, Q_o and Q_i sites of cytochrome *bc*₁).
• RYL-581 demonstrated efficacy against various drug-resistant malaria strains in vitro.
• The molecule exhibits good solubility and significant in vivo activity.

Conclusions:

• RYL-581 represents a novel class of antimalarials with a unique multi-targeting mechanism.
• The structure-based design strategy offers a promising approach for future antimalarial drug discovery.
• This approach may be particularly valuable for targeting membrane-associated proteins in drug discovery projects.