Spiroindolone

Spiroindolone is a class of antimalarial compounds that are synthetic and chemically novel. They are characterized by a spiro-fused pyrrolidine-indolinone core structure. Spiroindolones were first discovered in 2008 as part of a phenotypic screen for antimalarial activity.

Chemistry

The core structure of spiroindolones consists of a spiro-fused pyrrolidine-indolinone. This structure is unique among antimalarial compounds and is responsible for the compound's potent antimalarial activity. The spiroindolone scaffold is synthesized through a Michael addition followed by an intramolecular Mannich reaction.

Mechanism of Action

Spiroindolones exert their antimalarial activity by inhibiting the P-type ATPase PfATP4 in the Plasmodium falciparum parasite. PfATP4 is an essential ion pump that regulates the parasite's intracellular levels of sodium ions. Inhibition of PfATP4 disrupts the parasite's sodium homeostasis, leading to its death.

Clinical Development

The most advanced spiroindolone in clinical development is NITD609 (also known as KAE609 or cipargamin), which is being developed by the Novartis Institute for Tropical Diseases (NITD). NITD609 has shown potent activity against both drug-sensitive and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in preclinical studies. It is currently in Phase II clinical trials.

Potential Advantages

Spiroindolones have several potential advantages over existing antimalarial drugs. They have a novel mechanism of action, which means they can overcome existing drug resistance. They also have a rapid killing action and a long half-life, which could potentially allow for single-dose treatment.

See Also

• Antimalarial medication
• Drug resistance
• Novartis Institute for Tropical Diseases

References

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