A new class of antimalarial drugs, spiroindolones, has been developed and shown to be highly effective against malaria. The compound NITD609, a spiroindolone, exhibits low nanomolar potency against Plasmodium falciparum and Plasmodium vivax, and demonstrates single-dose efficacy in a rodent malaria model. It has an acceptable safety profile and pharmacokinetic properties compatible with once-daily oral dosing. NITD609 is effective against drug-resistant parasites and has a favorable pharmacological profile suitable for a new antimalarial drug candidate. The spiroindolones act by rapidly diminishing protein synthesis in Plasmodium falciparum, an effect that is ablated in parasites with mutations in the PfATP4 gene. NITD609 shows no evidence of diminished potency against drug-resistant strains. It is as effective as artesunate against both P. falciparum and P. vivax isolates. NITD609 also kills both mature and immature P. vivax ring stages, unlike chloroquine, which only affects trophozoite stages. NITD609 has a large selectivity index and displays an acceptable safety profile. It shows no significant cytotoxicity and has a low risk of cardiotoxicity. In vivo studies in rats showed that NITD609 is well tolerated and has favorable pharmacokinetic properties. It was effective in a malaria mouse model, with a single dose of 100 mg/kg completely clearing infection and a dose of 30 mg/kg achieving partial cure. Mutations in the PfATP4 gene confer low-level drug resistance to spiroindolones. These mutations are specific to the PfATP4 gene and are not cross-resistant to other antimalarial drugs. The mutations were identified through genomic analysis and were confirmed by sequencing. The mutations are located in the transmembrane regions of PfATP4 and are likely to be involved in the resistance mechanism. The study concludes that spiroindolones represent a new antimalarial chemotype with a novel mechanism of action. NITD609 is a promising new antimalarial drug candidate that meets all the criteria for a new antimalarial drug. Further safety and pharmacological preclinical evaluation is ongoing to support the initiation of human clinical trials.A new class of antimalarial drugs, spiroindolones, has been developed and shown to be highly effective against malaria. The compound NITD609, a spiroindolone, exhibits low nanomolar potency against Plasmodium falciparum and Plasmodium vivax, and demonstrates single-dose efficacy in a rodent malaria model. It has an acceptable safety profile and pharmacokinetic properties compatible with once-daily oral dosing. NITD609 is effective against drug-resistant parasites and has a favorable pharmacological profile suitable for a new antimalarial drug candidate. The spiroindolones act by rapidly diminishing protein synthesis in Plasmodium falciparum, an effect that is ablated in parasites with mutations in the PfATP4 gene. NITD609 shows no evidence of diminished potency against drug-resistant strains. It is as effective as artesunate against both P. falciparum and P. vivax isolates. NITD609 also kills both mature and immature P. vivax ring stages, unlike chloroquine, which only affects trophozoite stages. NITD609 has a large selectivity index and displays an acceptable safety profile. It shows no significant cytotoxicity and has a low risk of cardiotoxicity. In vivo studies in rats showed that NITD609 is well tolerated and has favorable pharmacokinetic properties. It was effective in a malaria mouse model, with a single dose of 100 mg/kg completely clearing infection and a dose of 30 mg/kg achieving partial cure. Mutations in the PfATP4 gene confer low-level drug resistance to spiroindolones. These mutations are specific to the PfATP4 gene and are not cross-resistant to other antimalarial drugs. The mutations were identified through genomic analysis and were confirmed by sequencing. The mutations are located in the transmembrane regions of PfATP4 and are likely to be involved in the resistance mechanism. The study concludes that spiroindolones represent a new antimalarial chemotype with a novel mechanism of action. NITD609 is a promising new antimalarial drug candidate that meets all the criteria for a new antimalarial drug. Further safety and pharmacological preclinical evaluation is ongoing to support the initiation of human clinical trials.