Antimalarial efficacy of isatin and oxindole derivatives: A comprehensive update

The efficacy of malaria therapeutics has repeatedly been compromised by the emergence of P. falciparum resistance, leading to partial or complete resistance to existing drugs. These alarming situations have driven further research to develop next-generation drugs with high barriers to resistance and simple treatment regimens that offer outstanding potency and a target-specific mode of action. In this context, isatin and oxindole derivatives have been explored continuously for their antimalarial potency over the past two decades. Cipargamin, a spiroindolone (NITD609 or KAE609)-class antimalarial drug (PfATP4 inhibitor), is currently in a phase II PLATINUM trial (NCT05750628), in uncomplicated P. falciparum malaria patients. A complete developmental journey of the NITD609 candidate, along with its mode of action, is described in detail. Despite increasing interest in the antiplasmodial potency of isatin and oxindole-class compounds, a focused and comprehensive report integrating antimalarial activity, structure-activity relationship (SAR), toxicity, and future drug development prospects remain limited. This report thematically discusses recent advances in the antimalarial efficacy of these scaffolds, while the chronological development of research is appropriately presented within each theme. The key SAR analyses and the importance of suitable substitutions are also discussed. The most active representative compounds from each study are summarised in Table 1, highlighting their antimalarial efficacy. This compilation will provide a comprehensive overview of the last two decades of literature, comprising the antimalarial activities with important SAR analysis, mammalian toxicity studies and selectivity information that will help medicinal chemists to gain explicit insight for further development of simple, novel, highly effective, and safe antimalarial therapeutics.