A critical review of quinoline hybrids as privileged scaffolds for anti-malarial therapy.

Malaria remains a life-threatening parasitic disease of global concern, with the emergence and spread of drug-resistant Plasmodium strains necessitating the development of novel, potent, and safe anti-malarial agents. As a privileged pharmacophore with inherent anti-malarial potential, quinoline exerts its anti-malarial effects primarily by inhibiting hemozoin crystallization, interfering with parasite metabolic pathways, disrupting DNA replication and protein synthesis, and targeting key enzymes involved in Plasmodium survival. Of note, quinoline hybrids exhibit prominent advantages, including potent antimalarial activity against both drug-sensitive and drug-resistant Plasmodium strains, structural versatility enabling rational modification, and tunable pharmacokinetic properties, making them superior to single quinoline derivatives in combating malaria and overcoming drug resistance. This critical review comprehensively delineates the research advances of quinoline hybrids as potent antimalarial agents from 2020 to the present, with a particular focus on their in vitro antiplasmodial and in vivo antimalarial therapeutic potential against various Plasmodium strains (including drug-resistant isolates). Furthermore, the structure-activity relationships (SARs) of these quinoline hybrids are systematically deciphered, and the molecular mechanisms are also discussed. Finally, the translational therapeutic prospects and future research directions of quinoline hybrids are prospectively discussed, offering valuable insights for the rational design and optimization of next-generation antimalarial candidates.