Display omitted •Six new hydantoins derivatives were designed, synthesized and evaluated for their in vitro antiplasmodial activity.•The most active compound 2c showed excellent inhibitory activity on the tested plasmodium 3D7 strain with an IC50 value of 3.97 ± 0.01 nM, which was three-fold better than that of chloroquine.•Substitution with a different R group at the N-5 position of the hydantoin scaffold resulted in a marked decrease in antimalarial potency.•All hydantoins derivatives tested were inactive against human MCR-5 normal cells with IC50 values exceeding 100 μM. Malaria, a devastating disease, has claimed numerous lives and caused considerable suffering, with young children and pregnant women being the most severely affected group. However, the emergence of multidrug-resistant strains of Plasmodium and the adverse side effects associated with existing antimalarial drugs underscore the urgent need for the development of novel, well-tolerated, and more efficient drugs to combat this global health threat. To address these challenges, six new hydantoins derivatives were synthesized and evaluated for their in vitro antiplasmodial activity. Notably, compound 2c exhibited excellent inhibitory activity against the tested Pf3D7 strain, with an IC50 value of 3.97 ± 0.01 nM, three-fold better than chloroquine. Following closely, compound 3b demonstrated an IC50 value of 27.52 ± 3.37 µM against the Pf3D7 strain in vitro. Additionally, all the hydantoins derivatives tested showed inactive against human MCR-5 cells, with an IC50 value exceeding 100 μM. In summary, the hydantoin derivative 2c emerges as a promising candidate for further exploration as an antiplasmodial compound.