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In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti- P. falciparum activity, with IC 50 values ranging from 0.030 to 9.1 μM. The [1,2,4]triazolo[1,5- a pyrimidine derivatives were more potent than the pyrazolo[1,5- a pyrimidine and quinoline analogues. Compounds 20 , 21 , 23 and 24 were the most potent inhibitors, with IC 50 values in the range of 0.030–0.086 μM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5- a pyrimidine derivatives inhibited Pf DHODH activity in the low micromolar to low nanomolar range (IC 50 values of 0.08–1.3 μM) and did not show significant inhibition against the Hs DHODH homologue (0–30% at 50 μM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5- a pyrimidine derivatives to Pf DHODH, and the highest interaction affinities for the Pf DHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF 3 , R 1 = F; IC 50 = 0.086 μM), 21 (R = CF 3 ; R 1 = CH 3 ; IC 50 = 0.032 μM), 23 , (R = CF 3 , R 1 = CF 3 ; IC 50 = 0.030 μM) and 24 (R = CF 3 , 2-naphthyl; IC 50 = 0.050 μM) and the most active inhibitor against Pf DHODH 19 (R = CF 3 , R 1 = Cl; IC 50 = 0.08 μM - Pf DHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the Pf DHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5- a pyrimidine derivatives. Image 1 • New triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors, showing no cytotoxic activity against the human hepatoma cell line HepG2. • The [1,2,4]triazolo[1,5- a pyrimidine derivatives were more potente series and were equipotent to chloroquine. • All compounds inhibited the activity of Pf DHODH and did not show significant inhibition against the Hs DHODH homologue. • Molecular docking studies indicated the binding mode of compounds to Pf DHODH. • Their combined activity against P. falciparum and inhibition of Pf DHODH enzyme suggest the mechanism of action. [ABSTRACT FROM AUTHOR]