Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design,synthesis and biological evaluation

Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme (IC₅₀ = 6.8 ± 1.8 μmol/L and IC₅₀ = 8.8 ± 0.3 μmol/L) and P. falciparum 3D7 strain (IC₅₀ = 2.9 μmol/L). Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P. falciparum Dd2 strain (IC₅₀ = 1.1 μmol/L) than pyrimethamine (IC₅₀ > 10 μmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9 (IC₅₀ = 2.6 μmol/L) and GB4 (IC₅₀ = 1.0 μmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.