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

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±1.8μmol/L and IC50 =8.8±0.3μmol/L) and P. falciparum 3D7 strain (IC50 =2.9μmol/L). Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P. falciparum Dd2 strain (IC50 =1.1μmol/L) than pyrimethamine (IC50 >10μmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9 (IC50 =2.6μmol/L) and GB4 (IC50 =1.0μmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria. Graphical abstract
Source: Chinese Chemical Letters - Category: Chemistry Source Type: research