Novel flexible biphenyl Pf DHFR inhibitors with improved antimalarial activity

Abstract

As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl PfDHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker. Interestingly, their mode of binding differs from previously reported compounds, taking advantage of strong hydrophobic interaction. The new flexible biphenyl compounds show overall improved antiparasitic activity compared to rigid ones, with the best compound displaying a 2 nM antiplasmodial IC₅₀ and suitable drug-like properties. This confirms the importance of compound flexibility for antimalarial activity and opens the way to new opportunities for antimalarial drug design.

Fig. 1. Molecular structures of folic acid and reported PfDHFR inhibitors.

Scheme 1. Synthesis of diaminopyrimidines attached to flexible linkers with biphenyl derivatives. Reagents and conditions: i) conc. H₂SO₄, EtOH, reflux, 20 h; ii) anhydrous K₂CO₃, DMF, 55 °C then 1,n-dibromoalkane (n = 3 or 4), 1 h; iii) LiOH·H₂O, DMF, r.t., 2 d; iv) diluted HCl, r.t., 3 h; v) LiOH·H₂O, 70 °C, 16 h.

Fig. 2. Snapshots from the crystal structures of FB6 (PDB 8YQ9) and FB8 (PDB 8YQ8). Co-crystallized NADPH appears in dark grey, polar contacts appear as dashed lines as generated by PyMOL.

Fig. 3. Superimposed molecular docking poses obtained for lead compounds in QM PfDHFR.