Metal-Drug Complexes as Long-Release Application for Antimalarial PfFNT-Inhibitors

Inhibition of the Plasmodium falciparum formate-nitrite transporter (PfFNT) has emerged as a promising strategy for antimalarial drug development. PfFNT inhibitors display high potency against blood-stage parasites and have shown efficacy in vivo. Here, we demonstrate activity against liver-stage parasites of the front-running compound, (Z)-4,4,5,5,5-pentafluoro-3-hydroxy-1-(pyridin-3-yl)pent-2-en-1-one (BH267m), highlighting the potential for chemopreventive applications. Consequently, we investigated the formation of metal complexes of PfFNT inhibitors as a strategy to generate long-acting depot formulations enabling sustained drug release. Complexes with Mg²⁺, Ca²⁺, and Zn²⁺ were prepared via chelation through the pharmacophoric vinylogous acid moiety and characterized by spectroscopic methods. The resulting solids formed amorphous particles in the low micrometer range with metal-dependent aqueous solubilities. In vitro release studies using a dialysis assay revealed sustained, near zero-order ligand release, with zinc-based complexes displaying particularly low solubility and slow release kinetics. Release rates varied by approximately one order of magnitude depending on metal ion and ligand structure. Simulated plasma concentrations suggested sustained exposure of one- to tenfold of the respective in vitro EC₅₀ values within the current ligand portfolio. These findings indicate that coordination of vinylogous acid motifs with metal ions may provide a basis for developing long-acting depot formulations of chelating anti-infective agents.