Acyclic Nucleoside Phosphonates As Potential Inhibitors of Plasmodium Falciparum Egress

The emergence of drug-resistant Plasmodium strains requires the development of novel antimalarial agents with original mechanisms of action. Here, we report the synthesis and biological evaluation of a new family of nucleotide analogues aiming to target an essential step of the development of the malaria parasite. Two series of acyclic nucleoside phosphonates were designed to incorporate strategic structural modifications either on the purine scaffold or on the acyclic chain. All synthesized compounds were evaluated against chloroquine-sensitive (3D7) Plasmodium falciparum strains. A few compounds demonstrated in vitro antimalarial activity with IC₅₀ values ranging from 11.3 to38.8 µM. In addition, a molecular docking study revealed some crucial interactions with the putative target and supports the biological data. The present study establishes this novel family of nucleotide analogues as promising antimalarial scaffolds, warranting further optimization and evaluation.