A phosphinic acid bioisostere of hydroxyethylamine as a novel antiplasmodial scaffold: design, synthesis, and in vitro and in silico evaluation.

Abstract

Malaria remains a major global health concern, and the emergence of drug-resistant Plasmodium falciparum strains highlights the need for new antimalarial scaffolds. In this study, a phosphinic acid-based analogue 2 was designed and synthesized through bioisosteric replacement of the hydroxyethylamine motif found in plasmepsin inhibitor scaffolds. The target compound was obtained through a multistep synthetic approach and evaluated for its antiplasmodial activity against the drug-resistant P. falciparum W2 strain. Compound 2 showed moderate whole-cell antiplasmodial activity with an IC50 value of 3.63 ± 0.11 µM. In silico ADMET analysis indicated favorable absorption-related properties and revealed several parameters requiring further experimental investigation. Molecular docking, 300 ns molecular dynamics simulations, and MM/PBSA calculations supported a plausible binding mode of compound 2 within the active site of plasmepsin II and provided insights into its interaction profile. Overall, this study supports the feasibility of phosphinic acid replacement as a bioisosteric modification strategy for plasmepsin inhibitor scaffolds. Compound 2 represents a preliminary lead scaffold for further optimization, where future studies including cytotoxicity evaluation, selectivity assessment, and enzymatic validation of plasmepsin II inhibition will be required.

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