Synergistic anti-malarial, cytotoxic, and antioxidant activities of trimetallic (Au-Pt-Pd) and bimetallic (Au-Pt) nanofluids: in vitro and computational insights

The global challenge of Plasmodium falciparum resistance to current therapeutics underscores the need for innovative, mechanism-driven antimalarial agents. Noble metal–based nanofluids, owing to their tunable redox and catalytic properties, offer a versatile platform for drug discovery and biointerface modulation. This study explores the antimalarial, antioxidant, and cytotoxic potential of bimetallic (Au–Pt) and trimetallic (Au–Pt–Pd) nanofluids through an integrated experimental–computational framework, aiming to elucidate structure–activity correlations and molecular interaction mechanisms. Au–Pt and Au–Pt–Pd nanofluids were synthesized via a green, one-pot microwave-assisted reduction method and evaluated for (i) antimalarial efficacy against P. falciparum (Pf3D7 strain), (ii) antioxidant activity using DPPH radical scavenging, and (iii) cytotoxicity in HepG2 liver cells. Complementary computational analyses—including DFT calculations, molecular docking against PfNDH2 (PDB: 5JWA), 200 ns molecular dynamics simulations, and ADMET predictions—were conducted to characterize electronic reactivity, binding stability, and pharmacokinetic profiles. Experimentally, the Au–Pt nanofluid exhibited the highest antimalarial potency (IC₅₀ = 0.93 µM) and antioxidant activity (IC₅₀ = 3.95 ± 0.05 µM), outperforming the trimetallic Au–Pt–Pd formulation (IC₅₀ = 1.04 µM and 5.54 ± 0.08 µM, respectively), with reduced cytotoxicity (IC₅₀ = 38.19 µM vs. quinine 28.11 µM). Computationally, Au–Pt–Pd nanoclusters demonstrated enhanced conformational stability through lower RMSD (0.221 nm) and persistent hydrogen bonding (average 4.12 bonds) with PfNDH2, while docking energies (–9.3 and − 8.7 kcal/mol for Au–Pt–Pd and Au–Pt, respectively) supported moderate binding affinity. DFT descriptors revealed strong electron-donating tendencies, and ADMET analysis predicted favorable intestinal absorption (> 80%), low hepatotoxicity, and non-mutagenicity for both systems. This synergistic in vitro–in silico investigation reveals that Au–Pt nanofluids possess potent antimalarial and antioxidant activity with minimal cytotoxicity, while Au–Pt–Pd nanofluids offer superior dynamic stability at the molecular level. Together, these findings suggest that rationally engineered noble-metal nanofluids hold significant potential as modular platforms for antimalarial drug development, meriting further in vivo and mechanistic exploration.