Keggin-TypePolyoxometalates as a Systematic AntiviralScaffold: Activity, Cytotoxicity, and Solution Stability across Heteroionand Addenda Metal Variations

Abstract Polyoxometalates (POMs) are promising antiviral agents, yet systematic structure–activity relationships remain scarce and biological stability is rarely assessed. Here we report the antiviral activity, cytotoxicity, and solution speciation of 11 Keggin-type POMs spanning three compositional series─PVxW12–x, PVxMo12–x, and SiMoxW12–x (x = 0–3)─alongside lacunary derivatives, and simple metal salt controls. Multinuclear NMR spectroscopy (31P, 51V, 183W) in cell culture medium under assay conditions revealed a direct correlation between cluster integrity and antiviral potency: compounds that decompose are uniformly inactive while structurally stable or partially transformed clusters show concentration-dependent inhibition. The silicomolybdotungstate series proved most promising, with [SiW12O40]4– and [SiMoW11O40]4– achieving IC50 values of 26.0 and 24.9 μM against HCoV-OC43. Antiviral potency correlates with overall cluster charge, with 4– anions consistently outperforming their 3– and 6– analogues─an observation rationalized through the superchaotropic ion concept.