Abstract
The emergence of drug-resistant influenza virus strains necessitates the development of novel antiviral agents with unique mechanisms of action. This study presents the synthesis and in vitro evaluation of a new class of antiviral compounds: sodium salts of amino acid ester conjugates based on the closo-dodecaborate anion [B(12)H(12)](2-), linked via a tetrahydropyran-derived spacer (Na(2)[B(12)H(11)O(CH(2))(6)C(O)X], where X = L-Trp-OMe (Na(2)2); L-His-OMe (Na(2)3); L-Met-OMe (Na(2)4); Pld-OMe (Na(2)5)). The antiviral activity was assessed against contemporary, multidrug-resistant influenza A virus strains, including A/Cheboksary/125/2020 (H1N1)pdm09 and A/IIV-Orenburg/83/2012 (H1N1)pdm09. Cross-platform comparison revealed that the dodecaborate-tryptophan conjugate Na(2)2 exhibited comparable efficacy to its lead decaborate analog against the Orenburg strain while demonstrating potent activity (IC(50) = 5.0 µg/mL) against the Cheboksary strain with reduced susceptibility to neuraminidase inhibitors (oseltamivir; zanamivir) and complete resistance to M2 channel blockers. The histidine-based conjugate Na(2)3 also showed significant efficacy against the Cheboksary strain, while methionine and lactam derivatives (Na(2)4; Na(2)5) remained inactive. This work confirms boron clusters as versatile platforms for antiviral development and establishes structure-activity relationships crucial for optimizing both B(10) and B(12)-based therapeutics against resistant influenza strains.