Exploring the Anti-Influenza Activity of closo-Borate Platforms: Structure–Activity Relationship of Amino Acid-Functionalized closo-Dodecaborate Derivatives Against Influenza Virus A/Cheboksary/125/2020 (H1N1)pdm09

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 [B12H12]2−, linked via a tetrahydropyran-derived spacer (Na2[B12H11O(CH2)6C(O)X], where X = L-Trp-OMe (Na22); L-His-OMe (Na23); L-Met-OMe (Na24); Pld-OMe (Na25)). 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 Na22 exhibited comparable efficacy to its lead decaborate analog against the Orenburg strain while demonstrating potent activity (IC50 = 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 Na23 also showed significant efficacy against the Cheboksary strain, while methionine and lactam derivatives (Na24; Na25) remained inactive. This work confirms boron clusters as versatile platforms for antiviral development and establishes structure–activity relationships crucial for optimizing both B10 and B12-based therapeutics against resistant influenza strains.