Discovery of adamantane-based α-hydroxycarboxylic acid derivatives as potent M2-S31N blockers of influenza A virus

The clinical discontinuation of amantadine and rimantadine due to widespread drug resistance highlights the need for new chemical entities that target the M2 ion channel to fight influenza outbreaks and pandemics. Based on the resistance mechanism of adamantane-based drugs and the crystal structure of the S31N mutant, we have designed and synthesized a series of adamantane-based α-hydroxycarboxylic acid derivatives using the molecular hybridization principle and induced fit docking studies. Their biological assays were performed on the wild-type influenza A virus A/HK/68 (H3N2) and adamantane-resistant A/M2-S31N mutant viruses A/WSN/33 (H1N1) were tested in vitro. Among them, the most potent compound 3p showed dual inhibitory activity against both the wild-type and the drug-resistant mutant viruses, with EC₅₀ values of 0.92 μM and 0.55 μM, respectively. Its activity was comparable to that of oseltamivir. Additionally, this compound had a higher selectivity index (SI = 651). Notably, compound 3p, as a proven M2-S31N blocker, strongly bound to the drug-binding sites through hydrophobic interactions, three π-π interactions, two hydrogen bonds, and a cation-π interaction. Furthermore, the ADMET properties were calculated using the QikProp of the Schrödinger suite, which showed desirable pharmacokinetic characteristics for further development. This work expands the chemical space of adamantane-based compounds and opens up a new direction for the development of anti-influenza drugs with diverse structures.

Adamantane derivatives; Anti-influenza activity; Drug resistance; M2 ion channel; Synthesis.