Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors

The adamantanes are a class of anti-influenza drugs that inhibit the M2 ion channel of the influenza A virus. However recently, the clinical effectiveness of these drugs has been called into question due to the emergence of adamantane-insensitive A/M2 mutants. Although we previously reported (1R,2R,3R,5S)-3-pinanamine 3 as a novel inhibitor of the wild type influenza A virus M2 protein (WT A/M2), limited inhibition was found for adamantane-resistant M2 mutants. In this study, we explored whether newly synthesized pinanamine derivatives were capable of inhibiting WT A/M2 and selected adamantane-resistant M2 mutants. Several imidazole and guanazole derivatives of pinanamine were found to inhibit WT A/M2 to a comparable degree as amantadine and one of these compounds 12 exhibits weak inhibition of A/M2-S31N mutant and it is marginally more effective in inhibiting S31N M2 than amantadine. This study provides a new insight into the structural nature of drugs required to inhibit WT A/M2 and its mutants.

Highlights► A series of pinanamine derivatives were design and synthesized for M2 inhibitors. ► Several imidazole and guanazole substituted compounds were found to inhibit WT A/M2 as potent as amantadine. ► Compound 12 was identified to be a novel inhibitor against both A/M2-WT and A/M2-S31N mutant channels.