Amantadine Variant – Aryl Conjugates that Inhibit Multiple M2 Mutant – Amantadine Resistant Influenza A Viruses

Abstract

Influenza A viruses can cause a serious future threat due to frequent mutations. The resistant to the drugs amantadine and rimantadine influenza A viruses bearing the S31N mutant in the M2 proton channel (such as the pandemic 2009 H1N1 and seasonal H3N2) can be inhibited by amantadine – aryl conjugate However, the amantadine / rimantadine viruses bearing one of the mutations L26F, V27A, A30T, G34E in M2 protein is a concern.

Here, starting from three amantadine-aryl conjugates that inhibit M2 S31N, we replaced amantadine with 16 amantadine variants and we synthesized 36 new compounds that were tested against all six amantadine resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses.

We identified 16 compounds that inhibit in vitro two influenza A virus with M2 WT or L26F channels. However, compounds 21 or 32 or 33, which are conjugates of a rimantadine variant or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl group, are in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound 21 inhibit also in vitro the M2 G34E virus and 32 inhibited also in vitro the M2 A30T virus. For these compounds we performed a preliminary drug metabolism and pharmacokinetics study. Also. using electrophysiology we showed that compound 21 is an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocks efficiently the M2 WT channel and compound 33 blocks the M2 WT, L26F and V27A channels.

Keywords: amantadine - aryl conjugate, antiviral activity, CPE, in vitro, electrophysiology, influenza A M2 protein, A30T, G34E, L26F, S31N, V27A, Synthesis, TEVC, WSN/33