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. 2014 Jun 12;57(11):4629-39.
doi: 10.1021/jm500598u. Epub 2014 May 15.

Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A

Antonios Kolocouris  1 , Christina Tzitzoglaki, F Brent Johnson, Roland Zell, Anna K Wright, Timothy A Cross, Ian Tietjen, David Fedida, David D Busath
Affiliations

Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A

Antonios Kolocouris et al. J Med Chem. .

Abstract

A series of 2-adamantanamines with alkyl adducts of various lengths were examined for efficacy against strains of influenza A including those having an S31N mutation in M2 proton channel that confer resistance to amantadine and rimantadine. The addition of as little as one CH2 group to the methyl adduct of the amantadine/rimantadine analogue, 2-methyl-2-aminoadamantane, led to activity in vitro against two M2 S31N viruses A/Calif/07/2009 (H1N1) and A/PR/8/34 (H1N1) but not to a third A/WS/33 (H1N1). Solid state NMR of the transmembrane domain (TMD) with a site mutation corresponding to S31N shows evidence of drug binding. But electrophysiology using the full length S31N M2 protein in HEK cells showed no blockade. A wild type strain, A/Hong Kong/1/68 (H3N2) developed resistance to representative drugs within one passage with mutations in M2 TMD, but A/Calif/07/2009 S31N was slow (>8 passages) to develop resistance in vitro, and the resistant virus had no mutations in M2 TMD. The results indicate that 2-alkyl-2-aminoadamantane derivatives with sufficient adducts can persistently block p2009 influenza A in vitro through an alternative mechanism. The observations of an HA1 mutation, N160D, near the sialic acid binding site in both 6-resistant A/Calif/07/2009(H1N1) and the broadly resistant A/WS/33(H1N1) and of an HA1 mutation, I325S, in the 6-resistant virus at a cell-culture stable site suggest that the drugs tested here may block infection by direct binding near these critical sites for virus entry to the host cell.

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Figures

Scheme 1
Scheme 1. Amantadine 1, Rimantadine 2, and 2-Alkyl-2-aminoadamantane Derivatives 3–11
Scheme 2
Scheme 2. Preparation of 2-n-Propyl-2-aminoadamantane 6
Reagents and conditions: (a) CH2=CHCH2MgBr, ether, THF, rt, 2 h, then NH4Cl/H2O (quant); (b) H2/PtO2 (quant); (c) NaN3, TFA, CH2Cl2, 0 °C, then rt (quant); (c) LiAlH4, ether, rt, 5 h (74%).
Scheme 3
Scheme 3. Preparation of 2-Alkyl-2-aminoadamantane Derivatives 4, 5, 7–11
Reagents and conditions: (a) RLi, Ar, ether, THF, 0 °C, 2 h rt for 17–20 or RMgCl, ether, THF, 2 h rt for 16, 20, 21, then NH4Cl/H2O (85–96%); (b) NaN3, TFA, CH2Cl2, 0 °C, then rt (50–96%); (c) LiAlH4, ether, rt, 5 h (23–65%).
Figure 1
Figure 1
Superimposed PISEMA spectra of the S31N M2 transmembrane domain (residues 22–46), 15N labeled at residues V28, A30, and I42, in dimyristoylphosphatidylcholine bilayers uniformly aligned on glass slides with (red) and without (black) compound 6. Assignments were made based on the known structure and spectra of WT M2 TMD. The assignments with drug follow based on the rotational orientation of the helices.
Figure 2
Figure 2
CPT structure of the HA trimer, produced by Gamblin et al. (1RVX, A/Puerto Rico/8/1934) with a bound NAG-GAL-SIA ligand as ball-and-stick (red) and with the two nearby 6-resistance sites highlighted in blue, residues 159 (above ligand) and 186 (left of ligand). The third 6-resistance site, 324, also in blue, is near the bottom of the structure. Because of a common insertion after residue 133 found in A/Calif/07/2009 (H1N1), these correspond to N160, S187, and I325, respectively, in the A/Calif/07/2009 6-resistant mutants.
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