Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus

Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (<b>44</b>) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections

NMR Chemical Shifts of Trace Impurities: Industrially Preferred Solvents Used in Process and Green Chemistry

The ¹H and ¹³C NMR chemical shifts of 48 industrially preferred solvents in six commonly used deuterated NMR solvents (CDCl₃, acetone-<i>d</i>₆, DMSO-<i>d</i>₆, acetonitrile-<i>d</i>₃, methanol-<i>d</i>₄, and D₂O) are reported. This work supplements the compilation of NMR data published by Gottlieb, Kotlyar, and Nudelman (J. Org. Chem. 1997, 62, 7512) by providing spectral parameters for solvents that were not commonly utilized at the time of their original report. Data are specifically included for solvents, such as 2-Me-THF, <i>n</i>-heptane, and <i>iso</i>-propyl acetate, which are being used more frequently as the chemical industry aims to adopt greener, safer, and more sustainable solvents. These spectral tables simplify the identification of these solvents as impurities in NMR spectra following their use in synthesis and workup protocols