Improved C5-amide bioisosteres for human neuraminidase 1 inhibitors based on 2-deoxy-2,3-didehydro-N-acetyl neuraminic acid (DANA)

Neuraminidase enzymes (NEU) play a crucial role in many physiological and pathological conditions. Humans have four isoenzymes of NEU and their specific roles continue to be investigated. Isoenzyme-selective inhibitors are needed as research tools and may lead to future therapeutics. We tested a series of new candidate inhibitors by replacing the C5-amide of 2-deoxy-2,3-dididehydro-N-acetyl neuraminic acid (DANA) with amide bioisosteres. Design of candidate inhibitors was accomplished using substituents that were components of previously identified NEU inhibitors combined with alternative amide bioisosteres. Compounds were tested for inhibition of the four human NEU, and inhibitory activities were compared to reference amide compounds. We observed that 1,4-disubstituted-1,2,3-triazole was the best bioisostere for inhibitors of NEU1. Inhibitor 542 showed high potency for NEU1 (K¬i = 0.4 ± 0.1 μM) and gave significant improvement in selectivity compared to the reference amide compound 502. Additionally, compound 542 had improved lipophilic characteristics which could provide improved pharmacokinetic properties. Screening of these inhibitors also identified a selective NEU2 inhibitor 543 (Ki = 2.6 ± 0.6 μM), illustrating that amide bioisostere replacement can identify improved inhibitors for multiple NEU isoenzymes.