Radwan Mostafa, Carvajal Elisa G, Cairo Christopher W
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
ChemMedChem. 2025 Jul 1;20(13):e202500099. doi: 10.1002/cmdc.202500099. Epub 2025 May 7.
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. A series of new candidate inhibitors are tested by replacing the C5-amide of 2-deoxy-2,3-dididehydro-N-acetyl neuraminic acid with amide bioisosteres. Design of candidate inhibitors is accomplished using substituents that are components of previously identified NEU inhibitors combined with alternative amide bioisosteres. Compounds are tested for inhibition of the four human NEU, and inhibitory activities are compared to reference amide compounds. 1,4-Disubstituted-1,2,3-triazole is the best bioisostere observed for inhibitors of NEU1. Inhibitor 542 shows high potency for NEU1 (K = 0.4 ± 0.1 μM) and give significant improvement in selectivity compared to the reference amide compound 502. Additionally, compound 542 has improved lipophilic characteristics, which could provide improved pharmacokinetic properties. Screening of these inhibitors also identify a selective NEU2 inhibitor 543 (K = 2.6 ± 0.6 μM), illustrating that amide bioisostere replacement can identify improved inhibitors for multiple NEU isoenzymes.
神经氨酸酶（NEU）在许多生理和病理状况中发挥着关键作用。人类有四种NEU同工酶，它们的具体作用仍在研究中。需要同工酶选择性抑制剂作为研究工具，并且可能会带来未来的治疗方法。通过用酰胺生物电子等排体取代2-脱氧-2,3-二脱氢-N-乙酰神经氨酸的C5-酰胺来测试一系列新的候选抑制剂。候选抑制剂的设计是通过使用先前鉴定的NEU抑制剂的组成部分取代基与替代酰胺生物电子等排体相结合来完成的。测试化合物对四种人类NEU的抑制作用，并将抑制活性与参考酰胺化合物进行比较。1,4-二取代-1,2,3-三唑是观察到的对NEU1抑制剂最佳的生物电子等排体。抑制剂542对NEU1显示出高效力（K = 0.4±0.1μM），与参考酰胺化合物502相比，选择性有显著提高。此外，化合物542具有改善的亲脂性特征，这可能会提供改善的药代动力学性质。对这些抑制剂的筛选还鉴定出一种选择性NEU2抑制剂543（K = 2.6±0.6μM），说明酰胺生物电子等排体取代可以鉴定出针对多种NEU同工酶的改进抑制剂。
