Hroch Lukas, Guest Patrick, Benek Ondrej, Soukup Ondrej, Janockova Jana, Dolezal Rafael, Kuca Kamil, Aitken Laura, Smith Terry K, Gunn-Moore Frank, Zala Dominykas, Ramsay Rona R, Musilek Kamil
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmaceutical Chemistry and Drug Control, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
University of St. Andrews, School of Biology, Medical and Biological Sciences Building or Biomedical Sciences Research Complex, North Haugh, St. Andrews KY16 9ST, United Kingdom.
Bioorg Med Chem. 2017 Feb 1;25(3):1143-1152. doi: 10.1016/j.bmc.2016.12.029. Epub 2016 Dec 27.
Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC values of 6.34μM and 0.30μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.
阿尔茨海默病（AD）是一种与β-淀粉样肽（Aβ）过度积累相关的神经退行性疾病。基于AD的多因素性质，制备多靶点导向配体为一次性解决更多病理事件提供了一个可行的选择。已设计并合成了一类新型的不对称二取代吲哚基硫脲，以与单胺氧化酶（MAO）和/或淀粉样蛋白结合醇脱氢酶（ABAD）相互作用。该设计结合了已知MAO抑制剂支架（如雷沙吉兰或拉多替吉）的特征以及具有与ABAD相互作用潜力的氟替唑部分。对MAO的评估确定了几种在低至中等微摩尔范围内具有抑制作用的化合物。最有前景的化合物（19）对人MAO-A和MAO-B的抑制常数（IC）值分别为6.34μM和0.30μM。ABAD活性评估未显示出任何高效的化合物，但该化合物系列有助于确定结构特征，以辅助未来ABAD抑制剂的开发。最后，发现其中几种化合物是辣根过氧化物酶（HRP）的强效抑制剂，这使得无法使用Amplex™ Red检测法来检测MAO产生的过氧化氢，突出了在使用酶联检测法时采取严格预防措施的必要性。
