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 IC50 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.

Charles University 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 Hospital Biomedical Research Center Sokolska 581 500 05 Hradec Kralove Czech Republic

University Hospital Biomedical Research Center Sokolska 581 500 05 Hradec Kralove Czech Republic; University of Hradec Kralove Faculty of Science Department of Chemistry Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

University Hospital Biomedical Research Center Sokolska 581 500 05 Hradec Kralove Czech Republic; University of Hradec Kralove Faculty of Science Department of Chemistry Rokitanskeho 62 500 03 Hradec Kralove Czech Republic; University of Hradec Kralove Faculty of Informatics and Management Center for Basic and Applied Research Rokitanskeho 62 500 03 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

Citace poskytuje Crossref.org

Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets

Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer's Disease Treatment

Novel Benzothiazole-based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer's Disease Treatment