title: Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment.
abstract: 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 IC50values 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.
authors.affiliation: 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.
authors.forename: Lukas
authors.initials: L
authors.lastname: Hroch
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Guest
authors.affiliation: 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.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Benek
authors.affiliation: University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janockova
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Dolezal
authors.affiliation: 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.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Aitken
authors.affiliation: 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.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.affiliation: 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.
authors.forename: Dominykas
authors.initials: D
authors.lastname: Zala
authors.affiliation: 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.
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.affiliation: 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. Electronic address: kamil.musilek@gmail.com.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; C013997:frentizole; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D008995:Monoamine Oxidase; D013890:Thiourea
keywords: 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10); Alzheimer's disease (AD); Amyloid-beta peptide (Aβ); Horseradish peroxidase (HRP); Mitochondrial amyloid-binding alcohol dehydrogenase (ABAD); Monoamine oxidase (MAO)