Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer's disease treatment.
Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.
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.
Lukas
L
Hroch
University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; University of Defence, Faculty of Military Health Sciences, Department of Toxicology, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Ondrej
O
Benek
University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, United Kingdom.
Patrick
P
Guest
University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, United Kingdom.
Laura
L
Aitken
University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Ondrej
O
Soukup
University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Jana
J
Janockova
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.
Karel
K
Musil
University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
Vlastimil
V
Dohnal
University Hospital, Biomedical Research Center, Sokolska 581, 500 05 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.
Rafael
R
Dolezal
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.
Kamil
K
Kuca
Biomedical Science Research Complex, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, United Kingdom.
Terry K
TK
Smith
University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, United Kingdom.
Frank
F
Gunn-Moore
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.
Kamil
K
Musilek
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D014508:Urea; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; C005465:benzothiazole
17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10); Alzheimer’s disease (AD); Amyloid binding alcohol dehydrogenase (ABAD); Amyloid-beta peptide (Aβ); Benzothiazole; Mitochondria; Riluzole