A series of tacrine – benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound – 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
|Early online date||28 Dec 2020|
|Publication status||Published - Feb 2021|
FunderFirst of all, the authors would like to express their gratitude to laboratory assistants Martina Techlovska, Pavlina Jelinkova, Maria Anna Jancovicova and Lucie Krbalek. Further, this work was supported by the project Excellence UHK, by the ERDF/ESF project “PharmaBrain” (No. CZ.02.1.01/0.0/0.0/16_025/0007444), by MH CZ-DRO (University Hospital Hradec Kralove, No. 00179906), by project PROGRES Q40 (Charles University in Prague, Czech Republic), by Long Term Development Plan of University of Hradec Kralove, by a grant of Ministry of Defence “Long Term Development Plan” Medical Aspects of Weapons of Mass Destruction of the Faculty of Military Health Sciences, University of Defence, by the National Institute of Mental Health (NIMH-CZ) project No. LO1611 with a financial support from the MEYS under the NPU I program and by the project PERSONMED - Center for the Development of Personalized Medicine in Age-Related Diseases (Reg. No. CZ.02.1.01/0.0/0.0/17_048/0007441), co-financed by ERDF and state budget of the Czech Republic, and by the Ministry of Education, Youth and Sports of Czech Republic (project ERDF IT4N No. CZ.02.1.01/0.0/0.0/18_069/0010054). This work was also supported by University of Hradec Kralove (No. SV2105-2020, VT2019-2021). Computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided within the programme “Projects of Large Research, Development, and Innovations Infrastructures”. This work was also supported by the research grants VEGA 2/0145/17, MVTS COST 083/14 action BM1405, Czech Science Foundation (Project No. 20-29633J) and by the Slovak Research and Development Agency under contract No. APVV – 18-0284. Last but not least, this work received funding from the European Uniońs Horizon 2020 research, innovation programme under grant agreement number 654148 Laserlab-Europe, Wellcome Trust (204821/Z/16/Z), The Rosetrees Trust and the RSMacDonald Charitable Trust.
- Alzheimer’s disease
- Acetylcholinesterase Inhibitors
- Amyloid β
ASJC Scopus subject areas
- Molecular Biology
- Drug Discovery
- Organic Chemistry