DISCOVERY AND CHARACTERIZATION OF TACRINE/HUPRINE-TRYPTOPHAN HETERODIMERS AS NOVEL MULTIPOTENT COMPOUNDS AGAINST ALZHEIMER'S DISEASEMeeting abstracts
- Jan Korabecny
ORCID...1,2, Katarina Spilovska1,3, Manuela Bartolini4, Barbara Monti4, Doriano Lamba5, Rosanna Caliandro5, Alessandro Pesaresi5, Vendula Hepnarova ORCID...2,6, Daniel Jun ORCID...2,6, Martina Hrabinova2,6, Rafael Dolezal ORCID...2, Jana Zdarova Karasova ORCID...2,6, Ondrej Soukup ORCID...1,2, Eva Mezeiova1,2, Eugenie Nepovimova3, Maria Laura Bolognesi4, Kamil Kuca ORCID...2,3 - 1 National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic
- 2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
- 3 Department of Chemistry, University of Hradec Kralove, Rokytanskeho 62, 500 03 Hradec Kralove, Czech Republic
- 4 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
- 5 Istituto di Crystallografia, Consiglio Nazionale delle Ricerche, Area Science Park-Basovizza, S.S. 14-Km 163.5, I-34149 Trieste, Italy
- 6 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
Combination of tacrine/huprine, connected through a different linker tether length, with tryptophan led to the generation of a novel, highly-potent family of multi-target directed ligands targeting key molecular mechanisms of Alzheimer’s disease. Based on in vitro biological profile, the 6-chloro-tacrine-(CH2)6-L-tryptophan heterodimer S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) within the series, with nanomolar IC50 values (6.31 and 9.07 nM, respectively). Moreover, S‑K1035 showed good ability to inhibit Aβ42 self-aggregation and hAChE-induced Aβ40 aggregation. The X-ray crystallographic analysis of TcAChE in complex with S-K1035 highlighted the utility of the hybridization approach used in the structure based drug design. S‑K1035 also exerted moderate inhibition against neuronal nitric oxide synthase (nNOS). In vivo studies displayed low toxicity profile compared to parent tacrine. S-K1035 also significantly ameliorated performances of scopolamine-treated animals.
Published: September 2, 2018 Show citation
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