Standard

Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease. / Hamulakova, Slavka; Kudlickova, Zuzana; Janovec, Ladislav; Mezencev, Roman; Deckner, Zachery J.; Chernoff, Yury O.; Janockova, Jana; Ihnatova, Veronika; Bzonek, Petr; Novakova, Nikola; Hepnarova, Vendula; Hrabinova, Martina; Jun, Daniel; Korabecny, Jan; Soukup, Ondrej; Kuca, Kamil.

In: Future Medicinal Chemistry, Vol. 13, No. 9, 01.05.2021, p. 785-804.

Research output: Contribution to journal › Article › peer-review

Harvard

Hamulakova, S, Kudlickova, Z, Janovec, L, Mezencev, R, Deckner, ZJ, Chernoff, YO, Janockova, J, Ihnatova, V, Bzonek, P, Novakova, N, Hepnarova, V, Hrabinova, M, Jun, D, Korabecny, J, Soukup, O & Kuca, K 2021, 'Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease', Future Medicinal Chemistry, vol. 13, no. 9, pp. 785-804. https://doi.org/10.4155/fmc-2020-0184

APA

Hamulakova, S., Kudlickova, Z., Janovec, L., Mezencev, R., Deckner, Z. J., Chernoff, Y. O., Janockova, J., Ihnatova, V., Bzonek, P., Novakova, N., Hepnarova, V., Hrabinova, M., Jun, D., Korabecny, J., Soukup, O., & Kuca, K. (2021). Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease. Future Medicinal Chemistry, 13(9), 785-804. https://doi.org/10.4155/fmc-2020-0184

Vancouver

Hamulakova S, Kudlickova Z, Janovec L, Mezencev R, Deckner ZJ, Chernoff YO et al. Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease. Future Medicinal Chemistry. 2021 May 1;13(9):785-804. https://doi.org/10.4155/fmc-2020-0184

Author

Hamulakova, Slavka ; Kudlickova, Zuzana ; Janovec, Ladislav ; Mezencev, Roman ; Deckner, Zachery J. ; Chernoff, Yury O. ; Janockova, Jana ; Ihnatova, Veronika ; Bzonek, Petr ; Novakova, Nikola ; Hepnarova, Vendula ; Hrabinova, Martina ; Jun, Daniel ; Korabecny, Jan ; Soukup, Ondrej ; Kuca, Kamil. / Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease. In: Future Medicinal Chemistry. 2021 ; Vol. 13, No. 9. pp. 785-804.

BibTeX

@article{d9177b13fd35473bab71fa02d5b96de1,
title = "Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease",
abstract = "The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood-brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.",
keywords = "7-methoxytacrine, Alzheimer's disease, cholinesterases, in vitro, indole, tacrine, Acetylcholinesterase/metabolism, Humans, Indoles/chemistry, Neuroprotective Agents/chemistry, Structure-Activity Relationship, Molecular Targeted Therapy, Cholinesterase Inhibitors/chemistry, Tacrine/chemistry, Inhibitory Concentration 50, Drug Evaluation, Preclinical, Dimerization, Amyloid beta-Peptides/metabolism, Molecular Dynamics Simulation, DNA/chemistry, Alzheimer Disease/drug therapy, Protein Binding, Ligands, Molecular Docking Simulation, Blood-Brain Barrier, Alzheimer&apos, s disease",
author = "Slavka Hamulakova and Zuzana Kudlickova and Ladislav Janovec and Roman Mezencev and Deckner, {Zachery J.} and Chernoff, {Yury O.} and Jana Janockova and Veronika Ihnatova and Petr Bzonek and Nikola Novakova and Vendula Hepnarova and Martina Hrabinova and Daniel Jun and Jan Korabecny and Ondrej Soukup and Kamil Kuca",
note = "Funding Information: This work was supported by the Czech Health Research Council (NU20-08-00296), Ministry of Education, Youth and Sports of Czech Republic (project ERDF: CZ.02.1.01/0.0/0.0/18 069/0010054), {\textquoteleft}Long-term organization development plan of the Faculty of Military Health Sciences, University of Defense{\textquoteright}, grant from the Slovak Academy of Sciences Grant Agency (1/0016/18), and by the sub-award from Emory University on the grant from National Institutes of Health (P50AG025688). YO Chernoff was also supported by Georgia Institute of Technology and St. Petersburg State University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.",
year = "2021",
month = may,
day = "1",
doi = "10.4155/fmc-2020-0184",
language = "English",
volume = "13",
pages = "785--804",
journal = "Future Medicinal Chemistry",
issn = "1756-8919",
publisher = "Future Science",
number = "9",

}

RIS

TY - JOUR

T1 - Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease

AU - Hamulakova, Slavka

AU - Kudlickova, Zuzana

AU - Janovec, Ladislav

AU - Mezencev, Roman

AU - Deckner, Zachery J.

AU - Chernoff, Yury O.

AU - Janockova, Jana

AU - Ihnatova, Veronika

AU - Bzonek, Petr

AU - Novakova, Nikola

AU - Hepnarova, Vendula

AU - Hrabinova, Martina

AU - Jun, Daniel

AU - Korabecny, Jan

AU - Soukup, Ondrej

AU - Kuca, Kamil

N1 - Funding Information: This work was supported by the Czech Health Research Council (NU20-08-00296), Ministry of Education, Youth and Sports of Czech Republic (project ERDF: CZ.02.1.01/0.0/0.0/18 069/0010054), ‘Long-term organization development plan of the Faculty of Military Health Sciences, University of Defense’, grant from the Slovak Academy of Sciences Grant Agency (1/0016/18), and by the sub-award from Emory University on the grant from National Institutes of Health (P50AG025688). YO Chernoff was also supported by Georgia Institute of Technology and St. Petersburg State University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

PY - 2021/5/1

Y1 - 2021/5/1

N2 - The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood-brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.

AB - The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood-brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.

KW - 7-methoxytacrine

KW - Alzheimer's disease

KW - cholinesterases

KW - in vitro

KW - indole

KW - tacrine

KW - Acetylcholinesterase/metabolism

KW - Humans

KW - Indoles/chemistry

KW - Neuroprotective Agents/chemistry

KW - Structure-Activity Relationship

KW - Molecular Targeted Therapy

KW - Cholinesterase Inhibitors/chemistry

KW - Tacrine/chemistry

KW - Inhibitory Concentration 50

KW - Drug Evaluation, Preclinical

KW - Dimerization

KW - Amyloid beta-Peptides/metabolism

KW - Molecular Dynamics Simulation

KW - DNA/chemistry

KW - Alzheimer Disease/drug therapy

KW - Protein Binding

KW - Ligands

KW - Molecular Docking Simulation

KW - Blood-Brain Barrier

KW - Alzheimer&apos

KW - s disease

UR - http://www.scopus.com/inward/record.url?scp=85105221156&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/a0744a71-3000-3cde-b6a0-f70de62711bd/

U2 - 10.4155/fmc-2020-0184

DO - 10.4155/fmc-2020-0184

M3 - Article

C2 - 33829876

AN - SCOPUS:85105221156

VL - 13

SP - 785

EP - 804

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

SN - 1756-8919

IS - 9

ER -

ID: 77118348