biostudies-literatureHamulakova SIT4NeurNIA NIH HHSDually Acting Cognitive Enhancers for Palliative Treatment of Alzheimer's DiseaseLong-term organization development plan of the Faculty of Military Health Sciences, University of DefenceŠtúdium cytotoxickej altivity nových kumarínových derivátov modifikovaných akridínovým, takrínovým a antracénovým skeletom785-804https://www.ebi.ac.uk/biostudies/studies/S-EPMC8488533biostudies-literatureUnknown13(9)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 <b>3c</b> and <b>4d</b> (IC<sub>50</sub> = 25 and 39 nM, respectively). Compound <b>3c</b> displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound <b>4d</b> (selectivity index: IC<sub>50</sub> [butyrylcholinesterase]/IC<sub>50</sub> [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound <b>3c</b> inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds <b>3c</b> and <b>4d</b> displayed a high probability of crossing the blood-brain barrier. The results support the potential of <b>3c</b> for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.Future medicinal chemistryDesign and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease.PMC8488533P50 AG025688Grant 1/0016/18NU20-08-00296ERDF no.CZ.02.1.01/0.0/0.0/18069/0010054Bzonek PKorabecny JMezencev RJanockova JHrabinova MKuca KSoukup OJun DIhnatova VHepnarova VNovakova NHamulakova SJanovec LDeckner ZJChernoff YOKudlickova ZfalseDesign and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease.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 <b>3c</b> and <b>4d</b> (IC<sub>50</sub> = 25 and 39 nM, respectively). Compound <b>3c</b> displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound <b>4d</b> (selectivity index: IC<sub>50</sub> [butyrylcholinesterase]/IC<sub>50</sub> [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound <b>3c</b> inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds <b>3c</b> and <b>4d</b> displayed a high probability of crossing the blood-brain barrier. The results support the potential of <b>3c</b> for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.2021-01-01T00:00:00Z2021 May2026-05-31T18:47:15.123Z2025-04-05T22:17:35.27ZS-EPMC84885333382987610.4155/fmc-2020-0184