Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT6R ligands with noticeable action on AChE/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease
Eur J Med Chem. 2023 Nov 5;259:115695. doi: 10.1016/j.ejmech.2023.115695.
Kinga Czarnota-Łydka 1, Sylwia Sudoł-Tałaj 2, Katarzyna Kucwaj-Brysz 3, Rafał Kurczab 4, Grzegorz Satała 5, Modesto de Candia 6, Francesco Samarelli 7, Cosimo Damiano Altomare 8, Alessia Carocci 9, Alexia Barbarossa 10, Ewa Żesławska 11, Monika Głuch-Lutwin 12, Barbara Mordyl 13, Monika Kubacka 14, Natalia Wilczyńska-Zawal 15, Magdalena Jastrzębska-Więsek 16, Anna Partyka 17, Nadia Khan 18, Małgorzata Więcek 19, Wojciech Nitek 20, Ewelina Honkisz-Orzechowska 21, Gniewomir Latacz 22, Anna Wesołowska 23, Antonio Carrieri 24, Jadwiga Handzlik 25
Affiliations
Affiliations
1 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 15, 31-530, Krakow, Poland. Electronic address: kinga.czarnota@doctoral.uj.edu.pl.
2 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 15, 31-530, Krakow, Poland. Electronic address: s.sudol@doctoral.uj.edu.pl.
3 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: katarzyna.kucwaj@uj.edu.pl.
4 Maj Institute of Pharmacology Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL 31-343, Krakow, Poland. Electronic address: kurczab@if-pan.krakow.pl.
5 Maj Institute of Pharmacology Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL 31-343, Krakow, Poland. Electronic address: satala@if-pan.krakow.pl.
6 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: modesto.decandia@uniba.it.
7 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: francesco.samarelli@uniba.it.
8 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: cosimodamiano.altomare@uniba.it.
9 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: alessia.carocci@uniba.it.
10 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: alexia.barbarossa@uniba.it.
11 Pedagogical University of Krakow, Institute of Biology and Earth Sciences, Podchorążych 2, PL 30-084, Krakow, Poland. Electronic address: ewa.zeslawska@up.krakow.pl.
12 Department of Pharmacobiology, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: monika.gluch-lutwin@uj.edu.pl.
13 Department of Pharmacobiology, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: barbara.mordyl@uj.edu.pl.
14 Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: monika.kubacka@uj.edu.pl.
15 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Cracow, Poland. Electronic address: natalia.wilczynska@uj.edu.pl.
16 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Cracow, Poland. Electronic address: m.jastrzebska-wiesek@uj.edu.pl.
17 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Cracow, Poland. Electronic address: annairena.partyka@uj.edu.pl.
18 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 15, 31-530, Krakow, Poland; Department of Pathophysiology, Jagiellonian University, Medical College, Czysta 18, PL 30-688, Krakow, Poland. Electronic address: nadia.khan@doctoral.uj.edu.pl.
19 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: malgorzata.wiecek@uj.edu.pl.
21 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: ewelina.honkisz@uj.edu.pl.
22 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: gniewomir.latacz@uj.edu.pl.
23 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Cracow, Poland. Electronic address: a.wesolowska@uj.edu.pl.
24 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: antonio.carrieri@uniba.it.
25 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland. Electronic address: j.handzlik@uj.edu.pl.
Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.
