Benzophenone Derivatives with Histamine H<sub>3</sub> Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer’s Disease
Justyna Godyń,
Paula Zaręba,
Dorota Stary,
Maria Kaleta,
Kamil J. Kuder,
Gniewomir Latacz,
Szczepan Mogilski,
David Reiner-Link,
Annika Frank,
Agata Doroz-Płonka,
Agnieszka Olejarz-Maciej,
Sylwia Sudoł-Tałaj,
Tobias Nolte,
Jadwiga Handzlik,
Holger Stark,
Anna Więckowska,
Barbara Malawska,
Katarzyna Kieć-Kononowicz,
Dorota Łażewska,
Marek Bajda
Affiliations
Justyna Godyń
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Paula Zaręba
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Dorota Stary
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Maria Kaleta
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Kamil J. Kuder
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Gniewomir Latacz
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Szczepan Mogilski
Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
David Reiner-Link
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany
Annika Frank
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany
Agata Doroz-Płonka
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Agnieszka Olejarz-Maciej
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Sylwia Sudoł-Tałaj
Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 16 St., 31-530 Krakow, Poland
Tobias Nolte
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Jadwiga Handzlik
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Holger Stark
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany
Anna Więckowska
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Barbara Malawska
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Katarzyna Kieć-Kononowicz
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Dorota Łażewska
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
Marek Bajda
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland
The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer’s disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10−6 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.