Benzophenone Derivatives with Histamine H3 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

doi:10.3390/molecules28010238

Benzophenone Derivatives with Histamine H₃ 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

5 Citations (Scopus)

Abstract

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 (K_i = 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 (P_e) 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.

Original language	English
Article number	238
Journal	Molecules
Volume	28
Issue number	1
ISSN	1420-3049
DOIs	https://doi.org/10.3390/molecules28010238
Publication status	Published - 2023
Externally published	Yes

Bibliographical note

Funding Information:
This research was funded by the National Science Centre, Poland grant: No UMO-2016/23/B/NZ7/02327 (D.Ł.) (synthesis; H3R, ChE and MAO B in vitro studies; molecular modeling; in vivo studies) and Jagiellonian University Medical College in Kraków, grant no. N42/DBS/000300 (PAMPA assay, metabolic study).

Publisher Copyright:
© 2022 by the authors.

Keywords

Alzheimer’s disease
benzophenone derivatives
cholinesterase inhibitors
histamine H receptor ligands
multitarget-directed ligands

Access to Document

10.3390/molecules28010238

Cite this

Godyń, J., Zaręba, P., Stary, D., Kaleta, M., Kuder, K. J., Latacz, G., Mogilski, S., Reiner-Link, D., Frank, A., Doroz-Płonka, A., Olejarz-Maciej, A., Sudoł-Tałaj, S., Nolte, T., Handzlik, J., Stark, H., Więckowska, A., Malawska, B., Kieć-Kononowicz, K., Łażewska, D., & Bajda, M. (2023). Benzophenone Derivatives with Histamine H₃ Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer’s Disease. Molecules, 28(1), [238]. https://doi.org/10.3390/molecules28010238

Benzophenone Derivatives with Histamine H₃ Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer’s Disease. / Godyń, Justyna; Zaręba, Paula; Stary, Dorota; Kaleta, Maria; Kuder, Kamil J.; Latacz, Gniewomir; Mogilski, Szczepan; Reiner-Link, David; Frank, Annika; Doroz-Płonka, Agata; Olejarz-Maciej, Agnieszka; Sudoł-Tałaj, Sylwia; Nolte, Tobias; Handzlik, Jadwiga; Stark, Holger; Więckowska, Anna; Malawska, Barbara; Kieć-Kononowicz, Katarzyna; Łażewska, Dorota; Bajda, Marek.

In: Molecules, Vol. 28, No. 1, 238, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Godyń, J, Zaręba, P, Stary, D, Kaleta, M, Kuder, KJ, Latacz, G, Mogilski, S, Reiner-Link, D, Frank, A, Doroz-Płonka, A, Olejarz-Maciej, A, Sudoł-Tałaj, S, Nolte, T, Handzlik, J, Stark, H, Więckowska, A, Malawska, B, Kieć-Kononowicz, K, Łażewska, D & Bajda, M 2023, 'Benzophenone Derivatives with Histamine H₃ Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer’s Disease', Molecules, vol. 28, no. 1, 238. https://doi.org/10.3390/molecules28010238

Godyń, Justyna ; Zaręba, Paula ; Stary, Dorota ; Kaleta, Maria ; Kuder, Kamil J. ; Latacz, Gniewomir ; Mogilski, Szczepan ; Reiner-Link, David ; Frank, Annika ; Doroz-Płonka, Agata ; Olejarz-Maciej, Agnieszka ; Sudoł-Tałaj, Sylwia ; Nolte, Tobias ; Handzlik, Jadwiga ; Stark, Holger ; Więckowska, Anna ; Malawska, Barbara ; Kieć-Kononowicz, Katarzyna ; Łażewska, Dorota ; Bajda, Marek. / Benzophenone Derivatives with Histamine H₃ Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer’s Disease. In: Molecules. 2023 ; Vol. 28, No. 1.

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title = "Benzophenone Derivatives with Histamine H3 Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer{\textquoteright}s Disease",

abstract = "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{\textquoteright}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.",

keywords = "Alzheimer{\textquoteright}s disease, benzophenone derivatives, cholinesterase inhibitors, histamine H receptor ligands, multitarget-directed ligands",

author = "Justyna Gody{\'n} and Paula Zar{\c e}ba and Dorota Stary and Maria Kaleta and Kuder, {Kamil J.} and Gniewomir Latacz and Szczepan Mogilski and David Reiner-Link and Annika Frank and Agata Doroz-P{\l}onka and Agnieszka Olejarz-Maciej and Sylwia Sudo{\l}-Ta{\l}aj and Tobias Nolte and Jadwiga Handzlik and Holger Stark and Anna Wi{\c e}ckowska and Barbara Malawska and Katarzyna Kie{\'c}-Kononowicz and Dorota {\L}a{\.z}ewska and Marek Bajda",

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AU - Godyń, Justyna

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AU - Stary, Dorota

AU - Kaleta, Maria

AU - Kuder, Kamil J.

AU - Latacz, Gniewomir

AU - Mogilski, Szczepan

AU - Reiner-Link, David

AU - Frank, Annika

AU - Doroz-Płonka, Agata

AU - Olejarz-Maciej, Agnieszka

AU - Sudoł-Tałaj, Sylwia

AU - Nolte, Tobias

AU - Handzlik, Jadwiga

AU - Stark, Holger

AU - Więckowska, Anna

AU - Malawska, Barbara

AU - Kieć-Kononowicz, Katarzyna

AU - Łażewska, Dorota

AU - Bajda, Marek

N1 - Funding Information: This research was funded by the National Science Centre, Poland grant: No UMO-2016/23/B/NZ7/02327 (D.Ł.) (synthesis; H3R, ChE and MAO B in vitro studies; molecular modeling; in vivo studies) and Jagiellonian University Medical College in Kraków, grant no. N42/DBS/000300 (PAMPA assay, metabolic study). Publisher Copyright: © 2022 by the authors.

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N2 - 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.

AB - 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.

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DO - 10.3390/molecules28010238

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JO - Molecules

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