Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases

Óscar M. Bautista-Aguilera; Stefanie Hagenow; Alejandra Palomino-Antolin; Víctor Farré-Alins; Lhassane Ismaili; Pierre-Louis Joffrin; María L. Jimeno; Ondřej Soukup; Jana Janočková; Lena Kalinowsky; Ewgenij Proschak; Isabel Iriepa; Ignacio Moraleda; Johannes S. Schwed; Alejandro Romero Martínez; Francisco López-Muñoz; Mourad Chioua; Javier Egea; Rona R. Ramsay; José Marco-Contelles; Holger Stark

doi:10.1002/anie.201706072

Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H₃R antagonism for neurodegenerative diseases

Óscar M. Bautista-Aguilera
, Stefanie Hagenow
, Alejandra Palomino-Antolin
, Víctor Farré-Alins
, Lhassane Ismaili
, Pierre-Louis Joffrin
, María L. Jimeno
, Ondřej Soukup
, Jana Janočková
, Lena Kalinowsky
, Ewgenij Proschak
, Isabel Iriepa
, Ignacio Moraleda
, Johannes S. Schwed
, Alejandro Romero Martínez
, Francisco López-Muñoz
, Mourad Chioua
, Javier Egea
, Rona R. Ramsay
, José Marco-Contelles

Holger Stark

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

Abstract

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg⁻¹ i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Original language	English
Article number	201706072R2
Pages (from-to)	12765–12769
Number of pages	5
Journal	Angewandte Chemie International Edition
Volume	56
Issue number	41
Early online date	1 Sept 2017
DOIs	https://doi.org/10.1002/anie.201706072
Publication status	Published - 27 Sept 2017

Keywords

Antioxidants
Drug design
Inhibitors
Multitarget drugs
Neurological agents

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10.1002/anie.201706072

Ramsay_2017_AngewChemie_Multi-target_AAM
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This work has been made available online in accordance with the publisher’s policies. This is the author created accepted version manuscript following peer review and as such may differ slightly from the final published version. The final published version of this work is available at: https://doi.org/10.1002/anie.201706072
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Bautista-Aguilera, Ó. M., Hagenow, S., Palomino-Antolin, A., Farré-Alins, V., Ismaili, L., Joffrin, P.-L., Jimeno, M. L., Soukup, O., Janočková, J., Kalinowsky, L., Proschak, E., Iriepa, I., Moraleda, I., Schwed, J. S., Romero Martínez, A., López-Muñoz, F., Chioua, M., Egea, J., Ramsay, R. R., ... Stark, H. (2017). Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H₃R antagonism for neurodegenerative diseases. Angewandte Chemie International Edition, 56(41), 12765–12769 . Article 201706072R2. https://doi.org/10.1002/anie.201706072

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title = "Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases",

abstract = "The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood{\textendash}brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.",

keywords = "Antioxidants, Drug design, Inhibitors, Multitarget drugs, Neurological agents",

author = "Bautista-Aguilera, \{{\'O}scar M.\} and Stefanie Hagenow and Alejandra Palomino-Antolin and V{\'i}ctor Farr{\'e}-Alins and Lhassane Ismaili and Pierre-Louis Joffrin and Jimeno, \{Mar{\'i}a L.\} and Ond{\v r}ej Soukup and Jana Jano{\v c}kov{\'a} and Lena Kalinowsky and Ewgenij Proschak and Isabel Iriepa and Ignacio Moraleda and Schwed, \{Johannes S.\} and Alejandro Romero Mart{\'i}nez and Francisco L{\'o}pez-Mu{\~n}oz and Mourad Chioua and Javier Egea and Ramsay, \{Rona R.\} and Jos{\'e} Marco-Contelles and Holger Stark",

note = "J.M.C. thanks MINECO (SAF2012-33304 and SAF2015-65586-R). J.M.C., F.L.M., and A.R. thank UCJC for grants 2015-12, 2014-35, and 2015-21, respectively. J.E. thanks the Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet: CP14/00008 and PI16/00735) and Fundaci{\'o}n Mutua Madrile{\~n}a. O.S. and J.J. thank MHCZ-DRO (UHHK 00179906) for support. R.R.R., H.S., and J.M.C. acknowledge the EU COST Actions CM1103 and CM15135. E.P. and H.S. thank the German Research Foundation (DFG; PRO 1405/2-2, PRO 1405/4-1, SFB 1039 A07, and INST208/664-1).",

year = "2017",

month = sep,

day = "27",

doi = "10.1002/anie.201706072",

language = "English",

volume = "56",

pages = "12765{\textendash}12769 ",

journal = "Angewandte Chemie International Edition",

issn = "1433-7851",

publisher = "John Wiley \& Sons, Ltd",

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Bautista-Aguilera, ÓM, Hagenow, S, Palomino-Antolin, A, Farré-Alins, V, Ismaili, L, Joffrin, P-L, Jimeno, ML, Soukup, O, Janočková, J, Kalinowsky, L, Proschak, E, Iriepa, I, Moraleda, I, Schwed, JS, Romero Martínez, A, López-Muñoz, F, Chioua, M, Egea, J, Ramsay, RR, Marco-Contelles, J & Stark, H 2017, 'Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H₃R antagonism for neurodegenerative diseases', Angewandte Chemie International Edition, vol. 56, no. 41, 201706072R2, pp. 12765–12769 . https://doi.org/10.1002/anie.201706072

Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H₃R antagonism for neurodegenerative diseases. / Bautista-Aguilera, Óscar M.; Hagenow, Stefanie; Palomino-Antolin, Alejandra et al.
In: Angewandte Chemie International Edition, Vol. 56, No. 41, 201706072R2, 27.09.2017, p. 12765–12769 .

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

TY - JOUR

T1 - Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases

AU - Bautista-Aguilera, Óscar M.

AU - Hagenow, Stefanie

AU - Palomino-Antolin, Alejandra

AU - Farré-Alins, Víctor

AU - Ismaili, Lhassane

AU - Joffrin, Pierre-Louis

AU - Jimeno, María L.

AU - Soukup, Ondřej

AU - Janočková, Jana

AU - Kalinowsky, Lena

AU - Proschak, Ewgenij

AU - Iriepa, Isabel

AU - Moraleda, Ignacio

AU - Schwed, Johannes S.

AU - Romero Martínez, Alejandro

AU - López-Muñoz, Francisco

AU - Chioua, Mourad

AU - Egea, Javier

AU - Ramsay, Rona R.

AU - Marco-Contelles, José

AU - Stark, Holger

N1 - J.M.C. thanks MINECO (SAF2012-33304 and SAF2015-65586-R). J.M.C., F.L.M., and A.R. thank UCJC for grants 2015-12, 2014-35, and 2015-21, respectively. J.E. thanks the Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet: CP14/00008 and PI16/00735) and Fundación Mutua Madrileña. O.S. and J.J. thank MHCZ-DRO (UHHK 00179906) for support. R.R.R., H.S., and J.M.C. acknowledge the EU COST Actions CM1103 and CM15135. E.P. and H.S. thank the German Research Foundation (DFG; PRO 1405/2-2, PRO 1405/4-1, SFB 1039 A07, and INST208/664-1).

PY - 2017/9/27

Y1 - 2017/9/27

N2 - The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

AB - The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

KW - Antioxidants

KW - Drug design

KW - Inhibitors

KW - Multitarget drugs

KW - Neurological agents

U2 - 10.1002/anie.201706072

DO - 10.1002/anie.201706072

M3 - Article

SN - 1433-7851

VL - 56

SP - 12765

EP - 12769

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 41

M1 - 201706072R2

ER -

Bautista-Aguilera ÓM, Hagenow S, Palomino-Antolin A, Farré-Alins V, Ismaili L, Joffrin PL et al. Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H₃R antagonism for neurodegenerative diseases. Angewandte Chemie International Edition. 2017 Sept 27;56(41):12765–12769 . 201706072R2. Epub 2017 Sept 1. doi: 10.1002/anie.201706072