Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases
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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.
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 , Marco-Contelles , J & Stark , H 2017 , ' Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H 3 R antagonism for neurodegenerative diseases ' , Angewandte Chemie International Edition , vol. 56 , no. 41 , 201706072R2 , pp. 12765–12769 . https://doi.org/10.1002/anie.201706072
Angewandte Chemie International Edition
© 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
DescriptionJ.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).
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