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Synthesis 2022; 54(19): 4304-4319
DOI: 10.1055/s-0041-1737343
special topic
SYNTHESIS Conference Special Topic ISySyCat21

Survey of New, Small-Molecule Isatin-Based Oxindole Hybrids as Multi-Targeted Drugs for the Treatment of Alzheimer’s Disease

Carolina S. Marques  ∗
a   LAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000 Évora, Portugal
,
Óscar López
b   Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, 41071 Seville, Spain
,
Luisa Leitzbach 
c   Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany
,
José G. Fernández-Bolaños
b   Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, 41071 Seville, Spain
,
Holger Stark 
c   Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany
,
Anthony J. Burke 
a   LAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000 Évora, Portugal
d   Chemistry Department, School of Science and Technology, University of Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal
e   Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
› Author AffiliationsThis work received financial support from PT national funds from Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES; UIDB/50006/2020 | UIDP/50006/2020). C.S.M. thanks the Norma transitória for funding through program DL 57/2016 (project UIDB/50006/2020 | UIDP/50006/2020). O.L. and J.G.F.B. also thank Ministerio de Ciencia e Innovación / Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033; Grant PID2020-116460RB-I00), and Junta de Andalucía (FQM-134).
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Abstract

In the last decade, our group has been very active at developing and assaying complex libraries of scaffolds with a focus on their potential to identify bioactive drug candidates for neurodegenerative diseases, particularly Alzheimer’s disease (AD). Attention has been focused on isatin-based oxindole scaffolds, for which promising results concerning butyrylcholinesterase (BuChE) inhibitory activity have previously been obtained. Considering some published reports and detailed analysis of the pharmacophores of commercially available drugs for AD (powerful cholinesterase (ChE) inhibitors), we performed a strategic structural modification of the isatin core and generated a new family of isatin-based oxindole hybrids (27 new compounds) possessing crucial key functional units in their framework. The syntheses were accomplished using multiple approaches, including simple N-alkylation reactions, copper-catalyzed amination reactions, and click chemistry. The resulting library was evaluated on ChE and MAO enzymes, both of which are involved in the pathophysiology of neurodegeneration. IC50 values of 1.6 and 2.6 μM (BuChE assays), were achieved for the best inhibitors.

Key words

isatin-oxindole - hybrids - Alzheimer’s disease (AD) - inhibition - cholinesterase (ChE) - monoamine oxidase (MAO)

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1737343.
  • Supporting Information


Publication History

Received: 30 November 2021

Accepted after revision: 04 January 2022

Article published online:
16 February 2022

© 2022. Thieme. All rights reserved

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