{rfName}
Co

Indexed in

Citations

13

Altmetrics

Analysis of institutional authors

Rodriguez Fernandez, Maria MercedesAuthor

Share

September 29, 2024
Publications
>
Early Access
No

Contilisant plus tubastatin a hybrids: polyfunctionalized indole derivatives as new HDAC inhibitor-based multitarget small molecules with in vitro and in vivo activity in neurodegenerative diseases

Publicated to: Journal Of Medicinal Chemistry. 67 (18): 16533-16555 - 2024-09-10 67(18), DOI: 10.1021/acs.jmedchem.4c01367

Authors:

Toledano-Pinedo M; …; Rodríguez-Fernández, M.M.; …;
[+]

Affiliations

Basque Fdn Sci, Ikerbasque, Bilbao 48009, Spain - Author
Biodonostia Hlth Res Inst, Cellular Oncol Grp, San Sebastian 20014, Spain - Author
Carlos III Inst, CIBERfes, Madrid 28029, Spain - Author
Inst Gen Organ Chem CSIC, Madrid 28006, Spain - Author
Inst Invest Sanitaria Castilla La Mancha IDISCAM, Grp DISCOBAC, Madrid 28805, Spain - Author
Inst Salud Carlos III, Spanish Biomed Res Ctr Neurodegenerat Dis CIBERNE, Madrid 28029, Spain - Author
Jagiellonian Univ Med Coll, Dept Technol & Biotechnol Drugs, PL-30688 Krakow, Poland - Author
Jagiellonian Univ Med Coll, Fac Pharm, Dept Pharmacobiol, PL-30688 Krakow, Poland - Author
Jagiellonian Univ Med Coll, Fac Pharm, Dept Physicochem Drug Anal, PL-30688 Krakow, Poland - Author
Polish Acad Sci, Maj Inst Pharmacol, PL-31343 Krakow, Poland - Author
Taras Shevchenko Natl Univ Kyiv, Chem Dept, UA-01033 Kiev, Ukraine - Author
United Arab Emirates Univ, Coll Sci, Dept Chem, Al Ain 15551, U Arab Emirates - Author
Univ Alcala, Dept Quim Organ & Quim Inorgan, Inst Invest Quim Andres M del Rio IQAR, Madrid 28805, Spain - Author
Univ Autonoma Barcelona, Dept Pharmacol Therapeut & Toxicol, E-08193 Barcelona, Spain - Author
Univ Autonoma Madrid, Dept Organ Chem, Madrid 28049, Spain - Author
Univ Barcelona NeuroUB, Inst Neurociencies, Barcelona 08035, Spain - Author
Univ Barcelona NeuroUB, Inst Neurosci, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem,Pharmacol, Barcelona 08028, Spain - Author
Univ Bonn, Pharmaceut Inst, D-53121 Bonn, Germany - Author
Univ Europea Valencia, Fac Ciencias Salud, Dept Fisioterapia, Valencia 46010, Spain - Author
Univ Jaume 1, Inst Adv Mat, INAM, Castellon de La Plana 12071, Spain - Author
Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia - Author
Univ Valencia, Fac CC Biol, Dept Genet, Burjassot 46100, Spain - Author
Univ Valencia, Inst Univ Biotecnol & Biomed BIOTECMED, Burjassot 46100, Spain - Author
See more

Abstract

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC50 = 0.012 mu M and 0.035 mu M, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.
[+]

Keywords

Combining cholinesteraseDesigDirected ligandsDrosophila dj-1 mutantsOxidative stressPhosphorylation

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Medicinal Chemistry due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 7/72, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Medicinal. Notably, the journal is positioned above the 90th percentile.

[+]

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-01-01:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 21.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 17 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 4.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).
[+]

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; Poland; Slovenia; Ukraine; United Arab Emirates.

[+]

Awards linked to the item

J.M.-C. thanks AEI (Government of Spain; Grant PID2019-105813RB-C21) and UCJC [Grant: "In vivo analysis of new analogues of Contilisant (MITOPI) (2022)"] for support. This work is part of the MINA-CM program (number S2022/BMD-7236) funded by the call for the implementation of programs of R&D activities between research groups of the Community of Madrid in Biomedicine 2022 (Order 1171/2022). M.T.-P. thanks MINA-CM program (number S2022/BMD-7236) for a contract. M.M.R.-F. and A.P.-P. thank Comunidad de Madrid for an "Investigo" Contract (2022-23). I.I. thanks AEI (Government of Spain; Grant PID2019-105813RB-C22) for support. A.S. thanks the UAEU for financial support by Strategic Research Program-Zayed Center for Health Sciences (Grant # G00003680) and by the SURE PLUS (grant #: G00003976) (2022). C.G.-F. thanks AEI (MINECO-FEDER, Government of Spain; Grant PID2022-139016OA-I00), Generalitat de Catalunya (Grant 2021 SGR 00357), and AGAUR (Grant 2023Llavor005). A.B.-S. acknowledges the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) for her FI-SDUR fellowship (2021FISDU 00182). Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). D.K. and S.G. thank the Slovenian Research and Innovation Agency (Research Core Funding grant P1-0208, and project J1-3018) for financial support. L.S.-H. wants to gratefully acknowledge experimental support by Philipp Stegen. LSH and FKH acknowledge partial funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-GRK2873 (494832089).
[+]