Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with In Vitro and In Vivo Activity in Neurodegenerative Diseases,Journal of Medicinal Chemistry

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Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with In Vitro and In Vivo Activity in Neurodegenerative Diseases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-10 , DOI: 10.1021/acs.jmedchem.4c01367
Mireia Toledano-Pinedo ₁ , Alicia Porro-Pérez ₁ , Linda Schäker-Hübner ₂ , Fernando Romero ₁ , Min Dong ₁ , Abdelouahid Samadi ₃ , Pedro Almendros ₁ , Isabel Iriepa _{4,

5} , Òscar M Bautista-Aguilera ₄ , M Mercedes Rodríguez-Fernández ₆ , Cristina Solana-Manrique _{7,

8,

9} , Inmaculada Sanchis _{7,

8} , Alba Mora-Morell _{7,

8} , Ania Canseco Rodrìguez ₁₀ , Ana M Sànchez-Pérez ₁₀ , Damijan Knez ₁₁ , Stanislav Gobec ₁₁ , Aina Bellver-Sanchis _{12,

13} , Belén Pérez ₁₄ , Alexey V Dobrydnev ₁₅ , Aizpea Artetxe-Zurutuza ₁₆ , Ander Matheu _{16,

17,

18} , Agata Siwek ₁₉ , Małgorzata Wolak ₁₉ , Grzegorz Satała ₂₀ , Andrzej J Bojarski ₂₀ , Agata Doroz-Płonka ₂₁ , Jadwiga Handzlik ₂₁ , Justyna Godyń ₂₂ , Anna Więckowska ₂₂ , Nuria Paricio _{7,

8} , Christian Griñán-Ferré _{12,

13,

23} , Finn K Hansen ₂ , José Marco-Contelles ₁

Affiliation

Institute of General Organic Chemistry (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Department of Chemistry, College of Science, United Arab Emirates University, Al Ain 15551, UAE.
Universidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR), 28805 Alcalá de Henares, Madrid, Spain.
Grupo DISCOBAC, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 28805 Alcalá de Henares, Madrid, Spain.
Department of Organic Chemistry, Universidad Autónoma de Madrid, Cantoblanco 28049 Madrid, Spain.
Departamento de Genética, Facultad CC Biológicas, Universidad de Valencia, 46100 Burjassot, Spain.
Instituto Universitario de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain.
Departamento de Fisioterapia, Facultad de Ciencias de la Salud, Universidad Europea de Valencia, 46010 Valencia, Spain.
Insitute of Advanced Materials, INAM, University of Jaume I, Castellón 12071, Spain.
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
Institut de Neurociències, Universitat de Barcelona (NeuroUB), 08035 Barcelona, Spain.
Department of Pharmacology, Therapeutic and Toxicology. Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain.
Chemistry Department, Taras Shevchenko National University of Kyiv, Lva Tolstoho Street 12, Kyiv 01033, Ukraine.
Cellular Oncology group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
CIBERfes, Carlos III Institute, 28029 Madrid, Spain.
IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain.
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, 9 Medyczna St., 30-688 Krakow, Poland.
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-Instituto de Salud Carlos III, 28029 Madrid, Spain.

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 μM and 0.035 μM, 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.

中文翻译：

Contilisant+Tubastatin A 杂交体：多功能吲哚衍生物作为基于 HDAC 抑制剂的新型多靶点小分子，在神经退行性疾病中具有体外和体内活性

在本文中，我们描述了 15 种 Contilisant + Tubastatin A 杂交体的设计、合成和生物学评价。这些配体是多官能化的吲哚衍生物，通过将 Contilisant 和 Tubastatin A 的选定药效团并置作为多功能配体而开发的。化合物 3 和 4 被鉴定为有效的 HDAC6 抑制剂（IC₅₀ = 0.012 μM 和 0.035 μM），因此在果蝇和帕金森病（PD）的人类细胞模型中进一步评估了它们。这两种化合物都减弱了 PD 模型果蝇的 PD 样表型，例如运动缺陷、氧化应激和线粒体功能障碍。配体 3 和 4 也在阿尔茨海默病（AD）的转基因秀丽隐杆线虫 CL2006 模型中进行了研究。两种化合物都是无毒的，不会诱导不良的动物功能变化，抑制与年龄相关的麻痹，并改善了 Thrashing 测定中的认知能力。这些结果突出了 3 和 4 作为新型多功能配体，可改善各自动物模型中 PD 和 AD 标志物的特征。

更新日期：2024-09-10

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