Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2

Manjula, R; Gokhale, Nikhila; Unni, Sruthi; Deshmukh, Prashant; Reddyrajula, Rajkumar; Bharath, M. M. Srinivas; Dalimba, Udayakumar; Padmanabhan, Balasundaram

doi:10.1016/j.bioorg.2019.103281

Cited by 12 publications

(9 citation statements)

References 52 publications

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“…However, severe neurotoxicity and other systemic side effects are severe disadvantages to its use in treatment (Peltier and Russell, 2002). The indole derivatives have been widely studied for the catalytic inhibition of SIRT1 protein (Huber et al, 2010;Manjula et al, 2019;Napper et al, 2007;Panathur et al, 2015;Zhao et al, 2016). In the study on the indole derivative, selisistat provided the NAD + inhibition mechanism of catalysis (Gertz et al, 2013).…”

Section: Name Of the Compound Structure Resolutionmentioning

confidence: 99%

“…Virtual screening, molecular docking and simulation studies have made a significant contribution to the discovery of novel sirtuin inhibitors (Padmanabhan et al, 2016;Eren et al, 2019). Based on previous studies, it is possible to design, synthesize and screen novel indole molecules that can potentially inhibit cofactor binding (Manjula et al, 2019). In recent years, scientists have made use of SirReal-based Proteolysis targeting chimaera (PROTAC) to inhibit SIRT2 (Schiedel et al, 2018).…”

Section: Name Of the Compound Structure Resolutionmentioning

confidence: 99%

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SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

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Section: Name Of the Compound Structure Resolutionmentioning

confidence: 99%

Section: Name Of the Compound Structure Resolutionmentioning

confidence: 99%

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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“…The structure of SIRT1 (5BTR) was downloaded from the RCSB PDB database. The structure of SIRT1 was composed of the N -terminal region and the histone deacetylases (HDACs) domain, which was utilized for docking studies according to the literature [ 64 ]. The active site, AD5, of the SIRT1 (A chain) protein was used for molecular docking.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a 4-Hydroxy-3′-Trifluoromethoxy-Substituted Resveratrol Derivative as an Anti-Aging Agent

Liang,

Chen,

Teng

et al. 2023

Molecules

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With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application in vivo. In this work, a 4-hydroxy-3′-trifluoromethoxy-substituted resveratrol derivative (4–6), owing to its superior cell accumulation, could inhibit NO production in an inflammatory cell model, inhibit oxidative cytotoxicity, and reduce ROS accumulation and the population of apoptotic cells in an oxidative stress cell model. In D-galactose (D-gal)-stimulated aging mice, 4–6 could reverse liver and kidney damage; protect the serum, brain, and liver against oxidative stress; and increase the body’s immunity in the spleen. Further D-gal-induced brain aging studies showed that 4–6 could improve the pathological changes in the hippocampus and the dysfunction of the cholinergic system. Moreover, protein expression related to aging, oxidative stress, and apoptosis in the brain tissue homogenate measured via Western blotting also showed that 4–6 could ameliorate brain aging by protecting against oxidative stress and reducing apoptosis. This work revealed that meta-trifluoromethoxy substituted 4–6 deserved to be further investigated as an effective anti-aging candidate drug.

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“…Successively, further efforts reported in the literature have allowed the discovery of a novel series of indole-based derivatives in association with an additional triazole moiety [104] that exhibit different selectivity profiles as SIRT1 and/or SIRT2Is. While four compounds have proven to be specific for SIRT1 inhibition, three were selective SIRT2Is and two were dual SIRT1 and SIRT2 inhibitors.…”

Section: Design Of Sirt2 Inhibitors Via Computational Approachesmentioning

confidence: 99%

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective

Scarano,

Brullo,

Musumeci

et al. 2024

Pharmaceuticals

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Sirtuins (SIRTs) are classified as class III histone deacetylases (HDACs), a family of enzymes that catalyze the removal of acetyl groups from the ε-N-acetyl lysine residues of histone proteins, thus counteracting the activity performed by histone acetyltransferares (HATs). Based on their involvement in different biological pathways, ranging from transcription to metabolism and genome stability, SIRT dysregulation was investigated in many diseases, such as cancer, neurodegenerative disorders, diabetes, and cardiovascular and autoimmune diseases. The elucidation of a consistent number of SIRT–ligand complexes helped to steer the identification of novel and more selective modulators. Due to the high diversity and quantity of the structural data thus far available, we reviewed some of the different ligands and structure-based methods that have recently been used to identify new promising SIRT1/2 modulators. The present review is structured into two sections: the first includes a comprehensive perspective of the successful computational approaches related to the discovery of SIRT1/2 inhibitors (SIRTIs); the second section deals with the most interesting SIRTIs that have recently appeared in the literature (from 2017). The data reported here are collected from different databases (SciFinder, Web of Science, Scopus, Google Scholar, and PubMed) using “SIRT”, “sirtuin”, and “sirtuin inhibitors” as keywords.

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Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2

Cited by 12 publications

References 52 publications

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

Discovery of a 4-Hydroxy-3′-Trifluoromethoxy-Substituted Resveratrol Derivative as an Anti-Aging Agent

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective

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