Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

ChemMedChem
Steffen VojacekAndreas Link

Abstract

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp3 hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1-3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC50 value of 0.98 μm ...Continue Reading

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
May 1, 1957·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·G G GLENNER
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Aug 10, 2005·Methods : a Companion to Methods in Enzymology·Birgit HeltwegManfred Jung
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Mar 14, 2013·Expert Opinion on Drug Discovery·Felix Wilde, Andreas Link
Jan 7, 2015·Methods in Molecular Biology·Nicole J Yang, Marlon J Hinner
Nov 26, 2015·Angewandte Chemie·Yong-An YuanHao Xu
Oct 19, 2016·Journal of Labelled Compounds & Radiopharmaceuticals·Kai SunYi Xu
Jan 31, 2017·Journal of Medicinal Chemistry·Sandeep SundriyalMatthew J Fuchter
Apr 14, 2018·Nature Reviews. Drug Discovery·Christopher J Gerry, Stuart L Schreiber

❮ Previous
Next ❯

Citations

Jan 13, 2021·Angewandte Chemie·Ivan A AndreevIgor V Trushkov
Jul 26, 2021·European Journal of Medicinal Chemistry·Eslam RoshdyTaha F S Ali

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.