| Affiliation: | 1. Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Strasse 17, 17489 Greifswald, Germany
These authors contributed equally to this work.;2. Institute of Pharmaceutical Sciences, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany;3. Institute of Biochemistry, University of Greifswald, Felix-Hausdorff-Strasse 4, 17487 Greifswald, Germany;4. Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian Albrechts University of Kiel, 24118 Kiel, Germany;5. Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Strasse 17, 17489 Greifswald, Germany |
| 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 and could serve as exquisite starting point for hit-to-lead profiling. |
