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Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors
Author(s) -
Vojacek Steffen,
Schulig Lukas,
Wössner Nathalie,
Geist Norman,
Langel Walter,
Jung Manfred,
Schade Dennis,
Link Andreas
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900054
Subject(s) - chemical space , indole test , drug discovery , sirtuin , combinatorial chemistry , chemistry , lead compound , enzyme , stereochemistry , sirt2 , chemical library , small molecule , biochemistry , in vitro , nad+ kinase
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 sp 3 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‐1 H ‐indole‐3‐carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC 50 value of 0.98 μ m and could serve as exquisite starting point for hit‐to‐lead profiling.