Indoles and Indole Isosteres

By: Mark Redlich, Chemfiles Volume 11 Article 1

Mark Redlich
Product Manager
mark.redlich@sial.com

Substituted indoles have frequently been referred to as “privileged structures” since they are capable of binding to multiple receptors with high affinity, and thus have applications across a wide range of therapeutic areas.1However, recent publications often demonstrate the need for a researcher to attenuate or amplify the activity of their target compound without altering the steric bulk of the structure; thus, isosteres of the indole ring have proven very valuable to synthetic and medicinal chemists.

The azaindole and indazole moieties differ only by the addition of an extra ring nitrogen, and thus exhibit excellent potential as bioisosteres of the indole ring system. Although more rare in nature, interest in these structures has surged over the past decade and they comprise essential subunits in many pharmaceutically relevant compounds.2,3 Indazoles have been widely reported to display significant activity as antifungals, anti-inflammatory agents, antiarrhythmic agents, analgesics, and nitric oxide synthase inhibitors.2a Of the various azaindoles, 7-azaindoles are of particular interest because of their ability to mimic purines in their roles as hydrogen-bonding partners. Similarly, imidazopyridines have proven effective as purine mimics in several recent studies.4

When two ring nitrogens are added to the indole subunit, it results in 7-deazapurines, an important class of compounds found in a wide variety of biological niches. Various ribonucleosides containing 7-deazapurines demonstrate a broad spectrum of biological activity, even at nanomolar concentrations.5

Aldrich is pleased to offer a wide variety of these useful building blocks for your research.

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Materials

     

References

  1. Horton, D. A. et al. Chem. Rev. 2003, 103, 893 and references therein.
  2. Recent reviews of indazoles: a) Schmidt, A. et al. Eur. J. Org. Chem. 2008, 4073. (b) Cerecetto, H. et al. Mini-Rev. Med. Chem. 2005, 5, 869. (c) Stadlbauer, W.; Camp, N. In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations; Bellus, D., Ley, S. V., Noyori, R., Regitz, M., Schaumann, E., Shinkai, E., Thomas, E. J., Trost, B. M., Reider, P. J., Eds.; Thieme: Stuttgart, Germany, 2002; Vol. 12, p 227.
  3. Recent reviews of azaindoles: (a) Popowycz, F. et al. Tetrahedron 2007, 63, 1031. (b) Popowycz, F. et al. Tetrahedron 2007, 63, 8689. (c) Song, J. J. et al. Chem. Soc. Rev. 2007, 36, 1120.
  4. Huang, W.-S. et al. J. Med. Chem. 2010, 53, 4701. (b) Buckley, G. M. et al. Bioorg. Med. Chem. Lett. 2008, 18, 3656. (c) Buckley, G. M. et al. Bioorg. Med. Chem. Lett. 2008, 18, 3291.
  5. (a) Suhadolnik, R. J. Pyrrolopyrimidine Nucleosides in Nucleoside Antibiotics; Wiley-Interscience: New York, 1970; 298 and references therein. (b) Kasai, H. et al. Biochemistry 1975, 14, 4198. (c) Nauš, P. et al. J. Med. Chem. 2010, 53, 460.

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