Chemfiles Volume 5 Article 2

Privileged Structures: Biaryls

Sigma-Aldrich is proud to offer the second installment of our Privileged Structures ChemFiles. This piece will highlight the biaryl scaffold. We will focus on application data and the biaryl products that Sigma-Aldrich offers.

Privileged structures are a class of molecules that are capable of binding to multiple receptors with high affinity. In order to be considered privileged, a substructure should represent a molecule’s core element and make up a significant portion of its total mass.

The biaryl scaffold has received increased attention as a privileged structure by the pharmaceutical industry. This motif has shown activity across a wide range of therapeutic classes, which include antifungal, anti-inflammatory, antirheumatic, antitumor, and antihypertensive agents.1 It also has shown the potential to treat infertility as a follicle-stimulating hormone (FSH) receptor agonist.2

Antiarthritic Non-steroidal Anti-inflammatory Drug3

Antihypertensive Drug4

When drugs that contain the biaryl moiety attach to proteins, they are dominated by interactions with aromatic and hydrophobic residues. Furthermore, it has been shown that the biaryls interact favorably with polar groups such as amides and hydroxyl groups. They have also combined with positively charged moieties. Since the biaryl is able to interact with these numerous binding sites, it is prevalent in pharmaceuticals.5

Recent literature has highlighted the use of the biaryl scaffold as a selective Histamine H3 receptor antagonist. The H3 receptors are presynaptic receptors and are mainly found in the central nervous system. These receptors control the production and release of histamine. Because the majority of the receptors are located in the central nervous system, it has been proposed that controlling this receptor could be a drug development target for neurological disorders such as Alzheimer’s disease, Parkinson's disease, and epilepsy.6

Histamine H3 Receptor Antagonist

Besides their potential use as an H3 receptor antagonists, biaryls have exhibited antibacterial activity against Gram-positive bacteria.7 Look et al. showed that the active members of two 1000-member libraries of biaryl acids and amides displayed antimicrobial activity in the low micromolecular range.

Heterocyclic biaryls have also exhibited biological activity. They have been shown to be useful as antibacterial agents by inhibiting Gram-positive and Gram-negative bacteria8 and as an anti-inflammatory. 2-Amino-4-(p-arylthio)phenylthiazoles have shown to be potential antagonists of LFA-1/ICAM-1 binding sites. Controlling LFA-1/ICAM-1 binding inhibits the over activation of leukocytes to a site where an injury or infection has occurred. The over activation may occur during a stroke or myocardial infarction and could lead to untoward tissue damage.9

Gram-positive and Gram-negative inhibitor

LFA-1/ICAM-1 antagonist

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  1. Horton et al. Chem. Rev. 2003, 103, 893–930.
  2. Guo et al. Bioorg. Med. Chem. Lett. 2004, 14, 1713–1716.
  3. American Cyanamid Co., US-3784701.
  4. Ciba-Geigy Corp., US-5399578.
  5. Hajduk et al. J. Med. Chem. 2000, 43, 3443–3447.
  6. Faghih et al. Bioorg. Med. Chem. Lett. 2003, 13, 1325–1328.
  7. Look et al. Bioorg. Med. Chem. Lett. 2004, 14, 1423–1426.
  8. Jefferson et al. Bioorg. Med. Chem. Lett. 2004, 14, 5257–5261.
  9. Wang et al. Bioorg. Med. Chem. Lett. 2005, 15, 195–201.

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