Aromatic Rings Building Blocks Commonly Used in Medicinal Chemistry

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Aromatic Rings in Marketed Drugs

In the past year, the FDA has approved several small molecule drugs, including Taiho Pharmaceutical's FGFR inhibitor Futibatinib for the treatment of locally advanced or metastatic bile duct cancer treated with FGFR2 gene rearrangement (including fusion). Bristol Myers Squibb's TYK2 allosteric inhibitor deucravacitinib for the treatment of adults with moderate to severe plaque psoriasis. Omidenepag isopropyl, an active component of selective prostaglandin EP2 receptor agonists jointly developed by Santen Pharmaceutical and UBE to reduce ocular pressure in patients with primary open-angle glaucoma or ocular hypertension. Dermavant Sciences' AhR agonist tapinarof for topical treatment of plaque psoriasis in adults (Fig. 1). All of these small molecules contain at least one aromatic ring skeleton, which proves to be an important and frequently used structure in drug development.

Fig. 1. FDA-approved small chemical molecules on the market containing aromatic ring structure in the past year.

The aromatic ring block (Arenes) contains a benzene ring. Its structure contains benzene, naphthalene, anthracene, phenanthrene, pyrene, and chrysene in one or more of the following. Benzene in aromatic rings is the most common ring structure in bioactive molecules and organic synthesis reactions. Aromatic ring blocks have extensive and important value in basic science research, chemical industrial synthesis, pharmaceutical pesticide synthesis, new material synthesis, and other fields.

Applications of Aromatic Rings in Drug Design

Fig. 2. An example of diversified aromatic ring blocks applied in drug design.

Varieties of molecular blocks may affect the diversity of developed small molecule drugs. Small molecules with better activity can be obtained by replacing the groups on the molecular blocks. Pleconaril is an effective drug for the treatment of enterovirus infection. It also has strong antiviral activity against RNA viruses that may cause different human diseases such as meningitis, encephalitis, fever, and respiratory diseases. However, the resistance of some enterovirus and rhinovirus to Pleconaril has limited its application. Schmidtke et al. designed and synthesized a series of novel Pleconaril derivatives substituted on isoxazole and benzene rings based on the structure of Pleconaril (Fig. 2), and evaluated their antiviral activity against Pleconaril sensitive and resistant enterovirus. The results of follow-up experiments indicated that Compound A could be used as a potential candidate for the broad-spectrum enterovirus and rhinovirus inhibitors for further preclinical studies.

Fig. 3. Structure of Compound A.

The substitution of aromatic rings with their bioisosteres in drug design is helpful for the discovery of novel drug molecules with completely new skeletons. In addition, due to the simple structure of aromatic rings and their ability to be introduced into small molecules through straightforward chemical synthesis, it is undoubtedly attractive to replace more complex ring systems with substituted aromatic ring structures. In the process of designing a novel HIF-1α inhibitor, Suh et al. replaced the chromene ring in the original small molecule structure with a heteroatomic-substituted benzene ring as the key fragment of the newly synthesized small molecules. They found a HIF-1α inhibitor with higher activity and simplified the chemical synthesis process (Fig. 4). This small molecule can be used to treat eye diseases associated with angiogenesis.

Fig. 4. Application of aromatic ring skeleton in drug design.

Synthesis of Drug Molecules Containing Aromatic Rings

Aromatic rings are common in bioactive molecules, among which benzene ring accounts for about 45% of small molecule drugs sold on the market. There can be multiple functional groups on the aromatic ring at the same time, resulting in various types of reactions, such as substitution reactions and coupling reactions. Suzuki coupling reaction is based on halogenated aromatics and aryl boric acid compounds as the main reaction substrate. Currently, aromatic ring blocks are the largely needed blocks in drug synthesis. BOC Sciences can offer a range of aromatic ring blocks, available in bulk and at affordable prices. More information about BOC Sciences' molecular block series can be found at the product hub.

References

1. Egorova, A. et al. Michaela Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses. European Journal of Medicinal Chemistry. 2020, 188: 112007.
2. An, H. et al. Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy. Journal of Medicinal Chemistry. 2018, 61(20): 9266-9286.