Application of benzimidazole in drugs

Benzimidazolium is a benzo heterocycle compound containing two nitrogen atoms. Benzimidazole has a special chemical structure which can form hydrogen bonds with enzymes and receptors in organisms, coordinate with metal ions, and have hydrophobic-hydrophobic and π-π interactions. Therefore, benzimidazole has many applications in chemical related fields, such as functional materials, pesticides, medicine and so on.

In the field of medicine, the extensive biological activity of benzimidazole is reflected incisively and vividly. The indications of these drugs include peptic ulcer, hypertension, schizophrenia, parasite infection, bacterial infection, virus infection, cancer and so on. The main targets involved are Proton Pum, Dopamine receptor (DRDs), Angiotensin II type 1 receptor (AT1), histamine H1 receptor (HRH1), Dual specificity mitogen-activated protein kinase kinase (MEK) and Cyclin-dependent kinase kinase (CDK).

Digestive system disease is the most important application field of benzimidazoles. 39% of the skeleton drugs were devoted to solving digestive system diseases, of which 68.8% were proton pump inhibitor (PPI), which also known as H+/K+-ATP inhibitor, prevents the formation of gastric acid by inhibiting the exchange of H+ and K+. PPI has the advantages of specificity, high selectivity and less side effects. According to the different binding mode of PPI and H+/K+-ATP enzyme, it can be divided into irreversible PPI and reversible PPI.

  • Irreversible PPI.

Irreversible PPI, as a pro-drug, is covalently bound to the disulfide bond of cysteine residues on the plasma side of H+/K+-ATP after the conversion of gastric parietal cells to active sulfonic acid or subsulfonamide. The steric hindrance of ion binding sites prevents the enzyme from binding to H + or K+ in the cytoplasm, so as to prevent the formation of gastric acid. Benzimidazoles irreversible PPI includes omeprazole, lansoprazole, pantoprazole, epprazole, esomeprazole salt and so on.

  • Reversible PPI.

Reversible proton pump inhibitors have characteristics such as strong lipophilic alkaline weak dissociation constant and stable at low temperature value. Reversible PPI was competitively binding with the binding of ionic bonds to inhibit the binding of K+ and enzyme to inhibit gastric acid secretion. Therefore, reversible PPI was called potassium competitive acid blocker (P-CAB). Among benzimidazole drugs, this inhibitor was newly listed Tegoprazan in 2018, which competitively blocked potassium ion and hydrogen ion and potassium ion-ATPase in gastric parietal cells secretion of gastric acid, which played a powerful and lasting inhibitory effect on gastric acid secretion.

Benzimidazole drug domperidone, as a peripheral dopamine D2 receptor antagonist, can promote gastrointestinal motility and does not have adverse reactions to the nervous system. And because of the antagonistic effect of dopamine D2 receptor on (5-hydroxytryptamine 3) 5-HT3 receptor in high dose, the drug also has antiemetic effect.

  • Angiotensin II type 1 receptor (AT1)

Cardiovascular and cerebrovascular diseases are the second largest field of benzimidazoles. So far, there are six drugs on the market, and the indications of these drugs are also focused on hypertension. Benzimidazoles in the treatment of hypertension target AT1 and lower blood pressure by blocking the effect of angiotensin II.

Histamine is a kind of substance which widely exists in animals, plants and microorganisms in nature. It is obtained by the removal of carboxyl group by histidine decarboxylase catalyzed by histidine decarboxylase. The action of histamine and histamine receptor can cause capillary relaxation, increase the permeability of blood vessel wall, produce edema and itching, and participate in the occurrence of allergic reaction. As a result, histamine receptor antagonists have been developed to combat allergic symptoms caused by histamine. Benzimidazoles, such as Billastine, Emesteen Fumarate and Mizolastine, are all these drugs. The indications mainly include urticaria, skin diseases, conjunctivitis and other allergic diseases.

MEK is a kind of serine/threonine kinase. The drug developed as a target is a popular anti-tumor drug-small molecule kinase inhibitor. As an important part of MAP (Mitogen-activated protein kinase) kinase signal transduction pathway, MEK1 can activate the downstream signal pathway and play an important role in regulating many biological functions, such as cell growth, adhesion, survival and differentiation. On June 27, 2018, Binimetinib, developed by Array BioPharma, was approved for listing by FDA in the United States. The drug is mainly used to treat BRAF (V-raf murine sarcoma viral oncogene homolog B1) mutant melanoma, and its therapeutic effect on colorectal cancer, fallopian tube cancer, ovarian cancer and abdominal cancer. It is currently in the third phase of clinical research.

CDK inhibitor is another serine / threonine kinase inhibitor. CDK4 is a component of cell cycle protein D-CDK4 complex, which can have an important effect on cell mitosis by regulating cell cycle G 1 phase. Once the complex is out of order, it may lead to cancer. CDK6 plays an important role in the development of thymus, which is helpful to promote cell proliferation and control cell cycle and differentiation. On September 28, 2017, Abemaciclib, developed by Lilly, went on sale in the United States as an inhibitor of CDK4 and CDK6, which can treat HR (Hormone receptor) positive/HER2 (human epidermal growth factor receptor-2) negative breast cancer, advanced breast cancer and metastatic breast cancer.


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