Palladium proves instrumental in synthesising new benzimidazole compounds for cancer treatments

Benzimidazole is an organic compound consisting of two fused rings – one benzene and one imidazole. This structure makes it a versatile compound with applications in various fields, including medicine, agriculture and industry.

Its most notable application is in medicine, where it can treat a wide range of diseases, including inflammatory processes, and certain types of cancer.

In medicine, benzimidazole and its derivatives are used to create drugs that combat infections caused by parasites, fungi and bacteria. Well-known examples include albendazole and mebendazole, which are derivatives of the benzimidazole molecule and are used to treat helminthiasis.

Benzimidazole’s unique ability to easily react with other substances allows new compounds with improved properties to be created. For instance, introducing different functional groups into its structure can boost its antimicrobial, antiviral or antitumour properties.

The most important step in synthesising new benzimidazole derivatives is forming a carbon–carbon bond. This bond plays a key role in creating complex molecular structures that may exhibit enhanced therapeutic properties.

Modern synthesis methods that use palladium-based catalysts allow such bonds to be formed efficiently. This increases the yield of the target product and ensures high selectivity, which is particularly important in creating new drug molecules.

Recent research in medical chemistry indicates a growing interest in benzimidazole derivatives with high biological activity. In this context, a group of scientists synthesised a new series of compounds, which are shown in the figure below and are reported on in the article Sundharaj, V. & Sarveswari, S. Microwave assisted palladium catalyzed carbon-carbon bond formation to synthesise novel benzimidazole derivatives and their Photophysical properties, molecular docking, and DFT study. Heliyon, Volume 11, Issue 3, e42105 DOI.

The synthesis process begins with the cyclisation of the benzimidazole skeleton, whereby 4-bromobenzene-1,2-diamine (1) and (tert-butoxycarbonyl)proline (2) undergo a reaction. The linking agent HATU is then used in combination with the base DIPEA to facilitate the formation of the structural fragment tert-butyl 2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (3). The resulting intermediate product is then subjected to a Suzuki reaction with 3- and 4-aminophenylboronic acid (4), in the presence of a palladium catalyst. This leads to the formation of the intermediate product tert-butyl 2-(5-(4-aminophenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (5).

Next, the amino group of compound 5 reacts with 2-(4-bromophenyl)acetic acid in the presence of HATU and the base DIPEA to form tert-butyl 2-(5-(4-(2-(4-bromophenyl)acetamido)phenyl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate (7). The final step is another Suzuki reaction, in which various substituted boronic acids react with a palladium catalyst and potassium carbonate. This results in the formation of the target compounds with a yield of 50–80%.

A comparative analysis of catalyst efficiency revealed that, unlike with its chloride forms, the use of pure palladium increases the yield of the target product to 80%. Pharmacological studies of the newly synthesised (9a-9p) compounds confirmed their potential as candidates for developing new anticancer drugs. Further in-depth biological tests are planned to evaluate their cytotoxic effect on tumour cells.

Source: https://doi.org/10.1016/j.heliyon.2025.e42105