Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine

Abstract

Cancer is the second leading cause of mortality globally which remains a continuing threat to human health today. Drug insensitivity and resistance are critical hurdles in cancer treatment; therefore, the development of new entities targeting malignant cells is considered a high priority. Targeted therapy is the cornerstone of precision medicine. The synthesis of benzimidazole has garnered the attention of medicinal chemists and biologists due to its remarkable medicinal and pharmacological properties. Benzimidazole has a heterocyclic pharmacophore, which is an essential scaffold in drug and pharmaceutical development. Multiple studies have demonstrated the bioactivities of benzimidazole and its derivatives as potential anticancer therapeutics, either through targeting specific molecules or non-gene-specific strategies. This review provides an update on the mechanism of actions of various benzimidazole derivatives and the structure‒activity relationship from conventional anticancer to precision healthcare and from bench to clinics.

Keywords: Anticancer; Benzimidazole derivatives; Precision medicine; Targeted therapy.

Graphical abstract

Figure 1

Key interactions between the benzimidazole pharmacophore of benzimidazole derivatives and target receptors. Representative structures illustrating key interactions between the benzimidazole moiety of various compounds with (a) kinases (PDB ID: 3DA6), (b) PARP proteins (PDB ID: 7AAC), (c) androgen receptors (PDB ID: 2YLO), (d) epigenetic regulators (PDB ID: 7KBG) and (e) DNA (PDB ID: 1VZK). Structures and interactions were obtained from the PDBe database and visualized using PyMOL 2.0 software. Receptors are presented as cartoons, and residue side chains are presented as licorice according to the elements: oxygen is red, nitrogen is blue, and sulfur is yellow. Crystal waters are presented as red spheres. Benzimidazole compounds are presented as green licorice.

Figure 2

Benzimidazole derivatives as topoisomerase inhibitors.

Figure 3

Benzimidazole derivatives as DNA intercalation and alkylating agents.

Figure 4

Benzimidazole derivatives used as microtubule inhibitors.

Figure 5

Benzimidazole derivatives as protein kinase inhibitors.

Figure 6

Benzimidazole derivatives used as PARP inhibitor.

Figure 7

Benzimidazole derivatives used as androgen receptor antagonist.

Figure 8

Benzimidazole derivatives as (i) aromatase inhibitor and (ii) dihydrofolate reductase (DHFR) inhibitor.

Figure 9

Benzimidazole derivatives used as epigenetic modulator.

Figure 10

Repurposed benzimidazole derivatives as anticancer agents.