CHEMICAL SYNTHESIS AND BIOLOGICAL EVALUATION OF BENZIMIDAZOLES AS CHEMOTHERAPEUTICS

Nitrogen-containing heterocycles are among the most important structural motifs of chemical substances, which are well represented among natural products, and pharmaceuticals. The presence of nitrogen in heterocycles help to modulates physicochemical properties and the pKa profile of therapeutic leads. Benzimidazole is a heterocyclic structure and a privileged scaffold that is routinely used during drug discovery efforts. The benzimidazole scaffold has structural similarity to purine which makes it a useful structural motif for the development of pharmaceutical or biological interesting molecules. Benzimidazole derivatives possess a wide variety of biological activities, including anti-bacterial, anti-cancer, and anti-inflammatory activities. Development of synthetic methods to access benzimidazoles have become a focus of synthetic organic chemists, as they are useful building blocks for drug discovery efforts. We have developed two new synthetic methodologies to access benzimidazoles and one new method to chemo-selectively alkylate indole-benzimidazole scaffold. We used these synthetic methodologies to synthesize new, drug-like benzimidazole compounds and evaluated their anticancer activity, and their ability to modulate Bone Morphogenetic Proteins (BMPs). Our results indicate that several indole-based, lipid-based, and bis- benzimidazoles exhibit promising anticancer activity against several cancer cell lines. A new class of bis-benzimidazoles, show topoisomerase II inhibitory activity. In addition, substituted aryl benzimidazoles have been identified as new class of small molecules with promising BMP receptor agonistic activity, where they stimulated downstream cascade canonical Smad-signaling pathways in C2C12 cells. Our findings suggest that further development of these scaffolds could provide drug leads towards new chemotherapeutic agents and a new class of small molecule activators of BMP signaling pathway for the treatment of bone-fracture