Benzimidazole is an important class of nitrogen containing heterocycle and has been widely investigated for its medicinal properties. Benzimidazole scaffold is found in several clinically used therapeutic agents and a privileged scaffold in small molecule-based drug discovery. The Yoganathan lab is interested in the synthesis and biological evaluation of pyridine or 4-pyridone containing bis-benzimidazoles. The benzimidazole motif is extended from the 2 and 6 position of the pyridine or pyridinone ring, providing a ‘V’ shaped scaffold. These compounds are useful molecules as potential inhibitors of topoisomerases and hence are useful leads as anticancer and antibacterial agents. Moreover, these types of molecules possess a cavity where the nitrogen atoms (one from pyridine, and two from benzimidazoles) act as ligands for metal ion binding. We have applied a simple and effective chemical method to synthesize a small library of bis-benzimidazoles from commercially available 2,6-pyridine-dicarboxylic acid and various 1,2-diaminobenzenes. The chemistry is scalable, and we readily accessed various analogs in gram scale for our initial structure activity relationship (SAR) studies. Our current effort is focused on establishing a library of about ten analogs and perform a preliminary antibacterial evaluation against a panel of bacteria, and metal ion binding studies. Moreover, biologically active analogs from our antibacterial studies will be evaluate for their ability to inhibit bacterial topoisomerases. The bioactivity guided approach will enable us to fine tune the structure and better understand the SAR.

<i>Chemical synthesis and evaluation of bis-benzimidazoles as potential ion chelators and antibacterial agents </i>

ACS Spring Meeting 2021

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