Design and Synthesis of Novel Benzimidazole Library for the Discovery and Development of the Next Generation Antibacterial Agents

Abstract

Tuberculosis, commonly known as&#34;TB,&#34; is a contagious infection that is caused by exposure to Mycobacterium tuberculosis. Many current anti-TB drugs target bacterial cell wall synthesis, protein synthesis, and fatty acid synthesis. It is important to explore new bacterial targets in fighting the progression of tuberculosis. The bacterial cellular division process as an anti-TB target has not been fully explored and holds great potential in future combinatorial treatment of drug resistant tuberculosis. Since FtsZ (Filamental temperature-sensitive protein Z) is the most essential and abundant protein in bacterial mitosis, more specifically the coordination of bacterial cytokinesis, it has been targeted as a means to eradicate tuberculosis. The specific targeting of FtsZ for the inhibition of bacterial growth is considered because of its notable similarities with eukaryotic tubulin, while maintaining key differences that can be manipulated for drug development. Previous research has shown that tubulin polymerization is effectively inhibited by albendazole and thiabendazole. Since FtsZ assembly is the only known prokaryotic mechanism analogous to tubulin polymerization, it was suggested that albendazole and thiobendazole would also inhibit FtsZ at inhibitory concentrations. The compounds interfered and delayed Mycobacterium tuberculosis cellular division processes at 16 &#956;g/mL. We have hypothesized that benzimidazoles, the core structure of FtsZ inhibitors, could be developed into broad-spectrum antibacterial agents with novel mechanisms of action. A library of trisubstituted benzimidazoles was synthesized by newly developed polymer-assisted solution phase methods. Several of the benzimidazole compounds exhibited < 0.5 &#956;g/mL MIC99 activity in the preliminary screening against Mtb H37RV strain. According to polymerization assays, these compounds arrested Mtb growth by inhibiting FtsZ in a dose dependent manner. Further optimization was pursued for diverse 2,5,6- and 2,5,7- trisubstituted benzimidazole compounds in the development of more effective antibacterial agents against tuberculosis.