Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents

作者：Park Bora; Awasthi Divya; Chowdhury Soumya R; Melief Eduard H; Kumar Kunal; Knudson Susan E; Slayden Richard A; Ojima Iwao^*

来源：Bioorganic & Medicinal Chemistry, 2014, 22(9): 2602-2612.

DOI：10.1016/j.bmc.2014.03.035

• Tuberculosis
• Antibacterial
• FtsZ
• Benzimidazole

Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 mu g/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 mu g/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the K-d of 5a with Mtb-FtsZ was determined to be 1.32 mu M.

• 出版日期2014-5-1