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

ABSTRACT: 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 ?g/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 ?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 Kd of 5a with Mtb-FtsZ was determined to be 1.32 ?M.

SUBMITTER: Park B

PROVIDER: S-EPMC4045703 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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

Park Bora B Awasthi Divya D Chowdhury Soumya R SR Melief Eduard H EH Kumar Kunal K Knudson Susan E SE Slayden Richard A RA Ojima Iwao I

Bioorganic & medicinal chemistry 20140401 9

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 concentratio ...[more]

PMID: 24726304

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