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

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

doi:10.1016/j.bmc.2014.03.035

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

Bora Park
, Divya Awasthi
, Soumya R. Chowdhury
, Eduard H. Melief
, Kunal Kumar
, Susan E. Knudson
, Richard A. Slayden
, Iwao Ojima

Chemistry

Stony Brook University

Stony Brook University
Colorado State University

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/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 μM.

Original language	English
Pages (from-to)	2602-2612
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	9
DOIs	https://doi.org/10.1016/j.bmc.2014.03.035
State	Published - May 1 2014

Keywords

Antibacterial
Benzimidazole
FtsZ
Tuberculosis

Access to Document

10.1016/j.bmc.2014.03.035

Cite this

@article{081c900564ef4a889d82f6315c39aa32,

title = "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 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/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 μM.",

keywords = "Antibacterial, Benzimidazole, FtsZ, Tuberculosis",

author = "Bora Park and Divya Awasthi and Chowdhury, \{Soumya R.\} and Melief, \{Eduard H.\} and Kunal Kumar and Knudson, \{Susan E.\} and Slayden, \{Richard A.\} and Iwao Ojima",

year = "2014",

month = may,

day = "1",

doi = "10.1016/j.bmc.2014.03.035",

language = "English",

volume = "22",

pages = "2602--2612",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd.",

number = "9",

}

TY - JOUR

T1 - Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents

AU - Park, Bora

AU - Awasthi, Divya

AU - Chowdhury, Soumya R.

AU - Melief, Eduard H.

AU - Kumar, Kunal

AU - Knudson, Susan E.

AU - Slayden, Richard A.

AU - Ojima, Iwao

PY - 2014/5/1

Y1 - 2014/5/1

N2 - 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 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/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 μM.

AB - 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 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/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 μM.

KW - Antibacterial

KW - Benzimidazole

KW - FtsZ

KW - Tuberculosis

UR - https://www.scopus.com/pages/publications/84899455729

U2 - 10.1016/j.bmc.2014.03.035

DO - 10.1016/j.bmc.2014.03.035

M3 - Article

C2 - 24726304

SN - 0968-0896

VL - 22

SP - 2602

EP - 2612

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 9

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this