Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results

Arkadius Pichota; Jeyaraj Duraiswamy; Zheng Yin; Thomas H. Keller; Jenefer Alam; Sarah Liung; Gladys Lee; Mei Ding; Gang Wang; Wai Ling Chan; Mark Schreiber; Ida Ma; David Beer; Xinyi Ngew; Kakoli Mukherjee; Mahesh Nanjundappa; Jeanette W.P. Teo; Pamela Thayalan; Amelia Yap; Thomas Dick; Wuyi Meng; Mei Xu; James Koehn; Shi Hao Pan; Kirk Clark; Xiaoling Xie; Carolyn Shoen; Michael Cynamon

doi:10.1016/j.bmcl.2008.10.040

Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results

Arkadius Pichota
, Jeyaraj Duraiswamy
, Zheng Yin
, Thomas H. Keller
, Jenefer Alam
, Sarah Liung
, Gladys Lee
, Mei Ding
, Gang Wang
, Wai Ling Chan
, Mark Schreiber
, Ida Ma
, David Beer
, Xinyi Ngew
, Kakoli Mukherjee
, Mahesh Nanjundappa
, Jeanette W.P. Teo
, Pamela Thayalan
, Amelia Yap
, Thomas Dick

Wuyi Meng, Mei Xu, James Koehn, Shi Hao Pan, Kirk Clark, Xiaoling Xie, Carolyn Shoen, Michael Cynamon

Center for Discovery and Innovation

Novartis
Infectious Disease Area
Department of Veterans Affairs

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

47 Scopus citations

Abstract

Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.

Original language	English
Pages (from-to)	6568-6572
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2008.10.040
State	Published - 15 Dec 2008

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antibacterial
Mycobacterium tuberculosis
PDF
SAR
X-Ray

Access to Document

10.1016/j.bmcl.2008.10.040

Cite this

Pichota, A., Duraiswamy, J., Yin, Z., Keller, T. H., Alam, J., Liung, S., Lee, G., Ding, M., Wang, G., Chan, W. L., Schreiber, M., Ma, I., Beer, D., Ngew, X., Mukherjee, K., Nanjundappa, M., Teo, J. W. P., Thayalan, P., Yap, A., ... Cynamon, M. (2008). Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results. Bioorganic and Medicinal Chemistry Letters, 18(24), 6568-6572. https://doi.org/10.1016/j.bmcl.2008.10.040

@article{b5ef2f774fcf41a0b3ac3c507a7861f6,

title = "Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results",

abstract = "Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.",

keywords = "Antibacterial, Mycobacterium tuberculosis, PDF, SAR, X-Ray",

author = "Arkadius Pichota and Jeyaraj Duraiswamy and Zheng Yin and Keller, \{Thomas H.\} and Jenefer Alam and Sarah Liung and Gladys Lee and Mei Ding and Gang Wang and Chan, \{Wai Ling\} and Mark Schreiber and Ida Ma and David Beer and Xinyi Ngew and Kakoli Mukherjee and Mahesh Nanjundappa and Teo, \{Jeanette W.P.\} and Pamela Thayalan and Amelia Yap and Thomas Dick and Wuyi Meng and Mei Xu and James Koehn and Pan, \{Shi Hao\} and Kirk Clark and Xiaoling Xie and Carolyn Shoen and Michael Cynamon",

year = "2008",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2008.10.040",

language = "English",

volume = "18",

pages = "6568--6572",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "24",

}

Pichota, A, Duraiswamy, J, Yin, Z, Keller, TH, Alam, J, Liung, S, Lee, G, Ding, M, Wang, G, Chan, WL, Schreiber, M, Ma, I, Beer, D, Ngew, X, Mukherjee, K, Nanjundappa, M, Teo, JWP, Thayalan, P, Yap, A, Dick, T, Meng, W, Xu, M, Koehn, J, Pan, SH, Clark, K, Xie, X, Shoen, C & Cynamon, M 2008, 'Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 24, pp. 6568-6572. https://doi.org/10.1016/j.bmcl.2008.10.040

TY - JOUR

T1 - Peptide deformylase inhibitors of Mycobacterium tuberculosis

T2 - Synthesis, structural investigations, and biological results

AU - Pichota, Arkadius

AU - Duraiswamy, Jeyaraj

AU - Yin, Zheng

AU - Keller, Thomas H.

AU - Alam, Jenefer

AU - Liung, Sarah

AU - Lee, Gladys

AU - Ding, Mei

AU - Wang, Gang

AU - Chan, Wai Ling

AU - Schreiber, Mark

AU - Ma, Ida

AU - Beer, David

AU - Ngew, Xinyi

AU - Mukherjee, Kakoli

AU - Nanjundappa, Mahesh

AU - Teo, Jeanette W.P.

AU - Thayalan, Pamela

AU - Yap, Amelia

AU - Dick, Thomas

AU - Meng, Wuyi

AU - Xu, Mei

AU - Koehn, James

AU - Pan, Shi Hao

AU - Clark, Kirk

AU - Xie, Xiaoling

AU - Shoen, Carolyn

AU - Cynamon, Michael

PY - 2008/12/15

Y1 - 2008/12/15

N2 - Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.

AB - Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.

KW - Antibacterial

KW - Mycobacterium tuberculosis

KW - PDF

KW - SAR

KW - X-Ray

UR - https://www.scopus.com/pages/publications/56249090355

U2 - 10.1016/j.bmcl.2008.10.040

DO - 10.1016/j.bmcl.2008.10.040

M3 - Article

C2 - 19008098

AN - SCOPUS:56249090355

SN - 0960-894X

VL - 18

SP - 6568

EP - 6572

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 24

ER -

Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this