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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-12, Vol.18 (24), p.6568-6572
Hauptverfasser:	Pichota, Arkadius, Duraiswamy, Jeyaraj, Yin, Zheng, Keller, Thomas H., Alam, Jenefer, Liung, Sarah, Lee, Gladys, Ding, Mei, Wang, Gang, Chan, Wai Ling, Schreiber, Mark, Ma, Ida, Beer, David, Ngew, Xinyi, Mukherjee, Kakoli, Nanjundappa, Mahesh, Teo, Jeanette W.P., Thayalan, Pamela, Yap, Amelia, Dick, Thomas, Meng, Wuyi, Xu, Mei, Koehn, James, Pan, Shi-Hao, Clark, Kirk, Xie, Xiaoling, Shoen, Carolyn, Cynamon, Michael
Format:	Artikel
Sprache:	eng
Schlagworte:	Amidohydrolases - antagonists & inhibitors Amidohydrolases - chemistry Antibacterial Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Antitubercular Agents - chemistry Antitubercular Agents - therapeutic use Biological and medical sciences Chemistry, Pharmaceutical - methods Crystallography, X-Ray - methods Drug Design Drug Resistance, Multiple Fluoroquinolones - pharmacology Humans Inhibitory Concentration 50 Medical sciences Microbial Sensitivity Tests Models, Chemical Molecular Conformation Mycobacterium bovis - metabolism Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - metabolism PDF Pharmacology. Drug treatments SAR Tuberculosis - drug therapy X-Ray
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Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.10.040