Macrocyclic inhibitors for peptide deformylase: a structure-activity relationship study of the ring size

Journal of Medicinal Chemistry
Xubo HuD Pei

Abstract

Peptide deformylase (PDF) catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria. Its essential role in bacterial cells but not in mammalian cells makes it an attractive target for antibacterial drug design. We have previously reported an N-formylhydroxylamine-based, metal-chelating macrocyclic PDF inhibitor, in which the P(1)' and P(3)' side chains are covalently joined. In this work, we have carried out a structure-activity relationship study on the size of the macrocycle and found that 15-17-membered macrocycles are optimal for binding to the PDF active site. Unlike the acyclic compounds, which are simple competitive inhibitors, the cyclic compounds all act as slow-binding inhibitors. As compared to their acyclic counterparts, the cyclic inhibitors displayed 20-50-fold higher potency against the PDF active site (K(I) as low as 70 pM), improved selectivity toward PDF, and improved the metabolic stability in rat plasma. Some of the macrocyclic inhibitors had potent, broad spectrum antibacterial activity against clinically significant Gram-positive and Gram-negative pathogens. These results suggest that the macrocyclic scaffold provides an excellent lead for the development of a n...Continue Reading

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Citations

Dec 26, 2012·ACS Combinatorial Science·Amit ThakkarDehua Pei
Jun 6, 2007·Journal of Medicinal Chemistry·Qing Xiao, Dehua Pei
Jul 2, 2008·Nature Reviews. Drug Discovery·Edward M DriggersNicholas K Terrett
Oct 27, 2009·PLoS Computational Biology·Wesley C Van VoorhisLance J Stewart
Aug 5, 2008·Drug Discovery Today·Matteo Colombo, Ilaria Peretto
Aug 30, 2005·Current Opinion in Microbiology·John F Barrett
Feb 7, 2006·Biochemical Pharmacology·Molly B Schmid
Oct 21, 2016·Scientific Reports·Sonia FieulaineCarmela Giglione
Mar 24, 2016·Chemistry : a European Journal·Anniefer N MagpusaoMark W Peczuh
Nov 6, 2007·Archives of Biochemistry and Biophysics·Kiet T NguyenDehua Pei
Jul 21, 2017·Journal of Chemical Information and Modeling·Dan SindhikaraShana L Posy
Nov 20, 2018·Chembiochem : a European Journal of Chemical Biology·Xiaohong TanBruce A Armitage

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