Synthesis, physico-chemical properties, and antimicrobial evaluation of a new series of iron(III) hexadentate chelators
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Med Chem Res (2013) 22:2351–2359 DOI 10.1007/s00044-012-0229-1
ORIGINAL RESEARCH
Synthesis, physico-chemical properties, and antimicrobial evaluation of a new series of iron(III) hexadentate chelators Yuan-Yuan Xie • Mu-Song Liu • Pan-Pan Hu Xiao-Le Kong • Di-Hong Qiu • Ji-Lin Xu • Robert C. Hider • Tao Zhou
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Received: 22 December 2011 / Accepted: 11 September 2012 / Published online: 22 September 2012 Ó Springer Science+Business Media, LLC 2012
Abstract A series of related 3-hydroxypyridin-4-one hexadentate ligands have been synthesized. These chelators were found to possess a high affinity for iron(III), with a pFe value of about 30. As iron is a critical element to the survival of bacteria, these chelators were predicted to inhibit the growth of bacteria by disrupting bacterial iron absorption. Indeed, they were demonstrated to possess appreciable inhibitory activity against both Gram-positive and Gram-negative bacteria, and therefore, they have potential as antimicrobial agents. 1c and 1g were found to be particularly effective against Gram-negative species. Keywords Iron chelator 3-Hydroxypyridin-4-one Hexadentate Antimicrobial activity
Y.-Y. Xie M.-S. Liu College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China P.-P. Hu T. Zhou (&) School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310035, People’s Republic of China e-mail: [email protected] X.-L. Kong R. C. Hider Division of Pharmaceutical Science, King’s College London, Franklin–Wilkins Building, 150 Stamford Street, London SE1 9NH, UK D.-H. Qiu J.-L. Xu Faculty of Life Science and Biotechnology, Ningbo University, Ningbo, Zhejiang 315211, People’s Republic of China
Introduction Bacterial and fungal resistance to antimicrobial agents is a growing problem worldwide (Nikaido and Zgurskaya, 1999; Mitscher et al., 1999; Hogan and Kolter, 2002). Consequently, there is an urgent need for the development of novel types of antimicrobial agents targeting unique mechanisms and pathways. Iron is an essential element for the growth of virtually all bacteria and fungi. Thus, limiting the iron absorption of microorganism should in principle be an effective strategy to inhibit microbial growth. Most microorganisms have developed efficient methods of absorbing iron from the environment and many microorganisms secrete siderophores to scavenge iron (Lewin, 1984; Hider and Kong, 2010). In principle, such uptake can be interrupted by the introduction of high affinity iron selective chelating agents (Lowe and Phillips, 1962; Bergan et al., 2001). The iron affinity of these agents must be extraordinally high, so that they can efficiently outcompete siderophores. Furthermore, the structure of chelators should differ appreciably from those of siderophores, otherwise the iron-chelator complex will be able to supply iron to the microorganism via the iron-siderophore transporter. Thus, iron(III)-selective hexadentate chelators with a high affinity for iron are p
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