Studies of a Tripodal Biomimetic Siderophore Analog: An Efficient Encapsulation for Fe(III) Ion

Document Type: Research Article


1 Department of Chemistry, National Institute of Technology, Kurukshetra-136119, Haryana, INDIA

2 Department of Chemistry, Sant Longowal Institute of Engineering & Technology, Longowal, Punjab-148106, INDIA


A new tris-(2-aminoethyl)amine (TREN) capped tripodal Schiff base ligand has been developed by mimicking structural features of a natural siderophore, Bacillibactin, by substituting the catechol units with salicylaldehyde and employing amino acid as spacer. Synthesis of the ligand N-[2-[bis[2-[[2-[(2-hydroxyphenyl)methylamino]acetyl] amino]ethyl]amino]ethyl]-2-[(2-hydroxyphenyl)methylamino]acetamide(TRENglySAL) includes condensation of salicylaldehyde  and amino acid (glycine) followed by an in-situ reduction of the produced Schiff base, followed by further condensation with TREN. The complexation behavior of the ligand with Fe(III) has been investigated by potentiometric and UV-Vis spectrophotometric method at temperature 25±1oC and 0.1 M ionic strength. Seven protonation constants were obtained of the ligand: three each for secondary amine and phenolic protons and one for tertiary nitrogen of capping TREN moiety. The formation constants (log β11n) of different complex species MLH3, MLH2, MLH, ML and MLH-1 are found to be 35.15, 32.09, 27.91, 25.32 and 17.32 respectively. These results indicate that the ligand is an excellent iron binding chelator. Significant electronic spectral variations during complex formation at higher pH also provide a scope for the ligand to act as an optical pH sensor towards Fe (III) metal ion in biological systems. Structures of the ligand and metal complexes are proposed through experimental findings along with the theoretical semi-empirical PM3 calculation. The theoretical spectroscopic results are found to be comparable with the experimental finding.


Main Subjects

[1] d'Hardemare A.D.M., Alnaga N., Serratrice G., Pierre J.L., Oxinobactin, a Siderophore Analogue to Enterobactin Involving 8-Hydroxyquinoline Subunits: Synthesis and Iron Binding Ability, Bioorg. Med. Chem. Lett., 18: 6476-6478 (2008).   
[2] Abergel R.J., Zawadzka A.M., Hoette T.M., Raymonds K.N., Enzymatic Hydrolysis of Trilactone Siderophores: Where Chiral Recognition Occurs in Enterobactin and Bacillibactin Iron Transport(1)J. Am. Chem. Soc., 131: 12682-12692 (2009).
[4] O'Brien I.G., Gibson F., The Structure of Enterochelin and Related 2,3-dihydroxy-N-benzoyne Conjugates from Eschericha Coli, Biochimica et Biophysica Acta, 215: 393-402 (1970).
[5] Pollack J.R., Nielands J.B., Enterobactin, an Iron Transport Compound from Salmonella Typhimurium,  Biochem. Biophys. Res. Commun., 38: 989-992 (1970).
[6] Moerlein S.M., Welch M.J., Raymond K.N., Weitle F.L., Tricatecholamide Analogs of Enterobactin as Gallium- and Indium-Binding Radiopharmaceuticals, J.  Nuc. Med., 22: 710-719 (1981).
[7] Tor Y., Libman J., Shanzer A., Felder C.E., Lifson S., Tripodal Peptides with Chiral Conformations Stabilized by Interstrand Hydrogen Bonds, J. Am. Chem.l  Soc., 114: 6653-6661 (1992).
[8] Imbert D., Thomas F., Baret P., Serratrice G., Gaude D., Pierre J.L., Laulhere J.P., Synthesis and Iron(III) Complexing Ability of CacCAM, a New Analog of Enterobactin Possessing a Free Carboxylic Anchor arm. Comparative Studies with TRENCAM, New J.  Chem., 24: 281-288 (2000).
[9] Piyamongkal S., Zhou T., Liu Z.D., Khodr H.H., Hider R.C., Design and Characterisation of Novel Hexadentate 3-hydroxypyridin-4-one Ligands, Tetrahedron Letters, 46: 1333-1336 (2005).
[10] Baral M., Sahoo S. K., Kanungo B. K., Tripodal Amine Catechol Ligands: A Fascinating Class of Chelators for Aluminium(III), J. Inorg. Biochem., 102: 1581-1588 (2008).
[11] Dertz E.A., Xu J., Raymond K.N., Tren-based Analogs of Bacillibactin: Structure and Stability, Inorg. Chem., 45: 5465-5478 (2006).
[12] Evans D.F., Jakubovic D.A., Water-Soluble Hexadentate Schiff-Base Ligands as Sequestrating Agents for Iron(III) and Gallium(III), J. Chem. Soc. Dalton Transactions, 56: 2927-2933 (1988).
[13] Evans D.F., Jakubovic D. A., Complexes of a Water-soluble tridentate schiff base Ligand with a Number of “Hard” Metal Ions, Polyhedron, 7: 1881-  (1988).
[14] Furniss B.S., Hannaford A.J., G.Smith P.W., Tatchell A.R., “Vogel’s Textbook of Practical Organic Chemistry”, Dorling Kindersley, India (2009).
[16] Alderighi L., Gans P., Lenco A., Peters D., Sabatini A., Vacca A., Hyperquad Simulation and Speciation (HySS): a Uility Program for the Investigation of Equilibria Involving Soluble and Partially Soluble Species, Coord. Chem. Rev., 184: 311-318 (1999).
[17] Gorkum R.V., Berding J., Tooke D.M.,  Spek A.L., Reedijk J., Bowman E., The Autoxidation Activity of New Mixed-Ligand Manganese and Iron Complexes with Tripodal Ligands, J. of Cat., 252: 110-118 (2007).
[18] Staab, H. A., “New Methods of Preparative Organic Chmistry IV. Syntheses Using Heterocyclic Amides”, Angewandte Chemie International Edition in English, 1, 351 (1962).
[20] Bismondo A., Comuzzi C., Di Bernardo P., Luigi Zanonato P., Complexation of Thorium(IV) by Tris((2,3-dihydroxybenzylamino)ethyl)amine—A New Strong Chelating Agent, Inorganica Chimica Acta, 286(1): 103–107 (1999).
     Sahoo S.K., Baral M., Kanungo B.K., Potentiometric and Spectrophotometric Studies on the Binding Ability of a Flexible Tripodal Catecholamine Ligand Towards Iron(III), J. Chem. Eng. Data, 56: 2849-2855 (2011);
     Sahoo S.K., Bera R.K., Kanungo B.K., Baral M., Spectroscopic and pH-Metric Studies on the Complexation of a Novel Tripodal Amine-Phenol Ligand Towards Al(III), Ga(III) and In(III), Spectrochimica Acta Part A, 89: 322-328 (2012).
[22] Muthu S. E., “Studies on Metal Complexes of some Multidentate and Macrocyclic Ligands”, Ph.D Thesis, Punjab Technical University, India (2004).
[23] Martell A.E., Smith R.M., “Critical Stability Constants”, Vols. 1-6, Plenum, New York (1974).
[24] Childers R.F., Wentworth R.A.D., Zompa L.J., Potentiometric and Spectrophotometric Studies on the Binding Ability of a Flexible Tripodal Catecholamine Ligand Towards Iron(III), Inorg. Chem., 10: 302-306 (1971).
[27] Topol I.A., Tawa G.J., Burt S.K., Rashin A.A., On the Structure and Thermodynamics of Solvated Monoatomic Ions Using a Hybrid Solvation Model, J. Chem. Phy., 111: 10998 (1999).