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Paper | Special issue | Vol 40, No. 1, 1995, pp.241-248
Published online, 1st January, 1970
DOI: 10.3987/COM-94-S16
Iron Chelators of the Pyridoxal 2-Pyridyl Hydrozone Class. Part III. Ionisation and Conformational Characteristics of the Ligands

Prayong Doungdee, Shalom Sarel, Israel Ringel, Dan Gibson, Nipon Wongvisetsirikul, and Shelly Avramovici-Grisaru

*Department of Pharmaceutical Chemistry, Hebrew University School of Pharmacy, P. O. Box 12065, Jerusalem 91120, Israel


pKa values of three biologically active iron chelators: pyridoxal 2-pyridyl hydrazone (PPH), 1-[N-methylpyridoxylidenium]-2-[2’-pyridyl]hydrazineiodide (MPH), 1-[N-ethoxycarbonylmethylpyridoxyidenium]-2-[2’-pyridyl]hydrazine (EPH) have been determined by a combination of ab initio calculations and pH-dependence of 13C nmr spectroscopy. In conformity with pyridoxal isonicotinoyl hydrazone (PIH), all ligands included in this study the pKa values invariably increase in the ordering: pyridinium protonation < pyridoxylidenium protonation < phenolate protonation < alkoxide protonation. Identical ordering was obtaind by ab initio calculations, based on STO-3G set. Mulliken population analysis indicates that the conformer of the lowest energy of PPH, (I), contains an internal 6-membered-ring H-bond. Rotation about C3 - C8 bond in (I), to yield conformer (IV), requires 8.8 kcal / mol, whereas its internal H-bonding (I → II) accounts for 5.8 kcal / mol. Protonation of (I) lowers significantly energies both of I → V (6.5 kcal), and I → VI (2.5 kcal) transitions.