A Series of Imidazolyl-Containing Bisphosphonates with Abundant Hydrogen-Bonding Interactions: Syntheses, Structures, and Bone-Binding Affinity

Abstract

A series of novel bisphosphonates (BPs) were designed and synthesised as longer-chain analogues of the clinically widely used BP–zoledronate (ZL). They were characterised by mass spectrometry, infrared spectroscopy, NMR spectroscopy, and single-crystal X-ray diffraction. All the crystals are zwitterions with one of the phosphonate oxygen atoms deprotonated and the hydrogen atom transferred to the nitrogen of the imidazole ring. A lot of strong hydrogen bonds are observed among the phosphonate oxygens, hydroxy groups, and protonated nitrogen atoms. An accurate, precise, and robust method was developed to determine the bone binding affinities of BPs based on high performance liquid chromatography. The results show that these five BPs have a strong affinity for hydroxyapatite and the binding capacity decreases when the substituted alkyl groups increase in size.