title: Crystal structure and bonding analysis of the first dinuclear calcium(II)-proton-pump inhibitor (PPI) `butterfly molecule': a combined microcrystal synchrotron and DFT study.
abstract: Proton-pump inhibitors (PPI) are prodrugs used widely to treat acid-related diseases since the late 1980s. After an extensive research effort it has become clear that the fundamental interactions between metal atoms and PPIs are of paramount importance for both drug release and long-term therapeutic safety. Unfortunately, until now, very little information has been available on this topic. In this paper, we report the crystal structure analysis of a novel calcium-PPI compound incorporating bridging and terminal deprotonated (R)-rabeprazole tricyclic ligands (L), namely bis[μ-(R)-2-({[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfinyl)-6,7-dihydro-3H-benzofuro[5,6-d]imidazol-1-ido]bis{dimethanol[(R)-2-({[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}sulfinyl)-6,7-dihydro-3H-benzofuro[5,6-d]imidazol-1-ido]calcium(II)} methanol hexasolvate, [Ca2(C20H22N3O4S)4(CH3OH)4]·6CH3OH or [Ca2(L)4(CH3OH)4]·6CH3OH, which crystallizes from methanol in the polar C2 space group. Using low-temperature microcrystal synchrotron radiation, we demonstrate that this compound is in the form of a beautiful `butterfly molecule', consisting of a C2-symmetric dinuclear (CH3OH)2LCa(II)(μ2-L)2Ca(II)L(HOCH3)2 framework. A large amount of disorder is found within the bridging L ligand and the conformation of the fused tetrahydrofuran ring exhibits great variety. All the sulfinyl groups remain intact and the nonbonded Ca...Ca distance is significantly longer than in other calcium dimers, indicating steric hindrance in the bridging ligands. Considerable hydrogen bonding and aromatic C-H...π interactions co-operate to stabilize the whole complex, as well as to facilitate supramolecular assembly. Additional investigations into the bond nature were made using density functional theory (DFT) methods at the B3LYP/6-31G(d) level; geometry optimization, Mulliken atomic charges, MEP (molecular electrostatic potential), HOMO-LUMO (highest occupied molecular orbital-lowest unoccupied molecular orbital), TDOS (total density of states), PDOS (partial density of states), COOP (crystal orbital overlap population) and vibrational spectra were calculated/recorded and assessed carefully.
authors.affiliation: College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, People's Republic of China.
authors.forename: Hengjiang
authors.initials: H
authors.lastname: Cong
mesh_terms: D002118:Calcium / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D054328:Proton Pump Inhibitors / Q000737:chemistry*; D011789:Quantum Theory; D064750:Rabeprazole / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D008024:Ligands; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D002118:Calcium
keywords: DFT analysis; PPI drugs; butterfly molecule; crystal structure; dinuclear calcium complex; pharmaceutical compounds; proton-pump inhibitor; rabeprazole; salt form; synchrotron radiation