Crystallographic studies of piperazine derivatives of 3-methyl-5-spirofluorenehydantoin in search of structural features of P-gp inhibitors.

Abstract

5-Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T-lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P-gp) inhibitory properties of arylpiperazine derivatives of 3-methyl-5-spirofluorenehydantoin, we have performed crystal structure analyses for 1-[3-(3'-methyl-2',4'-dioxospiro[fluorene-9,5'-imidazolidin]-1'-yl)propyl]-4-phenylpiperazine-1,4-diium dichloride monohydrate, C29H32N4O22+·2Cl-·H2O (1), 3'-methyl-1'-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5'-imidazolidine]-2',4'-dione, C29H29N5O4·H2O (2), 3'-methyl-1'-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5'-imidazolidine]-2',4'-dione, C31H33N5O4 (3), and 1-benzyl-4-[5-(3'-methyl-2',4'-dioxospiro[fluorene-9,5'-imidazolidin]-1'-yl)pentyl]piperazine-1,4-diium dichloride 0.613-hydrate, C32H38N4O22+·2Cl-·0.613H2O (4). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P21/n for 1 and 3, and P21/c for 2 and 4. The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N-H...Cl and O-H...Cl hydrogen bonds. In the crystal structure of 2, the intermolecular interactions are dominated by O-H...O and O-H...N hydrogen bonds, while in 3, which is lacking in classic hydrogen-bond donors, it is C-H...O contacts that dominate. Additionally, we have performed induced-fit docking studies for the investigated compounds docked to the P-gp human homology model.