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, C29H32N4O2 2+·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, C32H38N4O2 2+·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.

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

“…The angle between the corresponding planes amounts to 88.26 (5) • . This arrangement is similar to other 5spirofluorenehydantoin derivatives with determined crystal structures [32,33,37,38] 2. The spirofluorene moieties are engaged in π-π interactions (Figure 4) with a distance of 3.5 Å.…”

“…The angle between the corresponding planes amounts to 88.26(5)°. This arrangement is similar to other 5-spirofluorenehydantoin derivatives with determined crystal structures [32,33,37,38]. The linker between the hydantoin and piperazine rings, consisting of four methylene moieties, is flexible.…”

5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells

“…Rhodanine-derived compounds have been reported to possess a wide spectrum o biological activities, e.g., antidiabetic, antibacterial, antifungal, antimalarial, antitubercu lar, antiviral and anticancer [13][14][15][16], however, to our knowledge, they have not been stud ied before as potential modulators of the MDR efflux pump P-gp. On the other hand closely related in terms of scaffold structure, hydantoin derivatives have been widely re ported as inhibitors of P-gp [17][18][19][20][21][22][23]. With this in mind, we have decided to synthesize a series of 5-arylidenerhodanine-based compounds containing additionally one or two aro matic rings (Table 1), and evaluate their inhibition effect of ABCB1 efflux pump.…”