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.

中文翻译：

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3-methyl-5-spirofluorenehydantoin 哌嗪衍生物的晶体学研究以寻找 P-gp 抑制剂的结构特征

5-螺芴乙内酰脲衍生物在敏感和耐药的小鼠 T 淋巴瘤细胞中显示出外排调节、细胞毒性和抗增殖作用。为了扩展有关负责 3-甲基-5-螺芴乙内酰脲的芳基哌嗪衍生物的糖蛋白 P (P-gp) 抑制特性的药效特征的知识，我们对 1-[3-(3' -甲基-2',4'-二氧螺[芴-9,5'-咪唑啉]-1'-基)丙基]-4-苯基哌嗪-1,4-二氯化二鎓一水合物，C ₂₉ H ₃₂ N ₄ O ₂ ^{2 +} ·2Cl ^- ·H ₂ O ( 1)，3'-甲基-1'-{3-[4-(4-硝基苯基)哌嗪-1-基]丙基}螺[芴-9,5'-咪唑烷]-2',4'-二酮，C ₂₉ H ₂₉ N ₅ O ₄ ·H ₂ O ( 2 ), 3'-甲基-1'-{5-[4-(4-硝基苯基)哌嗪-1-基]戊基}螺[芴-9,5' -咪唑烷]-2',4'-二酮、C ₃₁ H ₃₃ N ₅ O ₄ ( 3 )和1-苄基-4-[5-(3'-甲基-2',4'-二氧螺[芴-] 9,5'-咪唑啉]-1'-基)戊基]哌嗪-1,4-二氯化二鎓0.613-水合物，C ₃₂ H ₃₈ N ₄ O ₂ ²⁺ ·2Cl ^- ·0.613H₂ O ( 4 )。结构3是无水的，但其他三个结构在存在水的情况下结晶。所研究的化合物结晶的单斜晶系，空间群P 2 ₁ / Ñ为1和3，和P 2 ₁ / ç为2和4。盐1和4的阳离子被双重质子化，质子位于哌嗪环的 N 原子上。1和4的包装晶体中以分子间 N—H…Cl 和 O—H…Cl 氢键为主。在2的晶体结构中，分子间相互作用以 O-H…O 和 O-H…N 氢键为主，而在3 中，缺乏经典的氢键供体，是 C-H…O 接触支配。此外，我们还对对接到 P-gp 人类同源模型的研究化合物进行了诱导拟合对接研究。