In order to extend knowledge about pharmacophoric features responsible for ABCB1 inhibitory properties of imidazolidin-2,4-dione derivatives, 1'-[4-(4-(o-methoxyphenyl)-piperazin-1-yl)butyl]-3'-methyl-spiro(fluoren-9,5'-imidazolidine)-2',4'-dione (3) and its salt (4) with rhodanine-3-acetic acid (RA) were prepared and investigated by X-ray diffraction method, as well as their efflux modulating effects in cancer cells (mouse T-lymphoma), cytotoxic and antiproliferative activities were evaluated in vitro. The molecular geometry, intermolecular interactions, and crystal packing of base and acid forms of 3 were analyzed to see, if conformational changes influence the biological activities. The geometry of 2-methoxyphenylpiperazine and 5-spirofluorenehydantoin moieties was compared with other crystal structures containing these fragments. Our results indicated a very potent inhibitory action on ABCB1 pump, and significant cytotoxic and antiproliferative properties of 3 in T-lymphoma, even more potent in the case of multidrug resistance cells. Furthermore, the compound 3 converted into the salt 4 of inactive acid (RA) has maintained both, the efflux pump inhibitory and antiproliferative activities, showing strong synergism with doxorubicin. A comparison of geometry of 3 in both crystal structures (3 and 4) shows a significant difference in the arrangement of piperazine ring with respect to the aliphatic linker.
Keywords: arylpiperazine derivative of hydantoin; crystal structure; efflux pump inhibitor; pharmacophor; rhodanine-3-acetic acid.
© 2019 John Wiley & Sons A/S.