A novel series of proflavine ureas, derivatives 11a-11i, were synthesized on the basis of molecular modeling design studies. The structure of the novel ureas was obtained from the pharmacological model, the parameters of which were determined from studies of the structure-activity relationship of previously prepared proflavine ureas bearing n-alkyl chains. The lipophilicity (LogP) and the changes in the standard entropy (ΔS°) of the urea models, the input parameters of the pharmacological model, were determined using quantum mechanics and cheminformatics. The anticancer activity of the synthesized derivatives was evaluated against NCI-60 human cancer cell lines. The urea derivatives azepyl 11b, phenyl 11c and phenylethyl 11f displayed the highest levels of anticancer activity, although the results were only a slight improvement over the hexyl urea, derivative 11j, which was reported in a previous publication. Several of the novel urea derivatives displayed GI50 values against the HCT-116 cancer cell line, which suggest the cytostatic effect of the compounds azepyl 11b-0.44 μM, phenyl 11c-0.23 μM, phenylethyl 11f-0.35 μM and hexyl 11j-0.36 μM. In contrast, the novel urea derivatives 11b, 11c and 11f exhibited levels of cytotoxicity three orders of magnitude lower than that of hexyl urea 11j or amsacrine.

Biomedical Research Center University Hospital Hradec Kralove Sokolovska 581 500 05 Hradec Kralove Czech Republic

Department of Biochemistry Faculty of Science P J Safarik University in Kosice Moyzesova 11 040 01 Kosice Slovakia

Department of Experimental Medicine Faculty of Medicine P J Safarik University in Kosice Trieda SNP1 040 11 Kosice Slovakia

Department of Medical Biology Faculty of Medicine P J Safarik University in Kosice Trieda SNP1 040 11 Kosice Slovakia

Department of Organic Chemistry Faculty of Science P J Safarik University in Kosice Moyzesova 11 040 01 Kosice Slovakia

Institute of Geotechnics Slovak Academy of Sciences Watsonova 45 040 01 Kosice Slovakia

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