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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Gensicka-Kowalewska M., Cholewiński G., Dzierzbicka K. Recent developments in the synthesis and biological activity of acridine/acridone analogues. RSC Adv. 2017;7:15776–15804. doi: 10.1039/C7RA01026E. DOI

Demeunynck M. Antitumour acridines. Expert Opin. Ther. Patents. 2004;14:55–70. doi: 10.1517/13543776.14.1.55. DOI

Lerman L.S. The structure of the DNA-acridine complex. Proc. Natl. Acad. Sci. USA. 1963;49:94–102. doi: 10.1073/pnas.49.1.94. PubMed DOI PMC

Adams A. Crystal structures of acridines complexed with nucleic acids. Curr. Med. Chem. 2002;9:1667–1675. doi: 10.2174/0929867023369259. PubMed DOI

Belmont P., Dorange I. Acridine/acridone: A simple scaffold with a wide range of application in oncology. Expert Opin. Ther. Patents. 2008;18:1211–1224. doi: 10.1517/13543776.18.11.1211. DOI

Blackburn G.M., Gait M.J., Loakes D., Williams D.M. Nucleic Acids in Chemistry and Biology. 3rd ed. The Royal Society of Chemistry; London, UK: 2006.

Belmont P., Bosson J., Godet T., Tiano M. Acridine and acridone derivatives, anticancer properties and synthetic methods: Where are we now? Anti-Cancer Agent. Med. Chem. 2007;7:139–169. doi: 10.2174/187152007780058669. PubMed DOI

Harrison R.J., Gowan S.M., Kelland L.R., Neidle S. Human telomerase inhibition by substituted acridine derivatives. Bioorg. Med. Chem. Lett. 1999;9:2463–2468. doi: 10.1016/S0960-894X(99)00394-7. PubMed DOI

Harrison R.J., Cuesta J., Chessari G., Read M.A., Basra S.K., Reszka A.P., Morrell J., Gowan S.M., Incles C.M., Tanious F.A., et al. Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. J. Med. Chem. 2003;46:4463–4476. doi: 10.1021/jm0308693. PubMed DOI

Hamissa M.F., Niederhafner P., Šafařík M., Telus M., Kolářová L., Koutná L., Šestáková H., Souček R., Šebestík J. Total synthesis of inubosin B. Tetrahedron Lett. 2020;61:152641. doi: 10.1016/j.tetlet.2020.152641. DOI

Gatasheh M.K., Kannan S., Hemalatha K., Imrana N. Proflavine an acridine DNA intercalating agent and strong antimicrobial possessing potential properties of carcinogen. Karbala Int. J. Mod. Sci. 2017;3:272–278. doi: 10.1016/j.kijoms.2017.07.003. DOI

Wainwright M. Acridine—A neglected antibacterial chromophore. J. Antimicrob. Chemoth. 2001;47:1–13. doi: 10.1093/jac/47.1.1. PubMed DOI

Valdés A.F.-C. Acridine and acridinones: Old and new structures with antimalarial activity. Open Med. Chem. J. 2011;5:11–20. doi: 10.2174/1874104501105010011. PubMed DOI PMC

Kožurková M., Sabolová D., Janovec L., Mikeš J., Koval’ J., Ungvarský J., Štefanišinová M., Fedoročko P., Kristian P., Imrich J. Cytotoxic activity of proflavine diureas: Synthesis, antitumor, evaluation and DNA binding properties of 1′,1″-(acridin-3,6-diyl)-3′,3″-dialkyldiureas. Bioorg. Med. Chem. 2008;16:3976–3984. doi: 10.1016/j.bmc.2008.01.026. PubMed DOI

Genheden S., Ryde U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov. 2015;10:449–461. doi: 10.1517/17460441.2015.1032936. PubMed DOI PMC

ACD ChemSketch Package 2020.2.0. [(accessed on 27 July 2021)]; Available online: www.acdlabs.com.

Stewart J.J.P. Stewart Computational Chemistry. [(accessed on 27 July 2021)]; Available online: http://openmopac.net.

Molinspiration Cheminformatics Free Web Services Slovensky Grob, Slovakia. [(accessed on 27 July 2021)]; Available online: https://www.molinspiration.com.

Allouche A.-R. Gabedit—A graphical user interface for computational chemistry softwares. J. Comput. Chem. 2011;32:174–182. doi: 10.1002/jcc.21600. PubMed DOI