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Novel Imidazolyl Derivatives of 1,8-Acridinedione as Potential DNA-Intercalating Agents

A. Jamalian^a, A. Shafiee^a,b, B. Hemmateenejad^c, M. Khoshneviszadeh^a, R. Miri^c,d, A. Madadkar-Sobhani^e, S.Z. Bathaie^f and A.A. Moosavi-Movahedi^e,g,*

^aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
^bPharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
^cMedicinal and Natural Product Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
^dDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
^eInstitute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
^fDepartment of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares
University, Tehran, Iran
^gCenter of Excellence in Biothermodynamics, University of Tehran, Tehran, Iran

      The effect of twelve novel imidazolyl derivatives of 1,8-acridinedione (ligands) on calf thymus DNA was studied applying different biophysical techniques including UV-Vis spectrophotometry, CD spectropolarimetry and fluorimetric methods to gain deeper insights into the mechanism of interaction of the ligands with DNA. The binding parameters such as C₅₀, K_app, ΔG^o_(H2O) and m-value, followed by Scatchard analysis, indicate that among the tested ligands, four compounds; 12b, 13b, 12f and 13f, containing nitro and benzyl imidazole substituents, revealed uncompetitive intercalative mode of interaction with DNA. UV-Vis studies imply that the compounds bind cooperatively to DNA at the concentration range of 100-200 μM. Based on biophysical data, QSAR analysis, and docking simulations, we propose that in cytotoxic 1,8-acridinediones, the imidazole moiety is essential for pharmacological activity and the introduction of more flexible and electron-withdrawing substituents on the imidazole ring serves to enhance their DNA intercalating ability.

Keywords: DNA-intercalation, Imidazolyl-1,8-acridinedione, Circular dichroism, Docking, QSAR