The B3LYP method with 6-31G* basis set was used to predict the geometries of five 9-aminoacridines (9-AA 1(a–e)), DNA base pairs, and respective complexes. Polarizabilities, charge distribution, frontier molecular orbital (FMO), and dipole moments were used to analyze the nature of interactions that allow reasonable drug diffusion levels. The results showed that charge delocalization, high polarizabilities, and high dipole moments play an important role in intermolecular interactions with DNA. The interactions of 9-AA 1(a–e) with GC are the strongest. 9-AA 1(d) displayed the strongest interaction and 9-AA 1(b) the weakest. 1. Introduction Intermolecular recognition is a key process for the interaction with biological systems. The strength of intermolecular weak interactions such as hydrogen bonding, Van der Waals forces, aromatic stacking, binding, and intercalation is closely related to biological activity. Acridines are known as antitumor [1–5], antiviral [6–8], antiprion [9, 10], antimicrobial [11], anti-inflammatory, and analgesic [12]. 9-Aminoacridines (9-AA) have also been considered for the treatment of protozoal infections [13], and anticancer activity was first considered in the 1940s [14]. Since then, a large number of 9-aminoacridine drugs, natural alkaloids, or synthetic molecules have been tested as antitumoral agents. 9-AA activity is due to the intercalation of the tricyclic aromatic ring between adjacent base-pairs [15]. Thereby high affinity for DNA is the result of stacking between base-pairs and enhanced by electrostatic and hydrophobic interactions with other substituents. Strong binding correlates cytotoxicity; however, extravascular distribution is limited by low levels of circulating free drug. Thus biological activity is the result of a compromise between binding and circulating drug levels. Sebestik et al. [16, 17] reported the synthesis of acridine conjugates 9-AA 1(a–e) possessing amino acids bonded to an ethylenediamine linker that showed low affinity to nucleic acids. Sebestik et al. reduced the DNA-binding constant of 9-aminoacridines by introduction of DNA binders with different base-pair affinity. 9-AA as a GC-DNA binder and peptide residues as AT-DNA binders were connected to the ethylenediamine linker. The peptide conjugates 9-AA 1(a–e) showed weak interactions with DNA due to the competitive role of substituents. DFT methods are accurate methods for computational studies [18, 19], and electrostatic interactions are described by available force fields [20–22]. However, the quest for DFT methods which accurately describe
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