Studies on nitracrine and its nitro isomers devoted to tautomeric phenomena, structural and physicochemical features, as well as surrounding electrostatic potential

Abstract

Relative stabilities and features of tautomers of N,N-dimethyl-N′-(1-nitro-9-acridinyl)-1,3-propanediamine (known as nitracrine by the World Health Organization (WHO) or as Ledakrin in Poland), which exhibits antitumour activity, and its three nitro isomers were examined by AM1 and, in some cases, by PM3 and ab initio (STO-3G) methods. The lowest energy form of three compounds was always an imino tautomer, while the energy of the amino tautomers was a few kcal mol−1 higher and that of the aci forms (in the case of the 2- and 4-nitro isomers) was more than 25 kcal mol−1 higher. Each tautomer can further exist in several structural forms (conformers or stereoisomers). In some of them internal hydrogen bonding interactions are feasible. The barriers to rotation of the -NHR group, as well as to inversion of the -NHR group (in amino tautomers of nitracrine and its 2-nitro isomer) and of the whole molecule (in the case of non-planar imino structures), were also evaluated, as were enthalpies of formation (total energies), entropies, free energies, dipole moments, and energies of HOMO and LUMO orbitals. Molecular electrostatic potential maps reveal that only in nitracrine are both -NO2 and -NHR groups surrounded by a negative electrostatic potential, whereas in other isomers the -NHR fragment is surrounded by a positive electrostatic potential while the -NO2 group remains in the region of a negative electrostatic potential. The possible influence of physicochemical features on the biological activity of the molecules is also considered.