Structural, harmonic force field and vibrational studies of cholinesterase inhibitor tacrine used for treatment of Alzheimer's disease

Different structures of free base (FB), two cationic forms (CA) and three hydrochloride forms (HCl) of cholinesterase inhibitor tacrine used for treatment of Alzheimer ’s disease was evaluated using hybrid B3LYP calculations in order to perform their complete vibrational assignments using the scaled harmonic force fields. Structures of anhydrous form of tacrine have been optimized in gas phase and in aqueous solution. The structure of form III HCl is in agreement with the experimental determined by X-ray diffraction while the predicted IR, Raman, (1)H– (13)C NMR and UV spectra show good correlations with the corresponding experimental ones. Energy values show that the three forms of HCl can exist in both media because these energetic values decrease from 35.15 kJ/mol in gas phase to 5.51 kJ/mol in solution. For the most stable species of tacrine, the following stability order using natural bond orbital (NBO) studies was found: form I HCl > form III HCl > form I CA > FB. CA presents the higher solvation energy value, as reported for hydrochloride species of alkaloids and antihypertensive agents. The structural parameters of form III of HCl present better concordance and corresponds to that experimental observed in the solid phase. Higher topological properties of form III together with the strong N2–H26⋯Cl31 interaction could justify the presence of this form in the solid phase and in solution and the higher stabilities in both media. The gap values support the higher reactivity of form III while FB is the less reactive species in both media. Complete vibrational assignments for FB, CA and HCl species together with the corresponding scaled force constants are reported.