A novel method for the synthesis of aryl-substituted guanidines in good overall yields is presented; it consists of the acidic cleavage of 2-(arylamino)-4,6-dimethoxypyrimidines, which were prepared by coupling aryl bromides with 2-amino-4,6-dimethoxypyrimidine. This methodology introduces a new means of protection for the guanidine functionality.

Based on our previous positive results with bis-guanidine-like diaromatic compounds as DNA minor groove binders, we propose a new family: bis-2-amino-1,4,5,6-tetrahydropyrimidines. According to calculated parameters, these dicationic systems would have a more suitable size and lipophilicity for binding into the minor groove than previous series. Moreover, their DFT-optimised structures and docking into an AT oligomer model show that they would bind in the minor groove with good strength and without energy penalty. Hence, we prepared compounds 4 a–c and evaluated their binding to ssDNA and poly(dA-dT)₂ by thermal denaturation experiments. The results showed that 4 a (CO) and 4 d (NH) were the best DNA binders. Compared to the previous series, 4 a–d are better binders than bis-guanidiniums but poorer than bis-2-aminoimidazolinium derivatives. Moreover, circular dichroism experiments using ssDNA and poly(dA-dT)₂ confirmed binding into the minor groove. Based on our computational design as well as biophysical studies, we have been able to determine that the optimal interaction of guanidine-like dications in the minor grove occurs with bis-2-aminoimidazolinium systems.

We have calculated the complexes formed by guanidine/guanidinium and HCl/Cl⁻, HNO₃/NO₃⁻ and H₂SO₄/HSO₄⁻ both in the gas and aqueous Polarizable Continuum Model (PCM) phase to understand the effect that solvation has on their interaction energies. In the gas phase, the cation–anion complexes are much more stable than the rest; however, when PCM-water is considered, this energetic difference is not as large due to the extra stabilization that the ions suffer when in aqueous solution. All the complexes were analyzed in terms of their AIM and NBO properties. In all cases, water solvation seems to “dampen” those properties observed in the gas phase. The values of Nucleus Independent Chemical Shift (NICS)(1) and NICS(2) indicate a huge influence of the proximity of the carbon atom for short distances; thus, the 3D NICS values on the van der Waal isosurfaces have been used to evaluate the possible Y-aromaticity of the guanidinium system. The isosurface in this system is more similar to cyclohexane than to benzene as indication of poor aromaticity. Copyright © 2013 John Wiley & Sons, Ltd.

The α₁-adrenoceptor is a target for the treatment of several conditions from hypertension to benign prostatic hyperplasia. In this paper, we describe a new analysis approach to explore the conformational space of several ligands of the α₁-adrenoceptor and we also present the calculation of their proton affinity and basicity. For each compound a conformational search followed by a semi-empirical optimisation was performed and a selection of conformations for each ligand was subjected to further optimisation using density functional theory methods. Different positions were explored to determine the favoured site of protonation, and then, the proton affinity (in the gas phase) and basicity (using the polarisable continuum model for the aqueous solution) were calculated for each of them. In addition, an alternative method using one explicit water molecule in combination with the polarisable continuum model for aqueous solvent was explored. Moreover, the acid dissociation constant (pK_a) in water of these 26 compounds was calculated because this is an important parameter for a ligand when binding to its receptor. The experimental pK_a values of six of these ligands and those of two compounds with a very low and a very large pK_a were used to validate the theoretical methodology. Copyright © 2011 John Wiley & Sons, Ltd.

A revision of the literature on the nitration of tetrahydroquinolines yielded a number of inconsistencies. Thus, we have carried out a thorough study on the nitration of tetrahydroquinoline and several of its N-protected derivatives both experimentally and at theoretical level. Usually, nitration is carried out in acidic conditions and, thus, tetrahydroquinoline would be N-protonated; however, if the amino group is protected, the neutral system will be the one undergoing nitration. Different protecting groups have been explored varying, not only electronic and steric effects, but also deprotection conditions. Additionally, different reagents and reaction conditions have been investigated. From this study we have been able to achieve total regioselectivity for nitration at the 6-position. A very detailed NMR study has been carried out to unequivocally characterise the four nitro isomers. In parallel, a computational study has been performed that is in agreement with the experimental results obtained. With this purpose, all the σ complexes of the four nitro isomers neutral and N-protonated have been optimized both in gas and water condensed phases by using the B3LYP/6-31++G** level of computation.