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  • The lack of biological activity http www

    2022-05-12

    The lack of biological activity of this family of compounds against T. cruzi is quite unexpected and cannot be attributable simply to the presence of a hydroxyl group at C-1. In fact, either compound 6 or risedronate (5), both bearing a hydroxyl group at C-1, are effective inhibitors of TcFPPS.21, 22, 53 Why our title compounds are devoid of antiparasitic activity against T. cruzi?. In risedronate the nitrogen Bindarit is bonded one position further than is bonded in our compounds. Evidently, the position of this nitrogen atom has a strong influence in the observed biological activity. Removal of the hydroxyl group keeping the nitrogen atom at C-3 results in extremely potent 2-alkylaminoethyl bisphosphonates, such as 12–14. Therefore, these two groups did not produce the expected synergistic effect. On the contrary, the combination of these two groups reduced their activity. We have attempted to rationalize this behavior using density functional theory (DFT) calculations. Analogs of 12–14 (12a) and 27–31 (27a) carrying, for the sake of simplicity, N-methylamino groups instead of longer alkylamino moieties were submitted to energy minimizations at the B3LYP/6-311+G(d,p) level, simulating the presence of water as solvent with the polarizable continuum method (PCM). In order to reproduce better the possible conformation of these compounds in the biological environment, the molecules 12a and 27a were considered to have the acidic hydrogen atoms expected to appear at physiological pH (≈6.5), that is two hydrogen atoms for 12a, and only one for the more acidic 27a.39, 40 One magnesium atom was added to complete each molecule (Fig. 3). Results show that the minimization always leads to the formation of a six-membered ring containing C-1, both P atoms, two O atoms and the Mg atom, being the distance between each O and the Mg of 1.91–1.96Å. However, the ‘exocyclic’ atoms generate different hydrogen bond patterns (even in the simulated water environment) with distinct geometries and energies. It is known that the strength of the hydrogen bonds depends, under the geometric criteria, on acceptor-hydrogen distances as short as possible (for very strong bonds, the distance can be even shorter than 2Å), and donor-hydrogen-acceptor angles as close to 180° as possible.54, 55Table 2 shows the results for the main conformers of each analog. For 12a, the most stable geometry shows a strong ‘1,3-diaxial’ hydrogen bond between an axial O–H and an axial O bonded to different P atoms (dH–O=1.82Å), and a very strong hydrogen bond between the other acidic hydrogen (equatorial) and the nearby nitrogen atom (dH–N=1.68Å), which fixes the conformation of the side chain (Fig. 4). Another conformer, with similar energy, has the same hydrogen bond features but a different conformation of the carbon chain. On the other hand, compound 27a does not have two acidic hydrogens. Thus, the only acidic hydrogen should be involved in either the 1,3-diaxial H-bond interaction or the interaction with the N. The most stable geometry (Fig. 4, Table 2) shows the strong diaxial interaction (dH–O=1.62Å, θ=161°), and two weaker interactions (Table 2), as deduced from directional factors (θ=124–134°). Other conformations, with higher energies show other bonding patterns: conformer 4 shows a similar pattern, whereas conformers 2 and 3 show a strong hydrogen bond between the acidic hydrogen and the nitrogen atom, as occurred with 12a (Table 2). However, these conformers have energies surpassing in about 2kcal/mol that of the most stable conformer. The strength of the bond in conformer 3 of 27a is equivalent to that observed for the main conformer of 12a, but the hydrogen bond in conformer 2 is slightly weaker, as deduced from the distance and angles (Table 2). These results might be a clue that in compounds like 12–14, having two acidic hydrogen atoms, the flexibility of the carbon chain is strongly reduced, to the point of giving an almost ‘fixed’ conformation carrying the nitrogen atom in a favorable arrangement for biological action. On the other hand, compounds like 27–31, which carry both a hydroxyl group at C-1 and a N atom on C-2 display a higher flexibility of the carbon chain, thus generating a manifold of conformations, for which only some (less stable) display the arrangement needed for an optimal molecular recognition.