A theoretical study of the interaction of anhydrotetracycline with Al(III).

In this article the complexation of anhydrotetracycline (AHTC), the major toxic decomposition product of the antibiotic tetracycline, with Al(III) has been investigated using the AM1 semiempirical and ab initio Hartree-Fock levels of theory. Different modes of complexation have been considered with the structure of tetra- and pentacoordinated complexes being fully optimized. In the gas phase, processes ii and iii, which lead to the complexes with stoichiometry MHL2+, are favored. Structure II ([AlLH2(OH)(H2O)]2+) has the metal coordinated to the O11 and O12 groups and the O3 group protonated and is the global minimum on the potential energy surface for the interaction. In water solution, the Al(III) is predicted to form predominantly a tetracoordinated complex at the Oam and O3 site (V) of the AHTC with the stoichiometry MH2L3+ (process i). The experimental proposal is the complexed form with the metal ion coordinated to the O11-O12 moiety (site II). The intramolecular proton transfer, which leads to the most stable Al(III)-AHTC MHL2+ complex, has not been considered by the experimentalists. The experimental structure was found to be unfavorable in our calculations in both gas phase and water solution. All the semiempirical results are in perfect agreement with the ab initio calculations. So, we suggest that the experimental assignments should be revised, taking into account the results obtained in the present study.

Conformational analysis of the anhydrotetracycline molecule: a toxic decomposition product of tetracycline.

Anhydrotetracycline (AHTC) is a toxic decomposition product of the widely used antibiotic tetracycline (TC). The side effects of AHTC have been attributed to the conformational changes in the ring system. In the present study a systematic conformational analysis has been carried out using the semiempirical quantum mechanical AM1 model. The conformational pH dependence has been analyzed through the study of all the ionized species. The results obtained showed two distinct families of conformation, referred to as A and B, with the interconversion process involving a rotation around the C4a-C12a bond. The solvent effect has been considered using the continuum model COSMO. From the population analysis in the gas phase, we conclude that form A should be dominant for the LH3+ and LH2 +/- species and B is the preferred conformer for the L2- ionized form (97.54%). For the LH- derivative, we predict that both conformations should be present in the equilibrium mixture in the gas phase, with the relative concentration found to be 68.47% (A) and 31.53% (B). The inclusion of the solvent does not change the A/B equilibrium for the LH3+ and LH2 +/- species. However, for the LH- form, the equilibrium is shifted to conformer A in water solution. The population analysis in water solution for the L2- suggest the following relative concentrations: A (34.46%) and B (65.54%). The biological activity of the TC parent compound is attributed to the zwitterionic species, which should adopt a twisted conformation. According to the results obtained in the present study, the most abundant form of the LH2 +/- zwitterionic species for the AHTC molecule is the extended one (100% in both the gas phase and water solution). Therefore, from a pharmacodynamic point of view, this conformational difference should be taken into account in order to explain the toxic effects of the anhydrous derivative. Another point related to the structure-activity relationship was analyzed through the investigation of the tautomerization process LH2(0)-->LH2 +/-. The result obtained suggests that the LH2(0) tautomer should be dominant in the gas phase (nonpolar solvent) and adopt a conformation classified as B. In water solution, the tautomer LH2 +/- is present as conformer A (96%). This result is in agreement with the conformation changes involved in the tautomerization process for the OTC active derivative.

Conformational analysis of the antimalarial agent quinidine.

Quinidine is an active antimalarial compound extracted from the bark of Cinchona trees. The activity differences among structurally related molecules appears to depend on the absolute stereochemistry of some functional groups, a result that stimulated a detailed conformational analysis of these molecules of biological interest. In the present study, the potential energy surface (PES) for the antimalarial agent quinidine (C20H24O2N2) has been comprehensively investigated using the molecular mechanics (MM) and quantum mechanical semiempirical AM1 and PM3 methods. Six distinct minimum energy conformations were located on the multidimensional PES and also characterized as true minima through harmonic frequency analysis. The relative stabilities and thermodynamic properties are reported. The coexistence of different conformers is discussed for the first time in the literature based on the transition state (TS) structures located on the PES for the quinidine molecule. The theoretical results reported in the present study are in agreement with the experimental proposal, based on NMR data, that there are two conformations existing in solution for the quinidine molecule.