DFT/TDDFT investigation of the stepwise deprotonation in tetracycline: pKa assignment and UV–vis spectroscopy

Regular Article

Abstract

Tetracyclines are a class of derivatives of polycyclic naphthacene carboxamide, which have attracted wide interest in the pharmaceutical field for their use as antibiotics. These molecules are characterized by a substantial conformational flexibility and by the presence of different binding sites which endow tetracycline with a noticeable capability in binding biological targets. A salient property of tetracyclines is the presence of multiple acidic groups: four equilibrium constants have been measured for the fully protonated tetracycline (TCH3+) but so far no clear information concerning the pKas of the various sites has been reported. We present here a computational investigation on the correlation between the acid–base and the spectroscopic properties of this important class of compounds. Starting from the TCH3+ species, the pKa of all the possible deprotonation sites has been computed by DFT calculations. The computed pKas nicely compare with the experimental data, within 1 pKa unit, allowing us to individuate the products of the first deprotonation. This procedure has been iteratively repeated using as starting species the products singled out from the previous deprotonation, thus individuating the stepwise products of each deprotonation step. Then, the optical absorption spectra have been computed for all the species involved in the protonation/deprotonation equilibria, comparing the results with the experimental data. The good agreement between theory and experiment has allowed us to rationalize the correlation between the solution pH and the absorption spectra.

Keywords

Theoretical pKa assignment DFT/TDDFT calculations Simulation of UV–vis spectra 

Supplementary material

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Supplementary material 1 (PDF 1598 kb)

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Authors and Affiliations

  1. 1.Istituto CNR di Scienze e Tecnologie Molecolari (ISTM), c/o Dipartimento di ChimicaUniversità di PerugiaPerugiaItaly
  2. 2.Dipartimento di Chimica and Centro di Eccellenza sui Materiali Innovativi Nanostrutturati (CEMIN)Università di PerugiaPerugiaItaly

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