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A theoretical study of salicylate oxidation for ADME prediction

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Abstract

The salicylic acid oxidation has been explained by a mechanism involving single electron transfer oxidation and single hydrogen transfer using quantum chemistry calculations at the B3LYP theory level, together with the 6-311G** basis set. These methods were employed to obtain energy (E), ionization potential (IP), bond dissociation energies (BDE), and spin density distribution of the salicylic acid. The results show no discrepant behaviors between electron and hydrogen transfer in the regioselective hydroxylation of salicylic acid by cytochrome P-450. The unpaired electron remains localized on the O7 phenolic oxygen (0.26 and 0.38), C1 carbon atoms at the carbonyl group (0.12 and 0.28), C2 carbon atom at the hydroxyl group (0.15 and 0.00), C3 carbon atom at the hydroxyl group (0.22 and 0.30), and C5 carbon atom (0.40 and 0.41) for cation free radical and semiquinone form, respectively. Calculations of spin densities showed that chemistry reactivity is more favored in the positions C5 > C3 > C1 to form salicylate derivatives. These results supported the salicylic acid as scavenger derivatives in the lipid peroxidation. Furthermore, we suggest a conventional proton and secondary electron abstraction, and semiquinone form by [1,5] hydrogen shift between phenol and carbonyl groups.

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Acknowledgments

LQF thanks the CNPq for the financial support.

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Authors and Affiliations

  1. Faculdade de Farmácia, Laboratório de Química Farmacêutica, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, PA, 66075-110, Brazil

    R. Santos Borges, A. P. Salgado Mendes & B. H. Souza e Silva

  2. Faculdade de Química, Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, PA, 66075-110, Brazil

    C. Nahum Alves

  3. Faculdade de Biologia e Biomedicina, Laboratório de Neuroquímica Molecular e Celular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, 66075-110, Brazil

    J. L. Martins do Nascimento

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  1. R. Santos Borges
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  2. A. P. Salgado Mendes
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  3. B. H. Souza e Silva
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  4. C. Nahum Alves
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  5. J. L. Martins do Nascimento
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Correspondence to R. Santos Borges.

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Santos Borges, R., Salgado Mendes, A.P., Souza e Silva, B.H. et al. A theoretical study of salicylate oxidation for ADME prediction. Med Chem Res 20, 269–273 (2011). https://doi.org/10.1007/s00044-010-9320-7

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  • DOI: https://doi.org/10.1007/s00044-010-9320-7

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