Skip to main content
SpringerLink
Log in

A theoretical investigation on decarboxylation mechanism of antibiotic para-aminosalicylic acid to highly toxic form meta-aminophenol

  • Original Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

The antibiotic para-aminosalicylic acid (PAS) is decomposed into its decarboxylated product, meta-aminophenol, with a series of toxicity symptoms including hemolytic anemia. The present trial investigates the decarboxylation mechanism of PAS, along with an in-detail assessment of the potential energy profiles, geometries, kinetic, and thermodynamic preference of the process. Further, the effects of solvent and pH on the process have been fully investigated. B3LYP-D3(BJ)/G4MP2 calculations have been executed on the para-aminosalicylic acid decomposition with a view to clarify the aqueous thermal decarboxylation and pH influences on the mechanism. The decomposition process can only be described accurately by the inclusion of solvent not only as a reaction medium but also as an active contributor to the chemical process. We further found an optimal preference with respect to energy barriers for the process with decreasing pH. Also, experiments showed the reduction in PAS absorbance with fall in pH. These together suggested the decrease of rate of decarboxylation with pH increase. Finally, we concluded that increasing pH reduces the reaction rate and in the pH around 10, the reaction rate reaches zero and it completely halts. We assume that this experiment can pave the way for advanced experimental and theoretical researches in the drug degradation mechanisms field and the effect of pH and solvent on the process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information file.

References

  1. Tao LJ, Chen WT, Jing L, Ji Q, Ren JL (2017) A network pharmacology approach to establish the pharmacological mechanism of JiaWeiXianJiTang on inflammatory bowel disease. Biomed Rep 6(3):272–278

  2. Dasgupta Q, Madras G, Chatterjee K (2016) Controlled release kinetics of p-aminosalicylic acid from biodegradable crosslinked polyesters for enhanced anti-mycobacterial activity. Acta Biomater 30:168–176

  3. Vetuschi C, Ragno G, Mazzeo P (1988) Determination of p-aminosalicylic acid and m-aminophenol by derivative UV-spectrophotometry. J Pharm Biomed Anal 6(4):383–391

    Article  CAS  Google Scholar 

  4. Kornblum SS, Sciarrone BJ (1964) Decarboxylation of p-aminosalicylic acid in the solid state. J Pharm Sci 53(8):935–941

    Article  CAS  Google Scholar 

  5. Pande GS (1967) Thermal decarboxylation. J Sci Ind Res India 26(9):393 

  6. Anderson DMW, Garbutt S (1963) 597. Studies on uronic acid materials. Part VII. The kinetics and mechanism of the decarboxylation of uronic acids. J Chem Soc 3204–3210

  7. Jivani SG, Stella VJ (1985) Mechanism of decarboxylation of p-aminosalicylic acid. J Pharm Sci 74(12):1274–1282

    Article  CAS  Google Scholar 

  8. Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132(15):154104

  9. Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J Chem Phys 98(45):11623–11627

  10. Pritchard BP, Altarawy D, Didier B, Gibson TD, Windus TL (2019) New basis set exchange: an open, up-to-date resource for the molecular sciences community. J Chem Inf Model 59(11):4814–4820

    Article  CAS  Google Scholar 

  11. Zahedi E, Shaabani S, Shiroudi A (2017) Following the molecular mechanism of decarbonylation of unsaturated cyclic ketones using bonding evolution theory coupled with NCI analysis. J Phys Chem A 121(44):8504–8517

    Article  CAS  Google Scholar 

  12. Li X, Frisch MJ (2006) Energy-represented direct inversion in the iterative subspace within a hybrid geometry optimization method. J Chem Theory Comput 2(3):835–839

    Article  CAS  Google Scholar 

  13. Jacobsen H, Bérces A, Swerhone DP, Ziegler T (1997) Analytic second derivatives of molecular energies: a density functional implementation. Comput Phys Commun 100(3):263–276

  14. Bérces A, Dickson RM, Fan L, Jacobsen H, Swerhone D, Ziegler T (1997) An implementation of the coupled perturbed Kohn-Sham equations: perturbation due to nuclear displacements. Comput Phys Commun 100(3):247–262

    Article  Google Scholar 

  15. Fukui K (1981) The path of chemical reactions-the IRC approach. Acc Chem Res 14(12):363–368

    Article  CAS  Google Scholar 

  16. Fukui K (1970) Formulation of the reaction coordinate. J Phys Chem 74(23):4161–4163

    Article  CAS  Google Scholar 

  17. Curtiss LA, Redfern PC, Raghavachari K (2007) Gaussian-4 theory using reduced order perturbation theory. J Chem Phys 127(12):124105

    Article  Google Scholar 

  18. Narayanan B, Redfern PC, Assary RS, Curtiss LA (2019) Accurate quantum chemical energies for 133000 organic molecules. Chem Sci 10(31):7449–7455

  19. Hadidi S, Shiri F, Norouzibazaz M (2020) Theoretical mechanistic insight into the gabapentin lactamization by an intramolecular attack: Degradation model and stabilization factors. J Pharm Biomed 178:112900

  20. Barone V, Cossi M (1998) Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J Phys Chem A 102(11):1995–2001

    Article  CAS  Google Scholar 

  21. Cossi M, Rega N, Scalmani G, Barone V (2003) Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J Comput Chem 24(6):669–681

    Article  CAS  Google Scholar 

  22. Neese F (2012) The ORCA program system. Wiley Interdiscip Rev Comput Mol Sci 2(1):73–78 

  23. Marvin 20.20 (2020) ChemAxon (http://www.chemaxon.com)

  24. Poater J, Fradera X, Duran M, Solà M (2003) The delocalization index as an electronic aromaticity criterion: application to a series of planar polycyclic aromatic hydrocarbons. Chem Eur J 9(2):400–406

  25. Poater J, Duran M, Sola M, Silvi B (2005) Theoretical evaluation of electron delocalization in aromatic molecules by means of atoms in molecules (AIM) and electron localization function (ELF) topological approaches. Chem Rev 105(10):3911–3947

  26. Kruszewski J, Krygowski TM (1972) Definition of aromaticity basing on the harmonic oscillator model. Tetrahedron Lett 13(36):3839–3842

  27. Krygowski T (1993) Crystallographic studies of inter-and intramolecular interactions reflected in aromatic character of. pi.-electron systems. J Chem Inf Comput Sci 33(1):70–78

    Article  CAS  Google Scholar 

  28. Dapprich S, Frenking G (1995) Investigation of donor-acceptor interactions: a charge decomposition analysis using fragment molecular orbitals. J Phys Chem 99(23):9352–9362

  29. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592

  30. Rodriquez C, Williams I (1997) Ring strain energy and enthalpy of formation of oxiranone: an ab initio theoretical determination. J Chem Soc, Perkin Trans 2 5: 953-958

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Internal Medicine Department, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Niloofar Hemati & Rasool Parvizi

  2. Department of Inorganic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran

    Farshad Shiri & Saba Hadidi

  3. Medical Biology Research Center (MBRC), Kermanshah University of Medical Sciences, Kermanshah, Iran

    Farshad Shiri

  4. R.R College of Pharmacy, Bangalore, India

    Elham Mohammadi

  5. Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Mohammad Hosein Farzaei

Authors
  1. Niloofar Hemati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farshad Shiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saba Hadidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elham Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rasool Parvizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad Hosein Farzaei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

• N. Hemati: Niloofar Hemati conceived of the presented idea and supervised the project.

• F. Shiri: Farshad Shiri planned and carried out the simulations.

• S. Hadidi: Saba Hadidi planned and carried out the simulations.

• E. Mohammadi: Elham Mohammadi took the lead in writing the manuscript.

• R. Parvizi: Rasool Parvizi took the lead in writing the manuscript.

• M. H. Farzaeie: Mohammad Hosein Farzaeie supervised the project.

• All authors provided critical feedback and helped shape the research, analysis, and manuscript.

• All authors drafted the work or revised it critically for important intellectual content.

Corresponding author

Correspondence to Mohammad Hosein Farzaei.

Ethics declarations

Conflict of interest

The authors declare they have no conflict of interests

Consent to publish

All authors approved the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethical approval

1) This material (partially or in full) is the authors’ own original work, which has not been previously published elsewhere.

2) The paper is not currently being considered for publication elsewhere.

3) The paper reflects the authors’ own research and analysis in a truthful and complete manner.

4) No data, text, or theories by others are presented as if they were the author’s own.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

1. PAS is decomposed into its decarboxylation product, meta-aminophenol.

2. The solvent is not only as a reaction medium but further it acts as an active contributor in the chemical process

3. The process shows a significant rate reduction by increasing pH.

Supplementary information

ESM 1

(DOCX 19393 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hemati, N., Shiri, F., Hadidi, S. et al. A theoretical investigation on decarboxylation mechanism of antibiotic para-aminosalicylic acid to highly toxic form meta-aminophenol. Struct Chem 32, 1053–1060 (2021). https://doi.org/10.1007/s11224-020-01676-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-020-01676-9

Keywords

Search

Navigation