Skip to main content
SpringerLink
Log in

Computational assessment of environmental hazards of nitroaromatic compounds: influence of the type and position of aromatic ring substituents on toxicity

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

In commemoration of Dr. Oleg Shishkin, an outstanding scientist, beloved colleague and good friend.

Abstract

This study summarizes the results of our recent QSAR and QSPR investigations on prediction of numerous aspects of environmental behavior of nitro compounds. In this study, we applied the QSAR/QSPR models previously developed by our group for virtual screening of energetic compounds, their precursors and other compounds containing nitro groups. To make predictions on the environmental impact of nitro compounds, we analyzed the trends in the change of the experimentally obtained and QSAR/QSPR-predicted values of aqueous solubility, lipophilicity, Ames mutagenicity, bioavailability, blood–brain barrier penetration, aquatic toxicity on T. pyriformis and acute oral toxicity on rats as a function of chemical structure of nitro compounds. All the models were developed using simplex descriptors in combination with random forest (RF) modeling techniques. We interpreted the possible environmental impact (different toxicological properties) in terms of dividing considered nitro compounds based on hydrophobic and hydrophilic characteristics and in terms of the influence of their molecular fragments that promote and interfere with toxicity. In particular, we found that, in general, the presence of amide or tertiary amine groups leads to an increase in toxicity. Also, it was predicted that compounds containing a NO2 group in the para-position of a benzene ring are more toxic than meta-isomers, which, in turn, are more toxic than ortho-isomers. In general, we concluded that hydrophobic nitroaromatic compounds, especially the ones with electron-accepting substituents, halogens and amino groups, are the most environmentally hazardous.

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

Similar content being viewed by others

References

  1. Zhu H, Tropsha A, Fourches D, Varnek A, Papa E, Gramatica P, Oberg T, Dao P, Cherkasov A, Tetko IV (2008) Combinatorial QSAR modeling of chemical toxicants tested against Tetrahymena pyriformis. J Chem Inf Model 48:766–784

    Article  CAS  Google Scholar 

  2. Donlon BA, Razo-Flores E, Field JA, Lettinga G (1995) Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge. Appl Environ Microbiol 61:3889–3893

    CAS  Google Scholar 

  3. Nemeikaitė-Čėnienė A, Miliukienė V, Šarlauskas V, Maldutis E, Čėnas N (2006) Chemical aspects of cytotoxicity of nitroaromatic explosives: a review. Chemija 17:34–41

    Google Scholar 

  4. Kuz’min VE, Artemenko AG, Kovdienko NA, Tetko IV, Livingstone DJ (2000) Lattice model for QSAR studies. J Mol Model 6:517–526

    Article  Google Scholar 

  5. Donlon BA, Razo-Flores E, Field JA, Lettinga G (1995) Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge. Appl Environ Microbiol 61:3889–3893

    CAS  Google Scholar 

  6. Agrawal WK, Khadikar PV (2001) QSAR prediction of toxicity of nitrobenzenes. Bioorg Med Chem 9:3035–3040

    Article  CAS  Google Scholar 

  7. Cronin MTD, Schultz TW (2001) Development of quantitative structure-activity relationships for the toxicity of aromatic compounds to Tetrahymena pyriformis: comparative assessment of the methodologies. Chem Res Toxicol 14:1284–1295

    Article  CAS  Google Scholar 

  8. Pouretedal HR, Keshavarz MH (2011) Prediction of toxicity of nitroaromatic compounds through their molecular structures. J Iran Chem Soc 8(1):78–89

    Article  CAS  Google Scholar 

  9. Ayyapan G (2013) Chemo Informatics QSAR analysis of nitroaromatic compounds toxicity. Int J Innov Res Sci En Technol 2(2):372–375

    Google Scholar 

  10. Isayev O, Rasulev B, Gorb L, Leszczynski J (2006) Structure-toxicity relationships of nitroaromatic compounds. Mol Divers 10:233–245

    Article  CAS  Google Scholar 

  11. Elidrissi B, Ousaa A, Ghamalia M, Chtitaa S, Ajanaa MA, Bouachrineb M, Lakhlifia T (2014) Toxicity in vivo of nitro-aromatic compounds: DFT and QSAR results. J Comput Aided Mol Des 4(3):28–37

    Google Scholar 

  12. Kuz’min VE, Artemenko AG, Muratov EN (2008) Hierarchical QSAR technology based on the simplex representation of molecular structure. J Comput Aided Mol Des 22:403–421

    Article  Google Scholar 

  13. Muratov EN, Artemenko AG, Kuz’min AG, Lozitsky VE, Fedchuk VP, Lozytska AS, Boschenko RN, Gridina YA (2005) Investigation of anti-influenza activity using hierarchic QSAR technology on the base of simplex representation of molecular structure. Antiv Res 65:A62–A63

    Google Scholar 

  14. Polishchuk PG, Muratov EN, Artemenko AG, Kolumbin OG, Muratov NN, Kuz’min VE (2009) Application of random forest approach to QSAR prediction of aquatic toxicity. J Chem Inf Model 49:2481–2488

    Article  CAS  Google Scholar 

  15. Kuz’min VE, Muratov EN, Artemenko AG, Gorb L, Qasim M, Leszczynski J (2008) The effect of nitroaromatics’ composition on their toxicity in vivo: novel, efficient non-additive 1D QSAR analysis. Chemosphere 72:1373–1380

    Article  Google Scholar 

  16. Kuz’min VE, Muratov EN, Artemenko AG, Gorb L, Qasim M, Leszczynski J (2008) The effects of characteristics of substituents on toxicity of the nitroaromatics: HiT QSAR study. J Comput Aided Mol Des 22:747–759

    Article  Google Scholar 

  17. Muratov EN, Kuz’min VE VE, Artemenko AG, Kovdienko NA, Gorb L, Hill F, Leszczynski J (2010) New QSPR equations for prediction of aqueous solubility for military compounds. Chemosphere 79:887–890

    Article  CAS  Google Scholar 

  18. Kovdienko NA, Polishchuk PG, Muratov EN, Artemenko AG, Kuz’min VE, Gorb L, Hill F, Leszczynski J (2010) Application of random forest and multiple linear regression techniques to QSPR prediction of an aqueous solubility for military compounds. Mol Inform 29:394–406

    Article  CAS  Google Scholar 

  19. Fourches D, Muratov EN, Tropsha A (2010) Trust, but verify: on the importance of chemical structure curation in cheminformatics and QSAR modeling research. J Chem Inf Model 50:1189–1204

    Article  CAS  Google Scholar 

  20. Ognichenko LN, Kuz’min VE, Gorb L, Hill F, Artemenko AG, Polischuk PG, Leszczynski J (2012) QSPR prediction of lipophilicity for organic compounds using random forest technique on the basis of simplex representation of molecular structure. Mol Inform 31:273–280

    Article  CAS  Google Scholar 

  21. Sushko Iu, Novotarskyi S, Korner R, Pandey AK et al (2010) Applicability domains for classification problems: benchmarking of distance to models for ames mutagenicity set. J Chem Inf Model 50:2094–2111

    Article  CAS  Google Scholar 

  22. Golovenko NYA, Kuz’min VE, Artemenko AG et al (2011) Prediction of bioavailability of drugs by the method of classification models. J Klin Inform Telemed 7:88–92

    Google Scholar 

  23. Kosinskaya AP, Ognichenko LN, Polishchuk PG, Kuz’min VE (2014) Structural and functional interpretation of 2D QSAR models of structure-blood-brain barrier permeability relationship of organic compounds. In: Abstracts of the 20th international conference on EuroQSAR (understanding chemical–biological interactions). St-Petersburg, Russia, 31 Aug–Sep 4, 2014, p 147

  24. Tinkov OV, Polishchuk PG, Artemenko AG, Kuz’min VE (2012) The investigation of acute toxicity and physical-chemical properties of organic compounds. J Sib Fed Univ 5:95–104

    CAS  Google Scholar 

  25. Li X, Chen L, Cheng F et al (2014) In silico prediction of chemical acute oral toxicity using multi-classification methods. J Chem Inf Model 54:1061–1069

    Article  CAS  Google Scholar 

  26. Heytler PG (1979) Uncouplers of oxidative phosphorylation. Methods Enzymol 55:442–462

    Google Scholar 

  27. Nelson DL, Cox MM (2000) Lehniger principles of biochemistry. Worth Publishers, New York

    Google Scholar 

Download references

Acknowledgments

We thank ERDC for financial support (grant number W912HZ-13-P-0037). The computation time was provided by the Extreme Science and Engineering Discovery Environment (XSEDE) by National Science Foundation Grant Number OCI-1053575 and XSEDE award allocation Number DMR110088 and by the Mississippi Center for Supercomputer Research. EM is grateful for financial support from the US National Institutes of Health (GM 096967 and GM66940). The use of trade, product or firm names in this report is for descriptive purposes only and does not imply endorsement by the US Government. Results in this study were funded and obtained from research conducted under the Environmental Quality Technology Program of the United States Army Corps of Engineers by the US Army ERDC. Permission was granted by the Chief of Engineers to publish this information. The findings of this report are not to be construed as an official Department of the Army position unless so designated by other authorized documents.

Author information

Authors and Affiliations

  1. Department of Chemistry, T.G. Shevchenko State University, 3300, Tiraspol, Moldova

    Oleg V. Tinkov

  2. Department of Molecular Structures and Chemoinformatics, A.V. Bogatsky Physical–Chemical Institute NAS of Ukraine, Odessa, 65080, Ukraine

    Luidmila N. Ognichenko, Victor E. Kuz’min & Anna P. Kosinskaya

  3. HX5, LLC, Vicksburg, MS, 39180, USA

    Leonid G. Gorb

  4. Odessa National Medical University, 2, Valikhovskiy Lane, Odessa, 65026, Ukraine

    Anna P. Kosinskaya

  5. Chemical-Technological Department, Odessa National Polytechnic University, Odessa, 65000, Ukraine

    Nail N. Muratov

  6. Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA

    Eugene N. Muratov

  7. US Army Research and Development Center, 3909 Halls Ferry Rd., Vicksburg, MS, 39180, USA

    Frances C. Hill

  8. Department of Civil and Environmental Engineering, Interdisciplinary Nanotoxicity Center, Jackson State University, Jackson, MS, 39217, USA

    Jerzy Leszczynski

Authors
  1. Oleg V. Tinkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luidmila N. Ognichenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor E. Kuz’min
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonid G. Gorb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna P. Kosinskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nail N. Muratov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eugene N. Muratov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Frances C. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jerzy Leszczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerzy Leszczynski.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLS 842 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tinkov, O.V., Ognichenko, L.N., Kuz’min, V.E. et al. Computational assessment of environmental hazards of nitroaromatic compounds: influence of the type and position of aromatic ring substituents on toxicity. Struct Chem 27, 191–198 (2016). https://doi.org/10.1007/s11224-015-0715-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-015-0715-4

Keywords

Search

Navigation