Skip to main content

Advertisement

SpringerLink
Log in

The Properties of Solutions of Isoniazid in Water and Dimethylsulfoxide

  • Published:
Journal of Solution Chemistry Aims and scope Submit manuscript

Abstract

The density, viscosity and conductivity of binary mixtures of the front line antitubercular drug isoniazid (INH), in aqueous solution and dimethylsulfoxide (DMSO) solution, were determined at various temperatures (25, 37 and 55 °C) up to 0.3 mol⋅L−1 of INH. The apparent molar volumes were calculated from the density data. In the INH + water system the apparent molar volume of INH changed smoothly, whereas in the INH + DMSO system it passes through a maximum. Also, both systems showed pronounced maxima in their viscosity and conductivity isotherms. In addition, UV–Vis, FT-IR and 1H NMR spectroscopy were performed on the solutions. On the basis of this data, the predominant molecular interactions occurring between INH and water and between INH and DMSO were found to be hydrogen bonds. Furthermore, the susceptibility profile of DMSO, INH and its combination was studied against M. tuberculosis H37Rv and the minimum inhibitory concentration (MIC) determined. The results suggest a synergistic effect of INH at sub-MIC concentrations and DMSO.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Aguilar, J.S., Roy, D., Ghazal, P., Wagner, E.K.: Dimethyl sulfoxide blocks herpes simplex virus-1 productive infection in vitro acting at different stages with positive cooperativity. Application of microarrays analysis. BMC Infect. Dis. 2, 9–19 (2002)

    Article  CAS  Google Scholar 

  2. Jagannath, C., Reddy, V.M., Gangadharam, P.R.: Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide. J. Antimicrob. Chemother. 35, 390–391 (1995)

    Article  Google Scholar 

  3. Brennan, M.J., Fruth, U.: Global forum on TB vaccine research and development. Tuberculosis 81, 365–368 (2001)

    Article  CAS  Google Scholar 

  4. Stover, C.K., Warrener, P., VanDevanter, D.R., Sherman, D.R., Arain, T.M., Langhorne, M.H., Anderson, S.W., Towell, J.A., Yan, Y., McMurray, D.N., Krelswirth, B.N., Barry, C.E., Baker, W.R.: A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962–966 (2000)

    Article  CAS  Google Scholar 

  5. Caldwell, G.W., Ritchie, D.M., Masucci, J.A., Hageman, W., Yan, Z.: The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery. Curr. Top. Med. Chem. 1, 353–366 (2001)

    Article  CAS  Google Scholar 

  6. Markarian, S.A., Terzyan, A.M.: Surface tension and refractive index of dialkylsulfoxide + water mixtures at several temperatures. J. Chem. Eng. Data 52, 1704–1709 (2007) and references cited therein

    Article  CAS  Google Scholar 

  7. Eisenberg, D., Kauzmann, W.: The Structure and Properties of Water. Oxford University Press, New York and Oxford (1969)

    Google Scholar 

  8. Jahagirdar, D.V., Arbad, B.R., Mirgane, S.R., Lande, M.K., Shankarwar, A.G.: Density, ultrasonic velocity and viscosity measurements of four pharmacologically significant drugs in methanol at 25 °C. J. Mol. Liq. 75, 33–43 (1998)

    Article  CAS  Google Scholar 

  9. Barsoum, B.N., Kamel, M.S., Diab, M.M.A.: Spectrophotometric determination of isoniazid and rifampicin from pharmaceutical preparations and biological fluids. Res. J. Agric. Biol. Sci. 4, 471–484 (2008)

    CAS  Google Scholar 

  10. Favila, A., Gallo, M., Glossman-Mitnik, D.: CHIH–DFT determination of the molecular structure infrared spectra, UV spectra and chemical reactivity of three antitubercular compounds: rifampicin, isoniazid and pyrazinamide. J. Mol. Model. 13, 505–518 (2007)

    Article  CAS  Google Scholar 

  11. Gunasekaran, S., Sailatha, E., Seshardi, S., Kumaresan, S.: FTIR, FT Raman spectra and molecular structural confirmation of isoniazid. Indian J. Pure Appl. Phys. 47, 12–18 (2009)

    CAS  Google Scholar 

  12. Evangelopoulos, D., Bhakta, S.: Rapid methods for testing inhibitors of mycobacterial growth. Methods Mol. Biol. 642, 193–201 (2010)

    Article  CAS  Google Scholar 

  13. Isoniazid. In: Handbook of Anti-Tuberculosis Agents. Tuberculosis, vol. 88, pp. 112–116. (2008)

Download references

Acknowledgements

This work was partly supported by the Armenian State Committee of Science. S.B. acknowledges a New Investigators Research Grant from Medical Research Council, UK (grant G0801956).

Author information

Authors and Affiliations

  1. Department of Chemistry, Yerevan State University, 0025, Yerevan, Armenia

    S. A. Markarian, L. R. Harutyunyan & E. K. Pepoyan

  2. Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX, UK

    D. Evangelopoulos, J. D. Guzman & S. Bhakta

  3. Department of Medical Microbiology, Royal Free Hospital, University College London, Rowland Hill Street, London, NW3 2PF, UK

    T. D. McHugh

Authors
  1. S. A. Markarian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Evangelopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. R. Harutyunyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. K. Pepoyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. D. Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. D. McHugh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Bhakta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. A. Markarian.

Appendices

Appendix A: Densities, Viscosities, and Conductivities of the INH + H2O and INH + DMSO systems

Table 1 Densities of the INH + H2O system at different temperatures
Full size table
Table 2 Densities of the INH + DMSO system at different temperatures
Full size table
Table 3 Relative viscosities of the INH + H2O system at different temperatures
Full size table
Table 4 Relative viscosities of the INH + DMSO system at different temperatures
Full size table
Table 5 Conductivity of the INH + H2O system at different temperatures
Full size table
Table 6 Conductivity of the INH + DMSO system at different temperatures
Full size table

Appendix B: In Vitro Susceptibility of M. tuberculosis in the Presence of INH–DMSO

M. tuberculosis H37Rv was grown at 37 °C as a standing culture in 30 mL universals in Middlebrook 7H9 broth medium supplemented with 10 % (v/v) albumin–dextrose–catalase (ADC; Difco), glycerol (0.2 % v/v) and 0.05 % Tween-80, until reaching a turbidity close to McFarland standard 1. The effect of DMSO, INH and the combination of the two (DMSO–INH) on the growth of M. tuberculosis was tested using spot culture growth inhibition assay [13]. Briefly, INH dissolved in sterile distilled water and DMSO was mixed with 5 mL of Middlebrook 7H10 agar medium, supplemented with 10 % (v/v) oleic acid–albumin–dextrose–catalase (OADC, Difco) and glycerol (0.5 % v/v) in a six well plate. Then, 10 μL of M. tuberculosis H37Rv cell suspension (105 cells⋅mL−1) was spotted in the center of each well. The plates were sealed and incubated at 37 °C for 2 weeks. Following incubation the plates were photographed using a digital camera.

The effect of DMSO in M. tuberculosis H37Rv viability was evaluated using the spot culture inhibition assay [13]. As shown in Fig. 11A, DMSO has nearly inhibited the growth of M. tuberculosis at 5 %. Previous reports have shown that DMSO at 5 % is able to stop the growth of M. tuberculosis [3]. In addition, when DMSO was tested against M. bovis BCG, the growth was completely inhibited at 3 % DMSO (Fig. 12). Using the same assay, the MIC of INH against M. tuberculosis H37Rv was determined to be 0.05 mg⋅L−1 (Fig. 11B), a value in agreement with previously published data [12]. M. tuberculosis cells were able to grow at 0.01 mg⋅L−1 INH; however, in the presence of different concentrations of DMSO, the susceptibility pattern changed. The combination of 0.01 mg⋅L−1 of INH and 0.5 % DMSO were able to inhibit the growth of M. tuberculosis (Fig. 11C). Neither INH alone at 0.01 mg⋅L−1 nor DMSO at 0.5 % were able to kill the bacteria. Therefore, we conclude that these two compounds have a synergistic relation between them making them more potent in combination. Further research should prove whether DMSO is able to act synergistically with other antimycobacterials, and whether the presence of DMSO sensitizes or modifies the cell wall of mycobacteria thereby making it more susceptible to antimicrobial agents.

Fig. 11
figure 11

Susceptibility to DMSO and INH alone and in combination against M. tuberculosis H37Rv using the spot culture growth inhibition assay. M. tuberculosis cells were grown as spots in the middle of each well. A well with no visible cell growth indicates the killing effect of the compound. A Susceptibility to DMSO against M. tuberculosis cells. The percentage (%) of DMSO concentration is mentioned for each well. B Susceptibility to INH against M. tuberculosis cells. The concentration of INH is given in mg⋅L−1. C Effect of DMSO in presence of INH at 0.01 mg⋅L−1 against M. tuberculosis cells. The percentage (%) of DMSO concentration is mentioned for each well

Full size image
Fig. 12
figure 12

Susceptibility of DMSO against M. bovis BCG using the spot culture growth inhibition assay. The percentage (%) of DMSO concentration is mentioned for each well. M. bovis BCG cells were grown as spots in the middle of each well. A well with no visible cell growth indicates the killing effect of the compound

Full size image

Rights and permissions

Reprints and permissions

About this article

Cite this article

Markarian, S.A., Evangelopoulos, D., Harutyunyan, L.R. et al. The Properties of Solutions of Isoniazid in Water and Dimethylsulfoxide. J Solution Chem 41, 1462–1476 (2012). https://doi.org/10.1007/s10953-012-9883-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10953-012-9883-7

Keywords

Search

Navigation