Research paper
Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies

https://doi.org/10.1016/j.ejmech.2018.07.041Get rights and content

Highlights

  • New fourteen 1,5-disubstituted tetrazole derivatives were synthesized.

  • Results showed that compounds exhibited high and broad antibacterial activity.

  • Tetrazole derivatives 7, 10 and 11 were found as most potent antimicrobial agents.

  • Minimal inhibitory concentrations of compound 10 and 11 were in the range 1–208 μM.

Abstract

A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1–208 μM (0.25–64 μg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S. aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 ≤ 60 μM).

Introduction

New classes of antimicrobials are needed due to the fact of increasing resistance of bacteria [[1], [2], [3]]. Different synthetic antimicrobial agents have been discovered and are being used in the clinical treatment in various communities, environments and hospital-acquired microbial infections [4,5]. In some cases presented results showed higher antibacterial activities against tested strains in comparison to reference drugs such as Fluconazole, Chlormycin or Norfloxacin [6,7].

After more than two decades of intensive studies it became clear that tetrazoles are one of the most promising class of compounds with medicinal inclination. The first tetrazole derivatives were synthesized in 1885, however till 1950 that type of compounds was not eye-catching for scientific community [8]. Wide range of synthetic techniques was developed in recent years and large number of reports presenting new facts related to chemistry of tetrazole scaffold and their applications was published [9,10]. Consequently, tetrazoles started to be more attractive for further studies due to interesting physicochemical properties and possibility of attachment of wide range of functional substituents to core arrangement. Great number of studies were concentrated to find new biologically active compounds possessing tetrazole as core moiety [[11], [12], [13], [14], [15], [16], [17]]. A few of highly effective drugs which active pharmaceutical ingredients contain the tetrazole ring are reported. Examples are Losartan, Valsartan, Irbesartan, Flomoxef and Cefonicid [[18], [19], [20], [21], [22]]. First three medications are used mainly to treat high blood pressure (hypertension), next two are semi synthetic cephalosporin antibiotics. Tetrazole ring is a common motif in all of mentioned medicines but more as a modification of structures core part. In position 1 and/or 5 of tetrazole ring are attached arrangements which are increasing solubility of compound (e.g. -sulfomethyl in Cefonicid). On the other hand this positions can be occupied by phenyl, benzoil rings substituted by –NO2, -Cl, -Br, -F to improve antimicrobial properties. Currently we can observe urgent call for development of new agents against Gram-positive, Gram-negative bacteria and yeasts. Since microbes are becoming multi-drug resistant it is very challenging to obtain new effective antibacterial agents.

It was found that incorporation of the tetrazole ring into a molecule of organic substrate relatively often leads, not only to an increase in the efficacy, but also to an enhance of the prolongation of drug action. As a rule, this is not accompanied by an increase in acute toxicity [23]. Nevertheless, the characteristic of these new molecules should show a low toxicity and known mechanism of action. According to the limited literature data, some tetrazole derivatives possess antimicrobial properties [[24], [25], [26]].

It could be stated that tetrazole based small molecules were not explored properly, especially as antimicrobial agents. It should be pointed that most of presented structures are complex and tetrazole is not dominating scaffold. Our studies are focused on small tetrazole based molecules and our major goal is to evaluate their potential in a struggle against multi-resistant bacterial strains. For the first time structural diversity of 1,5-disubstituted tetrazole derivatives have been presented and antimicrobial activity against Gram-positive and Gram-negative bacteria have been summarized followed by topoisomerase IV inhibition assay and suitable molecular docking studies.

Section snippets

Chemistry

Methods for synthesis of 1,5-disubstituted tetrazoles (5-substituted amino) are divided into four main groups [10,27]: (i) amino group or ring functionalization of 5-aminotetrazole, (ii) the nucleophilic substitution of a leaving group in the 5-position of tetrazole with amines, (iii) reactions of aminoguanidine derivatives with sodium nitrite, and (iv) various azide-mediated tetrazole ring constructions including addition of azide to carbodiimides, cyanamides, and nucleophilic substitution by

Conclusions

In this paper, a new fourteen 1H-tetrazol-5-amine based compounds have been designed, synthesized and evaluated for antimicrobial activity. Results showed that all except one of investigated compounds exhibited high and broad antibacterial activity, especially against standard Staphylococcus, Bacillus, Enterococcus, Micrococcus strains, presenting minimal inhibitory concentration values in the range 1–208 μM (0.25–64 μg/ml). Suitable thioureas used as starting material for synthesis were less

General procedure

Procedure of purchasing reagents, solvents, recording of spectra and other chemistry related methodology was already presented in previous papers [[28], [29], [30], [31],33,35].

Triethylamine (2–3 drops) was added to a suspension of suitable thiourea derivative (1 mmol), sodium azide (3.75 mmol) and mercuric chloride (1.25 mmol) in 5 ml of dry DMF. The resulting mixture was stirred for maximum 6 h at room temperature or until TLC showed end of reaction. The suspension was filtered through paper

Acknowledgments

This work was supported by the Medical University of Warsaw and carried out with the use of CePT infrastructure financed by the European Union - the European Regional Development Fund within the Operational Programme Innovative Economy for 2007–2013.

References (44)

  • B.T. Yin et al.

    Eur. J. Med. Chem.

    (2014)
  • S.F. Cui et al.

    Bioorg. Med. Chem. Lett

    (2013)
  • S.D. Diwakar et al.

    Bioorg. Med. Chem. Lett

    (2008)
  • A. Rajasekaran et al.

    Eur. J. Med. Chem.

    (2004)
  • M. Bondaryk et al.

    Bioorg. Med. Chem. Lett

    (2015)
  • K. Chauhan et al.

    Bioorg. Med. Chem. Lett

    (2014)
  • L. Pochini et al.

    Chem. Bio. Interract.

    (2008)
  • V.A. Ostrovskii et al.

    Comp. Heterocycl. Chem.

    (2008)
  • R.Y. Morjan et al.

    Bioorg. Med. Chem. Lett

    (2015)
  • Y.W. Jo et al.

    Bioorg. Med. Chem.

    (2004)
  • A. Bielenica et al.

    Eur. J. Med. Chem.

    (2015)
  • A. Bielenica et al.

    J. Inorg. Biochem.

    (2018)
  • A. Bielenica et al.

    Biomed. Pharmacother.

    (2017)
  • R.J. Scheffler et al.

    Appl. Microbiol. Biotechnol.

    (2013)
  • L. Zhang et al.

    Med. Res. Rev.

    (2014)
  • X.M. Peng et al.

    Curr. Pharmaceut. Des.

    (2013)
  • J. Davies et al.

    Microbiol. Mol. Biol. Rev.

    (2010)
  • M.J. Gemin et al.

    J. Med. Chem.

    (2000)
  • A.R. Katritsky et al.
  • L.V. Myznikov et al.

    Chem. Heterocycl. Comp.

    (2007)
  • P.S. Chaudhari et al.

    J. Org. Chem.

    (2012)
  • B. Bourdonnec

    J. Med. Chem.

    (2000)
  • Cited by (28)

    • Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis

      2022, European Journal of Medicinal Chemistry
      Citation Excerpt :

      After two decades of rigorous research, tetrazoles have been identified as one of the most promising compound classes with medicinal potential. These studies provided strong evidence that aminotetrazoles offer a favorable structural platform for developing various drugs, and agents with diverse chemotherapeutic properties, including anticancer [18], anti-inflammatory [19], antipsychotic [20], antibacterial [21,22], antitubercular [23,24], and antifungal activities [25,26] (Fig. 1). Several studies have emphasized the importance of the tetrazole moiety for potentiating the antifungal activity of various organic molecules against fungal pathogens.

    View all citing articles on Scopus
    View full text