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

Daniel Szulczyk; Michał A Dobrowolski; Piotr Roszkowski; Anna Bielenica; Joanna Stefańska; Michał Koliński; Sebastian Kmiecik; Michał Jóźwiak; Małgorzata Wrzosek; Wioletta Olejarz; Marta Struga

doi:10.1016/j.ejmech.2018.07.041

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

Eur J Med Chem. 2018 Aug 5:156:631-640. doi: 10.1016/j.ejmech.2018.07.041. Epub 2018 Jul 17.

Affiliations

¹ Chair and Department of Biochemistry, Medical University, 02-097 Warszawa, Poland. Electronic address: daniel.szulczyk@wum.edu.pl.
² Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
³ Chair and Department of Biochemistry, Medical University, 02-097 Warszawa, Poland.
⁴ Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; Department of Pharmaceutical Microbiology, Medical University, 02-007 Warszawa, Poland.
⁵ Bioinformatics Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
⁶ Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, 02-089 Warsaw, Poland.
⁷ Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warszawa, Poland; Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; Department of Biochemistry, Second Faculty of Medicine, Medical University of Warsaw, 02-097 Warszawa, Poland.
⁸ Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warszawa, Poland; Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
⁹ Chair and Department of Biochemistry, Medical University, 02-097 Warszawa, Poland; Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.

PMID: 30031974
DOI: 10.1016/j.ejmech.2018.07.041

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).

Keywords: 1H-tetrazol-5-amine; Antimicrobial activity; Cytotoxicity; DNA gyrase; Molecular docking; Topoisomerase type IV.

MeSH terms

Amination
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology*
Bacteria / drug effects*
Bacteria / enzymology
Bacterial Infections / drug therapy
Bacterial Infections / microbiology
Cell Line
DNA Gyrase / metabolism
DNA Topoisomerase IV / antagonists & inhibitors*
DNA Topoisomerase IV / metabolism
Drug Design
Humans
Microbial Sensitivity Tests
Models, Molecular
Molecular Docking Simulation
Tetrazoles / chemistry*
Tetrazoles / pharmacology*
Topoisomerase II Inhibitors / chemistry*
Topoisomerase II Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
Tetrazoles
Topoisomerase II Inhibitors
1H-tetrazole
DNA Topoisomerase IV
DNA Gyrase