1. Academic Validation
  2. Development of (4-methoxyphenyl)-1H-tetrazol-5-amine regioisomers as a new class of selective antitubercular agents

Development of (4-methoxyphenyl)-1H-tetrazol-5-amine regioisomers as a new class of selective antitubercular agents

  • Eur J Med Chem. 2020 Jan 15;186:111882. doi: 10.1016/j.ejmech.2019.111882.
Daniel Szulczyk 1 Anna Bielenica 2 Agnieszka Głogowska 3 Ewa Augustynowicz-Kopeć 3 Michał Dobrowolski 4 Piotr Roszkowski 4 Karolina Stępień 5 Alicja Chrzanowska 1 Marta Struga 1
Affiliations

Affiliations

  • 1 Chair and Department of Biochemistry, Medical University of Warsaw, 02-097, Warszawa, Poland.
  • 2 Chair and Department of Biochemistry, Medical University of Warsaw, 02-097, Warszawa, Poland. Electronic address: abielenica@wum.edu.pl.
  • 3 Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, 01-138, Warszawa, Poland.
  • 4 Faculty of Chemistry, University of Warsaw, 02-093, Warszawa, Poland.
  • 5 Department of Pharmaceutical Microbiology, Medical University, 02-007, Warszawa, Poland.
Abstract

A series of halogenated (4-methoxyphenyl)-1H-tetrazol-5-amine regioisomers (1a-9a, 1b-9b) were synthesized from their corresponding thiourea analogues (1-9). The synthesis pathway was confirmed by an X-ray crystallographic studies of 1a, 1b and 5a. Title derivatives were tested for their in vitro antitubercular activity against standard, "wild-type" and atypical mycobacteria. The highest therapeutic potential was attributed to isomeric N-(bromophenyl)tetrazoles 8a and 9a. Their growth-inhibitory effect against multidrug-resistant Mycobacterium tuberculosis Spec. 210 was 8-16-fold stronger than that of the first-line tuberculostatics. Other new tetrazole-derived compounds were also more or equally effective towards that pathogen comparing to the established pharmaceuticals. Among non-tuberculous strains, Mycobacterium scrofulaceum was the most susceptible to the presence of the majority of tetrazole derivatives. The synergistic interaction was found between 9a and streptomycin, as well as the additivity of both 8a and 9a in pairs with isoniazid, rifampicin and ethambutol. None of the studied compounds displayed Antibacterial or cytotoxic properties against normal and Cancer cell lines, which indicated their highly selective antimycobacterial effects.

Keywords

Antitubercular activity; Mycobacterium tuberculosis; Regioisomers; Tetrazole; Tuberculosis.

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