Mutually isomeric 2-and 4-(3-nitro-1,2,4-triazol-1yl)pyrimidines inspired by an antimycobacterial screening hit: Synthesis and biological activity against the eskape panel of pathogens

Sergey Chuprun, Dmitry Dar’in, Elizaveta Rogacheva, Liudmila Kraeva, Oleg Levin, Olga Manicheva, Marine Dogonadze, Tatiana Vinogradova, Olga Bakulina, Mikhail Krasavin

Research output

Abstract

Starting from the structure of antimycobacterial screening hit OTB-021 which was devoid of activity against ESKAPE pathogens, we designed, synthesized and tested two mutually isomeric series of novel simplified analogs, 2-and 4-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, bearing various amino side chains. These compounds demonstrated a reverse bioactivity profile being inactive against M. tuberculosis while inhibiting the growth of all ESKAPE pathogens (with variable potency patterns) except for Gram-negative P. aeruginosa. Reduction potentials (E1/2, V) measured for selected compounds by cyclic voltammetry were tightly grouped in the −1.3–−1.1 V range for a reversible single-electron reduction. No apparent correlation between the E1/2 values and the ESKAPE minimum inhibitory concentrations was established, suggesting possible significance of other factors, besides the compounds’ reduction potential, which determine the observed antibacterial activity. Generally, more negative E1/2 values were displayed by 2-(3-nitro-1,2,4-triazol-1yl)pyrimidines, which is in line with the frequently observed activity loss on moving the 3-nitro1,2,4-triazol-1-yl moiety from position 4 to position 2 of the pyrimidine nucleus.

Original languageEnglish
Article number666
Pages (from-to)1-21
Number of pages21
JournalAntibiotics
Volume9
Issue number10
DOIs
Publication statusPublished - 1 Oct 2020

Scopus subject areas

  • Microbiology
  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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