期刊
ANTIBIOTICS-BASEL
卷 9, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/antibiotics9100666
关键词
bioreducible prodrugs; nitroazoles; 3-nitro-1; 2; 4-triazole; nucleophilic aromatic substitution; antimycobacterial activity; ESKAPE pathogens; cyclic voltammetry; reversible single-electron reduction
资金
- Russian Federation Government Megagrant [14, W03.031.0025]
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 (E-1/2, 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 E-1/2 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 E-1/2 values were displayed by 2-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, which is in line with the frequently observed activity loss on moving the 3-nitro-1,2,4-triazol-1-yl moiety from position 4 to position 2 of the pyrimidine nucleus.
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