| Summary: | 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 <i>M. tuberculosis</i> while inhibiting the growth of all ESKAPE pathogens (with variable potency patterns) except for Gram-negative <i>P. aeruginosa</i>. Reduction potentials (E<sub>1/2</sub>, 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<sub>1/2</sub> 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<sub>1/2</sub> 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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