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Article

Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens

1
Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
2
Pasteur Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 Saint Petersburg, Russia
3
Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, Russia
4
Institute of Living Systems, Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russia
*
Author to whom correspondence should be addressed.
Antibiotics 2020, 9(10), 666; https://doi.org/10.3390/antibiotics9100666
Received: 6 September 2020 / Revised: 24 September 2020 / Accepted: 30 September 2020 / Published: 1 October 2020
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-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. View Full-Text
Keywords: bioreducible prodrugs; nitroazoles; 3-nitro-1,2,4-triazole; nucleophilic aromatic substitution; antimycobacterial activity; ESKAPE pathogens; cyclic voltammetry; reversible single-electron reduction bioreducible prodrugs; nitroazoles; 3-nitro-1,2,4-triazole; nucleophilic aromatic substitution; antimycobacterial activity; ESKAPE pathogens; cyclic voltammetry; reversible single-electron reduction
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MDPI and ACS Style

Chuprun, S.; Dar’in, D.; Rogacheva, E.; Kraeva, L.; Levin, O.; Manicheva, O.; Dogonadze, M.; Vinogradova, T.; Bakulina, O.; Krasavin, M. Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens. Antibiotics 2020, 9, 666. https://doi.org/10.3390/antibiotics9100666

AMA Style

Chuprun S, Dar’in D, Rogacheva E, Kraeva L, Levin O, Manicheva O, Dogonadze M, Vinogradova T, Bakulina O, Krasavin M. Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens. Antibiotics. 2020; 9(10):666. https://doi.org/10.3390/antibiotics9100666

Chicago/Turabian Style

Chuprun, Sergey, Dmitry Dar’in, Elizaveta Rogacheva, Liudmila Kraeva, Oleg Levin, Olga Manicheva, Marine Dogonadze, Tatiana Vinogradova, Olga Bakulina, and Mikhail Krasavin. 2020. "Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens" Antibiotics 9, no. 10: 666. https://doi.org/10.3390/antibiotics9100666

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