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
Sergey Chuprun,
Dmitry Dar’in,
Elizaveta Rogacheva,
Liudmila Kraeva,
Oleg Levin,
Olga Manicheva,
Marine Dogonadze,
Tatiana Vinogradova,
Olga Bakulina,
Mikhail Krasavin
Affiliations
Sergey Chuprun
Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Dmitry Dar’in
Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Elizaveta Rogacheva
Pasteur Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 Saint Petersburg, Russia
Liudmila Kraeva
Pasteur Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 Saint Petersburg, Russia
Oleg Levin
Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Olga Manicheva
Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, Russia
Marine Dogonadze
Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, Russia
Tatiana Vinogradova
Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, Russia
Olga Bakulina
Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Mikhail Krasavin
Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
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.
