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
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 cha...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/9/10/666 |
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| author | Sergey Chuprun Dmitry Dar’in Elizaveta Rogacheva Liudmila Kraeva Oleg Levin Olga Manicheva Marine Dogonadze Tatiana Vinogradova Olga Bakulina Mikhail Krasavin |
| author_facet | Sergey Chuprun Dmitry Dar’in Elizaveta Rogacheva Liudmila Kraeva Oleg Levin Olga Manicheva Marine Dogonadze Tatiana Vinogradova Olga Bakulina Mikhail Krasavin |
| author_sort | Sergey Chuprun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T15:54:07Z |
| format | Article |
| id | doaj.art-9b4e8bcc2c3549e784e50624700c3436 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T15:54:07Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-9b4e8bcc2c3549e784e50624700c34362023-11-20T15:52:05ZengMDPI AGAntibiotics2079-63822020-10-0191066610.3390/antibiotics9100666Mutually 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 PathogensSergey Chuprun0Dmitry Dar’in1Elizaveta Rogacheva2Liudmila Kraeva3Oleg Levin4Olga Manicheva5Marine Dogonadze6Tatiana Vinogradova7Olga Bakulina8Mikhail Krasavin9Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaPasteur Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 Saint Petersburg, RussiaPasteur Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaSaint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, RussiaSaint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, RussiaSaint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, 191036 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaStarting 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.https://www.mdpi.com/2079-6382/9/10/666bioreducible prodrugsnitroazoles3-nitro-1,2,4-triazolenucleophilic aromatic substitutionantimycobacterial activityESKAPE pathogens |
| spellingShingle | Sergey Chuprun Dmitry Dar’in Elizaveta Rogacheva Liudmila Kraeva Oleg Levin Olga Manicheva Marine Dogonadze Tatiana Vinogradova Olga Bakulina Mikhail Krasavin 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 bioreducible prodrugs nitroazoles 3-nitro-1,2,4-triazole nucleophilic aromatic substitution antimycobacterial activity ESKAPE pathogens |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | bioreducible prodrugs nitroazoles 3-nitro-1,2,4-triazole nucleophilic aromatic substitution antimycobacterial activity ESKAPE pathogens |
| url | https://www.mdpi.com/2079-6382/9/10/666 |
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