Research output: Contribution to journal › Article › peer-review
Mutually isomeric 2-and 4-(3-nitro-1,2,4-triazol-1yl)pyrimidines inspired by an antimycobacterial screening hit : Synthesis and biological activity against the eskape panel of pathogens. / Chuprun, Sergey; Dar’in, Dmitry; Rogacheva, Elizaveta; Kraeva, Liudmila; Levin, Oleg; Manicheva, Olga; Dogonadze, Marine; Vinogradova, Tatiana; Bakulina, Olga; Krasavin, Mikhail.
In: Antibiotics, Vol. 9, No. 10, 666, 01.10.2020, p. 1-21.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Mutually isomeric 2-and 4-(3-nitro-1,2,4-triazol-1yl)pyrimidines inspired by an antimycobacterial screening hit
T2 - Synthesis and biological activity against the eskape panel of pathogens
AU - Chuprun, Sergey
AU - Dar’in, Dmitry
AU - Rogacheva, Elizaveta
AU - Kraeva, Liudmila
AU - Levin, Oleg
AU - Manicheva, Olga
AU - Dogonadze, Marine
AU - Vinogradova, Tatiana
AU - Bakulina, Olga
AU - Krasavin, Mikhail
N1 - Funding Information: Funding: This research was supported by the Russian Federation Government Megagrant 14.W03.031.0025. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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-1yl)pyrimidines, which is in line with the frequently observed activity loss on moving the 3-nitro1,2,4-triazol-1-yl moiety from position 4 to position 2 of the pyrimidine nucleus.
AB - 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-1yl)pyrimidines, which is in line with the frequently observed activity loss on moving the 3-nitro1,2,4-triazol-1-yl moiety from position 4 to position 2 of the pyrimidine nucleus.
KW - 3-nitro-1,2,4-triazole
KW - Antimycobacterial activity
KW - Bioreducible prodrugs
KW - Cyclic voltammetry
KW - ESKAPE pathogens
KW - Nitroazoles
KW - Nucleophilic aromatic substitution
KW - Reversible singleelectron reduction
KW - MULTIDRUG-RESISTANT
KW - bioreducible prodrugs
KW - 4-triazole
KW - MOIETY
KW - antimycobacterial activity
KW - 3-nitro-1
KW - EFFICACIOUS IN-VITRO
KW - NONTOXIC NITROFURANS
KW - nitroazoles
KW - reversible single-electron reduction
KW - 2
KW - cyclic voltammetry
KW - DRUGS
KW - nucleophilic aromatic substitution
KW - NITRO
KW - DERIVATIVES
UR - http://www.scopus.com/inward/record.url?scp=85092018551&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/364331aa-2ca3-3e0a-b427-cbc78777cc2e/
U2 - 10.3390/antibiotics9100666
DO - 10.3390/antibiotics9100666
M3 - Article
AN - SCOPUS:85092018551
VL - 9
SP - 1
EP - 21
JO - Antibiotics
JF - Antibiotics
SN - 2079-6382
IS - 10
M1 - 666
ER -
ID: 69946287