Kuvaus
| Alkuperäiskieli | englanti |
|---|---|
| Lehti | European Journal of Medicinal Chemistry |
| Vuosikerta | 167 |
| Sivut | 269-290 |
| Sivumäärä | 22 |
| ISSN | 0223-5234 |
| DOI - pysyväislinkit | |
| Tila | Julkaistu - 1 huhtikuuta 2019 |
| OKM-julkaisutyyppi | A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu |
Tieteenalat
- 317 Farmasia
Lainaa tätä
}
An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors. / Benetto Tiz, Davide; Skok, Žiga; Durcik, Martina; Tomašič, Tihomir; Peterlin Mašič, Lucija; Ilaš, Janez; Draskovits, Gábor; Révész, Tamás; Nyerges, Ákos; Pál, Csaba; Cruz, Cristina D.; Tammela, Päivi Sirpa Marjaana; Žigon, Dušan; Kikelj, Danijel; Zidar, Nace.
julkaisussa: European Journal of Medicinal Chemistry, Vuosikerta 167, 01.04.2019, s. 269-290.Tutkimustuotos: Artikkelijulkaisu › Artikkeli › Tieteellinen › vertaisarvioitu
TY - JOUR
T1 - An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors
AU - Benetto Tiz, Davide
AU - Skok, Žiga
AU - Durcik, Martina
AU - Tomašič, Tihomir
AU - Peterlin Mašič, Lucija
AU - Ilaš, Janez
AU - Draskovits, Gábor
AU - Révész, Tamás
AU - Nyerges, Ákos
AU - Pál, Csaba
AU - Cruz, Cristina D.
AU - Tammela, Päivi Sirpa Marjaana
AU - Žigon, Dušan
AU - Kikelj, Danijel
AU - Zidar, Nace
PY - 2019/4/1
Y1 - 2019/4/1
N2 - ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 mu M range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 mu M, 1.56 mu M, 0.78 mu M and 0.72 mu M, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 mu M on both strains, and MIC value of 32 mu M against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. (C) 2019 Elsevier Masson SAS. All rights reserved.
AB - ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 mu M range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 mu M, 1.56 mu M, 0.78 mu M and 0.72 mu M, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 mu M on both strains, and MIC value of 32 mu M against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. (C) 2019 Elsevier Masson SAS. All rights reserved.
KW - 317 Pharmacy
KW - Antibacterial
KW - ATP competitive
KW - DNA gyrase
KW - GyrB
KW - Inhibitor
KW - N-phenylpyrrolamide
KW - ParE
KW - Topoisomerase IV
KW - BIOLOGICAL EVALUATION
KW - ATPASE INHIBITORS
KW - ANTIBACTERIAL
KW - ACID
KW - TOPOISOMERASE
KW - DESIGN
KW - DISCOVERY
KW - ANALOGS
KW - N-PHENYL-4,5-DIBROMOPYRROLAMIDES
KW - PHENYLINDOLAMIDES
U2 - 10.1016/j.ejmech.2019.02.004
DO - 10.1016/j.ejmech.2019.02.004
M3 - Article
VL - 167
SP - 269
EP - 290
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -