An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors

Davide Benetto Tiz, Žiga Skok, Martina Durcik, Tihomir Tomašič, Lucija Peterlin Mašič, Janez Ilaš, Gábor Draskovits, Tamás Révész, Ákos Nyerges, Csaba Pál, Cristina D. Cruz, Päivi Sirpa Marjaana Tammela, Dušan Žigon, Danijel Kikelj, Nace Zidar

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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.
Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Volume167
Pages (from-to)269-290
Number of pages22
ISSN0223-5234
DOIs
Publication statusPublished - 1 Apr 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • Antibacterial
  • ATP competitive
  • DNA gyrase
  • GyrB
  • Inhibitor
  • N-phenylpyrrolamide
  • ParE
  • Topoisomerase IV
  • BIOLOGICAL EVALUATION
  • ATPASE INHIBITORS
  • ANTIBACTERIAL
  • ACID
  • TOPOISOMERASE
  • DESIGN
  • DISCOVERY
  • ANALOGS
  • N-PHENYL-4,5-DIBROMOPYRROLAMIDES
  • PHENYLINDOLAMIDES

Cite this

Benetto Tiz, D., Skok, Ž., Durcik, M., Tomašič, T., Peterlin Mašič, L., Ilaš, J., ... Zidar, N. (2019). An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors. European Journal of Medicinal Chemistry, 167, 269-290. https://doi.org/10.1016/j.ejmech.2019.02.004
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. / An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 167. pp. 269-290.
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abstract = "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.",
keywords = "317 Pharmacy, Antibacterial, ATP competitive, DNA gyrase, GyrB, Inhibitor, N-phenylpyrrolamide, ParE, Topoisomerase IV, BIOLOGICAL EVALUATION, ATPASE INHIBITORS, ANTIBACTERIAL, ACID, TOPOISOMERASE, DESIGN, DISCOVERY, ANALOGS, N-PHENYL-4,5-DIBROMOPYRROLAMIDES, PHENYLINDOLAMIDES",
author = "{Benetto Tiz}, Davide and Žiga Skok and Martina Durcik and Tihomir Tomašič and {Peterlin Mašič}, Lucija and Janez Ilaš and G{\'a}bor Draskovits and Tam{\'a}s R{\'e}v{\'e}sz and {\'A}kos Nyerges and Csaba P{\'a}l and Cruz, {Cristina D.} and Tammela, {P{\"a}ivi Sirpa Marjaana} and Dušan Žigon and Danijel Kikelj and Nace Zidar",
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Benetto Tiz, D, Skok, Ž, Durcik, M, Tomašič, T, Peterlin Mašič, L, Ilaš, J, Draskovits, G, Révész, T, Nyerges, Á, Pál, C, Cruz, CD, Tammela, PSM, Žigon, D, Kikelj, D & Zidar, N 2019, 'An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors' European Journal of Medicinal Chemistry, vol. 167, pp. 269-290. https://doi.org/10.1016/j.ejmech.2019.02.004

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.

In: European Journal of Medicinal Chemistry, Vol. 167, 01.04.2019, p. 269-290.

Research output: Contribution to journalArticleScientificpeer-review

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 -

Benetto Tiz D, Skok Ž, Durcik M, Tomašič T, Peterlin Mašič L, Ilaš J et al. An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors. European Journal of Medicinal Chemistry. 2019 Apr 1;167:269-290. https://doi.org/10.1016/j.ejmech.2019.02.004