Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors

Tihomir Tomašič, Matic Mirt, Michaela Barančoková, Janez Ilaš, Nace Zidar, Päivi Sirpa Marjaana Tammela, Danijel Kikelj

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 mu M). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl) acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 mu M. Molecular docking experiments were conducted to study the binding modes of inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Volume25
Issue number1
Pages (from-to)338-349
Number of pages12
ISSN0968-0896
DOIs
Publication statusPublished - 1 Jan 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology
  • 317 Pharmacy
  • 116 Chemical sciences
  • Antibacterial
  • DNA gyrase
  • Docking
  • Inhibitor
  • Thiazole
  • SODIUM-CHANNEL MODULATORS
  • IN-SILICO DISCOVERY
  • TOPOISOMERASE-IV
  • ANTIBACTERIAL AGENTS
  • MARINE ALKALOIDS
  • STAPHYLOCOCCUS-AUREUS
  • IIA TOPOISOMERASES
  • ATPASE DOMAINS
  • CLATHRODIN
  • ANALOGS

Cite this

Tomašič, Tihomir ; Mirt, Matic ; Barančoková, Michaela ; Ilaš, Janez ; Zidar, Nace ; Tammela, Päivi Sirpa Marjaana ; Kikelj, Danijel. / Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors. In: Bioorganic & Medicinal Chemistry. 2017 ; Vol. 25, No. 1. pp. 338-349.
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abstract = "Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 mu M). Their {"}ring-opened{"} analogues, based on the 2-(2-aminothiazol-4-yl) acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 mu M. Molecular docking experiments were conducted to study the binding modes of inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.",
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author = "Tihomir Tomašič and Matic Mirt and Michaela Barančokov{\'a} and Janez Ilaš and Nace Zidar and Tammela, {P{\"a}ivi Sirpa Marjaana} and Danijel Kikelj",
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Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors. / Tomašič, Tihomir; Mirt, Matic; Barančoková, Michaela; Ilaš, Janez; Zidar, Nace; Tammela, Päivi Sirpa Marjaana; Kikelj, Danijel.

In: Bioorganic & Medicinal Chemistry, Vol. 25, No. 1, 01.01.2017, p. 338-349.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors

AU - Tomašič, Tihomir

AU - Mirt, Matic

AU - Barančoková, Michaela

AU - Ilaš, Janez

AU - Zidar, Nace

AU - Tammela, Päivi Sirpa Marjaana

AU - Kikelj, Danijel

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 mu M). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl) acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 mu M. Molecular docking experiments were conducted to study the binding modes of inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.

AB - Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 mu M). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl) acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 mu M. Molecular docking experiments were conducted to study the binding modes of inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.

KW - 1182 Biochemistry, cell and molecular biology

KW - 317 Pharmacy

KW - 116 Chemical sciences

KW - Antibacterial

KW - DNA gyrase

KW - Docking

KW - Inhibitor

KW - Thiazole

KW - SODIUM-CHANNEL MODULATORS

KW - IN-SILICO DISCOVERY

KW - TOPOISOMERASE-IV

KW - ANTIBACTERIAL AGENTS

KW - MARINE ALKALOIDS

KW - STAPHYLOCOCCUS-AUREUS

KW - IIA TOPOISOMERASES

KW - ATPASE DOMAINS

KW - CLATHRODIN

KW - ANALOGS

U2 - 10.1016/j.bmc.2016.10.038

DO - 10.1016/j.bmc.2016.10.038

M3 - Article

VL - 25

SP - 338

EP - 349

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 1

ER -