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

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