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

doi:10.1016/j.bmc.2016.10.038

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

Tutkimustuotos: Artikkelijulkaisu › Artikkeli › Tieteellinen › vertaisarvioitu

Abstrakti

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.

Alkuperäiskieli	englanti
Lehti	Bioorganic & Medicinal Chemistry
Vuosikerta	25
Numero	1
Sivut	338-349
Sivumäärä	12
ISSN	0968-0896
DOI - pysyväislinkit	https://doi.org/10.1016/j.bmc.2016.10.038
Tila	Julkaistu - 1 tammik. 2017
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

1182 Biokemia, solu- ja molekyylibiologia
317 Farmasia
116 Kemia

Pääsy asiakirjaan

10.1016/j.bmc.2016.10.038

TomasicT_etal_Manuscript_acceptedHyväksytty kirjoittajan käsikirjoitus, 1,48 MB

Phenotypic biosensor-based HTS and mode of action analysis by metabolomics and transcriptomics for enhancing antimicrobial drug discovery against Gram-negative bacteria
Tammela, P. (Principal Investigator)
01/09/2014 → 31/08/2019
Projekti: Tutkimusprojekti
EC-FP7-KBBE-2009-3-2-01-245137: Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications (MAREX)
Kiuru, P. (Muu), Lipiäinen, T. (Muu), Tammela, P. (Muu), Montalvão, S. (Osallistuja), Lillsunde, K.-E. (Osallistuja), Vuorela, H. (Muu) & Yli-Kauhaluoma, J. (Muu)
01/08/2010 → 31/07/2014
Projekti: Tutkimusprojekti

Siteeraa tätä

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

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.",

keywords = "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",

author = "Tihomir Toma{\v s}i{\v c} and Matic Mirt and Michaela Baran{\v c}okov{\'a} and Janez Ila{\v s} and Nace Zidar and Tammela, {P{\"a}ivi Sirpa Marjaana} and Danijel Kikelj",

year = "2017",

month = jan,

day = "1",

doi = "10.1016/j.bmc.2016.10.038",

language = "English",

volume = "25",

pages = "338--349",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd. ",

number = "1",

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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 et al.
julkaisussa: Bioorganic & Medicinal Chemistry, Vuosikerta 25, Nro 1, 01.01.2017, s. 338-349.

Tutkimustuotos: Artikkelijulkaisu › Artikkeli › Tieteellinen › vertaisarvioitu

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

SN - 0968-0896

VL - 25

SP - 338

EP - 349

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 1

ER -

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

Abstrakti

Tieteenalat

Pääsy asiakirjaan

Projektit

Phenotypic biosensor-based HTS and mode of action analysis by metabolomics and transcriptomics for enhancing antimicrobial drug discovery against Gram-negative bacteria

EC-FP7-KBBE-2009-3-2-01-245137: Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications (MAREX)

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