Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors

Andraž Lamut; Žiga Skok; Michaela Barančoková; Lucas J.  Gutierrez; Cristina Cruz; Päivi Tammela; Gábor Draskovits; Petra Éva Szili; Ákos Nyerges; Csaba Pál; Peter Molek; Tomaž Bratkovič; Janez Ilaš; Nace Zidar; Anamarija Zega; Ricardo D.  Enriz; Danijel Kikelj; Tihomir Tomašič

doi:10.4155/fmc-2019-0127

Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors

Andraž Lamut, Žiga Skok, Michaela Barančoková, Lucas J. Gutierrez, Cristina Cruz, Päivi Tammela, Gábor Draskovits, Petra Éva Szili, Ákos Nyerges, Csaba Pál, Peter Molek, Tomaž Bratkovič, Janez Ilaš, Nace Zidar, Anamarija Zega, Ricardo D. Enriz, Danijel Kikelj, Tihomir Tomašič

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

Sammanfattning

Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 mu g/ml, which represents good starting point for development of novel antibacterials.

Graphical abstract

Originalspråk	engelska
Tidskrift	Future Medicinal Chemistry
Volym	12
Nummer	4
Sidor (från-till)	277-297
Antal sidor	21
ISSN	1756-8919
DOI	https://doi.org/10.4155/fmc-2019-0127
Status	Publicerad - feb. 2020
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Vetenskapsgrenar

317 Farmaci

Åtkomst av dokument

10.4155/fmc-2019-0127

Lamut et al - FutureMedChem - Manuscript - revisedAccepterat manuskript från författare, 696 KB

Citera det här

Lamut, A., Skok, Ž., Barančoková, M., Gutierrez, L. J., Cruz, C., Tammela, P., Draskovits, G., Szili, P. É., Nyerges, Á., Pál, C., Molek, P., Bratkovič, T., Ilaš, J., Zidar, N., Zega, A., Enriz, R. D., Kikelj, D., & Tomašič, T. (2020). Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors. Future Medicinal Chemistry, 12(4), 277-297. https://doi.org/10.4155/fmc-2019-0127

@article{655e9d09c48745838808fc6ecd1ae9b2,

title = "Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors",

abstract = "Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 mu g/ml, which represents good starting point for development of novel antibacterials.Graphical abstract",

keywords = "ANTIBACTERIALS, ATPASE INHIBITORS, BINDING, DESIGN, DISCOVERY, DNA gyrase, MECHANISM, N-PHENYL-4,5-DIBROMOPYRROLAMIDES, N-PHENYLINDOLAMIDES, OPTIMIZATION, QTAIM, TOPOISOMERASES, antibacterial, inhibitor, pyrrolamide, thiazole, 317 Pharmacy",

author = "Andra{\v z} Lamut and {\v Z}iga Skok and Michaela Baran{\v c}okov{\'a} and Gutierrez, {Lucas J.} and Cristina Cruz and P{\"a}ivi Tammela and G{\'a}bor Draskovits and Szili, {Petra {\'E}va} and {\'A}kos Nyerges and Csaba P{\'a}l and Peter Molek and Toma{\v z} Bratkovi{\v c} and Janez Ila{\v s} and Nace Zidar and Anamarija Zega and Enriz, {Ricardo D.} and Danijel Kikelj and Tihomir Toma{\v s}i{\v c}",

year = "2020",

month = feb,

doi = "10.4155/fmc-2019-0127",

language = "English",

volume = "12",

pages = "277--297",

journal = "Future Medicinal Chemistry",

issn = "1756-8919",

publisher = "Future Science",

number = "4",

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Lamut, A, Skok, Ž, Barančoková, M, Gutierrez, LJ, Cruz, C , Tammela, P, Draskovits, G, Szili, PÉ, Nyerges, Á, Pál, C, Molek, P, Bratkovič, T, Ilaš, J, Zidar, N, Zega, A, Enriz, RD, Kikelj, D & Tomašič, T 2020, 'Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors', Future Medicinal Chemistry, vol. 12, nr. 4, s. 277-297. https://doi.org/10.4155/fmc-2019-0127

TY - JOUR

T1 - Second generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors

AU - Lamut, Andraž

AU - Skok, Žiga

AU - Barančoková, Michaela

AU - Gutierrez, Lucas J.

AU - Cruz, Cristina

AU - Tammela, Päivi

AU - Draskovits, Gábor

AU - Szili, Petra Éva

AU - Nyerges, Ákos

AU - Pál, Csaba

AU - Molek, Peter

AU - Bratkovič, Tomaž

AU - Ilaš, Janez

AU - Zidar, Nace

AU - Zega, Anamarija

AU - Enriz, Ricardo D.

AU - Kikelj, Danijel

AU - Tomašič, Tihomir

PY - 2020/2

Y1 - 2020/2

N2 - Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 mu g/ml, which represents good starting point for development of novel antibacterials.Graphical abstract

AB - Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 mu g/ml, which represents good starting point for development of novel antibacterials.Graphical abstract

KW - ANTIBACTERIALS

KW - ATPASE INHIBITORS

KW - BINDING

KW - DESIGN

KW - DISCOVERY

KW - DNA gyrase

KW - MECHANISM

KW - N-PHENYL-4,5-DIBROMOPYRROLAMIDES

KW - N-PHENYLINDOLAMIDES

KW - OPTIMIZATION

KW - QTAIM

KW - TOPOISOMERASES

KW - antibacterial

KW - inhibitor

KW - pyrrolamide

KW - thiazole

KW - 317 Pharmacy

U2 - 10.4155/fmc-2019-0127

DO - 10.4155/fmc-2019-0127

M3 - Article

SN - 1756-8919

VL - 12

SP - 277

EP - 297

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

IS - 4

ER -