Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Dec 17

PMID 33329764

Citations 10

Authors

Ziga Skok

Michaela Barancokova

Ondrej Benek

Cristina Durante Cruz

Paivi Tammela

Tihomir Tomasic

Nace Zidar

Lucija Peterlin Masic

Anamarija Zega

Clare E M Stevenson

Julia E A Mundy

David M Lawson

Anthony Maxwell

Danijel Kikelj

Janez Ilas

Affiliations

Soon will be listed here.

Abstract

We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound , bearing a primary amino group, in complex with the N-terminal domain of gyrase B (24 kDa) (PDB: ). Compound , with a low molecular weight of 383 Da, potent inhibitory activity on gyrase (IC = 9.5 nM), potent antibacterial activity on (MIC = 3.13 μM), and efflux impaired strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.

Citing Articles

Synthesis, antibacterial evaluation and in silico studies of novel 2-(benzo[d]thiazol-2-yl)-N-arylacetamides and their derivatives as potential DHFR inhibitors.

Metwally N, Elgemeie G, Abdelrazek A, Eldaly S BMC Chem. 2025; 19(1):29.

PMID: 39891220 PMC: 11784096. DOI: 10.1186/s13065-025-01386-5.

Design, Synthesis, Molecular Docking, and ADME-Tox Investigations of Imidazo[1,2-a]Pyrimidines Derivatives as Antimicrobial Agents.

Benzenine D, Daoud I, Aissaoui N, Kibou Z, Seijas J, Vazquez-Tato M Molecules. 2024; 29(21).

PMID: 39519699 PMC: 11547262. DOI: 10.3390/molecules29215058.

Discovery of Benzopyrone-Based Candidates as Potential Antimicrobial and Photochemotherapeutic Agents through Inhibition of DNA Gyrase Enzyme B: Design, Synthesis, In Vitro and In Silico Evaluation.

Abd El-Haleem A, Ammar U, Masci D, El-Ansary S, Abdel Rahman D, Abou-Elazm F Pharmaceuticals (Basel). 2024; 17(9).

PMID: 39338359 PMC: 11434840. DOI: 10.3390/ph17091197.

Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against and Hit Validation by Biological Assays.

Pakamwong B, Thongdee P, Kamsri B, Phusi N, Taveepanich S, Chayajarus K J Chem Inf Model. 2024; 64(15):5991-6002.

PMID: 38993154 PMC: 11323271. DOI: 10.1021/acs.jcim.4c00511.

In vitro study of the antioxidant, sun factor protection, antimicrobial, and antifungal activities with molecular docking of methanolic extracts from leaves and fruit of L.

Boufissiou A, Kadi I, Benamar-Aissa B, Boussoussa H, Harrat M, Yousfi M 3 Biotech. 2024; 14(2):41.

PMID: 38261869 PMC: 10794656. DOI: 10.1007/s13205-023-03877-5.

References

Vos S, Tretter E, Schmidt B, Berger J . All tangled up: how cells direct, manage and exploit topoisomerase function. Nat Rev Mol Cell Biol. 2011; 12(12):827-41. PMC: 4351964. DOI: 10.1038/nrm3228. View

Cascioferro S, Parrino B, Carbone D, Schillaci D, Giovannetti E, Cirrincione G . Thiazoles, Their Benzofused Systems, and Thiazolidinone Derivatives: Versatile and Promising Tools to Combat Antibiotic Resistance. J Med Chem. 2020; 63(15):7923-7956. PMC: 7997583. DOI: 10.1021/acs.jmedchem.9b01245. View

Uria-Nickelsen M, Blodgett A, Kamp H, Eakin A, Sherer B, Green O . Novel DNA gyrase inhibitors: microbiological characterisation of pyrrolamides. Int J Antimicrob Agents. 2012; 41(1):28-35. DOI: 10.1016/j.ijantimicag.2012.08.017. View

Cramer J, Krimmer S, Heine A, Klebe G . Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. J Med Chem. 2017; 60(13):5791-5799. DOI: 10.1021/acs.jmedchem.7b00490. View

Tohyama S, Takahashi Y, Akamatsu Y . Biosynthesis of amycolamicin: the biosynthetic origin of a branched alpha-aminoethyl moiety in the unusual sugar amycolose. J Antibiot (Tokyo). 2010; 63(3):147-9. DOI: 10.1038/ja.2010.1. View

Aminov R . A brief history of the antibiotic era: lessons learned and challenges for the future. Front Microbiol. 2011; 1:134. PMC: 3109405. DOI: 10.3389/fmicb.2010.00134. View

Tari L, Li X, Trzoss M, Bensen D, Chen Z, Lam T . Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents. PLoS One. 2014; 8(12):e84409. PMC: 3873466. DOI: 10.1371/journal.pone.0084409. View

Barancokova M, Kikelj D, Ilas J . Recent progress in the discovery and development of DNA gyrase B inhibitors. Future Med Chem. 2018; 10(10):1207-1227. DOI: 10.4155/fmc-2017-0257. View

Zidar N, Montalvao S, Hodnik Z, Nawrot D, Zula A, Ilas J . Antimicrobial activity of the marine alkaloids, clathrodin and oroidin, and their synthetic analogues. Mar Drugs. 2014; 12(2):940-63. PMC: 3944524. DOI: 10.3390/md12020940. View

10.

Lu J, Patel S, Sharma N, Soisson S, Kishii R, Takei M . Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode. ACS Chem Biol. 2014; 9(9):2023-31. DOI: 10.1021/cb5001197. View

11.

Gjorgjieva M, Tomasic T, Barancokova M, Katsamakas S, Ilas J, Tammela P . Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors. J Med Chem. 2016; 59(19):8941-8954. DOI: 10.1021/acs.jmedchem.6b00864. View

12.

Silver L . Challenges of antibacterial discovery. Clin Microbiol Rev. 2011; 24(1):71-109. PMC: 3021209. DOI: 10.1128/CMR.00030-10. View

13.

Sherer B, Hull K, Green O, Basarab G, Hauck S, Hill P . Pyrrolamide DNA gyrase inhibitors: optimization of antibacterial activity and efficacy. Bioorg Med Chem Lett. 2011; 21(24):7416-20. DOI: 10.1016/j.bmcl.2011.10.010. View

14.

Schoeffler A, Berger J . DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Q Rev Biophys. 2008; 41(1):41-101. DOI: 10.1017/S003358350800468X. View

15.

Singh S, Goetz M, Smith S, Zink D, Polishook J, Onishi R . Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities. Bioorg Med Chem Lett. 2012; 22(23):7127-30. DOI: 10.1016/j.bmcl.2012.09.071. View

16.

Nathan C, Cars O . Antibiotic resistance--problems, progress, and prospects. N Engl J Med. 2014; 371(19):1761-3. DOI: 10.1056/NEJMp1408040. View

17.

Eakin A, Green O, Hales N, Walkup G, Bist S, Singh A . Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents. Antimicrob Agents Chemother. 2011; 56(3):1240-6. PMC: 3294908. DOI: 10.1128/AAC.05485-11. View

18.

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

19.

Bisacchi G, Manchester J . A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS Infect Dis. 2016; 1(1):4-41. DOI: 10.1021/id500013t. View

20.

Zidar N, Tomasic T, Macut H, Sirc A, Brvar M, Montalvao S . New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase. Eur J Med Chem. 2016; 117:197-211. DOI: 10.1016/j.ejmech.2016.03.079. View