Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitors

Skok, Žiga (author), Barančokova, Michaela (author), Benek, Ondřej (author), Durante Cruz, Cristina (author), Tammela, Päivi (author), Tomašič, Tihomir (author), Zidar, Nace (author), Peterlin-Mašič, Lucija (author), Zega, Anamarija (author), Kikelj, Danijel (author), Ilaš, Janez (author)

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 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 [micro]M), and efflux impaired E. coli strain (MIC = 0.78 [micro]M), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.

• Language: English
• Keywords: DNA gyrase, topoisomerase IV, GyrB, ParE, antibacterial benzothiazole
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: Str. 2433-2440
• Numbering: Vol. 11, iss. 12
• PID: 20.500.12556/RUL-141912
• UDC: 615.4:54
• ISSN on article: 1948-5875
• DOI: 10.1021/acsmedchemlett.0c00416
• COBISS.SI-ID: 32932099
• Publication date in RUL: 11.10.2022

Record is a part of a journal

• Title: ACS medicinal chemistry letters
• Publisher: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

Secondary language

• Language: Slovenian
• Keywords: topoizomeraza IV, giraza DNA, antibakterijski benzotiazol, inibitorji giraze B