1. Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors
- Author
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Cristina D. Cruz, Danijel Kikelj, Michaela Barančoková, Ondřej Benek, Clare E. M. Stevenson, Päivi Tammela, Tihomir Tomašič, Lucija Peterlin Mašič, Janez Ilaš, Žiga Skok, Anamarija Zega, Nace Zidar, David M. Lawson, Anthony Maxwell, Julia E. A. Mundy, Division of Pharmaceutical Biosciences, Bioactivity Screening Group, Drug Research Program, Divisions of Faculty of Pharmacy, Global Development Studies, Helsinki Institute of Sustainability Science (HELSUS), University of Helsinki, Division of Pharmaceutical Biosciences, and University of Helsinki, Global Development Studies
- Subjects
topoizomeraza IV ,Letter ,N-PHENYLINDOLAMIDES ,Topoisomerase IV ,Stereochemistry ,ANTIBACTERIAL ACTIVITY ,Farmacevtska kemija ,Bacterial enzymes ,01 natural sciences ,Biochemistry ,DNA gyrase ,topoizomeraza IV, giraza DNA, antibakterijski benzotiazol, inibitorji giraze B ,AMYCOLAMICIN ,DNA Topoisomerase IV ,chemistry.chemical_compound ,udc:615.4:54 ,topoisomerase IV ,Drug Discovery ,ParE ,udc:615.4 ,GyrB ,CHALLENGES ,biology ,010405 organic chemistry ,Drug discovery ,Chemistry ,DNA gyrase, topoisomerase IV, GyrB, ParE, antibacterial benzothiazole ,Organic Chemistry ,antibakterijski benzotiazol ,giraza DNA ,benzothiazole ,KIBDELOMYCIN ,antibacterial benzothiazole ,N-PHENYL-4,5-DIBROMOPYRROLAMIDES ,Chemical space ,TRANSLOCATION ,0104 chemical sciences ,antibacterial ,010404 medicinal & biomolecular chemistry ,Benzothiazole ,317 Pharmacy ,inibitorji giraze B ,biology.protein ,Antibacterial activity ,ATPASE INHIBITORS ,RESISTANCE - 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 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. Abstract. Bibliografija: str. 2439-2440. EU H2020 ITN-ETN Project INTEGRATE EU FP7 Integrated Project MAREX Academy of Finland ARRS Biotechnology and Biosciences Research Council (UK) Institute Strategic Programme Grant B Wellcome Trust - (Investigator Award)
- Published
- 2020