Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor : a medicinal chemistry and QTAIM study

Zidar, Nace (author), Cotman, Andrej Emanuel (author), Sinnige, Wessel (author), Benek, Ondřej (author), Barančokova, Michaela (author), Zega, Anamarija (author), Peterlin-Mašič, Lucija (author), Tomašič, Tihomir (author), Ilaš, Janez (author), Enriz, Ricardo D. (author), Kikelj, Danijel (author)

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.

• Language: English
• Keywords: antibacterial agent, DNA gyrase, ATP-binding site, N-(benzothiazol-2-yl)pyrrolamide, inhibitor, QTAIM analysis
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 16 str.
• Numbering: Vol. 109, art. 117798
• PID: 20.500.12556/RUL-158805
• UDC: 615.4:54
• ISSN on article: 0968-0896
• DOI: 10.1016/j.bmc.2024.117798
• COBISS.SI-ID: 199171075
• Publication date in RUL: 20.06.2024

Record is a part of a journal

• Title: Bioorganic & medicinal chemistry
• Shortened title: Bioorg. med. chem.
• Publisher: Elsevier
• ISSN: 0968-0896
• COBISS.SI-ID: 756527

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• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: farmacevtska kemija