Details

Autor(en) / Beteiligte

• Zidar, Nace
• Emanuel Cotman, Andrej
• Sinnige, Wessel
• Benek, Ondrej
• Barančokova, Michaela
• Zega, Anamarija
• Peterlin Mašič, Lucija
• Tomašič, Tihomir
• Ilaš, Janez
• Henderson, Sara R.
• Mundy, Julia E.A.
• Maxwell, Anthony
• Stevenson, Clare E.M.
• Lawson, David M.
• Jan Sterk, Geert
• Tosso, Rodrigo
• Gutierrez, Lucas
• Enriz, Ricardo D.
• Kikelj, Danijel

Titel

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

Ist Teil von

• Bioorganic & medicinal chemistry, 2024-07, Vol.109, p.117798, Article 117798

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •The interactions of benzothiazole GyrB inhibitors with the lipophilic floor of the active site were studied.•The inhibition of E. coli GyrB was reduced when the benzyl group was shifted from the ring nitrogen to the carboxamide nitrogen.•The X-ray co-crystal structure of an exemplary inhibitor I with E. coli GyrB24 was solved.•The crucial binding interactions were rationalised by QTAIM analysis.•The results of the QTAIM analysis and the enzyme inhibition assay were in good agreement. 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.