New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Electronic address: nace.zidar@ffa.uni-lj.si.
Nace
N
Zidar
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Tihomir
T
Tomašič
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Helena
H
Macut
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Anja
A
Sirc
National Institute of Chemistry, Laboratory for Biocomputing and Bioinformatics, 1001 Ljubljana, Slovenia.
Matjaž
M
Brvar
Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FI-00014 Helsinki, Finland.
Sofia
S
Montalvão
Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FI-00014 Helsinki, Finland.
Päivi
P
Tammela
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Janez
J
Ilaš
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Danijel
D
Kikelj
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D000577:Amides; D000900:Anti-Bacterial Agents; D007211:Indoles; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors
4,5-Dibromopyrrole; Antibacterial; DNA gyrase; GyrB; Inhibitor; Topoisomerase IV