title: Biological and docking studies of topoisomerase IV inhibition by thiosemicarbazides.
abstract: 4-Benzoyl-1-(4-methyl-imidazol-5-yl)-carbonylthiosemicarbazide (1) was synthesized, and its antibacterial and type IIA topoisomerase (DNA gyrase and topoisomerase IV) activity evaluated. (1) was found to have high therapeutic potential against opportunistic Gram-positive bacteria, and inhibitory activity against topoisomerase IV (IC(50)=90 μM) but not against DNA gyrase. An increase in activity against topoisomerase IV (IC(50)=14 μM) was observed when the imidazole moiety of (1) was replaced with the indole group in 4-benzoyl-1-(indol-2-yl)-carbonylthiosemicarbazide (2). However, (2) showed only weak antibacterial activity. Although the results of the bacterial type IIA topoisomerases inhibition study did not parallel antibacterial activities, our observations strongly imply that a 4-benzoylthiosemicarbazide scaffold can be developed into an efficient Gram-positive antibacterial targeting topoisomerase IV. The difference in activity against type IIA topoisomerases between (1) and (2) was further investigated by docking studies, which suggested that these compounds target the ATP binding pocket.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Medical University, Staszica 6, 20-081, Lublin, Poland. agata.siwek@am.lublin.pl
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.forename: Paweł
authors.initials: P
authors.lastname: Stączek
authors.forename: Monika
authors.initials: M
authors.lastname: Wujec
authors.forename: Joanna
authors.initials: J
authors.lastname: Stefańska
authors.forename: Urszula
authors.initials: U
authors.lastname: Kosikowska
authors.forename: Anna
authors.initials: A
authors.lastname: Malm
authors.forename: Stefan
authors.initials: S
authors.lastname: Jankowski
authors.forename: Piotr
authors.initials: P
authors.lastname: Paneth
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001409:Bacillus cereus / Q000187:drug effects; D001412:Bacillus subtilis / Q000187:drug effects; D001665:Binding Sites; D003198:Computer Simulation; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052978:Disk Diffusion Antimicrobial Tests; D057075:Enzyme Assays; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D012663:Semicarbazides / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects
chemical_list: C569359:4-benzoyl-1-(4-methyl-imidazol-5-yl)carbonylthiosemicarbazide; D000900:Anti-Bacterial Agents; D007093:Imidazoles; D012663:Semicarbazides; D027101:DNA Topoisomerase IV