title: Synthesis and structure-activity relationship studies of 4-arylthiosemicarbazides as topoisomerase IV inhibitors with Gram-positive antibacterial activity. Search for molecular basis of antibacterial activity of thiosemicarbazides.
abstract: 1-(indol-2-carbonyl)-4-(4-nitrophenyl)-thiosemicarbazide was synthesized and antibacterial and type IIA topoisomerases (DNA gyrase and topoisomerase IV) activity was evaluated. It was found that it shows activity against Gram-positive bacteria with MICs of 50 μg/mL and inhibitory action against topoisomerase IV with an IC(50) of 14 μM. Although modification of its structure resulted in molecules with a lower biological profile, our observations strongly implicate that thiosemicarbazide derivatives participate in at least two different mechanisms of antibacterial activity; one is connected with the inhibition of topoisomerase IV, while the nature of the other cannot be elucidated from the limited data collected thus far. The differences in bioactivity further investigated by the molecular modeling approach and docking studies suggest that inhibitory activity of 4-arylthiosemicarbazides is connected with electronic structure rather than the geometry of the molecule.
authors: Department of Organic Chemistry, Faculty of Pharmacy, Medical University, Chodźki 4a, 20-093 Lublin, Poland. agata.siwek@am.lublin.pl
authors: Agata
authors: A
authors: Siwek
authors: Paweł
authors: P
authors: Stączek
authors: Joanna
authors: J
authors: Stefańska
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D012663:Semicarbazides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D012663:Semicarbazides; D059003:Topoisomerase Inhibitors; C005151:thiosemicarbazide; D027101:DNA Topoisomerase IV