Biological and docking studies of topoisomerase IV inhibition by thiosemicarbazides |
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Authors: | Agata Siwek Paweł Stączek Monika Wujec Joanna Stefańska Urszula Kosikowska Anna Malm Stefan Jankowski Piotr Paneth |
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Institution: | (1) Department of Organic Chemistry, Faculty of Pharmacy, Medical University, Staszica 6, 20-081 Lublin, Poland;(2) Department of Genetics of Microorganisms, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland;(3) Department of Pharmaceutical Microbiology, Medical University, Oczki 3, 02-007 Warsaw, Poland;(4) Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Medical University, Chodzki 1, 20-093 Lublin, Poland;(5) Institute of Organic Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland;(6) Institute of Applied Radiation Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland |
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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 (IC50 = 90 μM) but not against DNA gyrase. An increase in activity against topoisomerase IV (IC50 = 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. |
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