Cyclothialidine B
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| Category | Enzyme inhibitors |
| Catalog number | BBF-01119 |
| CAS | 194276-76-1 |
| Molecular Weight | 611.62 |
| Molecular Formula | C25H33N5O11S |
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Description
It is produced by the strain of Streptomyces sp. NR 0659. It and its homologues inhibit escherichia coli DNA helicases with IC50 of 0.7 μmol/L, and the reference neomycin was 1.2 μmol/L.
Specification
| IUPAC Name | (2S)-2-[[(5S,8S)-8-[[(2S,3R)-1-[(2S)-2-aminopropanoyl]-3-hydroxypyrrolidine-2-carbonyl]amino]-14,16-dihydroxy-7,11-dioxo-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(12),13,15-triene-5-carbonyl]amino]propanoic acid |
| Canonical SMILES | CC(C(=O)N1CCC(C1C(=O)NC2COC(=O)C3=C(CSCC(NC2=O)C(=O)NC(C)C(=O)O)C(=CC(=C3)O)O)O)N |
| InChI | InChI=1S/C25H33N5O11S/c1-10(26)23(37)30-4-3-17(32)19(30)22(36)28-15-7-41-25(40)13-5-12(31)6-18(33)14(13)8-42-9-16(29-20(15)34)21(35)27-11(2)24(38)39/h5-6,10-11,15-17,19,31-33H,3-4,7-9,26H2,1-2H3,(H,27,35)(H,28,36)(H,29,34)(H,38,39)/t10-,11-,15-,16+,17+,19-/m0/s1 |
| InChI Key | FYYGQGDAPAQONZ-PMMNEZAESA-N |
Properties
| Solubility | Soluble in Water, Methanol |
Reference Reading
1. Combining molecular docking and QSAR studies for modelling the antigyrase activity of cyclothialidine derivatives
Liane Saíz-Urra, Miguel Ángel Cabrera Pérez, Aliuska Morales Helguera, Matheus Froeyen Eur J Med Chem. 2011 Jul;46(7):2736-47. doi: 10.1016/j.ejmech.2011.03.061. Epub 2011 Apr 5.
DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A(2)B(2), where GyrB catalyzes the hydrolysis of ATP. Cyclothialidine (Ro 09-1437) has been considered as a promising inhibitor whose modifications might lead to more potent compounds against the enzyme. We report here for the first time, QSAR studies regarding to ATPase inhibitors of DNA Gyrase. 1D, 2D and 3D descriptors from DRAGON software were used on a set of 42 cyclothialidine derivatives. Based on the core of the cyclothialidine GR122222X, different conformations were created by using OMEGA. FRED was used to dock these conformers in the cavity of the GyrB subunit to select the best conformations, paying special attention to the 12-membered ring. Three QSAR models were developed considering the dimension of the descriptors. The models were robust, predictive and good in statistical significance, over 70% of the experimental variance was explained. Interpretability of the models was possible by extracting the SAR(s) encoded by these predictive models. Analyzing the compound-enzyme interactions of the complexes obtained by docking allowed us to increase the reliability of the information obtained for the QSAR models.
2. In silico discovery of 2-amino-4-(2,4-dihydroxyphenyl)thiazoles as novel inhibitors of DNA gyrase B
Matjaz Brvar, Andrej Perdih, Marko Oblak, Lucija Peterlin Masic, Tom Solmajer Bioorg Med Chem Lett. 2010 Feb 1;20(3):958-62. doi: 10.1016/j.bmcl.2009.12.060. Epub 2009 Dec 22.
Cyclothialidines are a class of bacterial DNA gyrase B (GyrB) subunit inhibitors, targeting its ATP-binding site. Starting from the available structural information on cyclothialidine GR122222X (2), an in silico virtual screening campaign was designed combining molecular docking calculations with three-dimensional structure-based pharmacophore information. A novel class of 2-amino-4-(2,4-dihydroxyphenyl)thiazole based inhibitors (5-9) with low micromolar antigyrase activity was discovered.
3. New antibacterial agents derived from the DNA gyrase inhibitor cyclothialidine
Peter Angehrn, Stefan Buchmann, Christoph Funk, Erwin Goetschi, Hans Gmuender, Paul Hebeisen, Dirk Kostrewa, Helmut Link, Thomas Luebbers, Raffaello Masciadri, Joergen Nielsen, Peter Reindl, Fabienne Ricklin, Anne Schmitt-Hoffmann, Frank-Peter Theil J Med Chem. 2004 Mar 11;47(6):1487-513. doi: 10.1021/jm0310232.
Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
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g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
