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Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2-thione derivatives with carbonic anhydrase inhibitory activity
- Source :
- Bioorganicmedicinal chemistry. 15(22)
- Publication Year :
- 2007
-
Abstract
- A new series of 1,3,4-thiadiazole-2-thione derivatives have been prepared and assayed for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. Against hCA I the investigated thiones, showed inhibition constants in the range of 2.55-222 microM, against hCA II in the range of 2.0-433 microM, and against hCA IX in the range of 1.25-148 microM. Compound 5c, 4-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)-1-(5-nitro-2-oxoindolin-3-ylidene)semicarbazide showed interesting inhibition of the tumor-associated hCA IX with K(I) value of 1.25 microM, being the first non-sulfonamide type inhibitor of such activity. This result is rather important taking into consideration the known antitumor activity of thiones. In addition, docking of the tested compounds into CA II active site was performed in order to predict the affinity and orientation of these compounds at the isozyme active site. The results showed similar orientation of the target compounds at CA II active site compared with reported sulfonamide type CAIs with the thione group acting as a zinc-binding moiety.
- Subjects :
- Models, Molecular
Carbonic Anhydrase I
Stereochemistry
Clinical Biochemistry
Pharmaceutical Science
Crystallography, X-Ray
Ligands
Biochemistry
Chemical synthesis
Carbonic Anhydrase II
chemistry.chemical_compound
Structure-Activity Relationship
Carbonic Anhydrase IV
Carbonic anhydrase
Drug Discovery
Thiadiazoles
Humans
Carbonic Anhydrase Inhibitors
Molecular Biology
Semicarbazone
chemistry.chemical_classification
Semicarbazide
biology
Molecular Structure
Chemistry
Organic Chemistry
Active site
Thiones
Protein Structure, Tertiary
Enzyme
Docking (molecular)
Enzyme inhibitor
Drug Design
biology.protein
Molecular Medicine
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 15
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....2a3ca44f8e209293c7e2d4f7a9fd4ccf