title: Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2-thione derivatives with carbonic anhydrase inhibitory activity.
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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. mohkam78@yahoo.com
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Abdel-Hamid
authors.forename: Atef A
authors.initials: AA
authors.lastname: Abdel-Hafez
authors.forename: Nawal A
authors.initials: NA
authors.lastname: El-Koussi
authors.forename: Nadia M
authors.initials: NM
authors.lastname: Mahfouz
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors*; D030741:Carbonic Anhydrase IV / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology