Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2thione derivatives with carbonic anhydrase inhibitory activity

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 mu M, against hCA II in the range of 2.0-433 mu M, and against hCA IX in the range of 1.25-148 mu M. Compound 5c, 4-(4,5-dihydro-5-thioxo-1,3,4thiadi izol-2-yl)-1-(5-nitro-2-oxoindolin-3-ylidene)semicarbazide showed interesting inhibition of the turnor-associated hCA IX with K-1 value of 1.25 mu M, being the first non-sulforiamide 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 CAls with the thione group acting as a zinc-binding moiety. (C) 2007 Elsevier Ltd. All rights reserved.