QSAR studies of sulfamate and sulfamide inhibitors targeting human carbonic anhydrase isozymes I, II, IX and XII

The last version of the PRECLAV algorithm was used to investigate a series of sulfamate/sulfamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. PRECLAV allows identification of outliers for lead hopping, significant molecular fragments and similarity computation of a calibration set vs. a prediction set of compounds, from the viewpoint of computed QSAR. In the current study the database included 65 sulfamates and sulfamides as calibration set and 51 not yet synthesized sulfamates and sulfamides as prediction set. The dependent property was inhibitory activity for human (h) CA isozymes I, II, IX and XII. There were no outliers for lead hopping in the calibration set. In some cases, replacing of the O-SO2-NH2 by the NH-SO2-NH2 moiety, led to modifications in the structure of molecular fragments in another regions of the molecule. According to the descriptors in the obtained models, the inhibition of all CA isozymes was strongly influenced by the molecular shape and size of the sulfamates/sulfamides (which incorporate a substituted aryl-ureido scaffold). The lipophilicity of the inhibitors seemed to be a minor factor influencing CA inhibitory action. The presence of specific PRECLAV molecular fragments such as a C-6 (totally substituted benzene), F, O and NO2 increases the activity of inhibitors against certain isoforms. The presence of molecular fragments such as C, CH, CxHy (substituted benzene/naphthalene) and NH decreased the activity of inhibitors against certain isoforms. In the prediction set, we evidenced seven compounds estimated to be highly active inhibitors for at least three of the investigated isozymes and eight molecules estimated to possess low activity against at least three CAs. The paper suggests the structure of some possible interesting inhibitors incorporating F, O and NO2 fragments that may have affinity for certain human CAs. (C) 2012 Elsevier Ltd. All rights reserved.