Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3-65.4 nM) and (11.9-72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.

Department of NEUROFARBA Pharmaceutical and Nutraceutical Section Laboratory of Molecular Modeling Cheminformatics and QSAR University of Firenze Via U Schiff 6 Sesto Fiorentino Firenze 50019 Italy

Department of NEUROFARBA Section of Pharmaceutical and Nutraceutical Sciences University of Florence Polo Scientifico Via U Schiff 6 50019 Sesto Fiorentino Firenze Italy

Department of NEUROFARBA Section of Pharmaceutical and Nutraceutical Sciences University of Florence Polo Scientifico Via U Schiff 6 50019 Sesto Fiorentino Firenze Italy; Department of NEUROFARBA Pharmaceutical and Nutraceutical Section Laboratory of Molecular Modeling Cheminformatics and QSAR University of Firenze Via U Schiff 6 Sesto Fiorentino Firenze 50019 Italy

Department of Pharmaceutical Chemistry Faculty of Pharmacy Egyptian Russian University Badr City Cairo 11829 Egypt

Department of Pharmaceutical Chemistry Faculty of Pharmacy Kafrelsheikh University Kafrelsheikh Egypt

Laboratory of Growth Regulators Palacky University and Institute of Experimental Botany The Czech Academy of Sciences Slechtitelu 27 78371 Olomouc Czech Republic

Pharmaceutical Chemistry Department Faculty of Pharmacy Cairo University El kasr Elaini Street Cairo Egypt

The Regional Center for Mycology and Biotechnology Al Azhar University Cairo Egypt

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