New aminobenzenesulfonamide–thiourea conjugates: Synthesis and carbonic anhydrase inhibition and docking studies

• A series of novel aminobenzenesulfonamide–thiourea conjugates were designed and synthesized.
• Newly synthesized conjugates were investigated as potent carbonic anhydrase inhibitors.
• Binding mode of aminobenzenesulfonamide–thiourea was observed using docking studies.

A variety of 1-substituted-3-(3-aminosulfonylphenyl)thioureas (3a–k) and two new 1-aroyl-3-(4-aminosulfonylphenyl)thiourea derivatives (5a and 5b) were synthesized by reaction of 3-aminobenzenesulfonamide and 4-aminobenzenesulfonamide respectively with freshly prepared aroyl/heteroaryl isothiocyanates in dry acetonitrile. FTIR, 1H NMR, 13C NMR, GC–MS and elemental analyses data confirmed the assigned structures to the synthesized compounds. Further structure of compound (3g) was also confirmed by single crystal XRD analysis. The compounds were investigated as inhibitors of the bovine erythrocyte carbonic anhydrase isoform II (bCA II). The inhibition constants of these compounds against bCA II were in the range 0.011–17.1 μM. Among the evaluated compounds, 1-substituted -3-(3-aminosulfonylphenyl)thiourea derivatives 3h and 5a were the most potent inhibitors with IC50 of 0.052 and 0.011 μM, respectively. In silico docking and molecular dynamics simulation studies were performed against bCA II and human CA II enzymes to rationalize the inhibitory properties of these compounds.

Binding modes and interactions of the compound inside the active site of hCA II. Compounds are shown in CPK model. Blue circles represent the coordination geometry around the Zn2+ atomFigure optionsDownload as PowerPoint slide