Synthesis, biological evaluation and theoretical studies of (E)-1-(4-sulfamoyl-phenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones as human carbonic anhydrase inhibitors

A series of 20 newly designed (E)-1-(4-sulphamoylphenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones was synthesised and assessed as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors towards four human isoforms of pharmaceutical interest, that is, hCA I, II, IX and XII. The compounds displayed low to high nanomolar potency against all the isoforms. Introducing strong electron withdrawing groups at the para position of the arylidene ring increased the binding affinity to the enzyme. All compounds showed acceptable pharmacokinetic range and physicochemical characteristics as determined by computational ADMET analysis. Density Functional Theory (DFT) calculations of 3n were carried to gain understanding on the stability of the E and Z isomers. The energy values clearly indicate the stability of E isomer over Z isomer by -8.2 kJ mol(-1). Our findings indicate that these molecules are useful as leads for discovering new CA inhibitors.

Automated summary

A series of newly designed (E)-1-(4-sulphamoylphenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones were synthesized and evaluated as inhibitors for four human isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with pharmaceutical potential, namely hCA I, II, IX, and XII. These compounds exhibited varying potencies in the low to high nanomolar range against all isoforms. Introducing strong electron-withdrawing groups at the para position of the arylidene ring enhanced the enzyme binding affinity. Computational ADMET analysis demonstrated that all compounds possessed acceptable pharmacokinetic range and physicochemical characteristics. Density Functional Theory (DFT) calculations of 3n revealed the stability of the E isomer over the Z isomer by -8.2 kJ mol(-1). Our findings suggest that these molecules serve as promising leads in the search for new CA inhibitors.