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

Abstract

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.

Graphical Abstract

Keywords:

• Human carbonic anhydrase
• benzenesulphonamide
• pyrrolone
• anticancer drugs
• enzyme inhibitors

Acknowledgements

The authors convey their profound sense of appreciation to Indian institute of Science, Bangalore, India, University Science instrumentation centre, Delhi university, New Delhi, India for providing NMR facility and Jamia Hamdard, New Delhi, India for providing Mass spectra Facility to carry out spectral analysis. The authors are also grateful to Dr. Mahesh Sundararajan, BARC, Mumbai, India for his valuable scientific inputs.

Disclosure statement

All authors except CTS report no conflict of interest. CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Correction Statement

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