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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 38; no. 1; p. 2189126
• Main Authors: Ramzan, Farhat, Nabi, Syed Ayaz, Lone, Mehak Saba, Bonardi, Alessandro, Hamid, Aabid, Bano, Sameena, Sharma, Kalicharan, Shafi, Syed, Samim, Mohammed, Javed, Kalim, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.12.2023; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: anticancer drugs; Antigens, Neoplasm - metabolism; benzenesulphonamide; Biochemistry & Molecular Biology; Cancer; Carbon dioxide; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase IX; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Chemistry; Chemistry, Medicinal; enzyme inhibitors; Enzymes; Fourier transforms; Human carbonic anhydrase; Humans; Hydrocarbons; Isoforms; Isomers; Life Sciences & Biomedicine; Models, Theoretical; Molecular Structure; Pharmaceuticals; Pharmacokinetics; Pharmacology & Pharmacy; pyrrolone; Research Paper; Science & Technology; Structure-Activity Relationship; SYSTEM; DESIGN; SULFONAMIDE; CONVENIENT; Human carbonic anhydrase; anticancer drugs; benzenesulphonamide; ANTICANCER; X-RAY; ISOZYME-II; pyrrolone; enzyme inhibitors; EFFICIENT; BINDING
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2023.2189126

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.