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<p>Indole, characterized by its favorable bioavailability, unique structural attributes, and a broad pharmacological profile, represents a privileged scaffold in anticancer drug discovery. Chalcones constitute another important scaffold in medicinal chemistry and numerous chalcone derivatives have been reported to exhibit diverse biological activities, including anticancer and enzyme inhibitory effects. Several chalcone-based compounds have also been investigated as carbonic anhydrase inhibitors. Sulfonamides are a classical class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors with diverse therapeutic relevance, being employed as diuretics, anticonvulsants, topical antiglaucoma agents and in the management of obesity and cancer. Herein, we designed and synthesized a novel series of indolylchalcone–benzenesulfonamide hybrids (<b>15a</b>−<b>m</b> and <b>16a</b>−<b>d</b>) and evaluated their inhibitory activities against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX and XII). Interestingly, most of the tested compounds inhibited the tumor-associated hCA IX and XII isoforms with single- to double-digit nanomolar inhibition constants (<i>K</i><sub>i</sub>s). In particular, compound <b>15h</b> ((<i>E</i>)-4-(3-(5-cyano-1<i>H</i>-indol-3-yl)acryloyl)benzenesulfonamide) showed potent inhibition of hCA IX (<i>K</i><sub>i</sub> = 8.9 nM) with marked selectivity over hCA I, II, and XII (SI = 61.9, 7.2, and 5.7, respectively), whereas compound <b>15j</b> ((<i>E</i>)-4-(3-(6-bromo-1<i>H</i>-indol-3-yl)acryloyl)benzenesulfonamide) exhibited strong inhibition of hCA XII (<i>K</i><sub>i</sub> = 4.9 nM) with pronounced selectivity over hCA I, II, and IX (SI = 628.4, 12.8, and 11.9, respectively), compared with the reference inhibitor acetazolamide (AAZ). Structure–activity relationship analysis revealed that electron withdrawing groups, particularly cyano and bromo substituents on the indole scaffold, conferred enhanced selectivity toward tumor-associated carbonic anhydrase isoforms. Molecular docking demonstrated that both compounds adopted the canonical sulfonamide-binding mode, coordinating with Zn²⁺ and engaging in stable hydrogen-bond interactions with key active-site residues. Complementary molecular dynamics simulations confirmed the persistence of these interactions, as reflected by lower RMSD values and the maintenance of critical contacts throughout the simulation period. In addition, in silico ADME prediction using the SwissADME server suggested that compound <b>15j</b> possesses a more favorable balance of lipophilicity and polarity, indicating improved membrane permeability and oral absorption potential compared to <b>15h</b> and acetazolamide (AAZ), whereas <b>15h</b> exhibited relatively higher polarity that may limit permeability despite comparable lipophilicity. Accordingly, these findings suggest that the novel indolylchalcone-benzenesulfonamide hybrids <b>15h</b> and <b>15j</b> represent promising leads for the development of potent and selective inhibitors of tumor-associated carbonic anhydrases.</p>

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Discovery of indolylchalcone benzenesulfonamides as selective inhibitors of tumor-associated carbonic anhydrase IX and XII

  • 期刊论文

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  • 发表日期：

    2026年7月8日

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  • Joohan Lee,
  • Karol Biernacki,
  • Simone Giovannuzzi,
  • Hossam Nada,
  • Shubham C Rivonker ,
  • Changseong Kim ,
  • Claudiu T. Supuran,
  • Ahmed Elkamhawy,
  • Kyeong Lee

摘要

Indole, characterized by its favorable bioavailability, unique structural attributes, and a broad pharmacological profile, represents a privileged scaffold in anticancer drug discovery. Chalcones constitute another important scaffold in medicinal chemistry and numerous chalcone derivatives have been reported to exhibit diverse biological activities, including anticancer and enzyme inhibitory effects. Several chalcone-based compounds have also been investigated as carbonic anhydrase inhibitors. Sulfonamides are a classical class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors with diverse therapeutic relevance, being employed as diuretics, anticonvulsants, topical antiglaucoma agents and in the management of obesity and cancer. Herein, we designed and synthesized a novel series of indolylchalcone–benzenesulfonamide hybrids (15a−m and 16a−d) and evaluated their inhibitory activities against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX and XII). Interestingly, most of the tested compounds inhibited the tumor-associated hCA IX and XII isoforms with single- to double-digit nanomolar inhibition constants (Kis). In particular, compound 15h ((E)-4-(3-(5-cyano-1H-indol-3-yl)acryloyl)benzenesulfonamide) showed potent inhibition of hCA IX (Ki = 8.9 nM) with marked selectivity over hCA I, II, and XII (SI = 61.9, 7.2, and 5.7, respectively), whereas compound 15j ((E)-4-(3-(6-bromo-1H-indol-3-yl)acryloyl)benzenesulfonamide) exhibited strong inhibition of hCA XII (Ki = 4.9 nM) with pronounced selectivity over hCA I, II, and IX (SI = 628.4, 12.8, and 11.9, respectively), compared with the reference inhibitor acetazolamide (AAZ). Structure–activity relationship analysis revealed that electron withdrawing groups, particularly cyano and bromo substituents on the indole scaffold, conferred enhanced selectivity toward tumor-associated carbonic anhydrase isoforms. Molecular docking demonstrated that both compounds adopted the canonical sulfonamide-binding mode, coordinating with Zn²⁺ and engaging in stable hydrogen-bond interactions with key active-site residues. Complementary molecular dynamics simulations confirmed the persistence of these interactions, as reflected by lower RMSD values and the maintenance of critical contacts throughout the simulation period. In addition, in silico ADME prediction using the SwissADME server suggested that compound 15j possesses a more favorable balance of lipophilicity and polarity, indicating improved membrane permeability and oral absorption potential compared to 15h and acetazolamide (AAZ), whereas 15h exhibited relatively higher polarity that may limit permeability despite comparable lipophilicity. Accordingly, these findings suggest that the novel indolylchalcone-benzenesulfonamide hybrids 15h and 15j represent promising leads for the development of potent and selective inhibitors of tumor-associated carbonic anhydrases.