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  3. Expanding chemical space of N-acyl sulfonamides for carbonic anhydrase inhibitor discovery

Expanding chemical space of N-acyl sulfonamides for carbonic anhydrase inhibitor discovery

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118296. doi: 10.1016/j.ejmech.2025.118296.
Oleksii V Gavrylenko 1,  Bohdan V Vashchenko 2,  Vasyl Naumchyk 3,  Oleksii Chuk 4,  Olga Kuchuk 5,  Alla Pogribna 6,  Anzhelika I Konovets 7,  Volodymyr S Brovarets 8,  Sergey A Zozulya 5,  Dmytro S Radchenko 7,  Oleksandr O Grygorenko 9,  Yurii S Moroz 10
Affiliations

Affiliations

  • 1 Enamine Ltd.(1), Winston Churchill Street 78, Kyїv, 02094, Ukraine; V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Akademik Kukhar Street 1, Kyїv, 02066, Ukraine.
  • 2 Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine; Enamine Scientific Research Institute, Winston Churchill Street 67, Kyїv, 02094, Ukraine.
  • 3 Enamine Ltd.(1), Winston Churchill Street 78, Kyїv, 02094, Ukraine; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine.
  • 4 Chemspace LLC(2), Winston Churchill Street 85, Kyїv, 02094, Ukraine; Palladin Institute of Biochemistry, NAS of Ukraine, Leontovycha Street 9, Kyїv, 01054, Ukraine.
  • 5 Enamine Biology (Bienta)/Enamine Ltd.(3), Winston Churchill Street 78, Kyїv, 02094, Ukraine.
  • 6 Enamine Biology (Bienta)/Enamine Ltd.(3), Winston Churchill Street 78, Kyїv, 02094, Ukraine; Institute of Molecular Biology and Genetics, NAS of Ukraine, Zabolotnogo Street 150, Kyїv, 03143, Ukraine.
  • 7 Enamine Ltd.(1), Winston Churchill Street 78, Kyїv, 02094, Ukraine.
  • 8 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Akademik Kukhar Street 1, Kyїv, 02066, Ukraine.
  • 9 Enamine Ltd.(1), Winston Churchill Street 78, Kyїv, 02094, Ukraine; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine; Enamine Scientific Research Institute, Winston Churchill Street 67, Kyїv, 02094, Ukraine. Electronic address: [email protected].
  • 10 Enamine Ltd.(1), Winston Churchill Street 78, Kyїv, 02094, Ukraine; Chemspace LLC(2), Winston Churchill Street 85, Kyїv, 02094, Ukraine; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601, Kyїv, Ukraine. Electronic address: [email protected].
PMID: 41161054 DOI: 10.1016/j.ejmech.2025.118296
Abstract

N-Acyl sulfonamides are widely recognized carboxylic acid isosteres that can fill the gap related to acidic compounds in chemical catalogs and bioactivity studies. This study presents the generation of synthetically tractable N-acyl sulfonamide chemical space based on the two-step parallel synthetic methodologies yielding structurally diverse compounds with high efficiency. Amide formation and SNAr combined with primary sulfonamide acylation proved to be highly effective in generating structurally diverse N-acyl sulfonamides with typically good synthesis success rates (up to 83 %) and average yields (up to 57 %). The approach demonstrated reliability across different substrates, supporting the efficient construction of a 526-member compound library (out of 3,258,356 possible combinations) with minor synthetic limitations. Biological evaluations of the synthesized library identified promising inhibitors of human Carbonic Anhydrase isoforms hCA-IX and hCA-II. Differential scanning fluorimetry screening and enzymatic assays revealed potent and selective compounds, with some derivatives exhibiting low micromolar IC50 values (i.e., N-((2-((2-(3-(dimethylamino)-1,2,4-oxadiazol-5-yl)ethyl)amino)thiazol-5-yl)sulfonyl)-2-(pyrrolidin-1-yl)isonicotinamide trifluoroacetate; hCA-IX IC50 = 1.2 μM; hCA-II IC50 = 6.7 μM) and selectivity toward hCA-IX (i.e., 3-chloro-N-((1-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)pyrrolidin-3-yl)sulfonyl)benzamide; hCA-IX IC50 = 11.5 μM; hCA-II IC50 = 192 μM). Several examples demonstrated moderate selectivity towards hCA-II, e.g. N-((5-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)furan-2-carboxamide (hCA-IX IC50 = 32.8 μM; hCA-II IC50 = 4.4 μM) and N-((2-methyl-4-((1-(phenoxymethyl)cyclopropyl)carbamoyl)phenyl)sulfonyl)-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide (hCA-IX IC50 = 46.3 μM; hCA-II IC50 = 5.5 μM). Molecular docking and molecular dynamics simulations provided further insights into binding interactions, confirming the stability of ligand-protein complexes. Thus, this work highlights the synthetic efficiency and pharmacological relevance of N-acyl sulfonamides, expanding the accessible chemical space for drug discovery.

Keywords

Acidic compounds; Carbonic anhydrase; Chemical space; Combinatorial chemistry; Organosulfur compounds.

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