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5-Substituted-(1,2,3-triazol-4-yl)thiophene-2-sulfonamides strongly inhibit human carbonic anhydrases I, II, IX and XII: solution and X-ray crystallographic studies.

Leitans J, Sprudza A, Tanc M, Vozny I, Zalubovskis R, Tars K, Supuran CT
Bioorg Med Chem 21 5130-8 (2013)
Cited: 14 times
EuropePMC logo PMID: 23859774

Abstract

We report here a series of 2-thiophene-sulfonamides incorporating 1-substituted aryl-1,2,3-triazolyl moieties, prepared by click chemistry from 5-ethynylthiophene-2-sulfonamide and substituted aryl azides. The new sulfonamides were investigated as inhibitors of the zinc metalloenzyme CA (EC 4.2.1.1), and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated ones hCA IX and XII: The new compounds were medium-weak hCA I inhibitors (KIs in the range of 224-7544nM), but were compactly, highly effective, low nanomolar hCA II inhibitors (KIs of 2.2-7.7nM). The tumor-associated hCA IX was inhibited with KIs ranging between 5.4 and 811nM, whereas hCA XII with inhibition constants in the range of 3.4-239nM. The X-ray crystal structure of the adducts of two such compounds bound to hCA II (one incorporating 1-naphthyl, the other one 3-cyanophenyl moieties) evidenced the reasons of the high affinity for hCA II. Highly favorable, predominantly hydrophobic interactions between the sulfonamide scaffold and the hCA II active site were responsible for the binding, in addition to the coordination of the sulfamoyl moiety to the zinc ion. The tails of the two inhibitors adopted very diverse orientations when bound to the active site, with the naphthyltriazolyl moiety orientated towards the hydrophobic half of the active site, and the 3-cyanophenyl one pointing towards the hydrophilic half. These data may be used for the structure-based drug design of even more effective hCA II inhibitors, with potential use as antiglaucoma agents or as diuretics.

Reviews - 4bf6 mentioned but not cited (2)

  1. Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications. Angeli A, Supuran CT. J Enzyme Inhib Med Chem 38 2166503 (2023)
  2. Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors. Angeli A, Paoletti N, Supuran CT. Molecules 28 3220 (2023)


Reviews citing this publication (4)

  1. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Supuran CT. Expert Opin Drug Discov 12 61-88 (2017)
  2. Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one. Supuran CT, Alterio V, Di Fiore A, D' Ambrosio K, Carta F, Monti SM, De Simone G. Med Res Rev 38 1799-1836 (2018)
  3. Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design. Linkuvienė V, Zubrienė A, Manakova E, Petrauskas V, Baranauskienė L, Zakšauskas A, Smirnov A, Gražulis S, Ladbury JE, Matulis D. Q Rev Biophys 51 e10 (2018)
  4. The Hitchhiker's Guide to Deep Learning Driven Generative Chemistry. Ivanenkov Y, Zagribelnyy B, Malyshev A, Evteev S, Terentiev V, Kamya P, Bezrukov D, Aliper A, Ren F, Zhavoronkov A. ACS Med Chem Lett 14 901-915 (2023)

Articles citing this publication (8)

  1. Combining the tail and the ring approaches for obtaining potent and isoform-selective carbonic anhydrase inhibitors: solution and X-ray crystallographic studies. Bozdag M, Ferraroni M, Nuti E, Vullo D, Rossello A, Carta F, Scozzafava A, Supuran CT. Bioorg Med Chem 22 334-340 (2014)
  2. 3H-1,2-benzoxathiepine 2,2-dioxides: a new class of isoform-selective carbonic anhydrase inhibitors. Pustenko A, Stepanovs D, Žalubovskis R, Vullo D, Kazaks A, Leitans J, Tars K, Supuran CT. J Enzyme Inhib Med Chem 32 767-775 (2017)
  3. Carbonic Anhydrase Inhibition with Benzenesulfonamides and Tetrafluorobenzenesulfonamides Obtained via Click Chemistry. Pala N, Micheletto L, Sechi M, Aggarwal M, Carta F, McKenna R, Supuran CT. ACS Med Chem Lett 5 927-930 (2014)
  4. N-Substituted and ring opened saccharin derivatives selectively inhibit transmembrane, tumor-associated carbonic anhydrases IX and XII. Ivanova J, Carta F, Vullo D, Leitans J, Kazaks A, Tars K, Žalubovskis R, Supuran CT. Bioorg Med Chem 25 3583-3589 (2017)
  5. 5-Substituted-benzylsulfanyl-thiophene-2-sulfonamides with effective carbonic anhydrase inhibitory activity: Solution and crystallographic investigations. Ivanova J, Balode A, Žalubovskis R, Leitans J, Kazaks A, Vullo D, Tars K, Supuran CT. Bioorg Med Chem 25 857-863 (2017)
  6. 4-Anilinoquinazoline-based benzenesulfonamides as nanomolar inhibitors of carbonic anhydrase isoforms I, II, IX, and XII: design, synthesis, in-vitro, and in-silico biological studies. Nada H, Elkamhawy A, Abdellattif MH, Angeli A, Lee CH, Supuran CT, Lee K. J Enzyme Inhib Med Chem 37 994-1004 (2022)
  7. Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells. Dos Santos FA, Pereira MC, de Oliveira TB, Mendonça Junior FJB, de Lima MDCA, Pitta MGDR, Pitta IDR, de Melo Rêgo MJB, da Rocha Pitta MG. Anticancer Drugs 29 157-166 (2018)
  8. Expression and characterization of a recombinant psychrophilic γ-carbonic anhydrase (NcoCA) identified in the genome of the Antarctic cyanobacteria belonging to the genus Nostoc. De Luca V, Del Prete S, Vullo D, Carginale V, Di Fonzo P, Osman SM, AlOthman Z, Supuran CT, Capasso C. J Enzyme Inhib Med Chem 31 810-817 (2016)


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