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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.
Bioorg Med Chem. 2013 Sep 01; 21(17):5130-8.BM

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.

Authors+Show Affiliations

Biomedical Research and Study Center, Ratsupites 1, LV 1067 Riga, Latvia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23859774

Citation

Leitans, Janis, et al. "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." Bioorganic & Medicinal Chemistry, vol. 21, no. 17, 2013, pp. 5130-8.
Leitans J, Sprudza A, Tanc M, et al. 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. Bioorg Med Chem. 2013;21(17):5130-8.
Leitans, J., Sprudza, A., Tanc, M., Vozny, I., Zalubovskis, R., Tars, K., & Supuran, C. T. (2013). 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. Bioorganic & Medicinal Chemistry, 21(17), 5130-8. https://doi.org/10.1016/j.bmc.2013.06.041
Leitans J, et al. 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. Bioorg Med Chem. 2013 Sep 1;21(17):5130-8. PubMed PMID: 23859774.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Leitans,Janis, AU - Sprudza,Agnese, AU - Tanc,Muhammet, AU - Vozny,Igor, AU - Zalubovskis,Raivis, AU - Tars,Kaspars, AU - Supuran,Claudiu T, Y1 - 2013/06/27/ PY - 2013/05/18/received PY - 2013/06/16/accepted PY - 2013/7/18/entrez PY - 2013/7/19/pubmed PY - 2014/3/19/medline KW - Carbonic anhydrase KW - Click chemistry KW - Enzyme inhibitor KW - Sulfonamide KW - Thiophene-2-sulfonamide KW - X-ray crystallography SP - 5130 EP - 8 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 21 IS - 17 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/23859774/5_Substituted__123_triazol_4_yl_thiophene_2_sulfonamides_strongly_inhibit_human_carbonic_anhydrases_I_II_IX_and_XII:_solution_and_X_ray_crystallographic_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(13)00572-5 DB - PRIME DP - Unbound Medicine ER -