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 |
| |
Authors: | Janis Leitans Agnese Sprudza Muhammet Tanc Igor Vozny Raivis Zalubovskis Kaspars Tars Claudiu T. Supuran |
| |
Affiliation: | 1. Biomedical Research and Study Center, Ratsupites 1, LV 1067 Riga, Latvia;2. Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia;3. Università degli Studi di Firenze, CSGI, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy;4. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Sesto Fiorentino, 50019 Florence, Italy |
| |
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 224–7544 nM), but were compactly, highly effective, low nanomolar hCA II inhibitors (KIs of 2.2–7.7 nM). The tumor-associated hCA IX was inhibited with KIs ranging between 5.4 and 811 nM, whereas hCA XII with inhibition constants in the range of 3.4–239 nM. 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. |
| |
Keywords: | Carbonic anhydrase Enzyme inhibitor Thiophene-2-sulfonamide Click chemistry X-ray crystallography Sulfonamide |
本文献已被 ScienceDirect 等数据库收录! |
|