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Transscleral Drug Delivery to the Retina and Choroid
Published in Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson, Intraocular Drug Delivery, 2006
The diffusion of small molecules across the sclera has been well characterized. Various sulfonamides diffuse across rabbit sclera (40,41). In patients undergoing cataract surgery, methazolamide, a hydrophilic compound, penetrated the sclera much faster than the cornea, but ethoxzolamide, which is lipophilic, had similar diffusion across the sclera and cornea (40). Other studies also have found greater scleral permeability to hydrophilic molecules than lipophilic ones (42,43).
Inhibition of the β-carbonic anhydrase from the protozoan pathogen Trichomonas vaginalis with sulphonamides
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Linda J. Urbański, Andrea Angeli, Vesa P. Hytönen, Anna Di Fiore, Giuseppina De Simone, Seppo Parkkila, Claudiu T. Supuran
We report the first inhibition study with sulphonamides of one of the β-CAs, TvaCA1, found in the protozoan parasite T. vaginalis. Only anion inhibitors and other small molecules were reported earlier to act as millimolar TvaCA1 inhibitors. Here we investigated 40 sulphonamides, some of which are clinically used drugs, for their inhibitory interaction with this enzyme. Only 16 of these agents showed inhibitory effects, most of them in the low micromolar range, whereas the most effective TvaCA1 inhibitors were acetazolamide AAZ and ethoxzolamide EZA, with KIs of 391 and 283 nM, respectively. Although no in vivo/ex vivo studies have been performed so far, inhibition of this protozoan enzyme may show anti-infective effects, as was reported for other protozoan species such as Leishmania donovani chagasi31 or Trypanosoma cruzi32, for which CAIs belonging to various classes showed potent anti-protozoan activity in vivo. Thus, effective TvaCA1 inhibitors may lead to the development of novel anti-infectives with a diverse mechanism of action.
Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Baijayantimala Swain, Andrea Angeli, Srinivas Angapelly, Pavitra S. Thacker, Priti Singh, Claudiu T. Supuran, Mohammed Arifuddin
The hCA isoforms differ in their subcellular location, tissue distribution, and molecular and kinetic properties. Basically, four isoforms are cytosolic (I, II, III, and VII), five membrane-bound (IV, IX, XII, XIV, and XV), two mitochondrial (VA and VB), and CAVI is secreted in saliva and milk. Among these CA IV and XV are having GPI (glycosylphosphatidylinositol) tails anchored to the membrane while CAs IX, XII, XIV are transmembrane proteins possessing just one membrane domain8. Despite that, all these five membrane-bound isoforms are commonly termed as extracellular CAs due to having their active sites outside the cell. Many sulfonamide-based drugs (Figure 2) such as acetazolamide (AAZ), methazolamide, ethoxzolamide, dorzolamide, brinzolamide, dichlorophenamide, and celecoxib are used clinically for many years as diuretics, anti-epileptics, anti-glaucoma, or as anti-tumor agents9,10.
New sulfonamides containing organometallic-acylhydrazones: synthesis, characterisation and biological evaluation as inhibitors of human carbonic anhydrases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Yosselin Huentupil, Luis Peña, Néstor Novoa, Emanuela Berrino, Rodrigo Arancibia, Claudiu T. Supuran
Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) are clinically used for several decades as diuretics1, antiglaucoma agents2, antiobesity drugs3, and more recently, a number of studies showed that CA inhibition has profound antitumor effects by inhibition of hypoxia-inducible isoforms CA IX and XII, overexpressed in many hypoxic tumors4. Several proof-of-concept studies demonstrated the involvement of some CA isoforms in neuropathic pain5 and arthritis6, with inhibitors of the sulfonamide/coumarin7 types demonstrating significant effects in vivo, in animal models of these diseases. This is obviously due to the fact that at least 15 different α-class CA isoforms are present in humans, and many of them are drug targets for the treatment or prevention of this large variety of pathologies1–7. Thus, the field of drug design, synthesis and in vivo investigations of various types of CAIs is a highly dynamic one, with a large number of interesting new chemotypes acting on these widespread enzymes constantly emerging1–7. Among the clinically used sulfonamide CAIs are acetazolamide (AAZ), methazolamide (MZA), ethoxzolamide (EZA), brinzolamide (BRZ) and dorzolamide (DRZ) – (Figure 1)1–3. Saccharin (SAC) is a sweetener widely used in beverages and food1–3.