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Claudiu T Supuran - One of the best experts on this subject based on the ideXlab platform.

  • handling drug target selectivity a study on ureido containing Carbonic Anhydrase Inhibitors
    European Journal of Medicinal Chemistry, 2021
    Co-Authors: Ozlem Akgul, Fabrizio Carta, Robert Mckenna, Srishti Singh, Andrea Angeli, Silvia Selleri, Jacob T Andring, Claudiu T Supuran
    Abstract:

    Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective Inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex.

  • n aryl n ureido o sulfamates as potent and selective Inhibitors of hca vb over hca va deciphering the binding mode of new potential agents in mitochondrial dysfunctions
    Bioorganic Chemistry, 2020
    Co-Authors: Giulio Poli, Fabrizio Carta, Andrea Angeli, Murat Bozdag, Emanuela Berrino, Tiziano Tuccinardi, Claudiu T Supuran
    Abstract:

    Abstract N-aryl-N′-ureido-O-sulfamates (AUSs) were recently reported as new class of Carbonic Anhydrase Inhibitors (CAIs), endowed of high potency and selectivity against hCA VII and XII. In this work, we extended the investigational study on this new class of CAIs profiling them against the mitochondrial CA isoforms hCA VA and VB. The results revealed a very interesting selectivity profile, with dramatic selectivity against hCA VB over the VA isoform observed for all the analyzed compounds 2–22. On derivative 15, selected as one of the most promising among the series, molecular modeling studies were conducted, highlighting the importance of small residue substitution between the two isoforms in substantially changing the tail orientation and interaction with the enzymes.

  • development of thiazolidinones as fungal Carbonic Anhydrase Inhibitors
    International Journal of Molecular Sciences, 2020
    Co-Authors: Ozlen Guzelakdemir, Claudiu T Supuran, Andrea Angeli, Simone Carradori, Rossella Grande, Kubra Demiryazici, Atilla Akdemir
    Abstract:

    In our efforts to find new and selective thiazolidinone-based anti-Candida agents, we synthesized and tested 26 thiazolidinones against several Candida spp. and Gram-positive and Gram-negative bacteria. The compounds showed selective antifungal activity with potency similar to fluconazole and clotrimazole, while lacking strong antibacterial activity. Molecular docking and molecular dynamics studies were performed on Candida CYP51a1 and Carbonic Anhydrase (CA) enzymes to further suggest putative targets that could mediate the antifungal effects of these compounds. Finally, the compounds were tested in enzyme inhibition assays to assess their putative mechanism of action and showed promising KI values in the 0.1-10 µM range against the Candida glabrata β-CA enzyme CgNce103.

  • glycomimetic based approach toward selective Carbonic Anhydrase Inhibitors
    ACS Medicinal Chemistry Letters, 2020
    Co-Authors: Debora Pratesi, Fabrizio Carta, Claudiu T Supuran, Andrea Angeli, Camilla Matassini, Andrea Goti, Rolando A Spanevello, Francesca Cardona
    Abstract:

    The synthesis of selective Inhibitors of human Carbonic Anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targ...

  • synthesis of benzensulfonamides linked to quinazoline scaffolds as novel Carbonic Anhydrase Inhibitors
    Bioorganic Chemistry, 2019
    Co-Authors: Adel S Elazab, Alessio Nocentini, Alaa A M Abdelaziz, Sivia Bua, Manal A Elgendy, Menshawy A Mohamed, Taghreed Z Shawer, Nawaf A Alsaif, Claudiu T Supuran
    Abstract:

    Abstract Carbonic Anhydrase (CA) inhibitory activities of newly synthesized quinazoline-linked benzensulfonamides 10–29, 31, 32, 35, 36, and 45–51 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared to that of acetazolamide (AAZ) as a standard inhibitor. Potent selective inhibitory activity against hCA I was exerted by compounds 14, 15, 17, 19, 20, 21, 24, 25, 28, 29, 31, 35, 45, 47, 49, and 51 with inhibition constant (KIs) values of 39.4–354.7 nM that were nearly equivalent or even greater than that of AAZ (KI, 250.0 nM). Compounds 15, 20, 24, 28, 29, 45 and 47 proved to have inhibitory activities against hCA II with (KIs, 0.73–16.5 nM) that were similar or improved to that of AAZ (KI, 12.0 nM). Compounds 13–29, 31–32, and 45–51 displayed potent hCA IX inhibitory activities (KIs, 1.6–32.2 nM) that were more effective than or nearly equal to AAZ (KI, 25.0 nM). Compounds 14, 15, 20, 21, 26, 45, and 47 exerted potent hCA XII inhibitory activities (KIs, 5.2–9.2 nM), indicating similar CAI activities as compared to that of AAZ (KI, 5.7 nM).

Fabrizio Carta - One of the best experts on this subject based on the ideXlab platform.

  • handling drug target selectivity a study on ureido containing Carbonic Anhydrase Inhibitors
    European Journal of Medicinal Chemistry, 2021
    Co-Authors: Ozlem Akgul, Fabrizio Carta, Robert Mckenna, Srishti Singh, Andrea Angeli, Silvia Selleri, Jacob T Andring, Claudiu T Supuran
    Abstract:

    Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective Inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex.

  • Carbonic Anhydrase Inhibitors targeting metabolism and tumor microenvironment
    Metabolites, 2020
    Co-Authors: Andrea Angeli, Fabrizio Carta, Jeanyves Winum, Clemente Capasso, Atilla Akdemir, Alessio Nocentini, Raivis Zalubovskis, Valentina Onnis, Wagdy M Eldehna, Giuseppina De Simone
    Abstract:

    The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several Carbonic Anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA Inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

  • n aryl n ureido o sulfamates as potent and selective Inhibitors of hca vb over hca va deciphering the binding mode of new potential agents in mitochondrial dysfunctions
    Bioorganic Chemistry, 2020
    Co-Authors: Giulio Poli, Fabrizio Carta, Andrea Angeli, Murat Bozdag, Emanuela Berrino, Tiziano Tuccinardi, Claudiu T Supuran
    Abstract:

    Abstract N-aryl-N′-ureido-O-sulfamates (AUSs) were recently reported as new class of Carbonic Anhydrase Inhibitors (CAIs), endowed of high potency and selectivity against hCA VII and XII. In this work, we extended the investigational study on this new class of CAIs profiling them against the mitochondrial CA isoforms hCA VA and VB. The results revealed a very interesting selectivity profile, with dramatic selectivity against hCA VB over the VA isoform observed for all the analyzed compounds 2–22. On derivative 15, selected as one of the most promising among the series, molecular modeling studies were conducted, highlighting the importance of small residue substitution between the two isoforms in substantially changing the tail orientation and interaction with the enzymes.

  • glycomimetic based approach toward selective Carbonic Anhydrase Inhibitors
    ACS Medicinal Chemistry Letters, 2020
    Co-Authors: Debora Pratesi, Fabrizio Carta, Claudiu T Supuran, Andrea Angeli, Camilla Matassini, Andrea Goti, Rolando A Spanevello, Francesca Cardona
    Abstract:

    The synthesis of selective Inhibitors of human Carbonic Anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targ...

  • n aryl n ureido o sulfamates potent and selective Inhibitors of the human Carbonic Anhydrase vii isoform with neuropathic pain relieving properties
    Bioorganic Chemistry, 2019
    Co-Authors: Murat Bozdag, Andrea Angeli, Jeanyves Winum, Silvia Selleri, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Giulio Poli, Elena Lucarini, Tiziano Tuccinardi, Fabrizio Carta
    Abstract:

    Herein we report for the first time an efficient synthetic procedure for the preparation of N-aryl-N'-ureido-O-sulfamates (AUSs) as a new class of Carbonic Anhydrase Inhibitors (CAIs). The compounds were tested for the inhibition of several human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) isoforms. Interesting inhibition activity and high selectivity against CA VII and XII versus CA I and II, with KIs in the low nanomolar range, were observed. Molecular modeling studies allowed us to decipher the structural features underpinning the selective inhibitory profile of AUSs towards isoforms CAs VII and XII. A selection of sulfamates showed promising neuropathic pain modulating effects in an in vivo animal model of oxaliplatin induced pain.

Andrea Scozzafava - One of the best experts on this subject based on the ideXlab platform.

  • a class of sulfonamide Carbonic Anhydrase Inhibitors with neuropathic pain modulating effects
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Fabrizio Carta, Robert Mckenna, Andrea Scozzafava, Lorenzo Di Cesare Mannelli, Melissa A Pinard, Carla Ghelardini, Claudiu T Supuran
    Abstract:

    A series of benzene sulfonamide Carbonic Anhydrase (CA, EC 4.2.1.1) Inhibitors which incorporate lipophilic 4-alkoxy- and 4-aryloxy moieties, together with several derivatives of ethoxzolamide and sulfanilamide are reported. These derivatives were investigated as Inhibitors of the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) of which multiple isoforms are known, and some appear to be involved in pain. These sulfonamides showed modest inhibition against the cytosolic isoform CA I, but were generally effective, low nanomolar CA II, VII, IX and XII Inhibitors. X-ray crystallographic data for the adduct of several such sulfonamides with CA II allowed us to rationalize the good inhibition data. In a mice model of neuropathic pain induced by oxaliplatin, one of the strong CA II/VII Inhibitors reported here induced a long lasting pain relieving effect, a fact never observed earlier. This is the first report of rationally designed sulfonamide CA Inhibitors with pain effective modulating effects.

  • sulfonamides and their isosters as Carbonic Anhydrase Inhibitors
    Future Medicinal Chemistry, 2014
    Co-Authors: Fabrizio Carta, Claudiu T Supuran, Andrea Scozzafava
    Abstract:

    Molecules containing the sulfonamide group (R-SO2NH2) as well as its structurally related isosters, sulfamido (R-NH-SO2NH2) and sulfamato (R-O-SO2NH2), constitute the most important class of Inhibitors acting on the metalloenzyme Carbonic Anhydrase (EC 4.2.1.1). Despite their presence in the literature, in general the reports lack of a clear and organic overview linking the main structural features of the clinically used Inhibitors with the therapeutic aspects. The current review is intended to highlight the structural basis of the interactions of sulfonamide-like groups within the active site of the Carbonic Anhydrases and will summarize the clinical use of the most interesting molecules for the treatment of relevant pathologies, such as glaucoma, obesity, cancer and CNS-affecting diseases.

  • glaucoma and the applications of Carbonic Anhydrase Inhibitors
    Sub-cellular biochemistry, 2014
    Co-Authors: Andrea Scozzafava, Claudiu T Supuran
    Abstract:

    Inhibition of Carbonic Anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the treatment of glaucoma, a disease affecting a large number of people and characterized by an elevated intraocular pressure (IOP). At least three isoforms, CA II, IV and XII are targeted by the sulfonamide Inhibitors, some of which are clinically used drugs. Acetazolamide, methazolamide and dichlorophenamide are first generation CA Inhibitors (CAIs) still used as systemic drugs for the management of this disease. Dorzolamide and brinzolamide represent the second generation Inhibitors, being used topically, as eye drops, with less side effects compared to the first generation drugs. Third generation Inhibitors have been developed by using the tail approach, but they did not reach the clinics yet. The most promising such derivatives are the sulfonamides incorporating either tails with nitric oxide releasing moieties or hybrid drugs possessing prostaglandin (PG) F agonist moieties in their molecules. Recently, the dithiocarbamates have also been described as CAIs possessing IOP lowering effects in animal models of glaucoma. CAIs are used alone or in combination with other drugs such as adrenergic agonist/antagonists, or PG analogs, being an important component of the antiglaucoma drugs armamentarium.

  • antiobesity Carbonic Anhydrase Inhibitors a literature and patent review
    Expert Opinion on Therapeutic Patents, 2013
    Co-Authors: Andrea Scozzafava, Claudiu T Supuran, Fabrizio Carta
    Abstract:

    Introduction: Obesity is ranked as one of the top 10 global health problems and the major concern deriving from it is the exposure of the population to a vast array of chronic pathologies such as cardiovascular and musculoskeletal disorders, type 2 diabetes, cancer, such as colon, breast and endometrial cancer, together with psychological disorders derived from this condition. The discovery that the clinically used anticonvulsants topiramate (TPM) and zonisamide (ZNS) induced weight loss in obese, epileptic patients, afforded the validation of the mitochondrial Carbonic Anhydrases (CAs, EC 4.2.1.1) VA and VB as targets for the development of antiobesity drugs. Areas covered: This review deals with the scientific and patent literature regarding obesity or obesity-related pathologies, being particularly focused on the use of Carbonic Anhydrase Inhibitors (CAI) such as TPM and ZNS which inhibit the de novo lipogenesis. Expert opinion: There is an urgent need of new drugs for the treatment of obesity. The ide...

  • antiglaucoma Carbonic Anhydrase Inhibitors a patent review
    Expert Opinion on Therapeutic Patents, 2013
    Co-Authors: Emanuela Masini, Fabrizio Carta, Andrea Scozzafava, Claudiu T Supuran
    Abstract:

    Introduction: Glaucoma is one of the major causes of blindness, affecting together with age-related macular degeneration > 70 million people worldwide. One of the therapeutic options for its management is based on the inhibition of the metalloenyme Carbonic Anhydrase (CA, EC 4.2.1.1). CA Inhibitors (CAIs) diminish intraocular pressure (IOP) by reducing the rate of bicarbonate formation and thus secretion of the aqueous humor. Areas covered: The main classes of clinically used antiglaucoma CAIs are the sulfonamides with systemic (acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide) and topical (dorzolamide and brinzolamide) action. A patent literature review covering the period 2007 – 2013 is presented. Expert opinion: This review presents an overview of the patent literature in the CAI antiglaucoma drug design field during the past 6 years. Most of the patents deal with sulfonamide/sulfamide/sulfamate CAIs, sulfonamides incorporating NO-donating moieties, as well as hybrids incorporating sul...

Giuseppina De Simone - One of the best experts on this subject based on the ideXlab platform.

  • Carbonic Anhydrase Inhibitors targeting metabolism and tumor microenvironment
    Metabolites, 2020
    Co-Authors: Andrea Angeli, Fabrizio Carta, Jeanyves Winum, Clemente Capasso, Atilla Akdemir, Alessio Nocentini, Raivis Zalubovskis, Valentina Onnis, Wagdy M Eldehna, Giuseppina De Simone
    Abstract:

    The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several Carbonic Anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA Inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

  • inhibition of Carbonic Anhydrases by a substrate analog benzyl carbamate directly coordinates the catalytic zinc ion mimicking bicarbonate binding
    Chemical Communications, 2018
    Co-Authors: Giuseppina De Simone, Claudiu T Supuran, Andrea Angeli, Murat Bozdag, Jeanyves Winum, Simona Maria Monti, Vincenzo Alterio
    Abstract:

    N-Unsubstituted carbamates have scarcely been investigated so far as Carbonic Anhydrase Inhibitors (CAIs). By means of kinetic and structural studies, in this paper we demonstrate that such molecules can effectively inhibit hCAs and can be used as lead compounds for the development of CAIs possessing a binding mode similar to one of the CA substrates, bicarbonate.

  • Crystal structure of the human Carbonic Anhydrase II adduct with 1-(4-sulfamoylphenyl-ethyl)-2,4,6-triphenylpyridinium perchlorate, a membrane-impermeant, isoform selective inhibitor
    Taylor & Francis Group, 2018
    Co-Authors: Vincenzo Alterio, Claudiu T Supuran, Simona Maria Monti, Davide Esposito, Giuseppina De Simone
    Abstract:

    Pyridinium containing sulfonamides have been largely investigated as Carbonic Anhydrase Inhibitors (CAIs), showing interesting selectivity features. Nevertheless, only few structural studies are so far available on adducts that these compounds form with diverse CA isoforms. In this paper, we report the structural characterization of the adduct that a triphenylpyridinium derivative forms with hCA II, showing that the substitution of the pyridinium ring plays a key role in determining the conformation of the inhibitor in the active site and consequently the binding affinity to the enzyme. These findings open new perspectives on the basic structural requirements for designing sulfonamide CAIs with a selective inhibition profile

  • out of the active site binding pocket for Carbonic Anhydrase Inhibitors
    Chemical Communications, 2015
    Co-Authors: Katia Dambrosio, Claudiu T Supuran, Simona Maria Monti, Daniela Vullo, Simone Carradori, Martina Buonanno, Daniela Secci, Giuseppina De Simone
    Abstract:

    A structural study of the adduct which 2-benzylsulfinylbenzoic acid forms with human Carbonic Anhydrase II is reported, showing a binding mode completely different from any other class of Carbonic Anhydrase Inhibitors investigated so far; this carboxylate binds in a pocket situated out of the enzyme active site.

  • exploiting the hydrophobic and hydrophilic binding sites for designing Carbonic Anhydrase Inhibitors
    Expert Opinion on Drug Discovery, 2013
    Co-Authors: Giuseppina De Simone, Vincenzo Alterio, Claudiu T Supuran
    Abstract:

    Introduction: Carbonic Anhydrases (CAs, EC 4.2.1.1) exist as five genetically distinct families (α, β, γ, δ and ζ) in organisms all over the phylogenetic tree. Due to the ubiquity of such enzymes, the selective inhibition and polypharmacology of Inhibitors is an important aspect of all drug design campaigns. There are several classes of CA Inhibitors (CAIs): i) metal ion binders (sulfonamides and their isosteres [sulfamates/sulfamides], dithiocarbamates, mercaptans and hydroxamates); ii) compounds anchoring to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, esters and sulfocoumarins) and iii) coumarins and related compounds which apparently bind even further away from the metal ion. Areas covered: The authors rationalize the drug design strategies of Inhibitors belonging to the first two classes, based on recent X-ray crystallographic data. More precisely, this is achieved by analyzing how the hydrophobic and hydrophilic halves of the enzyme active site interact with ...

Robert Mckenna - One of the best experts on this subject based on the ideXlab platform.

  • handling drug target selectivity a study on ureido containing Carbonic Anhydrase Inhibitors
    European Journal of Medicinal Chemistry, 2021
    Co-Authors: Ozlem Akgul, Fabrizio Carta, Robert Mckenna, Srishti Singh, Andrea Angeli, Silvia Selleri, Jacob T Andring, Claudiu T Supuran
    Abstract:

    Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective Inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex.

  • Cancer drug development of Carbonic Anhydrase Inhibitors beyond the active site
    Molecules, 2018
    Co-Authors: Srishti Singh, Carrie L. Lomelino, Mam Y. Mboge, Susan C Frost, Robert Mckenna
    Abstract:

    Carbonic Anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to produce bicarbonate and a proton. Multiple CA isoforms are implicated in a range of diseases, including cancer. In solid tumors, continuously dividing cells create hypoxic conditions that eventually lead to an acidic microenvironment. Hypoxic tumor cells have different mechanisms in place to regulate and adjust the surrounding microenvironment for survival. These mechanisms include expression of CA isoform IX (CA IX) and XII (CA XII). These enzymes help maintain a physiological intracellular pH while simultaneously contributing to an acidic extracellular pH, leading to tumor cell survival. Expression of CA IX and CA XII has also been shown to promote tumor cell invasion and metastasis. This review discusses the characteristics of CA IX and CA XII, their mechanism of action, and validates their prospective use as anticancer targets. We discuss the current status of small Inhibitors that target these isoforms, both classical and non-classical, and their future design in order to obtain isoform-specificity for CA IX and CA XII. Biologics, such as monoclonal antibodies, monoclonal-radionuclide conjugated chimeric antibodies, and antibody-small molecule conjugates are also discussed.

  • Carbonic Anhydrase Inhibitors a review on the progress of patent literature 2011 2016
    Expert Opinion on Therapeutic Patents, 2016
    Co-Authors: Carrie L. Lomelino, Robert Mckenna
    Abstract:

    ABSTRACTIntroduction: A large area of Carbonic Anhydrase (CA) research focuses on the inhibition of human CA IX and CA XII, as these isoforms have been designated as biomarkers and therapeutic targets for various cancer types.Areas covered: Recently, the majority of CA inhibitor (CAI) patents cover compound design, synthesis, and delivery methods for the treatment of glaucoma and cancer. The analysis of included patents highlights the need for isoform specific Inhibitors. This review covers the patents of medically relevant Carbonic Anhydrase Inhibitors between 2011–2016.Expert opinion: The improvement of structure-based drug design methods and access to the crystal structures of human CA isoforms have improved inhibitor development. This progress can be observed in relation to the selective inhibition of CA IX for cancer treatments, with one inhibitor in clinical trials. However, the design of nonclassical CAIs is essential to further improve isoform specificity and prevent sulfur allergies.

  • a class of sulfonamide Carbonic Anhydrase Inhibitors with neuropathic pain modulating effects
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Fabrizio Carta, Robert Mckenna, Andrea Scozzafava, Lorenzo Di Cesare Mannelli, Melissa A Pinard, Carla Ghelardini, Claudiu T Supuran
    Abstract:

    A series of benzene sulfonamide Carbonic Anhydrase (CA, EC 4.2.1.1) Inhibitors which incorporate lipophilic 4-alkoxy- and 4-aryloxy moieties, together with several derivatives of ethoxzolamide and sulfanilamide are reported. These derivatives were investigated as Inhibitors of the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) of which multiple isoforms are known, and some appear to be involved in pain. These sulfonamides showed modest inhibition against the cytosolic isoform CA I, but were generally effective, low nanomolar CA II, VII, IX and XII Inhibitors. X-ray crystallographic data for the adduct of several such sulfonamides with CA II allowed us to rationalize the good inhibition data. In a mice model of neuropathic pain induced by oxaliplatin, one of the strong CA II/VII Inhibitors reported here induced a long lasting pain relieving effect, a fact never observed earlier. This is the first report of rationally designed sulfonamide CA Inhibitors with pain effective modulating effects.

  • Carbonic Anhydrase Inhibitors drug design
    Sub-cellular biochemistry, 2014
    Co-Authors: Robert Mckenna, Claudiu T Supuran
    Abstract:

    Inhibition of the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the field of antiglaucoma, anticonvulsant, antiobesity, and anticancer agents but is also emerging for designing anti-infectives (antifungal and antibacterial agents) with a novel mechanism of action. As a consequence, the drug design of CA Inhibitors (CAIs) is a very dynamic field. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of CAIs which bind to the metal ion in the enzyme active site. Recently the dithiocarbamates, possessing a similar mechanism of action, were reported as a new class of Inhibitors. Other families of CAIs possess a distinct mechanism of action: phenols, polyamines, some carboxylates, and sulfocoumarins anchor to the zinc-coordinated water molecule. Coumarins and five/six-membered lactones are prodrug Inhibitors, binding in hydrolyzed form at the entrance of the active site cavity. Novel drug design strategies have been reported principally based on the tail approach for obtaining all these types of CAIs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Sugar-based tails as well as click chemistry were the most fruitful developments of the tail approach. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the dithiocarbamate, phenol and carboxylate types have also been reported.