Publications (62) View all
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Article: Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors.
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ABSTRACT: Abstract Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.Journal of Enzyme Inhibition and Medicinal Chemistry 04/2013; · 1.62 Impact Factor -
Article: Carbonic anhydrase inhibitors. Benzenesulfonamides incorporating cyanoacrylamide moieties strongly inhibit Saccharomyces cerevisiae β-carbonic anhydrase.
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ABSTRACT: A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogs) were assayed as inhibitors of the β-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. Some of these compounds were low nanomolar or subnanomolar ScCA inhibitors and showed selectivity ratios in the range of 4.91-69.86 for inhibiting the yeast enzyme over the offtarget human (h) isoforms hCA I and of 6.46-13.52 for inhibiting ScCA over hCA II. The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged. Indeed, some of these sulfonamides inhibited the growth of the yeast with CC50-s in the range of 0.73-6.54μM.Bioorganic & medicinal chemistry letters 04/2013; · 2.65 Impact Factor -
Article: Kinetic and anion inhibition studies of a β-carbonic anhydrase (FbiCA 1) from the C4 plant Flaveria bidentis.
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ABSTRACT: Several β-carbonic anhydrases (CAs, EC 4.2.1.1) are present in all land plants examined thus far. Here we report the first detailed biochemical characterization of one such isoform, FbiCA 1, from the C plant Flaveria bidentis, which was cloned, purified and characterized as recombinant protein. FbiCA 1 has an interesting CO hydrase catalytic activity (k of 1.2×10 and k/K of 7.5×10M×s) and was moderately inhibited by most simple/complex inorganic anions. Potent FbiCA 1 inhibitors were also detected, such as trithiocarbonate, diethyldithiocarbamate, sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid (Ks in the range of 4-60μM). Such inhibitors may be used as tools to better understand the role of various β-CA isoforms in photosynthesis.Bioorganic & medicinal chemistry letters 03/2013; 23(6):1626-30. · 2.65 Impact Factor -
Article: Anion inhibition studies of the α-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.
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ABSTRACT: An α-carbonic anhydrase (CA, EC 4.2.1.1) has been recently cloned and characterized in the human pathogenic bacterium Vibrio cholerae, denominated VchCA (Del Prete et al. J. Med. Chem.2012, 55, 10742). This enzyme shows a good catalytic activity for the CO hydration reaction, comparable to that of the human (h) isoform hCA I. Many inorganic anions and several small molecules were investigated as VchCA inhibitors. Inorganic anions such as cyanate, cyanide, hydrogen sulfide, hydrogen sulfite, and trithiocarbonate were effective VchCA inhibitors with inhibition constants in the range of 33-88μM. Other effective inhibitors were diethyldithiocarbamate, sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid, with Ks of 7-43μM. Halides (bromide, iodide), bicarbonate and carbonate were much less effective VchCA inhibitors, with Ks in the range of 4.64-28.0mM. The resistance of VchCA to bicarbonate inhibition may represent an evolutionary adaptation of this enzyme to living in an environment rich in this ion, such as the gastrointestinal tract, as bicarbonate is a virulence enhancer of this bacterium.Bioorganic & medicinal chemistry letters 03/2013; 23(6):1636-8. · 2.65 Impact Factor -
Article: Anti-infective carbonic anhydrase inhibitors: a patent and literature review.
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ABSTRACT: Introduction: All microorganisms that cause diseases or illnesses to their host are defined as pathogens. In this paper we will review the current state of the art for inhibiting parasite carbonic anhydrases (CAs, EC 4.2.1.1) with a goal of developing antibacterial, antifungal or antiprotozoan agents possessing a different mechanism of action compared with the clinically used drugs to which a considerable degree of drug resistance has been reported. Areas covered: Cloning of the genomes of many pathogenic microorganisms offered the possibility of exploring alternative pathways for inhibiting virulence factors or proteins essential for their life cycle, and such an approach was applied systematically for CAs from prokaryotic and eukaryotic microorganisms. Investigations of CAs in bacteria, fungi and protozoa domains will undoubtedly reveal novel aspects of microbial virulence, these efforts being part of a more general approach of using metalloenzyme inhibitors for designing novel classes of anti-infectives. Expert opinion: Covers an overview of the patent literature in the field of the anti-infective CA inhibitors. Most of the patents deal with sulfonamide CA inhibitors. Bacterial/fungal/protozoan CAs represent at this moment very promising targets for obtaining anti-infectives devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets.Expert Opinion on Therapeutic Patents 03/2013; · 3.57 Impact Factor
