Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors

Accepted Manuscript Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors Andrea Angeli, Damiano Tanini, Caterina Viglianisi, Lucia Panzella, Antonella Capperucci, Stefano Menichetti, Claudiu T. Supuran PII: DOI: Reference:

S0968-0896(17)30326-7 http://dx.doi.org/10.1016/j.bmc.2017.03.013 BMC 13609

To appear in:

Bioorganic & Medicinal Chemistry

Received Date: Revised Date: Accepted Date:

15 February 2017 27 February 2017 5 March 2017

Please cite this article as: Angeli, A., Tanini, D., Viglianisi, C., Panzella, L., Capperucci, A., Menichetti, S., Supuran, C.T., Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors, Bioorganic & Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.03.013

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Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors

Andrea Angeli, a Damiano Tanini, b Caterina Viglianisi, b Lucia Panzella,c Antonella Capperucci, b Stefano Menichetti,b Claudiu T. Supurana* a

Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy

b

Università degli Studi di Firenze, Department of Chemistry "Ugo Schiff", Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy. c

University of Naples “Federico II”, Department of Chemical Sciences, Via Cintia 4, I-80126 Naples, Italy

Abstract. A serie of selenides, diselenides and organoselenoheterocycles were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, IV, VII and IX, involved in a variety of diseases among which glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors etc. These investigated compounds showed inhibitory action against these isoforms and some of them were selective for inhibiting the cytosolic over the membrane-bound isoforms, thus making them interesting leads for the development of isoform-selective inhibitors.

Keywords: carbonic

anhydrase; inhibitors; metalloenzymes; selenium; diselenides; selenides;

selenoheterocycles

______ Corresponding author. Tel./fax:+39-055-4573729; e-mail: [email protected] (CTS)

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1. Introduction During the last decades, organoselenium compounds were the subject of intense interest, especially from the point of view of public health. Selenium plays an important role in biological systems as part of the active site in many proteins.1,2 Organoselenium derivatives show antioxidant,3 antitumor,4 antiviral5-6 and antimicrobial action7. Furthermore, some of them show inhibitory effects on a variety of enzymes such as nitric oxide synthase (NOS),8-9 inosine monophosphate dehydrogenase (IMDPH)10 and lipoxygenases (LOX).11 Some of these enzymes are involved in serious diseases, thus leading to possible applications as therapeutic agents for many selenium-containing derivatives.8-10 The reactive oxygen species ROS are generated by the normal metabolic activity, as well as lifestyle factors such as smoking, exercise, and diet.12 ROS overproduction is induced by different factors which lead to a perturbation of the normal cell redox balance, shifting cells into a state of oxidative stress. Since in conditions of severe stress, survival of the cells depends on their ability to adjust or resist to this stress,13–15 cells have developed an antioxidant defense system, involving among others gluthathione, antioxidant vitamins, sulfhydryl groups, and several antioxidant enzymes.16 In this context, a recent study from our group17 reported that the metalloenzyme carbonic anhydrase (CAs, EC 4.2.1.1), especially the isoform CA VII, is also involved in the oxidative stress defence processes interfering with the generation of ROS.18–20 This is the reason why we decided to investigate various selenides, diselenides and selenoheterocycle compounds with antioxidant properties,21-22 as human (h) CA inhibitors (CAIs). As mentioned above, CAs are metalloenzymes that catalyse a very simple reaction: the hydration of carbon dioxide to bicarbonate and proton.23 This reaction plays an important role in many physiological and pathological processes associated with pH control, ion transport, and fluid secretion.24,25

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2. Results and discussion

2.1. Chemistry Our drug design strategy consisted in synthesizing or testing as CA inhibitors compounds incorporating various selenium-containing functionalities, such as selenides, diselenides and selenium heterocycles reported in Chart 1. It should be mentioned that many of the analogous sulfur-containing compounds were shown to strongly inhibit many CA isoforms26.

Chart 1: Selenium-containing chemotypes investigated s CA inhibitors in the paper.

Benzo[b]selenophenes 1, 2 and 3 were synthesised from resveratrol, elemental selenium and sulfuryl chloride following our reported procedure (Scheme 1).21

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β-Hydroxy- and β-amino selenides 4 and 14 as well as β-hydroxy- and β -amino-diselenides 5, 9, 16 and 17 were obtained from the corresponding epoxides or N-Tosyl protected aziridines and bis(trimethylsilyl)selenide (Me3Si-Se-SiMe3) according to the literature (Scheme 2).27

β -Phenylseleno-alcohols 6, 7 and -amine 15 were synthesised from epoxides and N-Tosyl protected aziridines, respectively, upon treatment with phenylselenotrimethylsilane as reported in the left part of the Scheme 2.28 All spectroscopic data matched those previously reported for these types of compounds. 2-Aminoaryl diselenides 10-12, 2-nitroaryl diselenide 13 and selenazines 18-22 were prepared according to literature procedures (Scheme 3).22

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1,2-Bis(2-hydroxyphenyl)diselenide

8

was

prepared

according

to

literature

procedures.29

Benzeneseleninic acid 23 was commercially available and provided by Sigma Aldrich. 2.2. Carbonic anhydrase inhibition

All compounds 1-23 were tested in vitro for their inhibitory activity against the physiologically relevant hCA isoforms I, II, IV, VII and IX by means of the stopped-flow carbon dioxide hydration assay30 and their activities were compared to the standard CAI acetazolamide (AAZ) (Table 1).

Table 1. Inhibition data of human CA isoforms I, II, IV, VII and IX with compounds 1-23 and AAZ by a stopped flow CO2 hydrase assay.30

Cmp

hCA I

hCA II

KI (µM)* hCA IV

hCA VII

hCA IX

1 2 3 4 5

49.5 29.1 15.9 17.1 52.1

19.1 17.7 0.91 >100 >100

56.8 9.1 52.4 >100 >100

6.5 1.8 0.66 >100 >100

37.0 22.9 9.1 >100 >100

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6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 AAZ

>100 >100 29.6 >100 81.3 63.6 75.9 >100 89.8 67.3 23.2 >100 >100 >100 >100 80.1 79.1 >100 0.25

>100 >100 23.7 >100 30.9 61.6 >100 >100 5.6 3.2 13.1 96.1 >100 >100 >100 59.6 >100 >100 0.012

>100 >100 26.6 >100 78.9 6.2 >100 >100 >100 >100 23.5 >100 >100 >100 >100 >100 >100 >100 0.074

>100 >100 5.9 >100 5.8 4.6 >100 >100 >100 8.9 >100 7.8 >100 >100 >100 >100 >100 >100 0.006

>100 >100 >100 >100 1.6 8.4 >100 >100 >100 >100 29.5 >100 >100 >100 >100 >100 >100 >100 0.025

* Mean from 3 different assays, by a stopped flow technique (errors were in the range of ± 5-10 % of the reported values). We have investigated a range of selenides, diselenides and seleno-heterocycle derivatives for their interaction with the five hCA here considered, after a period of 15 min of incubation of the enzyme and inhibitor solutions.30–33 The following structure activity relationship (SAR) may be noted regarding the inhibition data of Table 1: (i) The cytosolic hCA I was inhibited by benzoselenophene compounds 1-3 with Ki ranging between 15.9 and 49.5 µM. The interesting case for these molecules was the presence of chlorine on the benzoselenophene ring. The inhibition potency increased when one or two halogen atoms were present in the molecule, 1.7 and 3 times, respectively, compared to the unsubstituted derivative. β-Hydroxy Selenide 4 was 3 times more potent than the analog diselenide 5 (Ki 17.1 µM for 4 and Ki 52.1 µM for 5, respectively). On the other hand, the β-phenylseleno-alcohols 6 and 7 did not inhibit hCA I. Phenol diselenide 8 showed an inhibition constant of 29.6 µM, but a further addition of an ortho-methoxyl group (9), led to a loss of activity. The introduction of a methyl group on the aromatic diselenide

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incorporating the secondary sulfonamide 10 decreased the potency of inhibition compared to the analog without it, i.e., compound 11 (Ki 81.3 and 63.6 µM respectively). The amino aromatic diselenide 12 inhibited in the high micromolar range (Ki 75.9 µM) hCA I, whereas the compound with nitro group 13 did not inhibit this isoform. The β-amino selenides and diselenides 14-17, bearing a secondary sulfonamide moiety, inhibited hCA I in the medium - high micromolar range (23.2- 89.9 µM). Furthermore, the diselenide 16 was three and respectively four times more potent than 14 and 15. The seleno heterocycles inhibited this cytosolic isoform in the high micromolar range (compounds 21-22: Ki 79.1 µM and Ki 80.1 µM). (ii) The dominant cytosolic human isoform, hCA II, was inhibited in low or low-medium micromolar range by the benzoselenophene derivatives 1-3 (Ki 0.91-19.1 µM). The presence of one and two chlorine atoms in the benzoselenophene ring, also for this isoform, increased the potency. Compound 3 was nearly twenty times more potent than the derivative without chlorine atoms 1. β-Hydroxy selenides and diselenides 4-7 did not inhibit this cytosolic isoform. hCA II was inhibited by the aromatic diselenide incorporating a phenol moiety (8) with a Ki of 23.7 µM, and the secondary sulfonamide group (10-11) in medium - high micromolar range. In the case of the last two compounds, the introduction of a methyl group on the aromatic ring halved the inhibition potency (Ki 61.6 to 30.9 µM). The selenides 4-15 inhibited in the low micromolar range (Ki 3.2 µM -5.6 µM) hCA II, whereas symmetrical diselenides 16 and 17 inhibited this cytosolic isoform in the medium (Ki 13.1 µM) or high micromolar ranges (Ki 96.1 µM). The only selenoheterocycle here studied, 21, inhibited this isoform in the medium-high micromolar range. (iii) The membrane-bound hCA IV was inhibited by benzoselenophene compounds 1-3 in the low medium micromolar range (Ki 9.1 µM -56.8 µM). The presence of chlorine atoms in these compounds increases the potency, but this time, compound 2 with one chlorine atom showed the best activity. βHydroxy selenide and diselenide 4-7 and β-amino selenide and diselenide 14-17 did not inhibited this

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isoform, except for compound 16 which showed a Ki of 23.5 µM. Aromatic diselenide 8 inhibited hCA IV in the medium micromolar range (Ki 26.6 µM), 10 and 11 between Ki 6.2 - 78.9 µM. The presence of methyl groups on the aromatic ring led to a significant decrease of the inhibitory potency. The other aromatic diselenides, seleno heterocycles and benzenseleninic acid 23 did not inhibit this isoform. (iv) The other cytosolic human isoform studied, hCA VII, was inhibited by benzoselenophene compounds 1 and 2 in the low micromolar range (Ki 6.5 µM -1.8 µM), whereas compound 3 in the high nanomolar (Ki 0.66 µM). Secondary sulfonamide (SO2NHR) compounds here considered, 10, 11, 15 and 17 inhibited this isoform in the low micromolar range (Ki 4.6 µM -8.9 µM). The substitution of the methyl group on aromatic diselenide 10 and 11, this time did not influence the potency of inhibition. (v) Transmembrane hCA IX was inhibited by compounds 1-3 in the medium and low micromolar range (Ki 37.0 µM -9.1 µM). The chlorine substitution on the benzoselenophene scaffold increased the potency as for the cytosolic isoforms discussed previously. The aromatic diselenides 10 and 11 inhibited hCA IX in low micromolar range (Ki 1.6 µM -8.4 µM). Methyl substitution on aromatic scaffold led to a decrease the potency of inhibition nearly four times. (vi) An interesting inhibition profile was observed for compounds 4, 5, 12 and 22, which showed selectivity for isoform hCA I. On the other hand, 14 and 21, showed selectivity for the two abundant cytosolic isoforms hCA I and hCA II. All isoforms here considered, except for the transmembrane hCA IX, were inhibited by the aromatic diselenide 8. Another interesting point, was the inhibitory activity of the secondary sulfonamides 15 and 17, as well as their selectivity for the cytosolic isoforms here investigated.

3. Conclusions We have investigated a series of selenides, diselenides and selenoheterocycles as inhibitors on five αcarbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, i.e., hCA I, II, IV, VII and IX.

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These isoforms are drug targets for antiglaucoma (hCA I, II and IV), antiepileptic (hCA VII) or antitumor (hCA IX) agents. Recently, a study from our group reported another potential role for isoform hCA VII as oxygen radical scavenger.20 In this contest, the investigated organoselenium compounds showed inhibitory action and in same case selectivity against the cytosolic over membrane-bound isoforms, among which aslo hCA VII.

4. Experimental Part 4.1. Chemistry All reactions were carried out in an oven-dried glassware under inert atmosphere (N2). Tetrahydrofuran (THF), dichloromethane (DCM) and N,N-dimethylformamide (DMF) were dried using a solvent purification system (Pure-Solv™). All commercial materials were used as received without further purification. Flash column chromatography purifications were performed on Silica gel 60 (230-400 mesh). Thin layer chromatography was performed on TLC plates Silica gel 60 F254. NMR spectra were recorded in CDCl3 with Varian Gemini 200 and Mercury 400 spectrometers operating at 200 and 400 MHz (for 1H), 50 and 100 MHz (for

13

C). NMR signals were referenced to nondeuterated residual

solvent signals (7.26 ppm for 1H, 77.0 ppm for 13C).

4.1.1 General procedure for preparation of the benzoselenophene derivatives 1-3. Fresh distilled SO2Cl2 (0.8 mmol, 1 mmol or 2 mmol to obtain 1, 2 or 3 as major products, in that order) was added dropwise to selenium powder (79 mg, 1 mmol) and stirred at rt for 10 min, and then 2.5mL of distilled THF was added. After 1 h, resveratrol (94 mg, 0.4 mmol) dissolved in 0.8 mL of dry DMF was added. The mixture was stirred for 24 h at rt. The brownish red product was filtered over Celite before extraction with ethyl acetate (3 × 15 mL), and the organic layer was washed with water and brine and

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dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to afford the crude product, which was purified by flash column chromatography (chloroform/methanol 9 : 1, 1% acetic acid). 4.1.2 General Procedure for preparation of β -hydroxy diselenides 5, 9. A solution of epoxide (1 mmol) and bis(trimethylsilyl)selenide (HMDSS) (1.6 mmol) in anhydrous THF (3 mL), was treated under an inert atmosphere with TBAF (1 M in THF, 0.64 mL, 0.64 mmol). After stirring for 4 h, the solution was diluted with diethyl ether, washed with water, and dried with Na2 SO4. The solvent was evaporated under vacuum to afford a crude product, which was purified by flash column chromatography eluting with an appropriate mixture of petroleum ether/ethyl acetate. 4.1.3 General Procedure for the preparation of N-Ts protected β -amino diselenides 16, 17. A solution of aziridine (1 mmol) and bis(trimethylsilyl)selenide (HMDSS) (1.6 mmol) in anhydrous THF (3 mL) was cooled under an inert atmosphere at 0 °C, and treated with TBAF (1 M in THF, 0.48 mL, 0.48 mmol). After warming to room temperature and stirring for ca. 1 h, the solution was diluted with diethyl ether, washed with water, and dried with Na2SO4. The solvent was evaporated under vacuum to afford a crude product, which was purified by flash column chromatography eluting with an appropriate mixture of petroleum ether/ethyl acetate. 4.1.4 General Procedure for the preparation of β-hydroxy selenide 4. A solution of epoxide (1 mmol) and bis(trimethylsilyl)selenide (HMDSS) (0.6 mmol) in anhydrous THF (3 mL), was treated under an inert atmosphere with TBAF (1 M in THF, 0.24 mL, 0.24 mmol). After stirring for 4 h, the solution was diluted with diethyl ether, washed with water, and dried with Na2 SO4. The solvent was evaporated under vacuum to afford a crude product, which was purified on silica gel eluting with petroleum ether/ethyl acetate 2:1. 4.1.5 General Procedure for the preparation of N-Ts protected β-amino selenide 14. A solution of aziridine (1 mmol) and bis(trimethylsilyl)selenide (HMDSS) (0.6 mmol) in anhydrous THF (3 mL) was cooled under inert atmosphere at 0 °C, and treated with TBAF (1 M in THF, 0.3 mL,

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0.3 mmol). After warming to room temperature and stirring for ca. 1 h, the solution was diluted with diethyl ether, washed with water, and dried with Na2SO4. The solvent was evaporated under vacuum to afford a crude product, which was purified by flash column chromatography (petroleum ether/ethyl acetate 3:1). 4.1.6 General Procedure for the preparation of 2-Nitroaryl diselenide 13. In a round-bottomed flask, a mixture of elemental selenium (158 mg, 2.0 mmol) and KOH (224 mg, 4.0 mmol) was melted with a thermal blower. The resulting mixture was cooled to room temperature, and diluted with distilled water (4 mL). Then the corresponding o-halonitrobenzene (1.0 mmol) and THF (1 mL) were added, and the mixture was stirred for 0.5 to 2 h, depending on the substrate. When the reaction was complete, the product was extracted with EtOAc (20 mL), and the organic phase was washed with H2O (3 × 20 mL). The organic phase was dried with MgSO4, and filtered, and the solvent was removed under reduced pressure. The product was purified by flash column chromatography (petroleum ether/ethyl acetate 2:1). 4.1.7 General Procedure for the preparation of 2-Aminoaryl diselenide 12 The appropriate 2-nitroaryl diselenide (1.0 mmol), methanol (20 mL), FeSO4·7H2O (5.0 mmol, 1.390 g), and distilled water (20 mL) were added to a two-necked round-bottomed flask equipped with a reflux condenser. The reaction mixture was stirred at reflux for 1.5 h. After this time, NH4OH (10 mL) was added, and the mixture was stirred under reflux for 10 min. A black mixture was formed after the addition of the NH4OH. Then the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), filtered, and washed with H2O (3 × 20 mL). The organic phase was dried with MgSO4, and filtered, and the solvent was removed under reduced pressure. The product was purified by flash column chromatography (petroleum ether/ethyl acetate 2:1). 4.1.8 General Procedure for preparation of 2-N-Sulfonylaminoaryl diselenides 10, 11.

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A solution of sulfonyl chloride (1.75 mmol) in dry CH2Cl2 (5 mL) was added dropwise under a nitrogen flow to a solution of bis(2-aminophenyl) diselenide (0.73· mmol) in dry CH2Cl2 (5 mL) and dry pyridine (0.118 mL, 1.46 mmol). The reaction mixture was heated at reflux for 44 h, then it was cooled to room temp. and diluted with CH2Cl2 (40 mL). The organic phase was washed with H2O (3 × 40 mL), and saturated aq. NH4Cl (2 × 40 mL), and dried with anhydrous Na2SO4. The solvents were evaporated under vacuum and the crude material was purified by flash column chromatography eluting with an appropriate mixture of petroleum ether/ethyl acetate. 4.1.9 General Procedure for the preparation of β-phenylseleno- alcohols 6, 7 and amine 15. A solution of epoxide or aziridine (1 mmol) in dry THF (4 mL) was treated under inert atmosphere with phenylseleno-trimethylsilane (1.1 mmol) and TBAF or PhONnBu4 (0.2 mmol).28 The mixture was stirred at rt. and progression of the reaction was monitored by TLC. After quenching with water, the product was extracted with diethyl ether. The resulting organic phase was washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum. TLC purification with an appropriate mixture of petroleum ether/ethyl acetate afforded products 6, 7, 15. 4.1.10 General Procedure for the preparation of selenazines 18-22. Cu(OTf)2 (0.016 mmol, 20 mol%), p-methoxystyrene (21 mg, 0.16 mmol, 1 equiv.) and Et3N (8 mg, 0.08 mmol, 0.5 equiv.) were added in sequence to a solution of 2-N-sulfonyl diselenide (0.08 mmol, 1 equiv.) in dry solvent (0.03 M) in a reaction vial. The mixture was heated at the right temperature until TLC showed complete disappearance of the diselenide. Then, the reaction mixture was diluted with dichloromethane (40 mL), washed with saturated NH4Cl (40 mL), and dried with anhydrous Na2SO4, and the solvents were evaporated to dryness. Purification by flash column chromatography eluting with an appropriate mixture of petroleum ether/ethyl acetate gave derivatives 18-22. 4.1.11 Procedure for preparation of 1,2-Bis(2-hydroxyphenyl)diselane 8.

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To a stirred solution of Se0 (2.0 mmol) and halides (1.0 mmol) in dry DMSO (2.0 mL) was added CuO nanoparticles (10.0 mol%) followed by KOH (2.0 equiv) under nitrogen atmosphere at 90 °C. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was allowed to cool, which was subjected to column chromatographic (petroleum ether/ethyl acetate 2:1) separation to give pure diselenide 8.

4.2. Carbonic anhydrase inhibition An Applied Photophysics stopped-flow instrument has been used for assaying the CA catalyzed CO2 hydration activity.30 Phenol red (at a concentration of 0.2 mM) has been used as indicator, working at the absorbance maximum of 557 nm, with 20 mMHepes (pH 7.5) as buffer, and 20 mM Na2SO4 (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10–100 s. The CO2 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor at least six traces of the initial 5–10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (0.1 mM) were prepared in distilled-deionized water and dilutions up to 0.01 nM were done thereafter with the assay buffer. Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E-I complex. The inhibition constants were obtained by non-linear least-squares methods using PRISM 3 and the Cheng–Prusoff equation, as reported earlier,31–33 and represent the mean from at least three different determinations. All CA isofoms were recombinant ones obtained in-house as reported earlier.31–33

Acknowledgments. This work was financed in part by two EU projects of the 7 th Framework programme, Metoxia and Dynano (to CTS).

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Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors

Andrea Angeli, a Damiano Tanini, b Caterina Viglianisi, b Lucia Panzella,c Antonella Capperucci, b Stefano Menichetti,b Claudiu T. Supurana*