Yannick Hermans

Céline Olivier

Henrik Junge

Andreas Klein

Wolfram Jaegermann

Thierry Toupance

Sun Light Selective Photodeposition of CoO x (OH) y and NiO x (OH) y on Truncated Bipyramidal BiVO 4 for Highly Efficient Photocatalysis

Keywords: Sun light photodeposition, Facet-engineered CoOx(OH)y-and NiOx(OH)ymonoclinic scheelite BiVO4 microcrystals, Photocatalysis, Sacrificial water oxidation

Facet-engineered monoclinic scheelite BiVO4 particles decorated with various co-catalysts were successfully synthesized by selective sun light photodeposition of metal or metal oxy(hydroxide) nanoparticles onto the facets of truncated bipyramidal BiVO4 monoclinic crystals co-exposing {010} and {110} facets. X-ray photoelectron spectroscopy, scanning electron microscopy and scanning Auger microscopy revealed that metallic silver (Ag) and cobalt (oxy)hydroxide (CoOx(OH)y) particles were selectively deposited onto the {010} and {110} facets, respectively, regardless of the co-catalyst amount. By contrast, the nickel (oxy)hydroxide (NiOx(OH)y) photodeposition depends on the nickel precursor amount with an unprecedented selectivity for 0.1 wt% NiOx(OH)y/BiVO4 with a preferential deposition onto the {010} facets and the edges between the {110} facets. Moreover, these noble metal-free heterostructures led to remarkable photocatalytic properties for rhodamine B photodecomposition and sacrificial water oxidation reactions. For instance, 0.2 wt% CoOx(OH)y/BiVO4 led to one of the highest oxygen evolution rate, i.e. 1538 mol.h -1 .g -1 , ever described which is ten times higher than that found for bare BiVO4. The selective deposition of cobalt (oxy)hydroxide species onto the more electrondeficient facet of truncated bipyramidal monoclinic BiVO4 particles favors photogenerated charge carrier separation and therefore plays a key role for efficient photochemical oxygen evolution.

INTRODUCTION

In the broad context of increasing energy demand and the various environmental issues related to the intensive use of fossil energy resources, water photolysis from solar light is one of the most attractive approaches to produce clean hydrogen fuel. [START_REF] Van De Krol | Perspectives on the Photoelectrochemical Storage of Solar Energy[END_REF] Photoelectrochemical (PEC) and powdered photocatalytic water splitting are the two main technologies which have been implemented to achieve the splitting of water into hydrogen (H2) and oxygen (O2) through a photocatalytic process. [START_REF] Ardo | Pathways to Electrochemical Solar-Hydrogen Technologies[END_REF][START_REF] Ahmed | A Review on Photoelectrochemical Hydrogen Production Systems: Challenge and Future Directions[END_REF] First of all, in a PEC design a photoelectrode drives the reduction or oxidation reaction, while, the other charge carrier is shuttled through a wire towards another electrode which catalyzes the opposite reaction with or without light. [START_REF] Sivula | Semiconducting Materials for Photoelectrochemical Energy Conversion[END_REF][START_REF] Jiang | Photoelectrochemical Devices for Solar Water Splitting -Materials and Challenges[END_REF] Conversely, particulate photocatalysts are dispersed as a colloid or anchored onto a substrate whereby photoreduction and photooxidation are catalysed by one photocatalyst or through a Z-scheme where a shuttle redox mediator transfers charge carriers between two different photocatalyts. [START_REF] Kudo | Heterogeneous Photocatalyst Materials for Water Splitting[END_REF][START_REF] Maeda | Z-Scheme Water Splitting Using Two Different Semiconductor Photocatalysts[END_REF][START_REF] Wang | Scalable Water Splitting on Particulate Photocatalyst Sheets with a Solar-to-Hydrogen Energy Conversion Efficiency Exceeding 1%[END_REF][START_REF] Wang | Particulate Photocatalyst Sheets Based on Carbon Conductor Layer for Efficient Z-Scheme Pure-Water Splitting at Ambient Pressure[END_REF][START_REF] Goto | Particulate Photocatalyst Sheets Based on Cabon Conductor Layer for Efficient Z-Scheme Pure-Water Splitting at Ambient Pressure[END_REF] Whereas the photoelectrochemical method requires a sophisticated cell set-up with noble metal counterelectrodes, necessitates an external potential bias, and leads to scale-up issues, particulate photocatalysis in principle only requires a suspension of photocatalyst powders in a water basin.

For instance, a thorough technoeconomic study on both designs for water splitting has shown that particulate water splitting based on baggies including particle slurries is expected to be economically viable considering 5% solar-to-H2 conversion efficiencies and five years lifetime. [START_REF] Pinaud | Technical and Economic Feasibility of Centralized Facilities for Solar Hydrogen Production via Photocatalysis and Photoelectrochemistry[END_REF] However, particulate based systems still lag behind in efficiency. [START_REF] Wang | Scalable Water Splitting on Particulate Photocatalyst Sheets with a Solar-to-Hydrogen Energy Conversion Efficiency Exceeding 1%[END_REF][START_REF] Goto | Particulate Photocatalyst Sheets Based on Cabon Conductor Layer for Efficient Z-Scheme Pure-Water Splitting at Ambient Pressure[END_REF] To improve the efficiency of particulate photocatalysts to promote H2 or O2 evolution reactions, materials with suitable band gaps need to be combined to optimize light absorption, particle sizes need to be adapted so that diffusion length and absorption length are both accommodated and additional contact materials should be applied to overcome intrinsic drawbacks of the main photoabsorber to create appropriate heterostructures. [START_REF] Kudo | Heterogeneous Photocatalyst Materials for Water Splitting[END_REF][START_REF] Hanna | Solar Conversion Efficiency of Photovoltaic and Photoelectrolysis Cells with Carrier Multiplication Absorbers[END_REF][START_REF] Osterloh | Inorganic Nanostructures for Photoelectrochemical and Photocatalytic Water Splitting[END_REF] Bismuth vanadate (BiVO4) is a non-toxic and medium band-gap (2.4 eV) n-type semiconductor which has attracted worldwide attention as a visible-light active photocatalyst. [START_REF] Yu | Effects of Structural Variation on the Photocatalytic Performance of Hydrothermally Synthesized BiVO4[END_REF][START_REF] Malathi | A Review on BiVO4 Photocatalyst : Activity Enhancement Methods for Solar Photocatalytic Applications[END_REF] Particularly, scheelite monoclinic BiVO4 is one of the most active polymorphs in photocatalytic oxygen evolution, [START_REF] Kudo | A Novel Aqueous Process for Preparation of Crystal Form-Controlled and Highly Crystalline BiVO4 Powder from Layered Vanadates at Room Temperature and Its Photocatalytic and Photophysical Properties[END_REF] having reached near to maximum efficiencies when implemented as a photoanode material in PEC devices. [START_REF] Abdi | Efficient Solar Water Splitting by Enhanced Charge Separation in a Bismuth Vanadate-silicon Tandem Photoelectrode[END_REF][START_REF] Sharp | Bismuth Vanadate as a Platform for Accelerating Discovery and Development of Complex Transition-Metal Oxide Photoanodes[END_REF] However, the oxidation capability of bare BiVO4 is hindered by weak charge carrier mobilities, short charge carrier diffusion lengths and a high charge recombination rate at the surface. [START_REF] Cho | Metal Doping of BiVO4 by Composite Electrodeposition with Improved Photoelectrochemical Water Oxidation[END_REF] To circumvent these inconveniences, heterostructuring by contacting BiVO4 with other materials such as TiO2, 20 WO3, [START_REF] Pihosh | Photocatalytic Generation of Hydrogen by Core-shell WO3/BiVO4 Nanorods with Ultimate Water Splitting Efficiency[END_REF][START_REF] Xia | A Highly Efficient BiVO4/WO3/W Heterojunction Photoanode for Visible-light Responsive Dual Photoelectrode Photocatalytic Fuel Cell[END_REF] RuOx 23 or (oxy)(hydr)oxides of first row transition metals (Co, Fe, Ni) [START_REF] Ye | Screening of Electrocatalysts for Photoelectrochemical Water Oxidation on W-Doped BiVO4 Photocatalysts by Scanning Electrochemical Microscopy[END_REF][START_REF] Mccrory | Benchmarking Heterogeneous Electrocatalysts for the Oxygen Evolution Reaction[END_REF] has been proposed. Thus, several studies have shown that BiVO4 photoanodes modified with NiOx(OH)y in combination with FeOxOHy yielded enhanced photocurrent densities in photoelectrochemical cells. [START_REF] Kim | Nanoporous BiVO4 Photoanodes with Dual-Layer Oxygen Evolution Catalysts for Solar Water Splitting[END_REF][START_REF] Qiu | Efficient Solar-driven Water Splitting by Nanocone BiVO4-perovskite Tandem Cells[END_REF][START_REF] Shi | Efficient Photoelectrochemical Hydrogen Production from Bismuth Vanadatedecorated Tungsten Trioxide Helix Nanostructures[END_REF][START_REF] Shi | Unassisted Photoelectrochemical Water Splitting Exceeding 7% Solar-to-Hydrogen Conversion Efficiency Using Photon Recycling[END_REF] In addition, Domen et al. found that a 6 nm thick conformal layer of NiOOH on a CoOx/BiVO4 anode led to a threefold increase in photocurrent, reaching 2.5 mA/cm 2 at 0.6 V vs RHE. [START_REF] Zhong | Surface Modification of CoOx Loaded BiVO4 Photoanodes with Ultrathin p-Type NiO Layers for Improved Solar Water Oxidation[END_REF] On the other hand, various spinel-type Co3O4 or CoOx/BiVO4-based heterostructures showed enhanced photocatalytic properties for water oxidation [START_REF] Yamakata | Identification of Individual Electron-and Hole-Transfer Kinetics at CoOx/BiVO4/SnO2 Double Heterojunctions[END_REF] or pollutant decomposition. [START_REF] Zhao | One-step Fabrication of Carbon Decorated Co3O4/BiVO4 p-n Heterostructure for Enhanced Visible-light Photocatalytic Properties[END_REF][START_REF] Petala | Synthesis and Characterization of CoOx/BiVO4 Photocatalysts for the Degradation of Propyl Paraben[END_REF] The exact advantages of the first row transition metal oxides is still under debate, as some authors relate the increased water oxidation efficiencies to enhanced charge carrier separation, [START_REF] Hermans | Analysis of the Interfacial Characteristics of BiVO4/Metal Oxide Heterostructures and its Implication on their Junction Properties[END_REF] surface passivation [START_REF] Zachäus | Photocurrent of BiVO4 is Limited by Surface Recombination, not Surface Catalysis[END_REF] or catalytic effects. [START_REF] Seh | Combining Theory and Experiment in Electrocatalysis: Insights into Materials Design[END_REF] Usually, contact materials are deposited in a random manner on particulate BiVO4-based photocatalysts. In this case no distinct flow path for photogenerated holes and electrons can exist which makes bulk and surface recombination still prominent due to insufficient charge carrier separation. Since the pioneer works of Ohno et al. on anatase and rutile TiO2 particles [START_REF] Ohno | Crystal Faces of Rutile and Anatase TiO2 Particles and Their Roles in Photocatalytic Reactions[END_REF] which have revealed the key role of exposed facets in the separation of photoinduced electron-hole pairs, [START_REF] D'arienzo | Crystal Surfaces and Fate of Photogenerated Defects in Shape-Controlled Anatase Nanocrystals: Drawing Useful Relations to Improve the H2 Yield in Methanol Photosteam Reforming[END_REF][START_REF] Hermans | Pinning of the Fermi Level in CuFeO2 by Polaron Formation Limiting the Photovoltage for Photochemical Water Splitting[END_REF] photodeposition is now considered as a sort of general route for synthesizing heterostructures. [START_REF] Wenderich | Mechanism, and Applications of Photodeposition in Photocatalysis: A Review[END_REF][START_REF] Mu | Enhancing Charge Separation on High Symmetry SrTiO3 Exposed with Anisotropic Facets for Photocatalytic Water Splitting[END_REF] metallic deposits were preferentially found on {010} facets after metal ion photoreduction, while metal oxide deposits were found on the {110} facets after metal ion photo-oxidation, evidencing that electrons and holes accumulate on different sites on anisotropic BiVO4 crystals. [START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF] Besides providing proof of enhanced charge carrier separation, the preferential photodeposition was used to construct BiVO4 photocatalysts with even better photocatalytic oxygen evolution efficiencies by depositing reduction cocatalysts on the more reducing {010} facets and oxidation cocatalysts on the more oxidative {110} facets, with Pt/BiVO4/CoOx reaching an oxygen evolution rate of 1070 µmol.h -1 .g -1 compared to only 7 µmol.h -1 .g -1 for bare BiVO4. [START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF] However, the dependence of the photodeposition as a function of the cocatalyst amount has not been studied in detail in particular due to the fact of the limitations of FESEM coupled to energy dispersive X-ray spectroscopy (EDS) analyses. Moreover, even though the photodeposition of nickel based compounds has been successfully achieved onto different semiconductors such as CdS, [START_REF] Chen | In Situ Photodeposition of Nickel Oxides on CdS for Highly Efficient Hydrogen Production via Visible-Light Driven Photocatalysis[END_REF] TiO2, [START_REF] Kashiwaya | Nickel Oxide Selectively Deposited on the {101} Facet of Anatase TiO2 Nanocrystal Bipyramids for Enhanced Photocatalysis[END_REF] or even BiVO4 films, [START_REF] Choi | Solar Water Oxidation Using Nickel-borate Coupled BiVO4 Photoelectrodes[END_REF] the regioselective deposition of nickel based oxides onto faceted BiVO4 crystals has not been envisaged so far, despite the interest of this co-catalyst for photocatalytic purposes. [START_REF] Kim | Nanoporous BiVO4 Photoanodes with Dual-Layer Oxygen Evolution Catalysts for Solar Water Splitting[END_REF][START_REF] Choi | Solar Water Oxidation Using Nickel-borate Coupled BiVO4 Photoelectrodes[END_REF] We have recently reported interface experiments showing that strong upwards band bending was observed for CoOx/BiVO4 and NiO/BiVO4 interfaces indicating that this kind of heterostructures should favor charge carrier separation. [START_REF] Hermans | Analysis of the Interfacial Characteristics of BiVO4/Metal Oxide Heterostructures and its Implication on their Junction Properties[END_REF] In this context, we herein report the photodeposition of CoOx(OH)y and NiOx(OH)y cocatalyst, via the original use of simulated sun light, on BiVO4 microcrystals exposing well-defined {010} and {110} facets. Both chemistry and regioselectivity of the deposition was investigated employing X-ray photoelectron spectroscopy and various electron microscopy techniques. Then, the photocatalytic efficiencies of the heterostructures prepared were tested for rhodamine B photodecomposition and water oxidation reactions, and were compared with previously studied Ag/BiVO4 systems.

EXPERIMENTAL SECTION

Photocatalysts preparation

All reagents were bought in analytical grade and employed as received. Aqueous solutions were prepared using deionized water. Truncated bipyramidal BiVO4 microparticles exposing well-defined facets were synthesized by optimizing and up-scaling a literature procedure. [START_REF] Li | Selective Deposition of Ag3PO4 on Monoclinic BiVO4 (040) for Highly Efficient Photocatalysis[END_REF] The particles in the 0.1-10 wt% range. Sodium iodate was used as a sacrificial agent for the CoOx(OH)y photo-deposition. A KBi buffer was used to maintain the pH at 9.2 for the NiOx(OH)y photo-deposition. [START_REF] Choi | Solar Water Oxidation Using Nickel-borate Coupled BiVO4 Photoelectrodes[END_REF] It is also worth mentioning that nickel amount of about 10 wt%, precipitation of nickel dihydroxide (Ni(OH)2) was observed which has required the elimination of the precipitate before putting the solution in contact with the BiVO4 microcrystals. In a typical procedure, a 100 mL aqueous solution of metal salts and additional agents was first prepared.

detailed
Subsequently, 500 mg BiVO4 powder was added and then sonicated for 10 min to obtain a good dispersion. The sides of the glass reaction vessel were then covered by aluminum foil so that the light source only illuminates the dispersion from the top. The suspension was then stirred during 1 h in the dark to reach adsorption equilibrium of the metal salts on the BiVO4 particle surfaces.

Next, the photodeposition of the metallic precursor on the BiVO4 particles was initiated by switching on the solar simulator, which was used as a light source. After stirring under static air for 1-5 h, the solar simulator was switched off and the heterostructured powder was washed at least 5 times with distilled water through cycles of centrifugation and redispersion in water via sonication. Finally, drying at 70 °C for 8 h yielded about 0.45 g of the desired heterostructured photocatalyst. The precise parameters used for each system are detailed in Table S1. The solar simulator was a class AAA Newport Oriel Sol3A, using a 450 W Xenon lamp as light source, an AM 1.5G filter. It was calibrated with a certified Si-based solar cell (Newport Oriel, 91150V) to provide an incident flux of 100 mW.cm -2 (1 sun) (Figure S1).

Photocatalysts characterization

X-ray diffractograms were recorded with a Bruker AXS diffractometer (D2 PHASER) using a Cu anode (Kα radiation). 2θ data were collected through continuous scanning from 10° to 70° with a 0.01° sampling pitch and a 6° min -1 scan rate. UV-Vis diffuse reflectance spectra of the powder samples were recorded using an UV-Vis-NIR spectrometer (Lambda 900) in the wavelength range of 300 to 800 nm. A JEOL JEM 2100F, equipped with a Schottky-type FEG and operated at an acceleration voltage of 200 kV, was used to perform high resolution transmission electron microscopy (HRTEM) and energy dispersive spectroscopy (EDS). The BiVO4 morphology was roughly determined through secondary electron imaging (SEI, up to 10.000X magnification) using a Hitachi TM 1000 microscope. To confirm the BiVO4 morphology and analyze the spatial distribution of the metal(oxide) deposits on BiVO4 high resolution secondary scanning electron microscopy (SEM) was performed with a JEOL 6700F or a JEOL 7600F, both equipped with a field emission gun and detectors for secondary electron imaging (SEI), back scattered electron imaging (BSE) and EDS. Scanning Auger microscopy (SAM) was performed with a PHI 710 scanning Auger nanoprobe, having a maximal lateral resolution of 10 nm and a maximal SEI resolution of 3 nm, to elucidate how the contact materials of the heterostructured powder samples were distributed along the particulate photoabsorbers.

Different types of measuring modes were used, including point measurements (Auger spectra acquisition on a certain point), zone measurements (Auger spectra acquisition on a certain area) and mapping (Auger intensity acquisition of a certain area by scanning the area in a raster like pattern). Also SAM depth profiling, was occasionally tried, whereby an Argon ion gun (sputter rate 10 nm/min) was used to gradually sputter a sample and Auger spectra were measured after each sputter step. The oxidation state of the metal(oxide) deposits was analyzed at the DArmstadt Integrated System for MATerials research (DAISY-MAT) through X-ray photoelectron spectroscopy (XPS), using a Physical Electronics PHI 5700 multi-technique surface analysis system. XPS powder samples were prepared by applying a bit of heterostructured BiVO4 powder on a thin piece of conductive indium foil placed onto a stainless steel holder. Details on the DAISY-MAT setup and handling of data are given elsewhere. 49,50

Photocatalytic tests

Photocatalytic behaviors of the prepared photocatalysts were first evaluated by decomposition of rhodamine B (RhB, Aldrich) under simulated sun light illumination using the solar simulator described above. All experiments were performed at neutral pH, under ambient pressure and temperature. In a typical dye degradation experiment, 50 mg of the photocatalyst powder was loaded into a glass beaker together with 100 mL of a RhB aqueous solution (10 mg.L -1 in distilled water). After sonication for 10 min to disperse the photocatalyst powder, the dispersion was stirred at 750 RPM in the dark for 30 min. At that point the shutter of the solar simulator was opened and the dispersion was illuminated. Then at time intervals of 30 min, 1.2 mL aliquots were taken from the dispersion during a period of 2 h. Next, all recuperated aliquots (normally 6 in total) were centrifuged to separate the photocatalyst powder from the RhB solution. For each aliquot, 1 mL was taken, diluted to 3 mL with distilled water, and loaded into a quartz cuvette with a 1 cm path length. The remaining RhB amount was followed by UVvisible spectroscopy monitoring the change in absorption at λmax = 554 nm using a Shimadzu, UV-1650 pc spectrophotometer. Blank experiments were also conducted with catalysts in the dark and without catalysts under light irradiation. All experiments were at least repeated twice to assess the reproducibility of the experiments, and the average data for two experiments are discussed in the following. Furthermore, free radical trap experiments were conducted using a previously reported procedure (see ESI). [START_REF] Kashiwaya | Nickel Oxide Selectively Deposited on the {101} Facet of Anatase TiO2 Nanocrystal Bipyramids for Enhanced Photocatalysis[END_REF] The sacrificial photochemical water oxidation tests were carried out under an argon atmosphere with exclusion of air. Solvents were distilled under an argon atmosphere, or degassed via standard procedures prior to use and stored under argon. Each experiment was conducted in a double-walled thermostatically controlled reaction vessel (at a constant temperature of 25 °C) which was connected via a condenser to an automatic gas burette, operated at a constant pressure (1 ± 0.05 bar). In a typical reaction, this setup was evacuated and flushed with argon three times to remove any other gases. The photocatalysts were introduced as a powder (50 mg) in the presence of sodium periodate (NaIO4, 1 mmol) as sacrificial agent and using a 10 mL phosphate (10 mmol.L -1 , pH 7.0) buffered solution as reaction medium. After stirring (300 rpm) for 5 min to reach thermal equilibrium, the photochemical oxygen evolution reaction was started by illuminating the reaction vessel with a 300 W Xe lamp (LOT-QuantumDesign GmbH) with an output power of 1.5 W and equipped with a 420 nm cut-off filter. The volume of evolved gases was continuously measured by the automatic gas burette, connected to a pressure sensor. After stopping the reaction, a 1 mL gas sample was taken and analysed with a GC (Agilent GC HP 6890N) equipped with a carboxen 1000 column and a thermal conductivity detector (TCD), having argon as carrier gas. Each catalytic test ran for 20 h.

RESULT AND DISCUSSION

Faceted BiVO4 microcrystals

Reproducible BiVO4 microcrystals were synthesized using a conventional hydrothermal route by fixing the pH value at 1.5. SEM images depicted in Figure 1a indicate that the synthesized BiVO4 powders exhibit truncated bipyramidal morphology. The large top faces of the microcrystals correspond to the {010} crystalline facets whereas the lateral sides can be assigned to the {110} crystalline facets. Moreover, XRD patterns reveal the formation of monoclinic scheelite BiVO4 microcrystals with no signal corresponding to tetragonal BiVO4 (Figure S2).

These monoclinic BiVO4 microcrystals were then used as substrate to photodeposit regioselectively various co-catalysts using simulated sun light.

Regioselective metal photodeposition under simulated solar light

The use of simulated sun light to achieve the photodeposition of co-catalysts onto BiVO4 microcrystals was first investigated in the case of metallic silver by adapting the procedure of Li et al. [START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF] FESEM images shown in Figure S3a suggest that the silver deposition occurs on the {010} facets of the BiVO4 microcrystals, whereby the size of the deposits ranges from a hundred to a few hundred nanometers. Moreover, EDS elemental maps (Figure S3b-e) show clearly welldefined silver-containing particles which therefore confirm the preparation of a heterostructured Ag/BiVO4 powder. The oxidation state of the silver deposit was then closely examined by XPS (Figure S4). Only, emissions characteristic of bismuth, vanadium, silver and oxygen were detected in the survey spectrum. The line shapes of the Bi 4f and V 2p3/2 core level spectra are symmetric and the corresponding features can be attributed to Bi 3+ and V 5+ species. [START_REF] Su | Macroporous V2O5-BiVO4 Composites: Effect of Heterojunction on the Behavior of Photogenerated Charges[END_REF][START_REF] Lin | One-pot Hydrothermal Synthesis of BiPO4/BiVO4 with Enhanced Visible-light Photocatalytic Activities for Methylene Blue Degradation[END_REF] The Ag 3d region exhibits two signals with binding energy maxima located at 368.3 eV and 374.3 eV which can be assigned to the Ag 3d5/2 and Ag 3d3/2 core levels arising from spin-orbit coupling.

These energy values along with the splitting between the Ag 3d doublet, i.e. 6 eV, are consistent with the formation of metallic silver. 53,[START_REF] Moulder | Handbook of X-ray Photoelectron Spectroscopy: A Reference Book of Standard Spectra for Identi€cation and Interpretation of XPS Data[END_REF] Those results therefore indicate that, after solar light absorption, silver cations are preferentially reduced on the {010} facets after sun light absorption probably due to the preferential accumulation of electrons onto the {010} facets as previously shown. [START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF][START_REF] Zhu | Direct Imaging of Highly Anisotropic Photogenerated Charge Separations on Different Facets of a Single BiVO4 Photocatalyst[END_REF]

Regioselective metal oxy(hydroxide) photodeposition under simulated solar light

Once the photoreduction was demonstrated, the photo-oxidation of cobalt nitrate onto BiVO4 microcrystals using simulated solar light was studied. FESEM micrographs showed an increased roughness of the {110} facets which can be attributed to the regioselective deposition of cobaltbased particles (Figure 1b). 44 SAM mapping confirms more clearly that cobalt is almost restricted to the {110} facets while the {010} facets remain largely uncovered (Figure 2). Another important finding inferred from the SAM maps is that bismuth and vanadium signal intensity varies for the different facets. Thus, the {110} facets seem to be more bismuth rich while vanadium seems to be more abundant on the {010} facets. So far, anisotropic charge carrier mobilities [START_REF] Liu | The nature of Photogenerated Charge Separation Among Different Crystal Facets of BiVO4 Studied by Density Functional Theory[END_REF] or higher upwards bend bending for the {110} facets [START_REF] Zhu | Direct Imaging of Highly Anisotropic Photogenerated Charge Separations on Different Facets of a Single BiVO4 Photocatalyst[END_REF][START_REF] Zhu | Visualizing the Nano Cocatalyst Aligned Electric Fields on Single Photocatalyst Particles[END_REF] have been mainly proposed to rationalize the stronger hole accumulation on these facets. The facet specificity of the V/Bi surface stoichiometry could also play a role in the charge carrier separation. Furthermore, XPS analyses provide further insight in the oxidation state of the cobalt species. Along with the expected features for Bi 3+ and V 5+ species, the XPS spectra show quite complicated signals in the Co 2p3/2 region consisting of an asymmetric main line and several satellites due to plasmon loss features, electron correlations and final-state processes. [START_REF] Biesinger | Resolving Surface Chemical States in XPS Analysis of First row Transition Metals, Oxides and Hydroxides: Cr, Mn, Fe, Co and Ni[END_REF][START_REF] Mayer | XPS Satellites in Transition Metal Oxides[END_REF] The Co 2p3/2 spectrum is similar to the one reported for CoO and Co(OH)2 with a broad main line at a binding energy around 780 eV and a shoulder at 786 eV. [START_REF] Biesinger | Resolving Surface Chemical States in XPS Analysis of First row Transition Metals, Oxides and Hydroxides: Cr, Mn, Fe, Co and Ni[END_REF][START_REF] Weidler | CoOx Thin Film Deposited by CVD as Efficient Water Oxidation Catalyst: Change of Oxidation State in XPS and its Correlation to Electrochemical Activity[END_REF] By contrast, the Co 2p3/2 satellite structure reported for CoOOH and Co3O4 species show a much smaller shoulder at 786 eV and an additional bump at a binding energy of 790 eV, [START_REF] Biesinger | Resolving Surface Chemical States in XPS Analysis of First row Transition Metals, Oxides and Hydroxides: Cr, Mn, Fe, Co and Ni[END_REF][START_REF] Yang | Synthesis and Characterization of Cobalt Hydroxide, Cobalt Oxyhydroxide, and Cobalt Oxide Nanodiscs[END_REF] which some authors explain by the (partial) cobalt oxidation state change from Co 2+ to Co 3+ for CoOOH and Co3O4. [START_REF] Weidler | CoOx Thin Film Deposited by CVD as Efficient Water Oxidation Catalyst: Change of Oxidation State in XPS and its Correlation to Electrochemical Activity[END_REF][START_REF] Mcintyre | X-ray Photoelectron Studies on Some Oxides and Hydroxides of Cobalt, Nickel, and Copper[END_REF] Thus, the samples prepared in this study contain seemingly more Co 2+ , indicating that cobalt is most likely only partly oxidized during the photodeposition process. The cobalt species should be therefore denoted as CoOx(OH)y which is more accurate than Co3O4 usually proposed in the literature with similar XPS spectra. [START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF] At this stage, it is also worthwhile to mention that the cobalt species has been found to change during the photo-oxidation of water which makes it difficult to propose an exact composition for the cobalt co-catalyst. [START_REF] Weidler | CoOx Thin Film Deposited by CVD as Efficient Water Oxidation Catalyst: Change of Oxidation State in XPS and its Correlation to Electrochemical Activity[END_REF][START_REF] Lin | Adaptive Semiconductor/electrocatalyst Junctions in Water Splitting Photoanodes[END_REF] The photodeposition of nickel oxide species onto BiVO4 microcrystals was then investigated for three different nominal nickel contents, i. e. 0.1, 1 and 10 wt% Ni. FESEM images suggest that the regioselectivity of the nickel-based deposit depends on the weight percentage of nickel (Figure 3). Thus, for the samples containing 1 and 10 wt% Ni, nickel seems to be unselectively deposited over the entirety of the BiVO4 particle surface. This was confirmed by EDS mapping of the nickel element which showed that nickel is present on the whole surface of the BiVO4 particles for the 10 wt% Ni sample (Figure 3c). By contrast, a certain regioselectivity was observed in the 0.1 wt% Ni heterostructure with a preferential nickel deposition on the edge between two {110} facets according to FESEM images (Figures 3e-f). These trends were then confirmed by SAM studies. SAM sputter profiles were run measuring the Ni L3VV Auger lines on zones corresponding to BiVO4 {010} facets and {110} facets defined by SEM images (Figure g-h). An intense Ni L3VV Auger signal was detected for each zone of the microcrystals for the 1 wt% Ni sample confirming the absence of regisoselectivity for a high amount of nickel (Figure 3i). After each sputter step the Ni L3VV Auger signal intensity decreases, confirming that Ni is predominantly located at the BiVO4 particle surface. Contrarily, for the 0.1 wt% Ni sample a Ni L3VV Auger signal is only visible when zones on the {010} facets were measured (Figure 3j). In addition, bright-field and dark-field STEM images on the edge of the {110} facets for the 0.1 wt% Ni sample reveal the presence of small particles which can be attributed to nickel oxide species according to EDS analyses (Figure S5). As a consequence, the nickel deposit appears to be limited to the {010} facets and the edges between the {110} facets in the 0.1 wt% Ni heterostructure. Further insights in the surface composition of the 0.1 wt% and 1 wt% Ni samples were inferred from XP core level spectra of Ni 2p, O 1s, V 2p3/2 and Bi 4f (Figure 4). As for the other heterostructures, the core level binding energies found for V 2p3/2 and Bi 4f are characteristic of V 5+ and Bi 3+ chemical states in BiVO4. [START_REF] Su | Macroporous V2O5-BiVO4 Composites: Effect of Heterojunction on the Behavior of Photogenerated Charges[END_REF][START_REF] Lin | One-pot Hydrothermal Synthesis of BiPO4/BiVO4 with Enhanced Visible-light Photocatalytic Activities for Methylene Blue Degradation[END_REF] As expected, the Ni 2p-to-Bi 4f intensity ratio is higher for the 1 wt% Ni sample compared to the 0.1 wt% Ni one. Furthermore, two main features are detected in the O 1s core level spectrum at 530.3 eV and 532.2 eV, respectively. The former can be assigned to metal oxides, i.e. O 2-sites, while the latter is typical for hydroxyl groups and organic carbon-oxygen bonds, commonly present in ex situ prepared samples due to adherence of water and organic compounds onto the sample surface. [START_REF] Lin | One-pot Hydrothermal Synthesis of BiPO4/BiVO4 with Enhanced Visible-light Photocatalytic Activities for Methylene Blue Degradation[END_REF] It is also worth underlining that the hydroxyl feature is considerably more intense than usual, even higher than the O [START_REF] Biesinger | The role of the Auger Parameter in XPS Studies of Nickel Metal, Halides and Oxides[END_REF] which are not observed here. Instead, the Ni 2p line shape resembles more to that reported for a mixed nickel oxyhydroxide. [START_REF] Grosvenor | New Interpretations of XPS Spectra of Nickel Metal and Oxides[END_REF][START_REF] Weidler | X-ray Photoelectron Spectroscopic Investigation of Plasma-Enhanced Chemical Vapor Deposited NiOx, NiOx(OH)y, and CoNiOx(OH)y: Influence of the Chemical Composition on the Catalytic Activity for the Oxygen Evolution Reaction[END_REF] As a result, the nickel species should be designated as NiOx(OH)y.

Photocatalytic properties

First of all, the optical band gaps of the different heterostructures prepared were determined by UV-visible diffuse reflectance spectroscopy (Figure S6a). It is generally admitted that BiVO4 is an indirect band gap semiconductor, [START_REF] Cooper | Indirect Bangap and Optical Properties of Monoclinic Bismuth Vanadate[END_REF] whereas light absorption involves direct transition. Thus, Tauc plots of [F(R)h] 2 vs. h led to direct optical band gap in the range of 2.48-2.52 eV while Tauc plots of [F(R)h] 1/2 vs. h yielded indirect optical band gap of about 2.41-2.43 eV (Figure S6b-c). This shows that the deposited contact materials do not have a strong influence on the light absorption properties of the heterophotocatalysts.

The photocatalytic properties were first examined by the photodecomposition of RhB over different photocatalysts (with a co-catalyst loading of 0.1 wt%) under simulated sun light (1 sun) and static air (Figure S7). A blank experiment in the absence of photocatalyst confirms that photolysis of RhB under sun light can be neglected. Thus, 0.1 wt% Ag/BiVO4 and 0.1 wt% NiOx(OH)y/BiVO4 photocatalysts appeared to be the most efficient with about 50% dye decomposition after 2h irradiation while 0.1 wt% CoOx(OH)y/BiVO4 showed a lower activity, similar to that of bare BiVO4. Photodegradation of RhB by these materials can be modeled by using a pseudo first order kinetic law, ln(C/C0) = kappt where kapp is the pseudo first-order rate constant and, C and C0 stand for the concentration of the dye in solution at time t and 0.

Apparent rate constants were estimated to be 3.3 10 -3 min -1 , 2.7 10 -3 min -1 , 5.5 10 -3 min -1 and 6.7 10 -3 min -1 for BiVO4, 0.1 wt% CoOx(OH)y/BiVO4, 0.1 wt% NiOx(OH)y/BiVO4 and 0.1 wt% Ag/BiVO4, respectively. While the beneficial effect of metallic silver particles in BiVO4 based photocatalysis is well-documented, [START_REF] Li | Silver-modified Specific (040) facet of BiVO4 with Enhanced Photoelectrochemical Performance[END_REF][START_REF] Wu | Preparation of Noble Metal Ag-modified BiVO4 Nanosheets and a Study on the Degradation Performance of Tetracyclines[END_REF] it is the first time that the same trend is reported for NiOx(OH)y deposits. For Ag/BiVO4 system, it has been reported that superoxide radicals (O2 •-) are the main species involved in the degradation of organics. [START_REF] Wu | Preparation of Noble Metal Ag-modified BiVO4 Nanosheets and a Study on the Degradation Performance of Tetracyclines[END_REF] To get an insight in the radicals involved in the case of the original 0.1 wt% NiOx(OH)y/BiVO4 photocatalyst, propan-2-ol (IPA), 1,4-benzoquinone (BQ) and potassium iodide (KI) were used as hydroxyl radical (OH • ), superoxide radical (O2 •-) and hole (h + ) scavengers, respectively for RhB photodecomposition. Then, photochemical sacrificial water splitting experiments were carried out to determine the ability of the different photocatalysts to promote O2 evolution reaction in the presence of an electron scavenger (sodium periodate). At this stage, it is worth mentioning that the use of sacrificial reagents may lead to undesired phenomena such as side reactions, deactivation and changing driving forces. [START_REF] Limburg | Molecular Water Oxidation Catalysts Based on Transition Metals and their Decomposition Pathways[END_REF] Nonetheless, this approach allows for a simplification of the complex system of overall water splitting and hence a more detailed understanding of the basic processes.

As depicted in Fig. 5A, no significant amount of O2 was generated in the absence of light while a volume increase of 1 mL was observed for a blank experiment without photocatalyst (Fig. S9).

In contrast irradiation for 6 h of 0.2 wt% CoOx(OH)y/BiVO4 suspensions in NaIO4/water mixture led to the production of about 12 mL of O2 evidencing the occurrence of an actual photocatalytic process. Typical plots of the time course of O2 evolution for the different photocatalysts investigated are shown in Fig. 5B. Regardless of the photocatalyst nature, the amount of evolved O2 was increasing linearly with time thus revealing the high stability of the photocatalysts to reach a plateau value which corresponds to the total consumption of the scavenger (see ESI).

This result evidences that reduction of IO4 -does not constitute the rate-limiting step. To get a more quantitative insight in the photocatalytic properties, a linear regression was performed on the linear part of the gas evolution curves, i.e. at a reaction time between 2 and 3 h, and the resulting rates are gathered in Table 1. Implementation of CoOx(OH)y as co-catalyst boosts the sacrificial water oxidation performance of BiVO4 by about 10 times, with respect to bare BiVO4. However, the NiOx(OH)y/BiVO4 heterostructures exhibited only a fair water oxidation rate compared to the other heterostructures, since the O2 evolution is only twice as high with respect to bare BiVO4. These results may be related to the highly regioselective deposition of the CoOx(OH)y oxidation co-catalyst on the electron-deficient {110} facets of BiVO4 microcrystals compared to NiOx(OH)y which is mainly located on the electron-rich {010} facets of BiVO4. The CoOx(OH)y regioselectivity, the preferential accumulation of holes on the {110} facets 44,55 and upwards band bending at CoOx/BiVO4 contacts [START_REF] Hermans | Analysis of the Interfacial Characteristics of BiVO4/Metal Oxide Heterostructures and its Implication on their Junction Properties[END_REF] favors the spatial charge separation of the photogenerated charge carriers which inhibits charge recombination and leads to enhanced photocatalytic O2 evolution rate.

Discussion

The photodeposition of various co-catalysts onto faceted BiVO4 microcrystals has been successfully achieved using 1 sun illumination with a regioselectivity strongly dependent upon the co-catalyst used. The expected facet-selectivity was actually observed for both silver and cobalt photodeposition carried out at pH 7. [START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF][START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF] Under these pH conditions, the main metallic precursor species are cationic, i.e. Ag + or Co 2+ , and BiVO4 truncated bipyramidal surfaces are negatively charged since the isoelectric point of these microparticles has been reported to be about 3.5. [START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF] As a consequence, specific adsorption of the metallic precursor cannot be at the origin in the difference of the regioselectivity observed. On the other hand, as the same counterion, i.e. NO3 -, was used in both cases, preferential chemisorption of anions on specific facets can be ruled out to interpret the facet selectivity. Finally, favored interactions of the neutral, i.e.

methanol, or negatively charged, i.e. IO3 -, hole or electron scavengers with specific facets is unlikely owing to the negative charge of the BiVO4 surfaces. The regioselectivity for the Ag and CoOx(OH)y deposition can therefore be assigned to the different electrochemical properties of the {010} and {110} facets under light irradiation which favors the reduction of silver cations on the electron-rich {010} facets and the oxidation of the cobalt precursor on the electron-deficient {110} facets of the BiVO4 microcrystals. These findings obtained at 1 sun are fully consistent with those previously reported with other light sources. [START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF][START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF] On the other hand, the regioselectivity of the nickel photodeposition strongly depends on the wt% of nickel in the reaction mixture since nickel species was selectively deposited onto the {010} facets and the edges between the {110} facets in the 0.1 wt% NiOx(OH)y/BiVO4 sample whereas no selectivity was detected for nickel amount equal to or higher than 1 wt%. Overall, the difference in regioselectivity of Co and Ni is striking due to their very similar chemistry. The standard oxidation potentials for the oxidation of Co 2+ to CoOOH (1.76 V) and Ni 2+ to NiOOH (2.05 V) are close and both allowed according to the BiVO4 VBM of about 2.8 V vs NHE.

Similarly, the standard reduction potentials for the reduction of Co 2+ to Co(s) (-0.282 V) and Ni 2+ to Ni(s) (-0.236 V) can thermodynamically not take place at the BiVO4 surface under light illumination, because of the more positive BiVO4 CBM. [START_REF] Bratsch | Standard Electrode Potentials and Temperature Coefficients in Water at 298[END_REF] Thus, only oxidation of Ni 2+ is assumed just as for Co 2+ . The difference in regioselectivity could have to do with the difference in pH, as Co 2+ was deposited at pH 7, while Ni 2+ was deposited at pH 9.2 using a KBi buffer.

The {010} facets could be more negatively charged, leading to a preferential adsorption of the Ni 2+ ions onto these facets. The Ni 2+ ions could then react with OH -leading to an impregnation onto the {010} facets. Regarding the suitable standard reduction potential (0.52 V) the impregnated Ni(OH)2 could then further oxidize to NiOOH during light illumination. [START_REF] Bratsch | Standard Electrode Potentials and Temperature Coefficients in Water at 298[END_REF] Additionally, the regioselective adsorption of Ni on the {110} edges could be due to even higher hole accumulation on these edges than on the {110} facets, so that for low Ni 2+ concentrations only photodeposition takes place on the{110} edges.

As far as the photocatalytic properties are concerned, the rates found for the photodecomposition of RhB in the presence of 0.1 wt% NiOx(OH)y/BiVO4 and 0.1 wt% Ag/BiVO4 under static air fall within the range of those reported by Li et al. for BiVO4 microcrystals endowed with a single co-catalyst under oxygen bubbling. [START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF] As a result, associated with BiVO4 particles, NiOx(OH)y is a good co-catalyst for the photodegradation of organics.

Moreover, comparison with literature indicates that the materials developed in this study compete well with the most efficient photocatalysts for sacrificial water oxidation reaction (Table 1). [START_REF] Yu | Effects of Structural Variation on the Photocatalytic Performance of Hydrothermally Synthesized BiVO4[END_REF][START_REF] Li | Spatial Separation of Photogenerated Electrons and Holes among {010} and {110} Crystal Facets of BiVO4[END_REF][START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF][START_REF] Tan | BiVO4 {010} and {110} Relative Exposure Extent: Governing Factor of Surface Charge Population and Photocatalytic Activity[END_REF][START_REF] Jo | Phosphate Doping into Monoclinic BiVO4 for Enhanced Photoelectrochemical Water Oxidation Activity[END_REF][START_REF] Kong | Sulfur-Doped g-C3N4/BiVO4 Composite Photocatalyst for Water Oxidation under Visible Light[END_REF][START_REF] Iwase | Reduced Graphene Oxide as Solid State Electron Mediator in Z-Scheme Photocatalytic Water Splitting under Visible Light[END_REF][START_REF] Melo | Surface Photovoltage Measurement on a Particle Tandem Photocatalyst for Overall Water Splitting[END_REF][START_REF] Wei | Multielectric Field Modulation for Photocatalytic Oxygen Evolution: Enhanced Charge Separation by Coupling Oxygen Vacancies with Faceted Heterostructures[END_REF] First of all, our results are on line with those reported by Li et al. for similar morphologies, [START_REF] Li | Highly Efficient Photocatalysts Constructed by Rational Assembly of Dual-cocatalysts Separately on Different Facets of BiVO4[END_REF] in the sense that boosted water oxidation performances were obtained for cobalt based materials. In addition, the O2 evolution reaction rates for BiVO4, 0. photodeposition shows no facet selectivity for nickel precursor amount higher than 1 wt% while an original selectivity was observed for 0.1 wt% NiOx(OH)y/BiVO4 with a preferential deposition onto the {010} facets and the edges between the {110} facets. In addition, most of the heterostructures prepared showed enhanced photocatalytic properties. Thus, 0.1 wt% Ag/BiVO4, and 0.1 wt% NiOx(OH)y/BiVO4 led to almost twice higher decomposition rates of RhB than bare BiVO4 under simulated sun illumination. More interestingly, for sacrificial water oxidation 0.2 wt% CoOx(OH)y/BiVO4 yielded one of the highest oxygen evolution rates, i.e. 1538 µmol.h -1 .g -1 , ever reported in the literature which represents a tenfold increase compared to bare BiVO4. Our study therefore emphasizes the key contribution of regioselective deposition of cobalt oxide species onto the more electron-deficient facet of truncated bipyramidal scheelite BiVO4 microcrystals for efficient oxygen evolution reaction. Finally, this work shed light on the potentialities of solar irradiation instead of conventional lamps to fabricate efficient heterostructured photocatalysts by associating an appropriate co-catalyst and selective deposition onto the specific facet of metal oxide photoabsorbers. The results obtained in our study support the idea to fabricate well defined heterostructures of absorber materials coupled to co-catalysts working as contact and catalytic center. A challenging but rewardable research direction of nanotechnology would be to form facetted nanocrystals with electronically well defined facets for electron and hole scavenging, the effect of which will be supported by cocatalyst materials with strongly deviating electronic properties. In short, a nano-sized cell arrangement with contact materials providing an adapted electronic contact, but also preferential catalytic properties would be favorable.

ASSOCIATED CONTENT

Supporting Information. XRD patterns, UV-visible spectroscopy data, complementary SEM, SAM and XPS data, RhB photodecomposition data.

Figure 1 .

 1 Figure 1. FESEM image of BiVO4 (a) and 2 wt% CoOx(OH)y/BiVO4 (b).

Figure 2 .

 2 Figure 2. SAM and XPS analyses for 2 wt% CoOx(OH)y/BiVO4. SAM elemental maps: Bi, V, O, Co and C (a); Core level XP spectra: Co2p3/2, Bi4f, V2p3/2 and O1s core level XP spectra (b). Dark areas in (a) correspond to regions where mapped element is not present.

Figure 3 .

 3 Figure 3. SEM images for bare BiVO4 (a), 10 wt% NiOx(OH)y/BiVO4 (b), 10 wt% NiOx(OH)y/BiVO4 with Ni EDS mapping (c), 1 wt% NiOx(OH)y/BiVO4 (d) and 0.1 wt% NiOx(OH)y/BiVO4 (e-f). SEM images for 1 wt% NiOx(OH)y/BiVO4 (g) and 0.1 wt% NiOx(OH)y/BiVO4 (h) indicating on which zones Ni L3VV SAM sputter profiles were measured. Ni L3VV SAM sputter profiles for 1 wt% NiOx(OH)y/BiVO4 (i) and 0.1 wt% NiOx(OH)y/BiVO4 (j) Areas 1 and 2 correspond to {110} facets while areas 3 and 4 stands for {010} facets.

Figure 4 .

 4 Figure 4. Core level XP spectra for 0.1 wt% and 1 wt% NiOx(OH)y/BiVO4: Ni 2p (a), O 1s (b), V 2p3/2 (c) and Bi 4f (d) core level XP spectra.

Figure

  Figure S8 reports on the kinetic rate constant found in each case normalized by that in the

Figure 5 .

 5 Figure 5. (A) Photocatalytic evolution of O2 under different conditions. (B) O2 evolution over bare BiVO4 (a, blue), 1 wt% NiOx(OH)y/BiVO4 (b, magenta) and 0.2 wt% CoOx(OH)y/BiVO4 (c, red).

Figure 6

 6 photocatalysts exhibited a better water oxidation efficiency than bare BiVO4 could be due to

  Indeed, photogenerated electrons and holes preferentially accumulate on different crystalline facets which renders cocatalyst deposition regioselective depending on whether the process involves an oxidation or reduction reaction. Systematic studies on single crystalline TiO2 (anatase) exposing different facets have shown that the different surfaces (100)

vs. (110) provide indeed different electronic surface properties including different work functions which promote charge carrier separation into different directions.

[START_REF] Kashiwaya | Fermi Level Positions and Induced Band Bending at Single Crystalline Anatase (101) and (001) Surfaces: Origin of the Enhanced Photocatalytic Activity of Facet Engineered Crystals[END_REF]

Anisotropic photodeposition on BiVO4 microcrystals has been extensively studied by Can Li et al. They have first shown using field emission secondary electron microscopy (FESEM) that

  2-signal, for the 1 wt% Ni sample which suggests a large amount of hydroxide species. Finally, the Ni 2p core level region is complex with four main features at 856.6 eV belonging to Ni 2p3/2, 861.5 eV The presence of pure NiO and metallic nickel can be excluded, since that would give rise to a noticeable peak splitting of the main Ni 2p3/2 line at 856.5 eV for NiO[START_REF] Grosvenor | New Interpretations of XPS Spectra of Nickel Metal and Oxides[END_REF] and a characteristic Ni 2p3/2 feature at 852.6 eV for Ni

	belonging to a Ni 2p3/2 satellite, 874.3 eV belonging to Ni 2p1/2 and 880.7 eV corresponding to a
	Ni 2p1/2 satellite.

Table 1 :

 1 O2 evolution rates of some photocatalysts prepared in this work in comparison with those reported in literature for state of the art photocatalysts based on BiVO4. All the literature data have been acquired under visible light ( > 420 nm) using a 300 W Xe lamp.

	Photocatalyst	Electron scavenger	O2	evolution	Ref
			(mol.h -1 .g -1 )
	BiVO4	0.1 M NaIO4	154		This work
	0.1 wt% NiOx(OH)y /BiVO4	0.1 M NaIO4	292		This work
	1 wt% NiOx(OH)y /BiVO4	0.1 M NaIO4	304		This work
	0.08 wt% CoOx(OH)y/BiVO4	0.1 M NaIO4	1330		This work
	0.2 wt% CoOx(OH)y/BiVO4	0.1 M NaIO4	1538		This work
	BiVO4	0.05 M AgNO3	835		14
	BiVO4	0.05 M AgNO3	920		72
	PO4-doped BiVO4	aqueous AgNO3	670		73
	S-doped-C3N4/BiVO4	0.05 M AgNO3	750		74
	Ru-SrTiO3:Rh-RGO/BiVO4	H2SO4	167		75
	Ru-SrTiO3:Rh/BiVO4	H2SO4	540		76
	Pt/BiVO4/MnOx	0.02M NaIO3	630		43
	Pt/BiVO4/Co3O4	0.02M NaIO3	1070		44
	Vo-ZnO/BiVO4	0.05 M AgNO3	1356		77

European Union's Horizon 2020 research and innovation program through the Marie

Sklodowska-Curie Grant Agreement No 641640. The authors acknowledge the "Université Franco-allemande" for funding the German-French Doctoral College in Functional Materials (contract CDFA 02-15 (2018-2021)). The PLACAMAT structure for its electron microscopy facilities and EMMI (European Multifunctional Material Institute) are also thanked.

crystalline studies with well defined surface facets would be of interest as have been performed on anatase TiO2. 42 E-mail address: thierry.toupance@u-bordeaux.fr

Author Contributions

The manuscript was written through contributions of all authors.

ACKNOWLEDGMENT

The researches described in this manuscript were performed in the framework of ITN-EJD-FunMat (European Joint Doctorate for Multifunctional Materials) and was supported by the


domain: chim sdv

text:
Matúš Hlaváč

Lucia Kováčiková

Marta Šoltésová Prnová

Gabriela Addová

Gilles Hanquet

Milan Štefek

Andrej Boháč

Novel substituted N-benzyl(oxotriazinoindole) inhibitors of aldose reductase exploiting ALR2 unoccupied interactive pocket

Keywords: aldose reductase (ALR2), interactive pocket, N-benzyl(oxotriazinoindole) ALR2 inhibitors, desolvation penalty

Recently we have developed novel oxotriazinoindole inhibitors (OTIs) of aldose reductase (ALR2), characterized by high efficacy and selectivity. Herein we describe novel OTI derivatives design of which is based on implementation of additional intermolecular interactions within an unoccupied pocket of the ALR2 enzyme. Four novel derivatives, OTI-(7-10), of the previously developed N-benzyl(oxotriazinoindole) inhibitor OTI-6 were synthetized and screened. All of them revealed 2 to 6 times higher ALR2 inhibitory efficacy when compared to their non-substituted lead compound OTI-6. Moreover, the most efficient ALR2 inhibitor OTI-7 (IC50 = 76 nM) possesses remarkably high inhibition selectivity (SF ≥ 1300) in relation to structurally related aldehyde reductase (ALR1). Derivatives OTI-(8-10) bearing the substituents -CONH2, -COOH and -CH2OH, possess 2-3 times lower inhibitory efficacy compared to OTI-7, but better than the reference inhibitor OTI-6. Desolvation penalty is suggested as a possible factor responsible for the drop in ALR2 inhibitory efficacy observed for derivatives OTI-(8-10) in comparison to OTI-7.

Introduction

Diabetes mellitus (DM), a wide-spread human disorder, has been recognized as a main cause of health problems such as blindness, neuronal diseases, hearth and kidney failures. 1 One of the most important therapeutic targets, implicated in late diabetic complications, is the polyol pathway. This pathway involves two steps, where D-glucose is converted to D-fructose via Dsorbitol. (Fig. 1) In the first step, aldose reductase (ALR2) catalyses reduction of D-glucose to D-sorbitol while NADPH is oxidized to NADP + . [START_REF] Brownlee | Biochemistry and molecular cell biology of diabetic complications[END_REF] Deficiency of NADPH hampers regeneration of glutathione (GSH) from its dimer (GSSG), causing high excess of intracellular reactive oxygen species (ROS) in various tissues including the heart, neurons, eyes and kidneys. [START_REF] Vistoli | Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation[END_REF] In addition, high concentration of highly polar D-sorbitol results in osmotic imbalances and cell swelling. [START_REF] Kyselova | Pharmacological prevention of diabetic cataract[END_REF] D-Fructose, formed in the second step of the polyol pathway, causes excessive glycation of proteins and lipids and enhances formation of advanced glycation and lipoxidation end products (AGEs and ALEs), also involved in inflammation and oxidative stress. According to all these facts, inhibition of ALR2 activity can indirectly suppress above mentioned pathological imbalances and slow down late diabetic complications. Reduction of the carbonyl functional group of lipid peroxidation products, namely 4hydroxynonenal (HNE), and its glutathione adduct (GS-HNE) by ALR2 may generate intermediates contributing to activation of pro-inflammatory signaling. It points to aldose reductase inhibitors (ARIs) as promising agents in therapy of chronic inflammatory disorders and even several types of tumors related to chronic inflammation. [5][START_REF] Srivastava | Aldose Reductase Inhibition Suppresses Oxidative Stress-Induced Inflammatory Disorders[END_REF][7][START_REF] Grewal | Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases[END_REF][START_REF] Ballekova | Does Inhibition of Aldose Reductase Contribute to the Anti-Inflammatory Action of Setipiprant?[END_REF] Moreover, interventions with ARIs may have potential in attenuation of pathological consequences of several genetic metabolic disorders including galactosemia and sorbitol dehydrogenase deficiency. [START_REF] Morava | Elevated sorbitol underlies a heritable neuropathy[END_REF] Over the last 40 years, numerous ARIs have been developed, but only epalrestat as ARI is therapeutically available in Japan, China and India. [START_REF] Vyas | Search for non-acidic ALR2 inhibitors: Evaluation of flavones as targeted agents for the management of diabetic complications[END_REF] Most of structurally different ARIs have been refused in clinical trials mainly for their low in vivo efficacies, pharmacokinetic drawbacks and/or side effects. The largest class of ARIs are carboxylic acids where carboxylate anion moiety occupies an anion binding pocket of the active site of ALR2. Štefek et al. developed the carboxymethylated thioxotriazinoindole cemtirestat (CMTI), 2-(3thioxo-2H- [1,2,4]triazino [5,6-b]indol-5(3H)-yl)acetic acid, as a novel lead-like candidate with excellent ALR2 inhibitory efficacy, selectivity and antioxidant activity. [START_REF] Stefek | Identification of Novel Aldose Reductase Based on Carboxymethylated Mercaptotriazinoindole Scaffold[END_REF] Very recently, the inhibition efficacy and selectivity of CMTI was improved by isosteric replacement of sulphur with oxygen, which led to the discovery of the oxotriazinoindole inhibitor OTI, 2-(3-oxo-2H-[1,2,4]triazino [5,6-b]indol-5(3H)-yl)acetic acid, with markedly increased inhibition selectivity. [START_REF] Hlaváč | Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur / Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity[END_REF] In this study, we aimed to exploit a previously unoccupied ALR2 pocket consisting of Trp219, Ala299 and Leu301 (PDB: 4QX4). In order to utilize this pocket to ensure additional interactions novel N-benzyl(oxotriazinoindole) derivatives were proposed.

Besides the leading unsubstituted N-benzyl derivative OTI-6 previously described by us, [START_REF] Hlaváč | Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur / Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity[END_REF] herein we proposed, synthesized and screened its substituted derivatives OTI-( 7

Results and discussion

In this study, we aimed to explore an unoccupied ALR2 pocket in close proximity to the triazine ring of CMTI inhibitor (PDB: 4QX4). This pocket contains important amino acid residues e.g. Trp219, Ala299 and Leu301. In order to utilize this pocket for additional ligand-

Synthesis of OTI-(7-10)

Compound 1 (OTI) [START_REF] Hlaváč | Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur / Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity[END_REF]

Determination of enzyme inhibitory activities

Inhibitors OTI-(7-10) were tested for their ability to inhibit the reduction of D,Lglyceraldehyde using ALR2 isolated from the rat eye lenses. Unsubstituted benzyl analogue OTI-6 was used as a reference inhibitor. To assess selectivity we used a structurally related detoxification enzyme (an antitarget), aldehyde reductase (ALR1) isolated from the rat kidneys. 13 According to the results we found out that all substituted N-(benzyl) derivatives OTI-(7-10)

exhibited from 2 to 6-fold better inhibitory efficacy than unsubstituted analogue OTI-6. In addition, they also revealed low inhibition of ALR1 antitarget, which resulted from a good to an excellent enzyme selectivity. (Table 1) In spite of predicted similar positions and interactions of the derivatives OTI-10 and OTI-7, OTI-10 exhibited about 3-times lower inhibitory activity characterized with IC50 = 241 nM.

The additional reason of lower activity of OTI-10 could be desolvation and rotation penalty caused by a -CH2OH group. Desolvation penalty effect has been a subject of our recent publication. [START_REF] Dobiáš | Medicinal chemistry: an efect of a desolvation penalty of an amide group in the development of kinase inhibitors[END_REF] Derivatives OTI-(8,9) (-CONH2, -COOH, resp.) revealed 2 to 3-fold lower inhibitory activity in comparison to OTI-7 (-CN). Besides desolvation penalty, the lower activity of a carbamoyl derivative OTI-8 could be also caused by conformational penalty of -CONH2 group. Symmetry of delocalized carboxylate group in OTI-9 (-COO -) exhibited better inhibition activity than OTI-8 (-CONH2) and OTI-10 (-CH2OH). In addition, outer part of a studied pocket and a benzyl group are well water accessible (Fig. 4) and hence a benzyl group could provide two conformers. A first conformer allows formation of the predicted Hbond with an orientation of a polar group inside the pocket and a second conformer prefers orientation toward the solvent. Consequently, very polar groups would not be oriented inside the pocket, where the predicted H-bonds could be formed, but owing to solvation they would remain oriented toward a water environment out of the pocket. Therefore significant H-bond with Ala299 or Leu301 would not be formed as was predicted and thus the least solvated derivative OTI-7 revealed the highest inhibitory activity. In order to determine drug-like parameters, molecular obesity indices for compounds OTI-(6-10) were calculated (Table 2). The parameters take into account size, inhibitory efficacy and lipophilicity.

Experimental Computer predictions

The structure of hu-ALR2 protein in a complex with NADP+ (PDB: 4QX4) [START_REF] Stefek | Identification of Novel Aldose Reductase Based on Carboxymethylated Mercaptotriazinoindole Scaffold[END_REF] was used for our predictions. The optimized conformers of the proposed ligands were docked into the enzyme-cofactor complex by UCSF software Dock Blaster methodology. [START_REF] Irwin | Automated docking screens: a feasibility study[END_REF] The predicted poses of ligands in an active site of ALR2 enzyme were analysed and used for composition of The most promising ligands were selected based on their score from docking experiments and the results of their intermolecular interaction analysis with target amino acid residues.

OTI

Chemistry

Melting points were measured by Barnstead Electrothermal IA9200 and are uncorrected. (2)

To a solution of 100 mg (0.41 mmol, 1.00 mol eq) of 1 (OTI) dissolved in 30 ml of EtOH (abs), 1.00 ml of H2SO4 (conc) was added and the reaction stirred at reflux under Ar. To a solution of 100 mg (0.26 mmol, 1.00 mol eq) ester 4 in 20 ml of MeOH, 20.6 mg (0.52 mmol, 2.00 mol eq) of NaOH in 3 ml water was added and the mixture refluxed for 30 min. 7, 169.1, 154.1, 153.7, 144.7, 136.0, 135.5, 132.9, 131.5, 130.4, 128.2, 127.5, 127.3, 123.6, 121.7, 117.7, 111.7, 55.2 and 42.5. FT-IR (solid, cm -1 ): 3357 (m), 3191 (m), 2959 (m), 2928 (m) 1, 168.6, 154.2, 153.6, 144.5, 138.3, 133.0, 132.7, 131.5, 131.0, 130.0, 127.7, 127.3, 123.6, 121.6, 117.7, 111.7, 55.2 and 42.5. FT-IR (solid, cm A solution of phthalic anhydride 8 (440 mg, 2.97 mmol, 1.00 mol eq) in 15 ml of THF (abs)

was added dropwise at 0 °C to the stirred suspension of LiAlH4 (226 mg, 5.96 mmol, 2.00 mol eq) in 20 ml of THF (abs) within 30 min. Then, the mixture was stirred overnight at room temperature. Afterwards, the reaction was cooled to 0 °C and 10 ml of isopropanol added slowly, followed by methanol (10 ml) and water (10 ml). Obtained wax-like precipitate was filtered through Celite and obtained filtrate washed with EA and DCM. Organic solution was evaporated and aqueous mixture extracted with EA (3x 20 ml) and DCM (3x 10 ml).

Combined organic layer was dried over Na2SO4, filtered and concentrated over reduced pressure totally yielding 385 mg (2.79 mmol, 94 %) of diol 9 as a colourless oil, which solidified by storing in a refrigerator. Novelty: 1,2-phenylenedimethanol ( 9) is described in the literature by its M.P., 1 H-NMR, [START_REF] Hlaváč | Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur / Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity[END_REF] C-NMR, IR and HRMS.

2-(Bromomethyl)phenyl]methanol (10)

A solution of 105 mg (0.76 mmol, 1.00 mol eq) 1,2-phenylenedimethanol ( 9) in 20 ml of toluene was heated to 70 °C. At this temperature, 80 µl (0.85 mmol, 1.12 mol eq) of 48 % solution of HBr was added dropwise. After 20 min, TLC analysis confirmed a presence of product 10 and a small amount of probably bis brominated side product. Reaction mixture was cooled down, neutralized with saturated aq solution of Na2CO3 and extracted with diethyl ether (3 x 15 ml). Combined organic layer was evaporated and resulted mixture purified by FLC (Hex / EA = 5 / 1) to afford 80.0 mg (0.40 mmol, 56 %) of desired product 10 as a white solid compound. Novelty: 2-(bromomethyl)phenyl]methanol (10) is described in the literature by its M.P., 1 H-NMR, IR [START_REF] Cowell | Synthesis of lactones by the palladium-catalyzed carbonylation of halo alcohols[END_REF] and MS spectra. is described in the literature by its 1 H-NMR and crystal property description. Enzyme assays: Preparation of ALR2 from the rat lens and ALR1 from the rat kidneys was previously reported. [START_REF] Stefek | Carboxymethylated pyridoindole antioxidants as aldose reductase inhibitors: synthesis, activity, partitioning, and molecular modeling[END_REF] Enzyme activities were assayed spectrophotometrically by determining NADPH consumption at 340 nm and were expressed as decrease of the optical density (O.D.) / s/mg protein. [START_REF] Stefek | Carboxymethylated pyridoindole antioxidants as aldose reductase inhibitors: synthesis, activity, partitioning, and molecular modeling[END_REF] The experimental procedures are in detail described in Supporting information to this paper.

experimental procedures comprising isolation of rat kidney ALR1, rat eye lens ALR2 and enzyme activity assays.

Figure 1 .

 1 Figure 1. An illustration of the polyol pathway and its implication in the diabetic complications.

Scheme 1 .

 1 Scheme 1. Design of novel benzyl derivatives OTI-(7-10) from OTI-6.

  enzyme interactions, novel N-benzyl(oxotriazinoindole) derivatives OTI-(7-10) have been designed and developed. Predictions and interaction diagrams of OTI-(7-10) Proposed derivatives OTI-(7-10) have been docked into the ALR2 protein conformer taken from the complex PDB: 4QX4. As expected, proposed derivatives possess additional H-bonds in the ALR2 unoccupied lipophilic pocket with Ala299 or Leu301 from backbone and two π-π interactions of OTI´s benzyl moiety with Trp219. Furthermore, the other important interactions e.g. of an acetate group in an anion binding pocket are crucial for a high ALR2 activity of all OTI derivatives (ionic interactions: with His110 and Lys77 and H-bonds with His110, Tyr48 and Trp111). Predicted interactions of OTI-(7-10) inhibitors are depicted in the diagrams (Fig. 2) as well as in the Supporting information of this paper.

Figure 2 .

 2 Figure 2. Predicted OTI-(7-10) interactions in a binding site of ALR2 enzyme (PDB: 4QX4).

Scheme 2 . 11 ,Scheme 3 .

 2113 Scheme 2. Preparation of OTI-(7-9) from OTI. Reagents and conditions: (a) EtOH (abs), cat H 2 SO 4 (conc), reflux, 6 h; (b) (1) CaH 2 (1.19 mol eq), DMF (abs), 80 °C, 30 min, (2) 2-(bromomethyl)benzonitrile (3) (1.19 mol eq), from rt to 80 °C, 1 h; (c) NaOH (2.00 mol eq), MeOH / H 2 O (1 / 1) reflux, 30 min; (d) TFA / H 2 SO 4 (conc) (4 / 1), 70 °C, 6 h; (e) H 2 O / H 2 SO 4 (conc) (1 / 1), 100 °C, 8 d.

Table 1 .

 1 Results of in vitro enzyme assays of the novel ALR2 inhibitors OTI-(7-10) in comparison with the unsubstituted parent compound OTI-6 and previously developed inhibitors Cemtirestat and Epalrestat. a Hlaváč et al. (2020), 13 b Majekova et al. (2017) (measured in 1 % DMSO), 26 n.d.-not determined. Results are means ± SD from minimum of three independent repetitions. I is the % of enzyme inhibition observed at 100 μM inhibitor concentration. Selectivity factor: S F = IC 50 (ALR1) / IC 50 (ALR2).

Figure 3 .

 3 Figure 3. Predicted pose and interactions of OTI-7 (5) in a binding site of an ALR2 (PDB: 4QX4).

Figure 4 .

 4 Figure 4. Solvents Accessible Surface of the unsubstituted benzyl derivative OTI-6. Blue colour indicates water accessible part.

  Calculated values of the ligand efficacy (LE) and the binding efficiency index (BEI) for all inhibitors OTI-(6-10) were found in the range of optimal values (>0.3 and >14.7, resp). In addition, all novel compounds exhibited favourable lipophilic ligand efficiency parameter (LLE) values above the limit 3.8, important for a successful lead. All compounds OTI-(6-10) showed ligand-efficiency-dependent lipophilicity (LELP) in recommended range (<7.5), which implies good drug-likeness of all developed inhibitors. Moreover, all compounds have appropriate topological polar surface area (TPSA) (60-140 Å 2 ) predicting good oral absorbtion.Based on the results from screening and the SAR conclusions, we have proposed other appropriate N-benzyl(oxotriazinoindole) analogues shown in Fig.5. These derivatives should preserve similar interactions as the parent compounds within a studied ALR2 pocket and they should have lower desolvation and/or conformational penalties. Acetyl derivative OTI-8a (an analogue to amide derivative OTI-8) possesses lower polarity and solvation. Methyl ester OTI-9a is a less polar analogue to carboxylic acid OTI-9. Besides its lower solvation, it could also possess better penetration through the cell membrane in contrast to OTI-9. In addition, nitro derivative OTI-9b should be less solvated because of its lower polarity and with no conformational penalty considering its symmetric delocalized structure (Fig.5) although -NO2 group is less favorable in drug development due its potential toxicity. More detailed predicted interaction diagrams of newly proposed analogues OTI-(8a-9a,b) are described in the Supporting information of this paper.

Figure 5 .Figure 6 .

 56 Figure 5. The structures of studied inhibitors OTI-(8,9) and their proposed promising analogues OTI-(8a-9a,b).

Figure 7 .

 7 Figure 7. Predicted ALR2 poses and interactions of proposed polycyclic derivatives OTI-14 and OTI-15.

-( 7 - 10 )

 710 intermolecular interactions diagrams. (Fig.2-3 and 5-6) The protein conformer of a human recombinant enzyme AKR1B1 from the complex (PDB: 4QX4), possessing two 3E2 (cemtirestat) ligands and NAP (NADP + ) cofactor, was used for modelling, grid generation and docking. The structures of ligands were proposed by molecular modelling in the Discovery Studio Visualizer software (release 2019) from Biovia.19 The optimal 3D structures of proposed ligands together with their protomers, tautomers and isomers were generated by a Ligand Preparation tool of the Maestro software (release 2016) from Schrodinger at software standard predifined conditions and pH = 7.0 / ± 1.20 The target protein was prepared for docking in a Protein Preparation Wizard tool of the Maestro software by standard predefined conditions at pH 7.0, while the present water molecules were removed. The target hydrogens were minimized, invalid bond order corrected, missing side chains added and detected amino acid alternative positions selected. Afterwards, a Receptor Glide Grid Generation tool of the Maestro software was used at standard predefined conditions exploiting binding position of 3E2 402 ligand, while the second 3E2 403 ligand was removed before grid generation. The optimal conformers of the ligands were docked into the enzyme-cofactor complex by a Glide Docking tool of the Maestro software at standard predefined conditions in an extra precision (XP) mode with flexible ligand sampling, rewarding intramolecular hydrogen bonds and enhancing planarity of conjugated pi groups. Only the best pose for each ligand was recorded.

4 %

 4 figures are deposited in the Supporting information of this paper.

  After 6 h TLC analysis confirmed a presence of a new product without any starting compound. The mixture was cooled down and excess of EtOH evaporated by RVE. Crude product was dissolved in 30 ml of DCM, washed with water (5 x 30 ml) and saturated aq solution of NaHCO3 (3 x 30 ml). Separated organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 85.0 mg (0.31 mmol, 76 %) of ester 2 as an orange solid product. Novelty: ethyl 2-(3-oxo-2,3-dihydro-5H-[1,2,4]triazino[5,6-b]indol-5yl)acetate (2) is described in the literature by its M.P., 1 H-NMR,[START_REF] Hlaváč | Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur / Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity[END_REF] C-NMR, IR, MS and elemental analysis.[START_REF] Hlaváč | Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur / Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity[END_REF] M.p.: 247.0 -253.0 °C [DCM], lit.: 248.0 -252.0 °C [MeOH / DCM]. 13 1 H NMR (300 MHz, DMSO-d6): δ 13.14 (br s, 1H, -NH-), 7.95 (dd, 1H, J(8,9) = 8.0 Hz, J(7,9) = 1.0 Hz, H-C(9)), 7.58 (ddd, 1H, J(6,7) = 8.0 Hz, J(7,8) = 7.3 Hz, J(7,9) = 1.0 Hz, H-C(7)), 7.56 (dd, 1H, J(6,7) = 8.0 Hz, J(6,8) = 1.0 Hz, H-C(6)), 7.34 (ddd, 1H, J(8,9) = 8.0 Hz, (m), 955 (m), 936 (m), 874 (w), 786 (m), 755 (s), 730 (m), 697 (m), 670 (m), 557 (m), 486 (w), 465 (w), 430 (s). MS (ESI m/z): 387.0 (95 %) [M-e -]. Anal. calcd for C21H17N5O3(387.39): C, 65.11; H, 4.42; N, 18.08; Found: C, 64.36; H, 4.49; N, 18.45.

After consumption of starting material 4 (Found

 4 confirmed by TLC analysis) the reaction mixture was cooled down in an ice bath and acidified with 1 M HCl to pH = 3. After 10 min of stirring, formed precipitate was filtered off, washed with ice water and dried under reduce pressure to yield 70.0 mg (0.19 mmol, 75 %) of acid 5 (OTI-7) as a brown solid product. Novelty: 2-[2-(2-cyanobenzyl)-3-oxo-2,3-dihydro-5H-[1,2,4]triazino[5,6-b]indol-5-yl]acetic acid 5 (OTI-7) has not been described in the literature. M.p.: 280.9 -284.5 °C [MeOH / H3O + ]. 314.0 (100 %) [M-CO2-H + ]. Anal. calcd for C19H13N5O3 (359.35): C, 63.51; H, 3.65; N, 19.49 20.0 mg (0.05 mmol, 1.00 mol eq) ester 4 in 1 ml of CF3COOH (TFA) and 0.25 ml of H2SO4 (conc) was stirred at 70 °C for 6 h. After complete consumption of the starting compound 4 (confirmed by a TLC analysis), the reaction was cooled down and 20 ml of H2O and 20 ml of brine added, and the mixture extracted with EA (5 x 15 ml). Combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. A crude product 6 (OTI-8) was purified by trituration with a mixture of Hex / EA to give 15.0 mg (0.04 mmol, 77 %) of acid 6 (OTI-8) as a solid compound. Novelty: 2-[2-(2carbamoylbenzyl)-3-oxo-2,3-dihydro-5H-[1,2,4]triazino[5,6-b]indol-5-yl]acetic acid 6 (OTI-8) has not been described in the literature. M.p.: 221.3 -225.1 °C [EA].1 H-NMR (600 MHz, DMSO-d6): δ 13.10 (br s, 1H, -COOH), 8.00 and 7.53 (2 x br s, 2 x 1H, -ArCONH2), 7.95, 7.58, 7.54 and 7.03 (4 x dd, 4 x 1H, J(6,7 or 8,9 and A3,A4 or A5,A6) = 7.7 or 7.1 Hz, J(6,8 or 7,9 or A3,A5 or A4,A6) = 1.0 Hz, H-C(6, 9, A3 and A6)), 7.62 and 7.38 -7.31 (1 x ddd and m, 1H and 3H, J(7,8 or A4,A5) = 8.0 Hz, J(6,7 or 8,9 or A3,A4 or A5,A6) = 7.7 Hz, J(6,8 or 7,9 or A3,A5 or A4,A6) = 1.0 Hz, H-C(7, 8, A4 and A5)), 5.60 and 4.95 (2 x s, 2 x 2H, -CH2COOH and -CH2Ar). 13 C-NMR (150 MHz, DMSO-d6): 170.

  30.0 mg (0.08 mmol, 1.00 mol eq) of ester 4 in 2 ml of H2SO4 (conc) and 2 ml of H2O was stirred at 100 °C within 8 d. After complete consumption of starting compound 4 and its amidic intermediate (confirmed by a TLC analysis), the reaction was cooled down, 20 ml of H2O added and the resulting mixture extracted with EA (5 x 15 ml). Combined organic layer was dried over Na2SO4, filtered and concentrated to a half of its volume. Then, the solution was placed into a refrigerator, where the product 7 (OTI-9) precipitated. After filtration, crude product was triturated with a mixture of Hex / EA to give 12.0 mg (0.03 mmol, 41 %) of bisacid 7 (OTI-9) as a yellow solid compound. Novelty: 2-{[5- (carboxymethyl)-3-oxo-3,5-dihydro-2H-[1,2,4]triazino[5,6-b]indol-2 yl]methyl}benzoic acid 7 (OTI-9) has not been described in the literature. M.p.: 260 -277 °C (dec) [EA].

  1 H-NMR (600 MHz, DMSO-d6): δ 13.15 (2 x br s, 2 x 1H, 2 x -COOH),7.96, 7.93, 7.58 and 7.00 (4 x dd, 4 x 1H, J(6,7 or 8,9 or A3,A4 or A5,A6) = 7.7 Hz, J(6,8 or 7,9 or A3,A5 or A4,A6) = 1.0 Hz, H-C(6, 9, A3 and A6)), 7.62, 7.48, 7.41 and 7.33 (4 x ddd, 4 x 1H, J(7,8 or A4,A5) = 8.0 Hz, J(6,7 or 8,9 or A3,A4 or A5,A6) = 7.7 Hz, J(6,8 or 7,9 or A3,A5 or A4,A6) = 1.0 Hz, H-C(7, 8, A4 and A5)), 5.74 and 4.95 (2 x s, 2 x 2H, -CH2COOH and -CH2Ar). 13 C-NMR (150 MHz, DMSO-d6): 169.

  21 M.p.: 52.0 -57.7 °C [EA / DCM], lit: 61 -63 °C [EA] 21 . 1 H-NMR (600 MHz, CDCl3): δ 7.38 -7.30 (m, 4H, 2 x H-C(3 and 4)), 4.73 (s, 4H, 2 x -CH2OH), 2.98 (br s, 2H, -CH2OH).

  23 M.p.: 61.0 -63.8 °C [Et2O], lit: 55 °C [hexane]. 22 1 H-NMR (600 MHz, CDCl3): δ 7.43 and 7.39 (2 x dd, 2 x 1H, J(3,4 or 5,6) = 7.5 Hz, J(3,5 or 4,6) = 1.5 Hz, H-C(3 and 6)), 7.35 and 7.31 (2 x ddd, 2 x 1H, J(4,5) = 7.9 Hz, J(3,4 or 5245 mg (1.22 mmol, 1.00 mol eq) of arylmethanol 10 in 20 ml of DCM (abs), 130 µl (1.42 mmol, 1.16 mol eq) of 3,4-dihydro-2H-pyran (DHP) and 30.6 mg (0.12 mmol, 0.10 mol eq) of PPTS (pyridinium p-toulenesulfonate), was stirred under Ar for 30 min at reflux. Subsequent TLC analysis confirmed presence of a new product and traces of two side products. Then, 20 ml of NaHCO3 (sat aq sol) was added and resulting mixture extracted with DCM (3 x 15 ml). Combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 310 mg (1.09 mmol, 89 %) of tetrahydropyran 11 as a colourless oily product. Novelty: 2-{[2-(bromomethyl)benzyl]oxy}tetrahydro-2H-pyran(11)

24

 24

1 H

 1 -NMR (600 MHz, CDCl3): δ 7.42 and 7.39 (2 x dd, 2 x 1H, J(3,4 or 5,6) = 7.4 Hz, J(3,5 or 4,6) = 1.9 Hz, H-C(3 and 6)), 7.32 and 7.30 (2 x ddd, 2 x 1H, J(4,5) = 8.0 Hz, J(3,4 or 5,6) = 7.4 Hz, J(3,5 or 4,6) = 1.9 Hz, H-C(4 and 5)), 4.94 (d, 1H, Jgem =12.3 Hz, -CH2OTHP), 4.74 (dd, 1H, J(A2,A3) = 8.5 Hz, J(A2,A3) = 3.0 Hz, H-CA(2)), 4.68 (d, 1H, Jgem = 10.2 Hz, -(s), 1116 (w), 1087 (w), 1045 (m), 997 (w), 954 (w), 937 (w), 893 (w), 786 (m), 751 (s), 670 (m), 610 (m), 585 (m), 478 (w), 434 (s). MS (ESI m/z): 363.0 (95 %) [M-H + ], 319.1 (95 %) [M-CO2-H + ]. Anal. calcd for C19H16N4O4 (364.36): C, 62.63; H, 4.43; N, 15.38 Found: C, 62.75; H, 4.49; N, 15.55. Animals: Male Wistar rats 8 -9 weeks old, weighing 200 -230 g, were used as organ donors. The animals came from the Breeding Facility of the Institute of Experimental Pharmacology Dobrá Voda (Slovak Republic). The study was approved by the Ethics Committee of the Institute and performed in accordance with the Principles of Laboratory Animal Care (NIH publication 83 -25, revised 1985) and the Slovak law regulating animal experiments (Decree 289, Part 139, July 9 th 2003).

Table 2 .

 2 Physicochemical properties and molecular obesity indices calculated for compounds

	Compound	MW	pKa b	pIC50 LogP a	LogD a LE c	BEI d	LLE e	LELP f	TPSA g
		<500 h			<5 h		>0.3 h	>14.7 h	>3.8 i	<7.5 h	60-140 h
	OTI6	334.33	4.14	6.36	2.04	-0.98	0.36 19.05 4.32	5.72	90.01
	OTI7	359.34	4.14	7.12	1.61	-1.24	0.37 19.83 5.51	4.37	113.8
	OTI8	377.35	4.14	6.63	1.05	-1.25	0.33 17.58 5.57	3.18	133.1
	OTI9	378.34 4.14/4.15* 6.86	1.39	-2.50	0.34 18.14 5.47	4.05	127.31
	OTI10	364.35	4.14	6.61	1.31	-1.53	0.34 18.17 5.30	3.82	110.24

OTI-(6-10).

a Calculated with MedChem Designer™ b Calculated with Pallas 3.112, log D represents the logarithm of the distribution ratio in octanol-buffer [pH 7] c Ligand efficiency, LE = -1.4log(IC 50 )/N, N: number of heavy atoms d Binding efficiency index, BEI = pIC 50 /MW e Lipophilic ligand efficiency, LLE = pIC 50 -logP f Ligand efficiency-dependent lipophilicity, LELP = log P/LE. g Topological polar surface area, TPSA calculated with MedChem Designer™ h Optimal drug values.

15-17 i

Mean value for successful lead. 17 * BnCOOH.

H-NMR (600 MHz, DMSO-d6): δ 13.35 (br s, 1H, -COOH), 7.94, 7.89, 7.59 and 7.43 (4 x dd, 4 x 1H, J(6,7 or 8,9 or A3,A4 or A5,A6) = 8.0 or 7.7 Hz, J(6,8 or 7,9 or A3,A5 or A4,A6) =

Acknowledgements

MH and AB equally contributed to writing of this paper. This research was supported by Biomagi, Ltd. (design of novel OTI inhibitors) and by VEGA 1/0670/18 project (synthesis).

Our gratitude belongs to LK, MSP and MS for biological assays and evaluation of a biological activity supported by VEGA 2/0005/2018. MH, GH contributed to the development of synthesis and AG to analysis of prepared compounds. We are grateful to Mgr. Juraj Filo, PhD., for the measurement of NMR spectra and Bc. Lenka Soboličová for synthesis of intermediates and the inhibitor OTI-7. Finally, we would like to thank bilateral project APVV SK-FR-2015-0014 and COST Action CA15135 MuTaLig for networking and Cotutelle joint PhD French-Slovak program for MH bilateral study.

Appendix A. Supplementary data

Supplementary data associated with this article can be found in the online version, at http://xxx. These data include spectra of compounds described in this article together with predicted poses and interaction analyses for all developed inhibitors. Included are also