Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides As Gpx Mimics

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Article Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides as GPx Mimics

Giancarlo V. Botteselle 1,*, Welman C. Elias 2, Luana Bettanin 2,Rômulo F. S. Canto 3, Drielly N. O. Salin 2, Flavio A. R. Barbosa 2, Sumbal Saba 4 , Hugo Gallardo 2 , Gianluca Ciancaleoni 5 , Josiel B. Domingos 2 , Jamal Raﬁque 6,* and Antonio L. Braga 2,7,*

1 Departamento de Química, Universidade Estadual do Centro-Oeste (UNICENTRO), Guarapuava 85040-167, PR, Brazil 2 Departamento de Química, Universidade Federal de Santa Catarina (UFSC), Florianópolis 88040-970, SC, Brazil; [email protected] (W.C.E.); [email protected] (L.B.); [email protected] (D.N.O.S.); ﬂ[email protected] (F.A.R.B.); [email protected] (H.G.); [email protected] (J.B.D.) 3 Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-170, RS, Brazil; [email protected] 4 Instituto de Química—IQ, Universidade Federal de Goiás—(UFG), Goiânia 74690-900, GO, Brazil; [email protected] 5 Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, I-56124 Pisa, Italy; [email protected] 6 Instituto de Química—INQUI, Universidade Federal do Mato Grosso do Sul (UFMS), Campo Grande 79074-460, MS, Brazil 7 Department of Chemical Sciences, Faculty of Science, University of Johannesburg, Doornfontein 2028, South Africa Citation: Botteselle, G.V.; Elias, W.C.; * Correspondence: [email protected] (G.V.B.); [email protected] (J.R.); Bettanin, L.; Canto, R.F.S.; Salin, [email protected] (A.L.B.) D.N.O.; Barbosa, F.A.R.; Saba, S.; Gallardo, H.; Ciancaleoni, G.; Abstract: Herein, we describe a simple and efﬁcient route to access aniline-derived diselenides and Domingos, J.B.; et al. Catalytic Antioxidant Activity of evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields Bis-Aniline-Derived Diselenides as via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These GPx Mimics. Molecules 2021, 26, 4446. diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard https://doi.org/10.3390/ GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the molecules26154446 electronic properties of the substituents determine the charge delocalization and the partial charge on selenium, which correlate with the catalytic performances. The amino group concurs in the Academic Editor: Luana Bagnoli stabilization of the selenolate intermediate through a hydrogen bond with the selenium.

Received: 23 June 2021 Keywords: organoselenides; GPx; DFT; non-bonding interaction; diselenides; anilines Accepted: 20 July 2021 Published: 23 July 2021

Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional afﬁl- In recent years, there has been an increasing interest in synthetic organoselenium iations. compounds, mainly due to their properties as synthetic intermediates in organic transformations [1–3] and material sciences [4,5], as well as in medicinal chemistry [6–9]. These compounds have been recently described as good antioxidants [10,11], also pre- senting anti-inﬂammatory [12,13], antibacterial [14], antiviral [15], anticancer [16–19], anti-Alzheimer’s [20–23] and other activities [24–28]. Furthermore, in relation to the Copyright: © 2021 by the authors. current pandemic of COVID-19, there are some interesting studies available that demon- Licensee MDPI, Basel, Switzerland. strate the effectiveness of organoselenium compound (Ebselen) as an antiviral molecule, This article is an open access article distributed under the terms and Figure1[29–31]. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Molecules 2021, 26, 4446. https://doi.org/10.3390/molecules26154446 https://www.mdpi.com/journal/molecules MoleculesMolecules 20212021,, 2626,, 4446xx FORFOR PEERPEER REVIEWREVIEW 22 of of 10 1110

FigureFigure 1. 1. Ebselen.Ebselen.

AmongAmong organoseleniumorganoselenium organoselenium compounds,compounds, compounds, diorganyldiorganyl diorganyl diselenidesdiselenides diselenides presentpresent present importantimportant important antiox-antiox- an- idanttioxidantidant andand andanticanceranticancer anticancer propertiesproperties properties mainlymainly mainly becausebecause because ofof thethe of abilityability the ability ofof thesethese of thesediselenidesdiselenides diselenides toto actact as toas mimeticsactmimetics as mimetics ofof thethe enzymeenzyme of the enzyme glutathioneglutathione glutathione peroxidaseperoxidase peroxidase (GPx)(GPx) [6,8,11][6,8,11] (GPx).. ThisThis [6,8 , selenoenzyme11selenoenzyme]. This selenoenzyme possessespossesses apossessesa residueresidue ofof a selenocysteine residueselenocysteine of selenocysteine inin itsits activeactive in sitesite its andand active isis rere sitesponsiblesponsible and is for responsiblefor thethe reductionreduction for the ofof reductionperoxidesperoxides toofto waterwater peroxides inin ourour to organism,organism, water in protectingprotecting our organism, itit fromfrom protecting oxidativeoxidative it stressstress from andand oxidative relatedrelated diseases stressdiseases and [32][32] related.. diseasesNotableNotable [32]. amongamong thethe polyfunctionalizedpolyfunctionalized diselenidesdiselenides,, thethe presencepresence ofof anan aminoamino oror car-car- bonylbonylNotable groupgroup inin among closeclose the proximityproximity polyfunctionalized toto thethe seleniumselenium diselenides, moietymoiety hashas the presencesomesome uniqueunique of an biologicalbiological amino or fea-fea- car- turesbonyltures duedue group toto nonnon in close--bondingbonding proximity interactionsinteractions to the selenium [33[33––3535]].. For moietyFor example,example, has some thethe uniquebisbis--22--anilineaniline biological diselenidediselenide features isis due to non-bonding interactions [33–35]. For example, the bis-2-aniline diselenide is re- reportedreported toto bebe aa goodgood antioxidant,antioxidant, preventingpreventing thethe oxidativeoxidative stressstress causedcaused byby peroxynitriteperoxynitrite ported to be a good antioxidant, preventing the oxidative stress caused by peroxynitrite andand hydroperoxideshydroperoxides [36[36––3838].]. Moreover,Moreover, thethe anilineaniline--derivedderived diselenides,diselenides, mainlymainly withwith anan and hydroperoxides [36–38]. Moreover, the aniline-derived diselenides, mainly with an aminoamino groupgroup inin thethe orthoortho position,position, givegive thesethese compoundscompounds twotwo possiblepossible reactivereactive centers,centers, amino group in the ortho position, give these compounds two possible reactive centers, SeSe--SeSe bondbond cleavagecleavage andand thethe unsharedunshared pairpair ofof electronselectrons onon thethe nitrogen.nitrogen. ThisThis makesmakes thisthis Se-Se bond cleavage and the unshared pair of electrons on the nitrogen. This makes this classclass ofof compocompoundsunds extremelyextremely flexibleflexible inin functionalfunctional groupgroup interconversions,interconversions, makingmaking itit ap-ap- class of compounds extremely flexible in functional group interconversions, making it propriatepropriate forfor severalseveral transformations,transformations, mainlymainly inin thethe formationformation ofof seleniumselenium--containingcontaining het-het- appropriate for several transformations, mainly in the formation of selenium-containing erocycles,erocycles, suchsuch asas selenamidesselenamides [[3939],], benzoselenazinesbenzoselenazines [4[400],], benzoselenazolesbenzoselenazoles [4[411]] andand tri-tri- heterocycles, such as selenamides [39], benzoselenazines [40], benzoselenazoles [41] and azolazolee diselenidesdiselenides [4[422].]. triazole diselenides [42]. Recently,Recently, wewe reportedreported aa newnew robustrobust methodologymethodology forfor thethe synthesissynthesis ofof oo--anilineaniline--de-de- Recently, we reported a new robust methodology for the synthesis of o-aniline-derived rivedrived diselenidesdiselenides fromfrom thethe reductionreduction ofof oo--nitrobenzenenitrobenzene diselenides.diselenides. AsAs partpart ofof ourour widerwider diselenides from the reduction of o-nitrobenzene diselenides. As part of our wider research research program aimed at efficient methodologies for the synthesis of organoselenium researchprogram program aimed at efficientaimed at methodologies efficient methodologies for the synthesis for the of synthesis organoselenium of organoselenium compounds compoundsandcompounds their biological andand theirtheir evaluation biologicalbiological evaluationevaluation [43–50], herein, [43[43––5050 we],], herein,herein, report wewe the reportreport application thethe applicationapplication of o-aniline- ofof oo-- anilinederivedaniline--derivedderived diselenides diselenidesdiselenides as potential asas potentialpotential GPx mimics. GPxGPx mimicsmimics For this.. For purpose,For thisthis purpose,purpose, different differentdifferent physical-chemical physicalphysical-- chemicalstudieschemical were studiesstudies performed werewere performedperformed to demonstrate toto demonstratedemonstrate their biological theirtheir biolbiol properties,ogicalogical propertiesproperties i.e., kinetic,, i.e.,i.e., profile.kinetickinetic profileFurthermore,profile.. Furthermore,Furthermore, DFT studies DFTDFT were studistudi alsoeses werewere carried alsoalso out carriedcarried in order outout to inin study orderorder the toto electronicstudystudy thethe propertieselectronicelectronic propertiesofproperties the substituents ofof thethe substituentssubstituents for determining forfor determindetermin the chargeinging delocalization thethe chargecharge delocalizationdelocalization on the selenium onon thethe atom seleniumselenium and its atominfluenceatom andand onitsits influence catalyticinfluence performance. onon catalyticcatalytic performance.performance.

2.2. ResultsResults andand DiscussionDiscussion TTheThehe bis bis-bis--oo--nitrobenzene-nitrobenzenenitrobenzene diselenides were initially initially prepared prepared throughthrough thethe nucleophilicnucleophilic aromaticaromatic substitutionsubstitutionsubstitution of ofofo o-halonitrobenzeneso--halonitrobenzeneshalonitrobenzenes with withwith K 2KKSe22SeSe2 (generated22 (generated(generated in inin situ) situsitu from)) fromfrom a modiﬁed aa modi-modi- fiedsimplefied simplesimple methodology methodologymethodology [51]. [51][51] After.. AfterAfter this, this,this, we carriedwewe ccarriedarried out theoutout reductionthethe reductionreduction of bis- ofof obisbis-nitrobenzene--oo--nitroben-nitroben- zenediselenideszene diselenidesdiselenides from fromfrom a well-established aa wellwell--establishedestablished procedure procedureprocedure described describeddescribed in the inin literature thethe literatureliterature [52] using [52][52] usingusing low- lowcostlow--cost ironcost sulfate iron iron sulfate sulfate heptahydrate heptahydrate heptahydrate (FeSO4 .7H (FeSO (FeSO2O)4 to4.7H.7H synthesize22O)O) to to synthesize synthesize the aniline-derived the the aniline aniline diselenides--derivedderived diselenides(Schemediselenides1). (Scheme(Scheme 1).1).

SchemeScheme 1. 1. ReactionReactionReaction conditions:conditions: conditions: (i)(i) (i) SeSe Se (3.0(3.0 (3.0 mmol),mmol), mmol), KOHKOH KOH (6.0(6.0 (6.0 mmol),mmol), mmol), heatedheated heated untiluntil until meltedmelted melted forfor 55 for minmin 5 and minand HH and22OO (6.0 H(6.02O mL);mL); (6.0 (ii)(ii) mL); oo-- (ii)halonitrobenzenehalonitrobenzeneo-halonitrobenzene 1a1a––ff (1.51a(1.5–f mmol)mmol)(1.5 mmol) andand THFTHF and THForor DMFDMF or DMF (1.5(1.5 mL),mL), (1.5 mL),r.t.,r.t., 22 r.t., h;h; (iii)(iii) 2 h; bisbis (iii)--nitrobenzenenitrobenzenebis-nitrobenzene diselenidediselenide diselenide 2a2a––ee 2a (1.5(1.5–e mmol)mmol)(1.5 mmol) andand FeSOFeSO44.7H.7H22OO (5.0(5.0 eq),eq), methanolmethanol (25.0(25.0 mL)mL) andand HH22OO (25.0(25.0 mL),mL), reflux,reflux, 11 h.h. NHNH44OHOH (15.0(15.0 mL),mL), reflux,reflux, 1010 min.min. and FeSO4.7H2O (5.0 eq), methanol (25.0 mL) and H2O (25.0 mL), reﬂux, 1 h. NH4OH (15.0 mL), reﬂux, 10 min.

Molecules 2021 26 MoleculesMolecules 2021 2021, ,,26 26, ,,x x 4446 FOR FOR PEER PEER REVIEW REVIEW 333 of of of 10 10 11

TheTheThe anilineaniline aniline-derived--derivedderived diselenidesdiselenides diselenides 3a3a3a–e––ee werewerewere evaluatedevaluated withwith regardregard toto GPxGPx GPx-like--likelike antiox- antioxi-antiox- idantidantdant activity. activity. activity. The The The catalytic catalytic catalytic parameters parameters parameters were were were obtained ob obtainedtained using using using the Tomoda the the Tomoda Tomoda [53] reaction [5 [533]] reaction reaction model, model,model,where thewherewhere synthesized thethe synthesizedsynthesized diselenides diselenidesdiselenides were applied werewere applied asapplied catalysts asas catalystscatalysts in the formation inin thethe formationformation of diphenyl ofof diphenyldiphenyldisulﬁde disulfidedisulfide (PhSSPh) (PhSSPh)(PhSSPh) through the throughthrough reduction thethe reduction ofreduction hydrogen ofof peroxidehydrogenhydrogen (H peroxideperoxide2O2) in the (H(H presence22OO22)) inin thethe of presencepresencethiophenol ofof thiophenol (PhSH),thiophenol which (PhSH),(PhSH), is accompanied whichwhich isis accompaccomp by an increaseaniedanied byby in anan UV/vis increaseincrease absorbance inin UV/UV/vvisis in absorb-absorb- 305 nm anceance(Figure inin 3052305a). nm Then,nm (Figure(Figure the absorbance 22a)a).. Then,Then, was thethe absorbance plottedabsorbance against waswas diphenyl plottedplotted againstagainst disulﬁde diphenyldiphenyl concentration disulfidedisulfide to concentrationconcentrationdetermine the toto molar determinedetermine absorptivity thethe molarmolar at 305 absorptivityabsorptivity nm (Figure atat2 305b).305 nmnm (Figure(Figure 22b).b).

FigureFigureFigure 22.. 2. ((aa)) UVUV(a)--VisVis UV-Vis spectrumspectrum spectrum ofof PhSHPhSH of oxidationoxidation PhSH oxidation inin thethe presencepresence in the ofof H presenceH22OO22 andand diselenidediselenide of H2O2 3b3band asas catalyst. diselenidecatalyst. [PhSH][PhSH]3b as == 1010 catalyst. mmolmmol −1 −1−1 −1 −1 −1 ◦ LL[PhSH]−1,, [ [3b3b]] = == 0 0 10..0101 mmol mmol mmol L L L−1 ,[and and3b ][H [H =22O 0.01O22]] = = mmol15 15 mmol mmol L L L−1and,, in in methanol [Hmethanol2O2] = at 15at 25 25 mmol ° °C;C; ( (bb L)) Absorbance Absorbance, in methanol plotted plotted at 25 against againstC; (b diphenyl )diphenyl Absorbance disulfide disulfide plot- concentration.concentration.ted against diphenyl TheThe redred disulfide lineline representsrepresents concentration. thethe linearlinear The fit.fit. red TheThe line coefficientcoefficient represents ofof molar themolar linear absorptivityabsorptivity fit. The coefficient inin 305305 nmnm of waswas molar 14151415 absorptivity LL molmol−1−1 cmcm−1 in−1 2 (R(R3052 == nm0.9996).0.9996). was 1415 L mol−1 cm−1 (R2 = 0.9996).

TheTheThe catalyticcatalytic catalytic parametersparameters parameters werewere were obtainedobtained obtained byby by fittingfitting ﬁtting thethe the kinetickinetic kinetic profiles,profiles, proﬁles, thatthat that is,is, is, initialinitial rateraterate versusversus versus initialinitial initial PhSHPhSH PhSH concentration,concentration, concentration, asas as showshow shownnn inin in FigureFigure Figure 33 forforfor diselenidediselenide 3b3b3b (for(for(for otherother other compoundscompoundscompounds,,, seesee see FiguresFigures Figures S31S31 S31–S38,––S38S38,, Pg.Pg. Pg. S22S22- S22–S25-2525 inin SSupplementaryupplementary in Supplementary MaterialsMaterials Materials),),), withwith thethe with Mich-Mich- the aelisaelisMichaelis–Menten––MentenMenten equationequation equation ((EqEquationuation (Equation ((11))).). (1)).

Figure 3. Initial rate (V ) plotted against substrate concentration. The initial rates were calculated FigureFigure 3 3.. Initial Initial rate rate (V (V00)) plotted 0plotted against against substrate substrate concentration. concentration. The The initial initial rates rates were were calculated calculated from from atatfrom least least at two two least experiments experiments two experiments for for each each forconcentration concentration each concentration of of PhSH. PhSH. ofThe The PhSH. concentrations concentrations The concentrations of of 3b 3b and and H H of22OO3b22 were wereand fixed Hfixed2O2 −5 −3 −1 atatwere 11 ×× 11 ﬁxed00−5−5 andand at 1 155 × ×× 110100−3−3 molmoland LL−1 15−1,, respectively.respectively.× 10 mol TheLThe , redred respectively. lineline representsrepresents The red thethe MichaelislineMichaelis represents––MentenMenten the fit. Michaelis–fit. Menten ﬁt. TableTable 11 showsshows thethe catalyticcatalytic constantconstant ((kkcatcat),), thethe MichaelisMichaelis––MentenMenten constantconstant ((KKmm)) andand thethe catalytic catalytic efficiency efficiency ( (ηη wherewhere ηη == kkcatcat//KKmm)) for for the the reaction reaction with with the the aniline aniline--derivedderived

Molecules 2021, 26, x FOR PEER REVIEW 4 of 11

Molecules 2021, 26, x FOR PEER REVIEW 4 of 11 diselenides 3a to 3e and, for comparison, the well-known catalysts ebselen [35] and diphenyl diselenide [53].

Molecules 2021, 26, x FOR PEER REVIEWTable 1. GPx-like catalytic evaluation of aniline-derived diselenides 3a-e. 4 of 11 diselenides 3a to 3e and, for comparison, the well-known catalysts ebselen [35] and diphenyl diselenide [53].

Tablediselenides 1. GPx -3alike to catalytic 3e and, evaluationfor comparison, of aniline the-derived well-known diselenides catalysts 3a-e. ebselen [35] and diphe- Molecules 2021, 26, x FOR PEER REVIEW 4 of 11 Molecules 2021, 26, 4446 nyl diselenide [53]. 4 of 11

Entry Catalyst (1 × 10−5 mol L−1) Km (mol L−1) kcat (min−1) η (L mol−1 min−1) Table 1. GPx-like catalytic evaluation of aniline-derived diselenides 3a-e. diselenides 3a to 3e and, for comparison, the well- known catalysts ebselen [35] and diphenyl diselenideTable1 shows [53]. the catalytic constant ( kcat), the Michaelis–Menten constant (Km) and −5 −1 −1 −1 −1 −1 the catalyticEntry Catalyst efﬁciency (1 (×η 1where0 molη L= k)cat /KKmm ()mol for theL ) reactionkcat with (min the) aniline-derivedη (L mol dise-min ) lenides 3a to 3e and, for comparison, the well-known catalysts ebselen [35] and diphenyl Table 1. 1GPx -like catalytic evaluation of aniline0.00170-derived diselenides 3a0.422-e. 248.65 diselenide [53]. −5 −1 −1 −1 −1 −1 Entry Catalyst (1 × 10 mol L ) Km (mol L ) kcat (min ) η (L mol min ) Table 1. GPx-like catalytic evaluation of aniline-derived diselenides 3a–e. 1 0.00170 0.422 248.65

Entry Catalyst (1 × 10−5 mol L−1) Km (mol L−1) kcat (min−1) η (L mol−1 min−1)

1 0.00170 0.422 248.65

Entry Catalyst (1 × 10−5 mol L−1) Km (mol L−1) kcat (min−1) η (L mol−1 min−1) 2 0.00114 0.601 527.78 −5 −1 −1 −1 −1 −1 Entry1 Catalyst (1 × 10 mol L ) K0.00170m (mol L ) kcat 0.422(min ) η (L mol248.65min )

Entry Catalyst2 (1 × 10−5 mol L−1) Km (mol0.00114 L−1) kcat (min0.601−1) η (L mol−1 527.78min−1) 1 1 0.001700.00170 0.4220.422 248.65248.65

2 0.00114 0.601 527.78 3 0.00134 0.446 333.40 1 0.00170 0.422 248.65

2 2 0.001140.00114 0.601 527.78527.78

3 0.00134 0.446 333.40

2 0.00114 0.601 527.78

3 3 0.001340.00134 0.4460.446 333.40333.40 4 0.00105 1.185 1128.57

Molecules 2021, 26, x FOR PEER REVIEW2 0.00114 0.601 527.78 5 of 11 3 0.00134 0.446 333.40 4 4 0.001050.00105 1.1851.185 1128.571128.57

Molecules 2021, 26, x FOR PEER REVIEW 5 of 11 3 0.00134 0.446 333.40 5 54 0.001870.001050.00187 0.4700.4701.185 251.511128.57251.51

3 4 0.001340.00105 0.4461.185 333.401128.57 6 5 0.001870.00081 0.4050.470 500.11251.51 6 0.00081 0.405 500.11

4 0.00105 1.185 1128.57 7 5 0.001870.00088 0.9180.470 1044.19251.51 7 0.00088 0.918 1044.19 6 0.00081 0.405 500.11

4 57 0.001050.001870.00088 1.1850.4700.918 1128.571044.19251.51 6 0.00081 0.405 500.11 The results show that the catalytic efﬁciency of the aniline-derived diselenides is structure-dependent,The results show especially that the regarding catalytic the efficiency electronic of character the aniline of- thederived substituents diselenides at is

the parastructure5 position-dependent, related toespecially selenium, regarding with0.00187 an increase the electronic in the 0.470 catalyticcharacter efﬁciency of the substituents251.51 withthe at the6 para position related to selenium, 0.00081with an increase in0.405 the catalytic efficiency500.11 with the electron-withdrawal capacity of the substituent (compound 3b), once cleavage of the Se-Se bondelectron is facilitated.The- withdrawal results These show capacity results that the suggest of catalyticthe substituent that efficiencythe mechanism (compound of the of aniline these3b), once catalyzed-derived cleavage diselenides reactions of the Se is-

involvesSestructure bond the formationis-dependent, facilitated. of a especiallyThese zwitterionic results regarding form suggest of thethe that selenolateelectronic the mechanism intermediatecharacter of ofthese withthe catalyzedsubstituents a negative reac- at 5 0.00187 0.470 251.51 densitytionsthe6 para charge involves position in the related formation selenium to selenium, atomof a zwitterionic (Scheme 0.00081with an2a), increaseform which of thein is0.405 the similarselenolate catalytic to theintermediate efficiency mechanism500.11 with with the a proposednegativeelectron by- withdrawal Tomodadensity charge et al. capacity [ 53in ]. the ofselenium the substituent atom (Scheme (compound 2a), w 3bhich), once is similar cleavage to the of mecha-the Se- nism proposed by Tomoda et al. [53]. Se bond is facilitated. These results suggest that the mechanism of these catalyzed reac- tionsThe involves structures the formation 3a–3e have of been a zwitterionic optimized form by Density of the Functionalselenolate intermediateTheory (DFT) with at the a 6 0.00081 0.405 500.11 BP86negative-D3/def2 density-TZVP charge level in of the theory, selenium using atom the (Schemezero-order 2a), regular which approximationis similar to the (ZORA) mecha- to take the relativistic effects into account. In all the optimized geometries (except 3b), an nism proposed by Tomoda et al. [53]. intramolecularThe structures hydrogen 3a–3e have bond been (HB) optimized exists between by Density the twoFunctional amine Theory moieties, (DFT) with at dis-the tancesBP86-D3/def2 that range-TZVP from level 2.624 of (theory,3d) to 3.139 using ( 3athe) Å zero . In -theorder case regular of 3b, approximationthe electron-withdraw- (ZORA) ingto take -CF the3 gro relativistiup likelyc makeseffects theinto lone account. pair of In the all nitrogenthe optimized less available geometries for (exceptHBs. The 3b elec-), an tronicintramolecular effect of hydrogen the group bond in the (HB) para existsposition between influences the two all theamine atomic moieties, charges with of dis- the diselenidetances that system.range from Indeed, 2.624 the (3d atomic) to 3.139 charges (3a) Å have . In the been case computed of 3b, the through electron the-withdraw- Natural Popuing -CFlation3 gro Analysisup likely (see makes Computational the lone pair Details) of the nitrogen as implemented less available in NBO for 6.0HBs., and The for elec- the selenium,tronic effect it ranges of the from group 0.063 in theto 0.123 para eposition for 3c (the influences most electron all the-donating atomic chargesgroup) and of the3b (thediselenide most electsystem.ron -Indeed,withdrawing the atomic one), chargesrespectively. have beenThe atomiccomputed charge through on the the seleni Naturalum qualitativelyPopulation Analysis correlates (see with Computational η, according Details)to which as the implemented best catalysts in haveNBO a 6.0 more, and positive for the chargeselenium, on itthe ranges selenium from and 0.063 a lessto 0.123 negative e for charge3c (the moston the electron nitrogen-donating (Figure group)4 and Supple- and 3b mentary(the most Materials electron).-withdrawing In addition, a one), similar respectively. correlation Thecan beatomic observed charge between on the the seleni atomicum chargequalitatively of the correlatesammonium with-selenolate η, according and ηto: inwhich this case,the best the catalystsbest catalysts have havea more a less positive neg- ativecharge charge on the on selenium the selenium, and a leading less negative to a larger charge degree on the of nitrogencharge delocalization (Figure 4 and and, Supple- consequently,mentary Materials a more stable). In addition, intermediate a similar. This correlation is in agreemen can bet with observed the mechanism between the proposed atomic bycharge Tomoda of the [53]. ammonium Furthermore,-selenolate the h andydrogen η: in thisbonding case, betweenthe best catalyststhe ammonium have a less protons neg- andative the charge seleno onlate the moiety selenium, is quite leading strong to aand larger stabilizes degree the of chargeintermediate delocalization, having anand, orbital con- interactionsequently, a ofmore 8–9 stable kcal/mol intermediate depending. This on is thein agreemen substituetnt with (Supplementary the mechanism Materials proposed), henby Tomodace making [53]. the Furthermore, catalyst more tactivehe hy.drogen bonding between the ammonium protons and the selenolate moiety is quite strong and stabilizes the intermediate, having an orbital interaction of 8–9 kcal/mol depending on the substituent (Supplementary Materials), hence making the catalyst more active.

Molecules 2021, 26, x FOR PEER REVIEW 6 of 10

Molecules 2021, 26, 4446 5 of 11 groups at the ortho position, reflected in their lower catalytic efficiency when compared with the diphenyl diselenide (Table 1, entries 3 and 2, respectively).

Scheme 2. Reactive intermediates: ( a) selenolate (a (a–e)–e) and ( b) selenyl sulfide. sulﬁde.

OfThe the structures aniline-derived3a–e have diselenides been optimized, the highest by Density catalytic Functional efficiency Theory was observed (DFT) at thefor compoundBP86-D3/def2-TZVP 3b (Table 1, level entry of theory,4), which using was the 5 and zero-order 2 times regularmore active approximation than the standards (ZORA) ebselento take theand relativistic diphenyl effectsdiselenide, into account.respectively. In all I thet is optimizedworth noting geometries that the (except diselenide3b), an3b wasintramolecular more effective hydrogen than ebse bondlen (HB), which exists is betweena pre-clinical the two drug amine candidate moieties, with with pronounced distances biologicalthat range activities from 2.624, includ (3d)ing to, 3.139 recently, (3a) Å.the In inhibition the case of of protease3b, the electron-withdrawing Mpro from COVID-19 -CF(SARS3 group-CoV- likely2) virus makes [29–31 the]. lone pair of the nitrogen less available for HBs. The elec- tronicDue effect to the of thehigh group antioxidant in the paraactivityposition of the inﬂuences diselenide all 3b the as atomica mimetic charges of GPx of, thewe decideddiselenide to system.investigate Indeed, the effectiveness the atomic charges of this havemethodology been computed at the gram through scale. the Thus, Natural we performedPopulation the Analysis reaction (see from Computational 20.0 mmol (5.40 Details) g) of the as o implemented-halonitrobenzene in NBO 1c to 6.0, afford and the for 3c desiredthe selenium, nitro-diselenide it ranges from2b, followed 0.063 to by 0.123 its reduction e for (the to obtain most the electron-donating bis-aniline-derived group) 3b and 3b (the most electron-withdrawing one), respectively. The atomic charge on the se- without a significant decrease in the yields (Scheme 3), proving that this protocol could lenium qualitatively correlates with η, according to which the best catalysts have a more be used as a robust method in the larger-scale synthesis of this privileged structure. positive charge on the selenium and a less negative charge on the nitrogen (Figure4 and Supplementary Materials). In addition, a similar correlation can be observed between the atomic charge of the ammonium-selenolate and η: in this case, the best catalysts have a less negative charge on the selenium, leading to a larger degree of charge delocalization and, consequently, a more stable intermediate. This is in agreement with the mechanism proposed by Tomoda [53]. Furthermore, the hydrogen bonding between the ammonium protons and the selenolate moiety is quite strong and stabilizes the intermediate, having an orbital interaction of 8–9 kcal/mol depending on the substituent (Supplementary

Materials), hence making the catalyst more active. Scheme 3. GramTomoda-scale reaction et al. [53 for] alsothe synthesis proposed of aniline that another-derived reactivediselenide intermediate 3b. is formed in the initial step from the reaction of the diselenide with PhSH, that is, the selenyl sulfide (Scheme3. Materials2b). and In the Methods case of the aniline-derived diselenides, it seems that the formation 3of.1. this GPx intermediate-Like Experimental is destabilized Procedureby the inductive electron donor capacity of the amine groupsThe at kinetic the ortho profile position, of the reflectedoxidation in reaction their lower was catalyticconducted efficiency in a UV when-vis Spectropho- compared withtometer, the diphenylfollowing diselenide the wavelength (Table1 of, entries diphenyl 3 and disulfide 2, respectively). formation at 305 nm. Spectro- scopicOf methanol the aniline-derived was used as diselenides, solvent in thethe highestoxidation catalytic reaction efficiency, and the was final observed volume for of cuvettescompound was3b kept(Table at 12000, entry µL. 4), The which H2O was2 and 5 catalyst and 2 times concentration more active were than fixed the in standards 15 × 10−3 mol.Lebselen−1 and and 1 diphenyl × 10−5 mol.L diselenide,−1 respectively, respectively. and the ItPhSH is worth concentration noting that was the varied diselenide from 0.3b5 was× 10−3 more to 15 effective × 10−3 mol than L−1 ebselen,. The temperature which is a pre-clinicalwas kept at drug 25 °C candidate, and each with experiment pronounced was pro runbiological at least activities, 2 times. including, recently, the inhibition of protease M from COVID-19 (SARS-CoV-2) virus [29–31]. 3.2. MichaelisDue to the–Menten high Equation antioxidant activity of the diselenide 3b as a mimetic of GPx, we decided to investigate the effectiveness of this methodology at the gram scale. Thus, we The GPx-like kinetic profiles were treated using the Michaelis–Menten nonlinear performed the reaction from 20.0 mmol (5.40 g) of the o-halonitrobenzene 1c to afford the Equation (1): desired nitro-diselenide 2b, followed by its reduction to obtain the bis-aniline-derived 3b without a significant decrease in the yields (Scheme3), proving that this protocol could be kcat[cat][PhSH] used as a robust method in the larger-scaleV  synthesis of this privileged structure. (1) (K  [PhSH]) m

where the V0 was the initial velocity and kcat and Km were the catalytic rate constant and Michaelis–Menten constant, respectively. The [cat] and [PhSH] represent the concentration of the catalyst and thiophenol, respectively.

Molecules 2021, 26, x FOR PEER REVIEW 5 of 10

intramolecular hydrogen bond (HB) exists between the two amine moieties, with distances that range from 2.624 (3d) to 3.139 (3a) Å . In the case of 3b, the electron-withdrawing -CF3 group likely makes the lone pair of the nitrogen less available for HBs. The electronic effect of the group in the para position influences all the atomic charges of the diselenide system. Indeed, the atomic charges have been computed through the Natural Population Analysis (see Computational Details) as implemented in NBO 6.0, and for the selenium, it ranges from 0.063 to 0.123 e for 3c (the most electron-donating group) and 3b (the most electron-withdrawing one), respectively. The atomic charge on the selenium qualitatively correlates with η, according to which the best catalysts have a more positive charge on the selenium and a less negative charge on the nitrogen (Figure 4 and Supple- mentary Materials). In addition, a similar correlation can be observed between the atomic charge of the ammonium-selenolate and η: in this case, the best catalysts have a less negative charge on the selenium, leading to a larger degree of charge delocalization and, consequently, a more stable intermediate. This is in agreement with the mechanism proposed by Tomoda [53]. Furthermore, the hydrogen bonding between the ammonium protons and the selenolate moiety is quite strong and stabilizes the intermediate, having an orbital Molecules 2021, 26, 4446 6 of 11 interaction of 8–9 kcal/mol depending on the substituent (Supplementary Materials), hence making the catalyst more active.

Molecules 2021, 26, x FOR PEER REVIEW 6 of 10

groups at the ortho position, reflected in their lower catalytic efficiency when compared with the diphenyl diselenide (Table 1, entries 3 and 2, respectively).

Scheme 2. Reactive intermediates: (a) selenolate (a–e) and (b) selenyl sulfide.

Of the aniline-derived diselenides, the highest catalytic efficiency was observed for compound 3b (Table 1, entry 4), which was 5 and 2 times more active than the standards ebselen and diphenyl diselenide, respectively. It is worth noting that the diselenide 3b was more effective than ebselen, which is a pre-clinical drug candidate with pronounced biological activities, including, recently, the inhibition of protease Mpro from COVID-19 (SARS-CoV-2) virus [29–31]. Due to the high antioxidant activity of the diselenide 3b as a mimetic of GPx, we decided to investigate the effectiveness of this methodology at the gram scale. Thus, we performed the reaction from 20.0 mmol (5.40 g) of the o-halonitrobenzene 1c to afford the desired nitro-diselenide 2b, followed by its reduction to obtain the bis-aniline- derived 3b Figure 4 4.. Catalytic efﬁciencyefficiencywithout ((ηη)) plottedplotted a significant againstagainst calculated calculated decrease atomic atomic in the charges charges yields for for ((Schemea )(a N) N atom atom 3 (q), N (provingq)N of) of aniline-derived aniline that-derived this diselenides,protocol diseleni- could des,(b) Se (b atom) Se atom (qSe) ( ofqSe aniline-derived) of anilinebe -usedderived diselenides, as diselenides,a robust and method and (c) Se (c atom)in Se the atom (q largerSe )(q ofSe) aniline-derived -ofscale aniline synthesis-derived selenolates. of selenolates. this privileged structure.

Tomoda et al. [53] also proposed that another reactive intermediate is formed in the initial step from the reaction of the diselenide with PhSH, that is, the selenyl sulfide (Scheme 2b). In the case of the aniline-derived diselenides, it seems that the formation of this intermediate is destabilized by the inductive electron donor capacity of the amine

Scheme 3. Gram-scale reaction for the synthesis of aniline-derived diselenide 3b. Gram-scale reaction for the synthesis of aniline-derived diselenide .

33.. Materials Materials and and Methods Methods 33.1..1. GPx GPx-Like-Like Experimental Experimental Procedure Procedure TheThe kinetic kinetic profile profile of of the the oxidation oxidation reaction reaction was was conducted conducted in in a a UV UV-vis-vis Spectropho- Spectropho- tometer,tometer, followingfollowing thethe wavelength wavelength of of diphenyl diphenyl disulfide disulfide formation formation at 305 at nm.305 Spectroscopicnm. Spectro- scopicmethanol methanol was used was as used solvent as solvent in the oxidation in the oxidation reaction, reaction and the, and final the volume final ofvolume cuvettes of −3 −1 cuvetteswas kept was at 2000 keptµ L.at The2000 H µL.2O 2Theand H catalyst2O2 and concentration catalyst concentration were fixed were in 15 fixed× 10 in 1mol5 × 1 L0−3 mol.Land 1 −1× and10− 15 mol× 10−5 L −mol.L1 respectively,−1 respectively, and the and PhSH the concentrationPhSH concentration was varied was fromvaried0.5 from× 10 0.−53 − − ◦ ×to 1 150−3 ×to10 15 3× mol10−3 Lmol1. L The−1. The temperature temperature was keptwas kept at 25 atC, 25 and °C, each and experimenteach experiment was run was at runleast at 2 least times. 2 times.

33.2..2. Michaelis Michaelis–Menten–Menten Equation Equation TheThe GPx GPx-like-like kinetic kinetic profiles proﬁles were treated using the Michaelis–MentenMichaelis–Menten nonlinear EquationEquation ( (1):1): k [cat][PhSH] V = cat (1) ( + [ ]) kcatKm[catPhSH][PhSH] V  (1) (K  [PhSH]) m

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3.3. Computational Details All geometries were optimized with ORCA 4.1.0, [54] using the BP86 functional in conjunction with a triple-ζ quality basis set (ZORA-TZVP) and def2/J auxiliary basis. For heavy elements (such as selenium and bromine), relativistic effects have been accounted by using the Zeroth Order Regular Approximation (ZORA) scalar correction. The dispersion corrections were introduced using the Grimme D3-parametrized correction and the Becke−Johnson damping to the DFT energy [55]. All the diselenide structures were conﬁrmed to be local energy minima (no imaginary frequencies). Selenolate species show an unavoidable imaginary frequency correlated with the rotation of the -NH3 moiety. The atomic charges have been computed by the Natural Population Analysis (NPA) as implemented in NBO6 [56].

4. Conclusions In conclusion, we have developed a short and robust synthetic route for the synthesis of nitro aryl and aniline-derived diselenides in good overall yields. The aniline-derived diselenides were evaluated as GPx mimetics and the diselenide 3b substituted with the CF3 group showed the best results, being 5 and 2 times more effective as a GPx mimetic than the standard catalysts ebselen and diphenyl diselenide, respectively. Furthermore, DFT analysis was performed for all the diselenides, which demonstrated non-bonding interaction. This correlates with the GPx activities of these diselenides.

Supplementary Materials: The following are available online, 1H, and 13C NMR spectra of the 1 synthesized compounds (3a–e). Figure S1: H NMR (200 MHz, CDCl3) Spectrum of compound 2a. 13 Figure S2: C NMR (50 MHz, CDCl3) Spectrum of compound 2a. Figure S3: HRMS spectrum of 1 13 compound 2a. Figure S4: H NMR (200 MHz, CDCl3) Spectrum of compound 2b. Figure S5: C NMR (50 MHz, CDCl3) Spectrum of compound 2b. Figure S6: HRMS spectrum of compound 2b. 1 13 Figure S7: H NMR (200 MHz, CDCl3) Spectrum of compound 2c. Figure S8: C NMR (50 MHz, 1 CDCl3) Spectrum of compound 2c. Figure S9: HRMS spectrum of compound 2c. Figure S10: H NMR 13 (200 MHz, CDCl3) Spectrum of compound 2d. Figure S11: C NMR (50 MHz, CDCl3) Spectrum of compound 2d. Figure S12: HRMS spectrum of compound 2d. Figure S13: 1H NMR (200 MHz, 13 CDCl3) Spectrum of compound 2e. Figure S14: C NMR (50 MHz, CDCl3) Spectrum of compound 1 2e. Figure S15: ESI-MS spectrum of compound 2e. Figure S16: H NMR (200 MHz, CDCl3) Spectrum 13 of compound 3a. Figure S17: C NMR (50 MHz, CDCl3) Spectrum of compound 3a. Figure S18: 1 13 H NMR (200 MHz, CDCl3) Spectrum of compound 3b. Figure S19: C NMR (50 MHz, CDCl3) Spectrum of compound 3b. Figure S20: HRMS spectrum of compound 3b. Figure S21: 1H NMR 13 (200 MHz, CDCl3) Spectrum of compound 3c. Figure S22: C NMR (50 MHz, CDCl3) Spectrum of compound 3c. Figure S23: HRMS spectrum of compound 3c. Figure S24: 1H NMR (200 MHz, 13 CDCl3) Spectrum of compound 3d. Figure S25: C NMR (50 MHz, CDCl3) Spectrum of compound 1 3d. Figure S26: HRMS spectrum of compound 3d. Figure S27: H NMR (200 MHz, CDCl3) Spectrum 13 of compound 3e. Figure S28: C NMR (50 MHz, CDCl3) Spectrum of compound 3e. Figure S29: 77 ESI-MS spectrum of compound 3e. Figure S30: Se NMR (76 MHz, CDCl3) Spectrum of compound 3b. Figure S31: Absorbance plotted against diphenyl disulfide concentration. The red line represents the linear fit. The coefficient of molar absorptivity in 305 nm was 1415 L mol−1 cm−1 (R2 = 0.9996). Figure S32: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments for each concentration of PhSH. The concentrations of ebselen and −5 −3 −1 H2O2 were fixed at 5 × 10 and 15 × 10 mol L , respectively. The red line represents the Michaelis-Menten fit. Figure S33: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments for each concentration of PhSH. The −5 −3 −1 concentrations of diphenyl disulfide and H2O2 were fixed at 5 × 10 and 15 × 10 mol L , respectively. The red line represents the Michaelis-Menten fit. Figure S34: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments −5 for each concentration of PhSH. The concentrations of 3c and H2O2 were fixed at 5 × 10 and Molecules 2021, 26, 4446 8 of 11

15 × 10−3 mol L−1, respectively. The red line represents the Michaelis-Menten fit. Figure S35: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments for each concentration of PhSH. The concentrations of 3a and H2O2 were fixed at 5 × 10−5 and 15 × 10−3 mol L−1, respectively. The red line represents the Michaelis-Menten fit. Figure S36: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments for each concentration of PhSH. The concentrations of 3b and H2O2 were fixed at 5 × 10−5 and 15 × 10−3 mol L−1, respectively. The red line represents the Michaelis- Menten fit. Figure S37: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments for each concentration of PhSH. The concentrations of −5 −3 −1 3d and H2O2 were fixed at 5 × 10 and 15 × 10 mol L , respectively. The red line represents the Michaelis-Menten fit. Figure S38: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated from at least two experiments for each concentration of PhSH. The −5 −3 −1 concentrations of 3e and H2O2 were fixed at 5 × 10 and 15 × 10 mol L , respectively. The red line represents the Michaelis-Menten fit. Table S1: Atomic charges of nitrogen and selenium according to NPA. Table S2: Donor-acceptor second order perturbation analysis. Table S3: DFT-computed energies for optimized geometries (in kcal/mol). Author Contributions: Conceptualization, G.V.B., J.R. and A.L.B.; synthesis, spectral analysis, char- acterizations, and reagents/materials, G.V.B., L.B., R.F.S.C., F.A.R.B., S.S., H.G. and J.R.; GPX studies, W.C.E., D.N.O.S. and J.B.D.; DFT analysis, G.C.; writing—original draft, G.V.B. and J.R. writing— review and editing, G.V.B., J.R. and A.L.B. wrote the paper. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not Applicable. Informed Consent Statement: Not Applicable. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Acknowledgments: We gratefully acknowledge “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES” (Finance Code 001), “Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq”, “Instituto Nacional de Ciência e Tecnologia de Catálise em Sistemas Molecu- lares e Nanoestruturados—INCT-Catálise/CNPq/FAPESC”, “Centro de Excelência para Pesquisa em Química Sustentável—CERSusChem” (grant 2014/50249-8), “Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP”, (grant 2014/50249-8) “GlaxoSmithKline—GSK” (grant 2014/50249- 8). G.V.B. would like to acknowledge CNPq (429831/2018-8). J.R. would like to acknowledge CNPq (433896/2018-3 and 315399/2020-1). The authors acknowledge “Laboratório Central de Biologia Molecular Estrutural (CEBIME)” (UFSC-Brazil) for the HRMS analysis. Conflicts of Interest: The authors declare no conflict of interest. Sample Availability: Samples of the compounds can be checked with the author, G.V.B.

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