Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides As Gpx Mimics
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molecules 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 trans- formations [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