molecules

Review : Drugs with Chemical Skeletons Suitable for the Preparation of Metallacycles with Potential Pharmacological Activity

Artur V. da Silva, Simoni M. P. Meneghetti and Mario R. Meneghetti *

Grupo de Catálise e Reatividade Química, Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió/AL 57072-900, Brazil; [email protected] (A.V.d.S.); [email protected] (S.M.P.M.) * Correspondence: [email protected]; Tel.: +55-82-3214-1744

Abstract: The synthesis of organometallic compounds with potential pharmacological activity has attracted the attention of many research groups, aiming to take advantage of aspects that the presence of the metal-carbon bond can bring to the design of new pharmaceutical drugs. In this context, we have gathered studies reported in the literature in which psychoactive drugs were used as ligands in the preparation of organometallic and metal complexes and provide details on some of their biological effects. We also highlight that most commonly known benzodiazepine-based drugs display molecular features that allow the preparation of metallacycles via C-H activation. These organometallic compounds merit further attention regarding their potential biological effects, not only in terms of psychoactive drugs but also in the search for drug replacements, for example, for   cancer treatments.

Citation: da Silva, A.V.; Meneghetti, Keywords: organometallic complexes; biological activity; benzodiazepines; metallodrugs S.M.P.; Meneghetti, M.R. Benzodiazepines: Drugs with Chemical Skeletons Suitable for the Preparation of Metallacycles with Potential Pharmacological Activity. 1. Introduction Molecules 2021, 26, 2796. https:// Benzodiazepine (BZD) drugs are a family of compounds widely used in the treatment doi.org/10.3390/molecules26092796 of neurological pathologies that offer similar pharmacological properties, with , , , skeletal , amnesic, and anticonvulsant effects [1,2], Academic Editor: Vincent Ritleng with a very well-established mechanism of action and metabolization in the organism [3]. These drugs have a chemical structure based on a core formed by the fusion of Received: 19 April 2021 and diazepine rings [4,5], and they act as positive allosteric modulators of the GABAA Accepted: 7 May 2021 receptor complex present in neural tissue [6,7]. They are commonly used in the treatment Published: 10 May 2021 of sleep and anxiety disorders, with safe use in the short term [8]. Most of the pharmaco- logically active BZDs are 5-aryl or pyridinyl substituted on the benzo [1,4] diazepine core Publisher’s Note: MDPI stays neutral (see Figure1 ) and the most common classes are ketone and triazole derivatives. Ketone with regard to jurisdictional claims in derivatives contain a ketone oxygen bond at C(2) of the 1,4-benzodiazepine ring and are published maps and institutional affil- distinguished by their suffix “-azepam” contain a triazole ring iations. condensed at the 1,4-benzodiazepine ring and are distinguished by the suffix “-zolam.” Figure2 shows some examples of BZDs that can be found on the market [ 9], where some are sold as designer drugs [10]. A close look at the molecular structure of the BZDs in Figure2 reveals why these Copyright: © 2021 by the authors. compounds attract the attention of organometallic chemists, since they can be used as Licensee MDPI, Basel, Switzerland. ligands in the formation of metallo-derivatives. Part of their molecular skeleton contains This article is an open access article functional groups derived from pyridinylmethanimine or phenylmethanimine, allowing distributed under the terms and the formation of chelated metal complexes via ligand association, or ortho-metallation (see conditions of the Creative Commons Figure3). However, despite these interesting features, few studies on the transformation of Attribution (CC BY) license (https:// BZD drugs into their metallo-derivatives have been reported. creativecommons.org/licenses/by/ 4.0/).

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FigureFigure 1.1. GeneralGeneral molecularmolecular structuresstructures of of the the most most commercialized commercialized 1,4-benzodiazepines: 1,4-benzodiazepines: ketone ketone and Figure 1. General molecular structures of the most commercialized 1,4-benzodiazepines: ketone triazoleFigureand triazole 1. derivatives. General derivatives. molecular The 1,4-benzodizapineThe structures 1,4-benzodizapine of the core most iscore highlightedcommercialized is highlighted in blue. 1,4-benzodiazepines:in blue. ketone andand triazoletriazole derivatives.derivatives. The 1,4-benzodizapine corecore isis highlighted highlighted in in blue. blue. H O H O O O H O NH O HN O N O N O HN O HN O NH O N O N O NH O N N N N N OH OH Br N O2N N Cl N O2N N Cl N OH Br N O2N N Cl N O2N N Cl N Br N O2N N Cl N O2N N Cl N N Cl F Cl N Cl F Cl N Cl F Cl Bromazepam Clonazepam Diazepam Flunitrazepam Lorazepam Bromazepam Clonazepam Diazepam Flunitrazepam Lorazepam

N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N Cl N N N Cl N N Cl N Br N ClCl N Cl N ClCl N Cl N Br N Cl N Cl N Cl N ClCl Cl

AlprazolamAlprazolam Bromazolam EstazolamEstazolam TriazolamTriazolam PyrazolamPyrazolam Bromazolam

NH OO HH OO OO N N N N NH N O NH O N O N N N N Cl N O N NN N Cl N Cl O2N OO22NN N Cl N N O N Cl O2N O2N N Cl N O

ChlordiazepoxideChlordiazepoxide NitrazepamNitrazepam PrazepamPrazepam Nimetazepam FigureFigureFigure 2.2. SomeSome examplesexamples ofof BZDsBZDs thatthat cancan bebe foundfound on on the thethe market. market.market. Figure 2. Some examples of BZDs that can be found on the market.

FigureFigure 3. The fragments present inin BZDBZD drugs,drugs, derive derivedd from from phenylmethanimine phenylmethanimine or or pyridinylme- pyridinylme- Figurethanimine,thanimine, 3.3. The which fragmentsfragments are responsible presentpresent inin forfor BZDBZD thethe drugs, drugs, reactivityreactivity derived derive of of these dthese from from co co phenylmethanimine mpounds,phenylmethaniminempounds, leading leading to orto metalor pyridinylmetha-metal pyridinylme- com- com- plexes via ortho-metallation or chelation. nimine,thanimine,plexes via which ortho which are-metallation responsibleare responsible or for chelation. thefor reactivitythe reactivity of these of these compounds, compounds, leading leading to metal to metal complexes com- via orthoplexes-metallation via ortho-metallation or chelation. or chelation.

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Prior to discussing metal derivatives of benzodiazepine drugs in detail, it should be noted that, for centuries, metal compounds have been used to treat diseases and heal wounds [11]. In the early 20th century, compounds containing arsenic, antimony, bismuth and gold were commonly prescribed to treat diseases like syphilis, leishmania, diarrhea, arthritis and others [12,13]. However, with the rapid progress in the area of organic chem- istry in the last century, combined with the large-scale production of very effective new Molecules 2021, 26, 2796 3 of 16 fully-organic drugs, there has been a decrease in some aspects associated with studies aimed at the discovery of new metal-based drugs. In fact, inorganic and organometallic chemists have mostly concentrated on the application of these compounds in areas like catalysisPrior and to discussingstructural chemistry. metal derivatives Even so, so ofme benzodiazepine metallodrugs have drugs been in detail, used for it shouldspecific beapplications noted that, (see for Figure centuries, 4) and metal the developmen compoundst have of these been drugs used has to treatbeen diseasesexpanding and within heal woundsmedicinal [11 chemistry]. In the early [14]. 20th More century, and more compounds coordination containing and organometallic arsenic, antimony, compounds bismuth andare being gold werestudied, commonly whether prescribed they are linked to treat to diseasesorganic drugs like syphilis, or to organic leishmania, fragments diarrhea, that, arthritisindividually, and othersdo not have [12,13 phar]. However,macological with activity the rapid [15,16]. progress in the area of organic chemistryThe most in the prominent last century, example combined is the with anti-c theancer large-scale platinum production complex ofcisplatin very effective and its newanalogues, fully-organic which, drugs, since their there clinical has been use a decreasefrom the in1970s, some account aspects for associated about 50% with of studiescurrent aimedchemotherapeutic at the discovery protocols of new for metal-based cancer treatmen drugs.t [17]. In fact,Radiopharmaceuticals inorganic and organometallic also play an chemistsimportant have role mostlyin medical concentrated diagnostics on and the therapy application [18,19]. of these In fact, compounds these medical in areas applica- like catalysistions have and trigged structural research chemistry. to further Even explor so, somee inorganic metallodrugs and organometallic have been used chemistry. for specific In applicationsthis regard, (seeit should Figure be4) noted and the that development several important of these drugsenzymes has in been our expanding organism withinrequire medicinalmetals in their chemistry structure [14]. (metalloenzymes) More and more coordinationfor their functional and organometallic catalytic activity compounds in the or- areganism. being Cytochrome studied, whether P450 and they plastocyanin, are linked to fo organicr instance, drugs contain or to Fe organic and Cu, fragments respectively, that, individually,in their structure do not [20]. have pharmacological activity [15,16].

FigureFigure 4.4. SomeSome examplesexamples ofof appliedapplied metallodrugsmetallodrugs oror thosethose inin thethe advancedadvanced trialtrial stage.stage.

The most prominent example is the anti-cancer platinum complex cisplatin and its analogues, which, since their clinical use from the 1970s, account for about 50% of current chemotherapeutic protocols for cancer treatment [17]. Radiopharmaceuticals also play an important role in medical diagnostics and therapy [18,19]. In fact, these medical applica- tions have trigged research to further explore inorganic and organometallic chemistry. In this regard, it should be noted that several important enzymes in our organism require metals in their structure (metalloenzymes) for their functional catalytic activity in the or- ganism. Cytochrome P450 and plastocyanin, for instance, contain Fe and Cu, respectively, in their structure [20]. Molecules 2021, 26, 2796 4 of 16

Coordination and organometallic chemistry could lead to the preparation of potential metallodrugs with wide molecular structures and chemical reactivity, i.e., with different geometries, coordination numbers, oxidation states, redox potential and ligands, which can be exploited to develop new drugs that cannot be produced using only organic com- pounds [21,22]. One approach to the design and development of new efficient and potent metallodrugs is based on the association of well-known organic drugs modified with the addition of the metal atoms. Here, the challenge is to maintain the pharmacological activity of the organic drug after modification, with its coordination to the metal center, since its physiological profile can be completely changed, affecting its properties and toxicity [23]. For example, the modification of an organic drug with the coordination of a metal, can significantly change the log D values of the former compound, affecting the access of the drug in tissues or organs like the brain. In this context, this short review gathers some of the main research studies that illus- trate the potential for the preparation of metallo-derivatives of BZDs, such as metallacycles and other metal complexes. In addition, their potential application as metallodrugs, taking advantage of the previously confirmed pharmacological activity provided by the ligand moiety, is discussed. Details of studies reported in the literature involving the synthesis of BZD organometallic and coordination compounds and their pharmacological applications are provided. The aim is to encourage further research involving these compounds in the field of inorganic medicinal chemistry.

2. Coordination and Organometallic Chemistry of BZDs In this section, we present a historical sequence of the development of the coordination and organometallic chemistry of BZDs, with the most relevant publications summarized in Table1. The first studies related to the preparation of coordination compounds (adducts) containing the benzodiazepine core as ligands were published in the early 1970s, indicating the classical aspects of the coordination chemistry of the benzodiazepine core considering several metal ions [24,25]. Soon after, a series of metal-BZD adducts was prepared (see Table1). The first examples of BZD drugs coordinated to metal ions—Co(II), Ni(II), and Cu(II)—were published by Preti and Tosi [26,27] (see Table1, Entry 1). At that time, they suggested that the Co(II) and Ni(II) complexes could have a pseudotetrahedral symmetry, whereas the Cu(II) complexes were octahedral. In the late 1970s, the same researchers appeared to have obtained square planar BZD coordination compounds with Pd(II) and Pt(II) ions [28] (see Table1, Entry 2). However, in 1980, more accurate analysis, using X-ray diffraction, NMR, and EPR studies, demonstrated that diazepam is, in fact, coordinated to the Cu(II) ions via its atom N(4), leading to a trans square-planar complex [29] (see Table1, Entry 3). In the early 1980s, Minghetti and coworkers prepared square planar adducts of BZDs with Au(III) [30,31] (see Table1, Entry 4). Benedetti and coworkers obtained the first well characterized 5-member ring chelated Pt(II)-BZD complex, using bromazepam as the ligand. In this case, platinum(II) is in a square-planar environment, as expected, with bromazepam coordinated to the metal via both the imino and the pyridyl nitrogen atoms [32] (see Table1, Entry 5). The analogous Pd(II) derivative was prepared by Antolini and coworkers [33] from K2PdCl4 as palladium (see Table1, Entry 9). The first organometallic BZD derivatives were reported in 1988, when Cinellu and coworkers published an important paper indicating the preparation of the adducts trans- L2PdCl2 (L = diazepam or prazepam) through the reaction of PdCl2 or (PhCN)2PdC12 with diazepam and prazepam, in which the BZDs act as monodentate ligands through the N(4) atom. However, they obtained dimeric forms of palladacycles using the same BZDs in the presence of Na2PdCl4 (see Table1). These palladacycles were obtained through chelation-assisted C–H activation, i.e., deprotonation of the 5-phenyl substituent (ortho- metallation) [34]. In addition, the dimers, with halide-bridges, were easily split in the presence of PPh3 or Tl(acac) [35] (see Table1, Entry 6). At that time, Cinellu and coworkers stated that the first assignments of 1:1 BZD:Pd(II) as chelated adducts [28], in 1976, were Molecules 2021, 26, x FOR PEER REVIEW 5 of 15 Molecules 2021, 26, 2796 5 of 16

first assignments of 1:1 BZD:Pd(II) as chelated adducts [28], in 1976, were most probably mostpalladacycles probably of palladacycles BZDs. It should of be BZDs. noted It that should an important be noted publication that an important reported publication the prep- reportedaration of the air-stable preparation organometallic of air-stable derivatives organometallic of BZDs, derivatives allowing their of BZDs,use in a allowing wide range their useof applications in a wide range [36]. of applications [36]. InIn 1990, Cinellu and and coworkers coworkers prepared prepared a aseries series of of neutral neutral and and cationic cationic BZD-Au(I) BZD-Au(I) derivativesderivatives [37], [37], as as seen seen in in Figure Figure 5 and5 and Table Table 1, 1Entry, Entry 7. In 7. this In thiscase, case,the BZDs the BZDswere coor- were coordinateddinated to the to metal the metal center center via the via imino the imino nitrogen nitrogen atom. atom. However, However, in the in presence the presence of al- of alkali,kali, (PPh (PPh3)AuCl3)AuCl reacts reacts with with 1-unsubstituted 1-unsubstituted 1,4-benzodiazepin-2-ones, 1,4-benzodiazepin-2-ones, i.e., i.e., nitrazepam nitrazepam andand lorazepam,lorazepam, to give neutral Au(I) Au(I) species species (L-H)Au(PPh (L-H)Au(PPh3),3 ),as as shown shown in inFigure Figure 5C.5C. For For thesethese neutral complexes, the the coordination coordination to to the the metal metal center center occurs occurs via via the the deprotonated deprotonated µ aminoamino nitrogen atom. atom. The The same same authors authors also also prepared prepared a cationic a cationic species species [(Ph3P)Au{µ-(ni- [(Ph3P)Au{ - (nitrazepam-H)}Au(PPhtrazepam-H)}Au(PPh3)][BF3)][BF4] where4] where the the deprotonated deprotonated nitrazepam nitrazepam bridges bridges two two (Ph (Ph3P)Au3P)Au groupsgroups through the N(1) and and N(4) N(4) atoms atoms (Figure (Figure 5D).5D). The The above above examples examples highlight highlight the the greatgreat potential of the c coordinationoordination and and organometa organometallicllic chemistry chemistry of of BZDs. BZDs.

FigureFigure 5. A series of BZD-Au(I) BZD-Au(I) derivatives derivatives pr preparedepared by by Cinellu Cinellu and and coworkers coworkers (A (–AD–).D ).

InIn 1991,1991, Aversa and coworkers [38] [38] also also prepared prepared BZD BZD organometallic organometallic compounds compounds derivedderived from from bromazepam. bromazepam. They They obtained obtained adducts adducts of bromazepam-Pt(II), of bromazepam-Pt(II), using using the or- the organometallicganometallic precursors precursors cis-PtMecis-PtMe2(Me2(Me2SO)2SO)2 and2 and[PtPh [PtPh2(Et22S)](Et2 2(seeS)]2 Table(see Table1, Entry1, Entry 8). 8). The first results showing some aspects of the chemical reactivity of palladacycles derived from BZDs were published by Cinellu and coworkers in 1991, increasing the

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TheThe firstfirst resultsresults showingshowing somesome aspectsaspects ofof ththee chemicalchemical reactivityreactivity ofof palladacyclespalladacycles de-de- rivedrived fromfrom BZDsBZDs werewere publishedpublished byby CinelluCinellu andand coworkerscoworkers inin 1991,1991, increasingincreasing thethe possi-possi- possibilitybilitybility ofof preparingpreparing of preparing newnew BZDBZD new derivativesderivatives BZD derivatives [39].[39]. TheyThey [39]. demonstrateddemonstrated They demonstrated thatthat dimericdimeric that dimeric palladacy-palladacy- pal- ladacycleclecle derivativesderivatives derivatives ofof BZDsBZDs of BZDsareare ableable are toto able reactreact to reactwithwith withcarboncarbon carbon monoxide,monoxide, monoxide, leadingleading leading toto tetracyclictetracyclic to tetracyclic de-de- derivativesrivativesrivatives havinghaving having anan an isoindoloisoindolo isoindolo ringring ring condensedcondensed condensed onon on thethe the benzodiazepinicbenzodiazepinic benzodiazepinic core.core. core. AnAn An exampleexample example ofof ofthisthis this reactionreaction reaction isis shown isshown shown inin inFigureFigure Figure 6.6. 6 .

FigureFigure 6. 6. ExampleExampleExample ofof of anan an insertioninsertion insertion reactionreaction reaction ofof COCO of in COin thethe in Pd-CPd-C the Pd-Cbondbond of bondof palladacyclespalladacycles of palladacycles derivedderived derived fromfrom fromBZDs.BZDs. BZDs.

SimilarSimilar chemistrychemistry to to thatthat observedobserved in in relation relation to to thethe synthesissynthesis and and reactivity reactivity of of pal- pal- ladacyclesladacycles derivedderived fromfrom BZDsBZDsBZDs waswaswas verifiedverifiedverified forfoforr theirtheirtheir platinacycleplatinacycleplatinacycle counterparts.counterparts.counterparts. InIn 1994,1994, StoccoroStoccoro andand coworkerscoworkers [[40][40]40] preparedprepared platinacyclesplatinacyclesplatinacycles derivedderivedderived fromfromfrom diazepamdiazepamdiazepam (dimeric(dimeric(dimeric andandand monomericmonomeric forms).forms). Interestingly, Interestingly, they they preparedpreparprepareded mostmost ofof thethethe monomericmonomericmonomeric formsformsforms fromfromfrom thethethe monomericmonomeric complexcomplex containingcontaining twotwo diazepamdiazepam ligands,ligands, oneone ofofof themthemthem cyclopalladatedcyclopalladatedcyclopalladated andandand thethe otherother justjust coordinatedcoordinated (see(see(see TableTableTable1 1,,1, entry entryentry 10). 10).10). InIn 1998,1998, MinghettiMinghetti andand coworkerscoworkers [[41][41]41] preparedpreppreparedared thethe firstfirstfirst exampleexample ofof organogold(I)organogold(I)organogold(I) derivedderived fromfrom BZDsBZDs BZDs (see(see (see TableTable Table 1,1,1, EntryEntry Entry 11)11) 11) usus usinginging anan an approachapproach approach thatthat that differeddiffered differed fromfrom from thethe thepre-pre- previouslyviouslyviously reportedreported reported reactionsreactions reactions [37].[37]. [37 ToTo]. Toattainattain attain thethe the ororganogold(I)ganogold(I) organogold(I) derivatives,derivatives, derivatives, inin thisthis in this reactionreaction reaction anan anethanolicethanolic ethanolic solutionsolution solution ofof thethe of basebase the base waswas addedadded was added atat rroomoom at temperature, roomtemperature, temperature, dropdrop byby drop drop,drop, by toto drop, aa suspen-suspen- to a suspensionsionsion ofof PhPh33PAuClPAuCl of Ph3 PAuCl andand thethe and BZDBZD the inin BZD thethe same insame the solvent.solvent. same solvent. InIn allall cases,cases, In all cases, thethe BZDsBZDs the BZDs employedemployed employed werewere werealkylalkyl alkylsubstitutedsubstituted substituted inin N(1),N(1), in N(1), seesee FigureFigure see Figure 7.7. 7.

FigureFigure 7.7. FirstFirst exampleexample ofof organogold(I)organogold(I) derivedderived fromfrom BZDs.BZDs.

InIn thethethe earlyearlyearly 2000s,2000s,2000s, VisnjevacVisnjevacVisnjevac andandand coworkerscoworkercoworkerss [[42,43][42,43]42,43] demonstrateddemonstrateddemonstrated thatthatthat adductsadductsadducts ofofof 0 Cu(II),Cu(II), Zn(II)Zn(II) andandand Pd(II)Pd(II)Pd(II) and anandd chiral chiralchiral 3-substituted 3-substituted3-substituted 5-(2 5-(25-(2-pyridyl)-1,4-benzodiazepin-2-one′′-pyridyl)-1,4-benzodiazepin-2-one-pyridyl)-1,4-benzodiazepin-2-one derivativesderivatives can cancan be bebe easily easilyeasily attained attainedattained (see (see(see Table TableTable1, 1, Entries1, EntriesEntries 12 1212 and andand 13). 13).13). They TheyThey report reportreport that thatthat the thethe C(3) C(3)C(3) of theofof thethe benzodiazepinic benzodiazepinicbenzodiazepinic ring ringring can caca undergonn undergoundergo substitution substitutionsubstitution and andand even eveneven ring ringring contraction contractioncontraction reactions reactionsreactions [42]. Around[42].[42]. AroundAround the same thethe samesame time, time,time, Pérez PérezPérez and coworkers andand coworkcowork [44ersers] prepared [44][44] preparedprepared the first thethe organometallic firstfirst organometallicorganometallic com- poundscompoundscompounds of ruthenium ofof rutheniumruthenium derived derivedderived from fromfrom BZDs BZDsBZDs (see (see Table(see TableTable1, Entry 1,1, EntryEntry 14). They 14).14). TheyThey prepared preparedprepared 5- and 5-5- 3-memberedandand 3-membered3-membered rings ringsrings of ruthenacycles ofof ruthenacyclesruthenacycles derived derivedderived from fromfrom diazepam, diazepam,diazepam, see Figure seesee FigureFigure8A,B. 8A,B.8A,B. InIn 2005,2005,2005, Spencer SpencerSpencer and andand coworkers coworkerscoworkers demonstrated demonstrateddemonstrated that thatthat the thethe 1,4-benzodiazepine 1,4-benzodiazepine1,4-benzodiazepine derivatives deriva-deriva- couldtivestives couldcould be used bebe as usedused versatile asas versatileversatile ligands ligandsligands for the forfor preparation thethe preparationpreparation of metal ofof complexes metalmetal complexescomplexes [45] (see [45][45]Table (see(see1 , EntryTableTable 1, 15).1, EntryEntry Through 15).15). ThroughThrough the addition thethe additionaddition of suitable ofof suitablesuitable substituents substituentssubstituents on the onon benzodiazepine thethe benzodiazepinebenzodiazepine core, theycore,core, synthesizedtheythey synthesizedsynthesized palladacycles palladacyclespalladacycles via C-H viavia C-HC-H activation, activation,activation, in which inin whichwhich the the benzodiazepinethe benzodiazepinebenzodiazepine acts actsacts as aasas CNS-pincer aa CNS-pincerCNS-pincer ligand ligandligand when whenwhen using usingusing the thethe right righrigh palladiumtt palladiumpalladium precursor precursorprecursor (see (see(see Figure FigureFigure9). 9).9). In InIn the thethe samesame publication,publication, the thethe authors authorsauthors showed showedshowed that thatthatortho orthoortho-substituted-substituted-substituted 5-phenyl-1,4-benzodiazepin-2- 5-phenyl-1,4-benzodiazepin-5-phenyl-1,4-benzodiazepin- ones2-ones2-ones could couldcould be bebe produced producedproduced via viavia stoichiometric stoichiometricstoichiometric reactions reactionsreactions of the ofof corresponding thethe correspondingcorresponding cyclopalladated cyclopalla-cyclopalla- benzodiazepine in the presence of arylboronic acids (see Figure 10). Moreover, they dateddated benzodiazepinebenzodiazepine inin thethe presencepresence ofof arylboronicarylboronic acidsacids (see(see FigureFigure 10).10). Moreover,Moreover, theythey confirmed that palladacycles of 1,4-benzodiazepine are able to catalyze Suzuki and Heck C-C coupling reactions [46].

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Molecules 2021, 26, 2796 confirmed that palladacycles of 1,4-benzodiazepine are able to catalyze Suzuki and7 Heck of 16 confirmedC-C coupling that reactions palladacycles [46]. of 1,4-benzodiazepine are able to catalyze Suzuki and Heck C-C coupling reactions [46].

Figure 8. Organometallic compounds of ruthenium derived from BZDs (A and B). Figure 8. Organometallic compounds compounds of of ruthenium ruthenium derived derived from from BZDs BZDs (A (A and,B). B).

Figure 9. First example of a metallacycle in which the benzodiazepine derivative acts as a pincer Figure 9. First example of a metallacycle in which the benzodiazepine derivative acts as a pincer Figureligand. 9. First example of a metallacycle in which the benzodiazepine derivative acts as a pincer ligand. ligand.

FigureFigure 10.10. OrthoOrtho-functionalization-functionalization-functionalization of ofof cyclopalladated cyclopalladatedcyclopalladated 5-phenyl-1,4-benzodiazepine. 5-phenyl-1,4-benzodiazepine.5-phenyl-1,4-benzodiazepine.

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It is important to note that most of these BZD coordination and organometallic com- ItIt isis importantimportant toto notenote thatthat mostmost ofof thesethese BZDBZD coordinationcoordination andand organometallicorganometallic com-com- pounds are stable in air, allowing studies on their potential application as metallodrugs. poundspounds areare stablestable inin air,air, allowingallowing studiesstudies onon theirtheir potentialpotential applicationapplication asas metallodrugs.metallodrugs. Molecules 2021However,, 26, 2796 few examples of metallo-BZDs have been produced and not all of them have 8 of 16 However,However, fewfew examplesexamples ofof metallo-BZDsmetallo-BZDs havehave beenbeen producedproduced andand notnot allall ofof themthem havehave been evaluated with regard to their pharmacological potential. beenbeen evaluatedevaluated withwith regardregard toto theirtheir pharmacologicalpharmacological potential.potential. Table 1. Examples of organometallic and coordination compounds containing BZDs as ligands, TableTableTable 1. Examples 1.1. ExamplesExamples of organometallic ofof organometallicorganometallic and coordination andand coordinationcoordination compounds compoundscompounds containing containing BZDscontaining as ligands, BZDsBZDs illustrating asas ligands,ligands, the chronological illustrating the chronological evolution of the theme. evolutionillustratingillustrating of the theme. thethe chronologicalchronological evolutionevolution ofof thethe theme.theme. Entry Compound Reference EntryEntryEntry CompoundCompound Compound Reference Reference Reference

Preti and PretiPreti andand 1 Tosi,ΞΞPreti1976 and [26] Tosi, 1 11 Tosi,Tosi,ΞΞΞΞ19761976 [26][26] and1976 1979 [26 ][27]. and 1979 [27]. andand 19791979 [27].[27].

Preti and 2 PretiPretiPreti andand and Tosi, 2 22 Tosi,ΞΞ1976 [28]. Tosi,Tosi,ΞΞΞΞ197619761976 [28].[28]. [28].

Mosset et 3 MossetMossetMosset etet et al., 3 3 Mosset et 33 al.,ΞΞ19801980 [29]. [29 ]. al.,al.,ΞΞΞΞ19801980 [29].[29].

Minghetti et Minghetti et MinghettiMinghettiMinghetti etet et al., 4 4 al.,ΞΞ1982 [30] 44 al.,al.,ΞΞ1982ΞΞ19821982 [30] and[30][30] 1984 [31] and 1984 [31] andand 19841984 [31][31]

BenedettiBenedetti et et al., 5 5 BenedettiBenedetti etet 55 al.,ΞΞ19871987 [32]. [32 ]. al.,al.,ΞΞΞΞ19871987 [32].[32].

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Molecules 2021, 26, x FOR PEER REVIEW 9 of 15 MoleculesMoleculesMolecules 2021 2021 ,2021 26,, x26, 26FOR, x, xFOR FORPEER PEER PEER REVIEW REVIEW REVIEW 9 of9 15 9of of 15 15 Table 1. Cont.

Entry Compound Reference

Cinellu et 6 CinelluCinelluCinelluCinellu et et et et al., 6 6 66 al.,ΞΞ1988 [35].a al.,al.,ΞΞal.,ΞΞ1988ΞΞ19881988 1988[35]. [35]. [35].a [ 35].a a

Cinellu et 7 CinelluCinelluCinelluCinellu et et et et al., 7 7 77 al.,ΞΞ1990 [37] al.,al.,ΞΞal.,ΞΞ1990ΞΞ19901990 1990[37] [37] [37] [ 37 ]

Aversa et 8 AversaAversaAversaAversa et et et et al., 8 8 88 al.,ΞΞ1991 [38]. al.,al.,ΞΞal.,ΞΞ1991ΞΞ19911991 1991[38]. [38]. [38]. [38].

O O O HN O HN HNHN N Cl N NClN Cl AntoliniAntolini et et al., Br Pd Cl AntoliniAntoliniAntolini et et et 9 9 Br BrBr Pd PdPd 9 99 N Cl al.,ΞΞ1992 [33]1992 [33] N NNCl ClCl al.,al.,ΞΞal.,ΞΞ1992ΞΞ19921992 [33] [33] [33]

Chelated complex Pd(II)-bromazepam Chelated complex Pd(II)-bromazepam ChelatedChelated complex complex Pd(II)-bromazepam Pd(II)-bromazepam

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MoleculesMolecules Molecules2021 2021, ,26 26, , x 2021x FOR FOR, 26 PEER PEER, x FOR REVIEW REVIEW PEER REVIEW 1010 of of 15 15 10 of 15

Table 1. Cont.

Entry Compound Reference

Stoccoro et 10 StoccoroStoccoroStoccoro etet al., et 1010 10 a al.,al.,ΞΞΞΞ199419941994al., [40ΞΞ [40].].[40].a 1994a [40].a

Minghetti et 11 MinghettiMinghettiMinghetti et et al., et 1111 11 al.,al.,ΞΞΞΞ199819981998al., [41ΞΞ [41].[41].]. 1998 [41].

S O S S O O N O N O N O NN OO Br Cu N O Br Br Cu Cu OO NN N O ClCl N N N Cl OH DMSO OH DMSOOH DMSO NN ClCl Br Cu N Cl Visnjevac et Br Br Cu Cu VisnjevacVisnjevacVisnjevac et et al., et 121212 N Cl O 12 N Cl N Cl O O al.,ΞΞ20012001 [42 [42].]. N O al.,ΞΞ2001al.,ΞΞ [42].2001 [42]. N ON O EtOHEtOH OH EtOH NN OH Cl OH Br Cu Cl N Cl Br Br Cu Cu NN Cl Cl N Cl

Pentacoordinated Cu(II) complexes of PentacoordinatedPentacoordinated Cu(II) complexes Cu(II) complexes of of 3-substituted 5-(2'-pyridyl)-1,4-benzodiazepin-2-one derivatives 3-substituted3-substituted 5-(2'-pyridyl)-1,4- 5-(2'-pyridyl)-1,4-benzodiazepin-2-onebenzodiazepin-2-one derivatives derivatives

Molecules 2021, 26, 2796 11 of 16

MoleculesMolecules 2021 2021, 26, ,26 x ,FOR x FOR PEER PEER REVIEW REVIEW 11 11of 15of 15 MoleculesMolecules 2021 2021, ,26 26, ,x x FOR FOR PEER PEER REVIEW REVIEW 1111 of of 15 15

Table 1. Cont.

Entry Compound Reference

VisnjevacVisnjevac et et VisnjevacVisnjevacVisnjevac etet et al., 13131313 13 al.,al.,al.,al.,ΞΞΞΞΞΞΞΞ20022002200220022002 [43 [43]. [43].[43].]. [43].

PérezPérezPérezPPérezérez etetet al., et 14141414 14 al.,al.,al.,al.,ΞΞΞΞΞΞΞΞ20022002200220022002 [44 [44]. [44].[44].]. [44].

SpencerSpencerSpencer etet al., et 1515 SpencerSpencer et et 151515 2005 [45]. al.,al.,al.,al.,ΞΞΞΞΞΞΞΞ2005200520052005 [45]. [45].[45]. [45].

SpencerSpencerSpencerSpencer etetet al., et 161616 Spencer eta 1616 2008 [47]. a a al.,al.,al.,al.,ΞΞΞΞΞΞΞΞ2008200820082008 [47]. [47].[47]. [47].aa

SpencerSpencerSpencerSpencer et etet et 171717 17 al.,al.,al.,al.,ΞΞΞΞΞΞΞΞ2009200920092009 [48,49]. [48,49].[48,49]. [48,49].

Molecules 2021, 26, x FOR PEER REVIEW 11 of 15

Visnjevac et 13 al.,ΞΞ2002 [43].

Pérez et 14 al.,ΞΞ2002 [44].

Spencer et 15 al.,ΞΞ2005 [45].

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Spencer et 16 al.,ΞΞ2008 [47].a Table 1. Cont.

Entry Compound Reference

SpencerSpencer et et al., 17 17 al.,ΞΞ20092009 [48,49]. [48,49 ].

Molecules 2021, 26, x FOR PEER REVIEW 12 of 15

Barros Barroset et al., 18 18 a al.,ΞΞ2016 [50].2016a [ 50].

a The dimers are a mixturea The ofdimers their cisoid are a mixture or transoid of their forms cisoid [50,51]. or transoid forms [50,51].

3. Biological Activity ofIt Metallo-BZD is important toDerivatives note that most of these BZD coordination and organometallic com- pounds are stable in air, allowing studies on their potential application as metallodrugs. As mentioned above, BZDs are important drugs that are widely used in the treatment However, few examples of metallo-BZDs have been produced and not all of them have of a series of neurologicalbeen evaluated pathologies. with regardHowever, to their these pharmacological drugs and derivatives potential. have also demonstrated potential pharmacological activity and can act, for instance, against cancer [52], allergy [53], bacterial3. Biological [54], fungal Activity infections of Metallo-BZD [55], and Derivativesalso as targeting agents for the cholecystokinin 2 receptorAs mentioned(CCK2R), which above, is BZDs overexpressed are important in some drugs people that are [56,57]. widely Alt- used in the treatment hough reviews haveof been a series published of neurological on the di pathologies.fferent pharmacological However, these activities drugs ofand benzo- derivatives have also diazepine-based compoundsdemonstrated and potentialtheir mechanism pharmacological of action activity[4,5], studies and can in the act, field for instance, of against can- drug discovery basedcer [on52 ],their allergy metallo-derivatives [53], bacterial [54 are], fungalscarce. infections [55], and also as targeting agents for The first publicationsthe cholecystokinin describing pharmacological 2 receptor (CCK2R), tests with which metal is overexpressed complexes bearing in some people [56,57]. BZD-like drugs as Althoughligands appeared reviews in have the ea beenrly 2000s, published and were on the not different related to pharmacological neurolog- activities of ical aspects. Visnjevacbenzodiazepine-based and coworkers [43] compounds evaluated andthe in their vitro mechanism cytostatic of and action antiviral [4,5], studies in the field activity of adductsof of drug Cu(II), discovery Zn(II) and based Pd(II) on theirand chiral metallo-derivatives 3-substituted 5-(2 are scarce.′-pyridyl)-1,4- benzodiazepin-2-one derivativesThe first publications (see Table 1, describing Entries 12 pharmacologicaland 13) and compared tests with the results metal complexes bearing with those obtainedBZD-like for free ligands. drugs as Althou ligandsgh appeared the complexes in the and early the 2000s, free ligands and were did not not related to neurolog- present good activity,ical these aspects. studies Visnjevac appear and to be coworkers the first aimed [43] evaluated at evaluating the in the vitro biologi-cytostatic and antiviral cal activity of metallo-BZDs.activity of adducts of Cu(II), Zn(II) and Pd(II) and chiral 3-substituted 5-(20-pyridyl)-1,4- Based on the benzodiazepin-2-oneanticancer activity previously derivatives demonstrated (see Table1, Entries for BZDs, 12 and Spencer 13) and and compared the results coworkers, in 2009,with carried those out obtained in vitro for stud freeies ligands. with palladacycles Although the derived complexes from and 1,4-ben- the free ligands did not zodiazepin-2-ones present(see Table good 1, activity,Entry 18) these usin studiesg human appear cancer to becells. the They first aimedconducted at evaluating as- the biological says to determine activitythe inhibitory of metallo-BZDs. activity of cathepsin B bovine, an enzyme involved in cancer-related events [48,49].Based The on thepalladacyc anticancerles with activity two previouslymetal centers demonstrated linked by a dppe for BZDs, Spencer and bridge and with ancoworkers, iso-Pr substituent in 2009, on carriedC(3) in the out benzodiazepinein vitro studies ring with showed palladacycles promis- derived from 1,4- ing results in termsbenzodiazepin-2-ones of cytotoxicity and inhibition (see Table of1, Entrythe bovine 18) using cathepsin human B, cancer with IC50 cells. They conducted values in the low mMassays range. to determine the inhibitory activity of cathepsin B bovine, an enzyme involved More recently,in Barros cancer-related and coworkers events carried [48,49]. out, The for palladacycles the first time, with anticonvulsant two metal centers linked by a studies in vivo withdppe palladacycle-derived bridge and with anBZD iso-Pr drugs substituent (diazepam) on [50]. C(3) The in theanticonvulsant benzodiazepine ring showed potential of the dimeric complexes (see Table 1, Entry 19) was evaluated using two animal models (mice): pentylenetetrazole (PTZ)- and picrotoxin (PTX)-induced convulsions. The dimer with an acetate bridge significantly increased latency and protected the animals against convulsions induced by PTZ and PTX, while the analogous chloro derivative was effective (p b 0.01) only in the PTZ model. These effects appear to be mediated through the GABAergic system. A possible mechanism of action of the Pd(II)-diazepam-H com- plexes was also confirmed with the use of (FLU), a GABAA-benzodiazepine receptor complex site antagonist. This was the first report of the anticonvulsant properties of metallo-BZD drugs, opening a new area in the development of novel drugs for the treatment of neurological pathologies.

4. Conclusions Benzodiazepines represent an important family of compounds in modern medicinal chemistry, possessing a wide spectrum of biological activity with applications in several different fields. The enormous amount of data reported regarding the molecular struc- ture–activity relationship of BZD drugs allows efficient approaches to the design of more

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promising results in terms of cytotoxicity and inhibition of the bovine cathepsin B, with IC50 values in the low mM range. More recently, Barros and coworkers carried out, for the first time, anticonvulsant studies in vivo with palladacycle-derived BZD drugs (diazepam) [50]. The anticonvulsant potential of the dimeric complexes (see Table1, Entry 19) was evaluated using two animal models (mice): pentylenetetrazole (PTZ)- and picrotoxin (PTX)-induced convulsions. The dimer with an acetate bridge significantly increased latency and protected the animals against convulsions induced by PTZ and PTX, while the analogous chloro derivative was effective (p b 0.01) only in the PTZ model. These effects appear to be mediated through the GABAergic system. A possible mechanism of action of the Pd(II)-diazepam-H complexes was also confirmed with the use of flumazenil (FLU), a GABAA-benzodiazepine receptor complex site antagonist. This was the first report of the anticonvulsant properties of metallo- BZD drugs, opening a new area in the development of novel drugs for the treatment of neurological pathologies.

4. Conclusions Benzodiazepines represent an important family of compounds in modern medicinal chemistry, possessing a wide spectrum of biological activity with applications in several different fields. The enormous amount of data reported regarding the molecular structure– activity relationship of BZD drugs allows efficient approaches to the design of more effective drugs. This review provides details of studies that confirm the formation of organometallic complexes derived from benzodiazepines, with several metals coordinated to the organic portion. This characteristic allows alternative compounds and candidates for new drugs to be obtained. However, although the rich chemistry of BZD drug molecules allows the incorporation of metal atoms into their molecular skeleton (as discussed in this review paper), few examples have been synthesized and not all of them have been evaluated to determine their pharmacological potential. This review highlights the need for more research groups to explore the potential of the pharmacological activity of metallo- BZD compounds in the near future.

Funding: This research was supported by Conselho Nacional de Desenvolvimento Científico e Tec- nológico (CNPq) project No. 408139/2018-8, Financiadora de Estudos e Projetos (FINEP), Fundação de Amparo à Pesquisa do Estado de Alagoas (FAPEAL), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Instituto Nacional de Ciência e Tecnologia de Catálise em Sistemas Moleculares e Nanoestruturados (INCT-Catálise). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: The authors are grateful for the general financial support of CNPq, FINEP, FAPEAL, CAPES, and INCT-Catálise. MRM and SMPM are grateful to CNPq for a research fellowship and AVS acknowledges CAPES for scholarships. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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