Research Article Novel Organotin(IV) Schiff Base Complexes with Histidine Derivatives ...downloads.hindawi.com/journals/bca/2013/502713.pdf · 2019-07-31 · logical importance. In

Hindawi Publishing CorporationBioinorganic Chemistry and ApplicationsVolume 2013, Article ID 502713, 12 pageshttp://dx.doi.org/10.1155/2013/502713

Research ArticleNovel Organotin(IV) Schiff Base Complexes with HistidineDerivatives: Synthesis, Characterization, and Biological Activity

Ariadna Garza-Ortiz,1 Carlos Camacho-Camacho,1 Teresita Sainz-Espuñes,1

Irma Rojas-Oviedo,1 Luis Raúl Gutiérrez-Lucas,1

Atilano Gutierrez Carrillo,2 and Marco A. Vera Ramirez2

1 Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-Unidad Xochimilco, Calzada de Hueso 1100,Colonia Villa Quietud, 04960 Coyoacán, D.F., Mexico

2Departamento de Resonancia Magnética Nuclear, Universidad Autónoma Metropolitana, Unidad Iztapalapa, San Rafael Atlixco,No. 186, Col. Vicentina, 09340 Iztapalapa, D.F., Mexico

Correspondence should be addressed to Carlos Camacho-Camacho; [email protected]

Received 18 March 2013; Accepted 2 June 2013

Academic Editor: Claudio Pettinari

Copyright © 2013 Ariadna Garza-Ortiz et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Five novel tin Schiff base complexes with histidine analogues (derived from the condensation reaction between L-histidine and3,5-di-tert-butyl-2-hydroxybenzaldehyde) have been synthesized and characterized. Characterization has been completed by IRand high-resolution mass spectroscopy, 1D and 2D solution NMR (1H, 13C and 119Sn), as well as solid state 119Sn NMR. Thespectroscopic evidence shows two types of structures: a trigonal bipyramidal stereochemistry with the tin atom coordinated tofive donating atoms (two oxygen atoms, one nitrogen atom, and two carbon atoms belonging to the alkyl moieties), where onemolecule of ligand is coordinated in a three dentate fashion.The second structure is spectroscopically described as a tetrahedral tincomplex with four donating atoms (one oxygen atom coordinated to themetal and three carbon atoms belonging to the alkyl or arylsubstituents), with one molecule of ligand attached. The antimicrobial activity of the tin compounds has been tested against thegrowth of bacteria in vitro to assess their bactericidal properties. While pentacoordinated compounds 1, 2, and 3 are describedas moderate effective to noneffective drugs against both Gram-positive and Gram-negative bacteria, tetracoordinated tin(IV)compounds 4 and 5 are considered as moderate effective and most effective compounds, respectively, against the methicillin-resistant Staphylococcus aureus strains (Gram-positive).

1. Introduction

Theuse ofmetal complexes as chemotherapeutic agents in thetreatment of illness, which are a major public health concern,appears as a very attractive alternative.The success of cisplatinfor the treatment of testicular and ovarian cancer attractedresearch attention to othermetal-based antineoplastic agents.Metal-based compounds are of particular interest due to theirphysical and chemical properties. Properties such as ligandexchange rates, redox properties, oxidation states, coordina-tion affinities, solubility, biodisponibility, and biodistributioncould be modified in order to increase the therapeutic effectwhile reducing the side effects.

Although the design of a metal-based compound withgood therapeutic index is still rather empirical, a numberof potential metal-based bactericide compounds have beenfully described in the literature. The evidence about specificor selective bonding of metals and organometallic species todonor sites in biological structures is very limited, so trustablemechanisms of biological activity and valid structure-activityrelationships are limited as well.

One approach that could produce successful resultsinvolves the metal coordination of ligands with well-knownbiological activity. In this way, the designed metal-basedcompound combines ligands with an important biologicalactivity and pharmacologically active metals in a single

2 Bioinorganic Chemistry and Applications

chemical moiety. This strategy could produce enhancedefficacy and reduced toxic or side effects while loweringthe therapeutic doses and/or overcoming drug resistancemechanisms. Additionally the metal could act as a carrierand/or stabilizer of the drug until it is able to reach thetarget. At the same time, the organic ligand with well-knownbiological activity could transport and protect themetal, thenavoiding side reactions on its route to the potential targets.Themetal-ligand combined effectsmay result in an importantimprovement in the activity of the resulting coordinationcompounds [1, 2].

Amino acids and their derivatives are excellent ligandcandidates due to their coordination properties and bio-logical importance. In addition, their solubility propertiesand specific mechanisms of transport could facilitate theirbiological uptake. In particular histidine is a very importantbioactive amino acid with multiple physiological functions.

The histidine binding to transition metal ions in bio-logical systems has a major physicochemical role in severalproteins, as the X-ray structural determination studies ofmetalloproteins like carbonic anhydrase, carboxypeptidase,plastocyanin, or azurin among others have demonstrated[3]. Additionally, histidine plays a major role in the zincmetabolism acting as themajor zinc bindingmoiety in serum[4].

Schiff bases represent an important group of compoundsin organic chemistry because they are starting materials inthe synthesis of industrial products where carbon-nitrogenbonds are present [5]. In particular, thisN–Cbond is involvedin several biological functions allowing the Schiff basesto behave, for instance, as antimicrobial, anti-inflamatory,antitumour, or antiviral drugs [6].

The design of organotin derivatives with biologicallyimportant ligands, like antibiotics [7, 8], anticancer drugs,[9] and some other biologically relevant substrates [10], hasbeen explored in the past years [11]. Organotin derivatives ofamino acids have been of interest as possible biocides [12]; forexample, tricyclohexyltin alaninate is a powerful fungicideand bactericide [13]. This compound has been described asa substrate of peptide syntheses as well [14]. Amino acidsand dipeptides which are considered potentially polydentateligands could afford interesting structural possibilities whencoordinated to organotin(IV) groups, since organotin(IV)compounds adopt higher coordination numbers wheneverfavorable conditions exist [15].

One of our research goals is the study of organotin(IV)compounds with important biological activity. In this orderof ideas we designed, prepared, and characterized diorgan-otin and triorganotin derivatives of an L-histidine Schiffbase analogue, with biological application as antibacterialcompounds. The L-histidine derivative was obtained bycondensation reaction of L-histidine and 3,5-di-tert-butyl-2-hydroxybenzaldehyde. Posterior complexation of the L-histidine analogue was achieved with tin(IV) organometallicreagents.

To the best of our knowledge there are no reports onorganotin(IV) compounds of L-histidine Schiff base deriva-tives. We have characterized these compounds not only

spectroscopically but also with regard to their antibacte-rial activity against Escherichia coli, Staphylococcus aureus,Pseudomona aeruginosa, Shigella dysenteriae, Salmonellatyphimurium, Salmonella typhi, Proteus mirabilis, Kleb-siella pneumonia, and Serratia marcescens. The compoundsdescribed in this work are all new and some of them show-ing promising antibacterial activity for methicillin-resistantStaphylococcus aureus strains (Gram-positive).

2. Experimental

2.1. Materials and Methodology. Di-n-methyltin oxide,Di-n-butyltin oxide, di-n-phenyl oxide, bis-n-tributyltinoxide, triphenyltin hydroxide, L-histidine 99%, and 3,5-di-tert.butyl-2-hydroxybenzaldehyde 99%were purchased fromAldrich and were used without further purification. Solventswere freshly distilled before use following the standardprocedures. Elemental analyses were performed in an Eager300 analyzer. IR spectra were obtained on a Nicolet FT-55Xapparatus as KBr discs of each compound. Melting pointswere measured on a Fisher-Johns melting point apparatusand are uncorrected. 1H, 13C and 119Sn NMR spectra wererecorded with a Varian spectrometer operating at 300MHzusing CDCl

3or CD

3OD as solvent and TMS as a reference.

Solid state 119Sn NMR spectra were recorded with a BrukerAVANCE-II, 300MHz NMR spectrometer, using a 4mmCP-MAS probe. 119Sn chemical shift referencing is towardtetramethyltin. High-resolution mass spectra were obtainedby LC/MSD TOF on an Agilent Technologies instrumentwith APCI as ionization source.

2.1.1. Synthesis of Tin Derivatives

Compounds 1–5. To a solution of 3,5-di-tert-butyl-2-hydroxybenzaldehyde (2mmol, 468mg) in 16mL of tolueneat RT, L-histidine (2mmol, 310.32mg), 6mL of ethanol, andthe corresponding tin derivative (2mmol) were successivelyadded to a flask equipped with a Dean-Stark moisture trap(filled with dry toluene). After 24 h under gentle reflux,the solvents were evaporated giving yellow solids in allcases. Purification was achieved by recrystallization fromdichloromethane-hexane (3 : 1) mixtures.[(C21H27N3O3)Sn(CH

3)2](0.4CH

2Cl2) (1). A yellow crys-

talline solid 1 was obtained in moderate yield (350mg,33.76%). Elemental analysis for C

23,4H33,8

Cl0,8N3O3Sn: Calcd

(%): C, 50.90; N, 7.61; H, 6.17. Found (%): C, 50.96; N,7.27; H, 5.75. IR (KBr disk) cm−1: 3445 s, 2958–2869 s, 1659 s,1613 s, 1539m, 1461 w, 1429m, 1362m, 1172m, 784w, 746w,655w, 623w, 530w, 470w. mp = 171–174∘C. Electrospraymass (masses given based on 1H, 12C, 16O, 14N, and120Sn): the isotopic distributions were compared with thecalculated. Only tin-containing fragments are given, m/z:[M+] ([(C

21H28N3O3)Sn(CH

3)2]+), 520 (100%); (3[M+] +

CH2Cl2), 542 (16%); ([M+] + M), 1037 (7%).

[(C21H27N3O3)Sn(CH

2CH2CH2CH3)2](0.5CH

2Cl2) (2). A

yellow crystalline solid 2 was obtained in moderate yield(520mg, 43.16%). Elemental analysis for C

29,5H46ClN3O3Sn:

Bioinorganic Chemistry and Applications 3

Calcd(%): C, 54.94; N, 6.52; H, 7.19. Found (%): C, 54.70;N, 6.08; H, 7.32. IR (KBr disk) cm−1: 3447m, 3276m, 2958–2869 s, 1668 s, 1611 s, 1539m, 1460–1426m, 1363m, 1172m,840w, 746w, 655w, 622w, 532w, 480w. mp = 110–116∘C.Electrospray mass (masses given based on 1H, 12C, 16O,14N, and 120Sn): the isotopic distributions were comparedwith the calculated. Only tin-containing fragments are given,m/z: [M+] ([(C

21H28N3O3)Sn(CH

2CH2CH2CH3)2]+), 604

(100%); (4[M+] + CH2Cl2), 625 (11%); ([M+] +M), 1205 (3%).

[(C21H27N3O3)Sn(C

6H5)2] (3). A yellow solid 3 was

obtained in moderate yield (660mg, 47.66%). Elementalanalysis for C

33H37N3O3Sn: Calcd(%): C, 61.70; N, 6.54;

H, 5.81. Found(%): C, 61.59; N, 6.39; H, 5.21. IR (KBrdisk) cm−1: 3448m, 3306m, 2957–2870 s, 1668w, 1618 s,1538m, 1461m, 1431m, 1361m, 1253m, 1171m, 837w, 731m,654w, 620w, 536w, 450w. mp = 181–185∘C. Electrospraymass (masses given based on 1H, 12C, 16O, 14N, and120Sn): the isotopic distributions were compared with thecalculated. Only tin-containing fragments are given, m/z:[M+] ([(C

21H28N3O3)Sn(C

5H5)2]+), 643 (100%); (4[M+] +

CH2Cl2), 666 (12%); ([M+] + M), 1285 (6%).

[(C21H28N3O3)Sn(CH

2CH2CH2CH3)3] (4). A yellow crys-

talline solid 4 was obtained in moderate yield (410mg,31.03%). Elemental analysis for C

33H55N3O3Sn: Calcd(%):

C, 60.01; N, 6.36; H, 8.39. Found(%): C, 60.29; N, 6.46;H, 7.99. IR (KBr disk) cm−1: 3091 w br, 2955–2866 s, 1611 s,1460–1439m, 1366 s, 1269–1239m, 1174w, 818 s, 655m, 450w.mp = 200–203∘C. Electrospray mass (masses given basedon 1H, 12C, 16O, 14N, and 120Sn): the isotopic distributionswere compared with the calculated. Only tin-containingfragments are given, m/z: [HSn(CH

2CH2CH2CH3)3

+], 291(87%); [M+] ([(C

21H29N3O3)Sn(CH

2CH2CH2CH3)3]+), 662

(100%); ([M+] + Bu3Sn), 951 (41%).

[(C21H28N3O3)Sn(C

6H5)3](2.2CH

2Cl2)(3.6C

6H5CH3) (5).

A yellow solid 5 was obtained in moderate yield (380mg,15.52%). Elemental analysis for C

66.4H76.2

N3O3SnCl4.4

Calcd(%): C, 64.37; N, 3.39; H, 6.20. Found(%): C, 64.27;N, 3.35; H, 5.56. IR (KBr disk) cm−1: 3266–3060m, 2958–2864 s, 1962–1716w, 1631–1595 s, 1479m, 1427 s, 1361m,1260w, 1180w, 1073 s, 729 (CH

2Cl2) s, 697 (CH

2Cl2) s,

657m, 455m, 443m. mp = 203–205∘C. Electrospray mass(masses given based on 1H, 12C, 16O, 14N, and 120Sn): theisotopic distributions were compared with the calculated.Only tin-containing fragments are given, m/z: [M+]([(C21H29N3O3)Sn(C

6H5)3]+), 722 (23%); [C

21H29N3O3]+,

371 (22%); [C6H5]+, 77 (100%).

2.1.2. Biological Activity: Antibacterial Screening

Bacterial Strains. Bacterial reference cultures and self-collection strains were used to test a broad spectrumof bacteria. The strains used in this study wereEnterohemorrhagic Escherichia coli EDL933, StaphylococcusaureusMRSA, Pseudomona aeruginosa ATCC27853, Shigelladysenteriae FMUNAM98863, Salmonella typhimuriumATCC14028, Salmonella typhi FMUNAM95073, Proteus

mirabilis RTX339, Klebsiella pneumoniae ATCC8045, andSerratia marcescens TSUAM1.

Isolates of methicillin-resistant S. aureus (MRSA) wereobtained from our collection [16]. Identification of S. aureuswas performed by the coagulase test with human plasma.MRSA strains were confirmed to be methicillin resistant bytesting for methicillin susceptibility and by PCR detection ofthemecA gene.

The organotin compounds were tested in vitro for theantibacterial activity against clinical pathogen and referencestrains using the disk diffusion test, in accordance with theprocedures outlined by CLSI (formerly the NCCLS) [17].Muller-Hinton agar was used for this method. Inocula wereadjusted to 1.5 × 108 CFUmL (0.5 McFarland). BD BBLTMSensi-Discs (Becton Dickinson and Company, Sparks, MD,USA)were used as growth inhibition controls.The antibioticstested were Kanamycin (30 𝜇g), Vancomycin (30𝜇g), Chlo-ranphenicol (30𝜇g), Cloxacillin (1 𝜇g), and Penicillin (10 IU).

The degree of effectiveness was measured by determin-ing the diameters of the zone of inhibition caused by thecompound. Compounds (1–5) were used, each one with aconcentration of 6mg per disc. The plates were incubated at37∘C for 24 h. During incubation time the complexes diffusedfrom the disc to the medium. Effectiveness was classifiedinto four different categories based on diameter of the zoneof inhibition: (+++) most effective, (++) moderate effective,(+) slightly effective, and (−) noneffective. The results werecompared against those of controls, which were screenedsimultaneously. The determinations were performed by trip-licate and the results are reported as average values.

3. Results and Discussion

3.1. Synthesis. Compounds 1–5 are prepared by in situcondensation of L-histidine with 3,5-di-tert-butyl-2-hydroxybenzaldehyde in the presence of the correspondingtin(IV) derivatives: di-n-methyltin oxide, di-n-butyltin oxide,di-n-phenyltin oxide, bis-tri-n-butyltin oxide, or triphenyltinhydroxide. These conditions affording compounds 1, 2, 3,4, and 5, respectively, and the proposed structures areshown in Figure 1. In all complexes, the Schiff base histidinederivative is coordinated to the alkyl- or aryl-tin(IV) ionthrough the oxygen atom belonging to the carboxylate group.Compounds 1, 2, and 3 are also coordinated to the Schiffderivative through the imino nitrogen and the phenolicoxygen in order to stabilize a 5-coordinated tin(IV) core. Incompounds 4 and 5, tin is 4-coordinated.

All complexes are light yellow crystalline solids which arestable in air. Most of them are soluble in organic solvents.Compound 5 shows a very limited solubility in ethanol.Empirical formulae and proposed structures for all thecompounds are confirmed by analytical and spectral datawhich are described in the following lines.

3.2. Infrared Spectroscopy. The coordination sphere on com-pounds 1–5 has been analyzed by means of FT-IR. Thebinding mode of the L-histidine Schiff base derivative to


HN

NN

O

O

OSn

HN

N

NO

O

OSn

HN

NN

O

O

OSn

CH3CH3

HN

HN

NN

O

OSn

OHN

N

OH

O

O

Sn

N

H2N OH

OH

O

O

HN

H+

n-Me2SnO

n-Bu2SnO

n-Ph2SnO

(n-Bu3Sn)2O

Ph3SnOH

1

2

3

4 5

3

Figure 1: Schematic representation of compounds 1–5 and their synthetic procedure.

metal in the complexes has been studied by comparison ofIR spectra of free ligand precursors and metal complexes.The absence of the broad O–H stretching frequencies inthe region 3170–2870 cm−1 denotes that deprotonation andcoordination of the carboxylate group to tin have taken partduring the complex formation in all compounds.

Free L-histidine shows a strong band at 1630 cm−1, whichis assigned to the stretching vibration of the C=O bond.There are also medium strength bands at 1589–1571 cm−1that are assigned to the C=N and C=C stretching vibration.The corresponding bands in the tin compounds are shiftedto higher frequencies as expected, due to tin coordination.For pentacoordinated compounds 1, 2, and 3, the observedshifts are in the range 40–30 cm−1. For tetracoordinated tincompounds 4 and 5, the shifts are smaller in the range 11–2 cm−1. This observation is compatible with some other 4-coordinated structures described in the literature [9, 18].

Moreover, the azomethine band is easily observed at 1539–1538 cm−1 region for compounds 1, 2, and 3. This red shiftis considered the result of coordination of this moiety to themetal center (see Figure 1) [6]. For compounds 4 and 5, this](C=N) band is not observed in such region, evidence thatdemonstrates that the azomethine moiety is not involved incoordination to tin.

The carboxylatemoiety in compounds 1–5has been struc-turally characterized by the intense and broad absorptions inthe range 1660–1330 cm−1, due to asymmetric and symmetricstretching modes. The difference between asymmetric andsymmetric O–C=O stretching vibrations (Δ]) has been usedto determine the mode of coordination of a carboxylate lig-and with metals [9, 19, 20]. Differences larger than 250 cm−1are indicative of monodentate carboxylate complexes, whileΔ] values in the range 150–250 cm−1 are indicative of com-pounds with carboxylate-bridged structures. Finally, it is


presumed that a chelation is present, if this parameter is lowerthan 150 cm−1.

The Δ] = ]as(OCO) − ]s(OCO) for the proposedpentacoordinated compounds 1, 2, and 3 is the following: Δ]= 297, 305, and 307 cm−1, respectively. For the tetracoordi-nated compounds 4 and 5, Δ] is Δ] = 245 and 270 cm−1,respectively. All values of Δ] for compounds 1–5 are in therange 310–245 cm−1, and this evidence strongly suggests thatthe carboxylate group in all compounds adopted a unidentatenature.

Some other stretching frequencies of interest are thosecharacteristics of the ](Sn–C), ](Sn–O), and ](Sn–N)bonds frequencies. All these values are consistent withthose detected in a number of organotin(IV)-oxygen,organotin(IV)-carbon, and organotin(IV)-nitrogen deriva-tives [10, 21, 22]. Worthy mentioning is the presence oftwo ](Sn–O) weak bond frequencies for compounds 1 (655,623 cm−1), 2 (655, 622 cm−1), and 3 (654, 620 cm−1) [23].Thisevidence could be explained in views of two different Sn–Obonds. Compounds 4 and 5 only show one stretching Sn–Ovibration.Then it suggests that just one type of Sn–O bond isobserved, confirming the tetracoordinated sphere for tin inthe compounds.

The recorded high-resolution mass spectra of 1–5 andmolecular ion peaks are in agreement with the proposedstructures. The MS peaks present the correct isotopomerdistribution, as expected for the tin isotope distribution.

For instance, in complex 1, the degradation patternshows peaks at 520 (100%m/z) that indicates molecular ionpeak [M+, [(C

21H28N3O3)Sn(CH

3)2]+], whereas peaks at 542

(16%m/z) and 1037 (7%m/z) show 3[M+] + CH2Cl2and

[M+] + M, respectively (Figure 2). Complex 2 shows thenormal trends of degradation patterns (Figure 3).The variousdegradation peaks at 604 (100% m/z) showmolecular ion; thepeaks at 625 (11%m/z) show 4[M+] + CH

2Cl2; peaks at 1205

(3%m/z) show [M+] + M.Complexes 3–5 again show a similar pattern of degrada-

tion.

3.3. Multinuclear NMR Spectroscopy. The 1H, 13C, and 119SnNMR spectra of compounds 1–4 have been recorded inCDCl

3or MeOD and the assignments obtained through 1D

and 2D experiments. When necessary, 119Sn NMR spectrahave also been recorded in the solid state. The very limitedsolubility of compound 5 prompted us to obtain the 13C and119Sn spectra in the solid state only.

The 1H NMR spectra assignment of compounds1–5 is based on integration values, chemical shifts,coupling constants, and 1H-13C HMQC experiments.Starting and model compounds spectra were alsouseful for comparison reasons [18]. The expectedresonances are observed for L-histidine, 3,5-di-tert-butyl-2-hydroxybenzaldehyde, tributyltin(IV), triphenyltin(IV),dibutyltin(IV), dimethyltin(IV), and dibutyltin(IV)moieties.Due to rapid exchange between the two nitrogen atoms of theimidazole ring and probably with deuterium from solvent,the N–H proton from the imidazole moiety is not observedin the spectra.

The results obtained are listed in Tables 1 and 2. Forcomparative purposes the data are tabulated using a generalnumbering scheme (Figure 4).

The characteristic resonance peak in the 1HNMR spectraof compounds 1–5, at 8.4–7.9 ppm, reveals the presence of theimino moiety H–C11=N, which confirms the condensationof the L-histidine derivative (Figure 1). Additionally, forcompounds 1, 2, and 3, coordination to Sn(IV) is confirmedby small coupling peaks associated to the H–C11=N reso-nance peak.This spin-spin coupling between the azomethineproton and the tin nucleus, 3𝐽(Sn–N=CH), presents cou-pling constants in the range 52–70 ppm, values that are inagreement with a magnetic coupling between the tin nucleilocated in a transposition with respect to the azomethineproton [23, 24]. In complex 1, characteristic peaks of themethyl groups attached to the tin atom are observed at 0.64and 0.56 ppm as expected [25]. In complex 2, the presence ofthe Sn–Bu

2resonance peaks, H𝛼, H𝛽, H𝛾, and H𝛿, confirms

the chemical nature of the dibutyl moiety of 2. In compound4, the butyl protons appear in the range 0.80–1.53 cm−1, withmultiplicity and integration values in agreement with theproposed structure. For complex 3 the signals correspondingto the phenyl groups are clearly observed.

The 1H NMR spectra of all the complexes present aresonance peak assigned to H–C12 moiety. This moiety isattached to the carboxylic group and it is observed in therange 4.14–4.59 ppm. These are clearly downfield shiftedwhen comparing with the resonance peak in the free ligandat around 3.98 ppm (D

2O). This evidence suggests that the

downfield effect is due to coordination to tin. In this orderof ideas, the 1H NMR spectra of all complexes present aresonance for H–C14 with the same downfield shift effect(3.15–3.47), with a minimal shift for compounds 3 and 4. Thesignals corresponding to the tert-butyl protons of the ligandhave also been assigned and all data is presented in Table 1.

Table 2 presents the 13C NMR and 119Sn NMR data forthe synthesized organotin compounds following the samenumbering scheme presented on Figure 4. The very limitedsolubility of compound 5 prompted us to obtain the 13C and119Sn spectra in the solid state.The 13CNMRcharacterizationwas obtained through comparison with starting materials,and structural related analogues.

The 13CNMRdata explicitly resolved the resonances of allthe distinct carbon atoms present in all the complexes. The13C NMR data for all compounds show that the resonancepeak of the carboxyl carbon, C13, appears in the range from173 to 177 ppm, in agreement with the data reported foranalogous derivatives [18]. The signal of the imine carbon,C11, appears in the 166–177 ppm range, showing in some casesa marked deshielding effect with respect to the imine group.The Sn–N coordination should produce anN–Cpolarization.Thebiggest polarization effect could be observed, as expected,in compound 3 where phenyl groups are attached to tin.

For compounds 4 and 5, the signal of the imine carbon,C11, appears in the range 165–167 ppm, which is consistentwith the lack of the Sn–N coordination. The same high fieldshift effect could be observed in case of C2.


1.7e51.7e51.6e51.6e51.5e51.5e51.4e51.4e51.3e51.3e51.2e51.2e51.1e51.1e51.0e59.5e49.0e48.5e48.0e47.5e47.0e46.5e46.0e45.5e45.0e44.5e44.0e43.5e43.0e42.5e42.0e41.5e41.0e4

5000.00.0

1.7e51.7e51.6e51.6e51.5e51.5e51.4e51.4e51.3e51.3e51.2e51.2e51.1e51.1e51.0e59.5e49.0e48.5e48.0e47.5e47.0e46.5e46.0e45.5e45.0e44.5e44.0e43.5e43.0e42.5e42.0e41.5e41.0e4

5000.00.0

N NHN

O

O

O

Sn CH3CH3

Molecular weight: 520.15Chemical formula: C23 H33N3O3SnH

+

511.0 512.0 513.0 514.0 515.0 516.0 517.0 518.0 519.0 520.0 521.0 522.0 523.0 524.0 525.0 526.0 527.0 528.0

516.1615

517.1634

518.1617

519.1640

520.1622

521.1656

522.1652 524.1657

(b) Simulated spectrum

(a) Observed spectrum

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

520.1622

521.1656

542.1451

1037.3198

500 505 510 515 520 525 530 535

512.1643

516.1613

517.1631

518.1616

519.1635

520.1621

521.1650

522.1640

523.1665

524.1649

525.1679

Inte

nsity

(cou

nts)

Inte

nsity

(cou

nts)

m/z (amu)

m/z (amu)

m/z (amu)

Figure 2: Observed mass spectrum (a) and simulated spectrum (b) of complex 1.

O

O

O

SnNN

HN

Molecular weight: 604.407

Chemical formula: C29 H45N3O3SnH+

(b) Simulated spectrum

(a) Observed spectrum

596 598 600 602 604 606 608 610

600.2554

601.2571

602.2558

602.5581

603.2575

604.2565

604.5582

605.2590

606.2583 608.2589

590 600 610 620

596.2582 599.2578

600.2552

601.2571

602.2556

603.2576

604.2562

605.2590

606.2584608.2589

609.2619

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

101.0107229.1427

242.285626.2382

604.2565

605.2590

1205.4860

8.9e58.5e5

8.0e5

7.5e5

7.0e5

6.5e5

6.0e5

5.5e5

5.0e5

4.5e5

4.0e5

3.5e5

3.0e5

2.5e5

2.0e5

1.5e5

1.0e5

5.0e4

0.0

Inte

nsity

(cou

nts)

m/z (amu)

m/z (amu)

m/z (amu)

Figure 3: Observed mass spectrum (a) and simulated spectrum (b) of complex 2.


HN

N

N

C1

C2C3

C4

C5C6

C7

C8

C8C8

C9

C10

C10

C10

C11

C12 C13

C14C15C17

C19

O

O

O

R

R

Sn

HN

N

N

C1

C2C3

C4

C5C6

C7

C8

C8C8

C9

C10

C10

C10

C11

C12 C13

C14C15C17

C19

O

OH

O

R

R

R

Sn

Figure 4:Numbering systemused in pentacoordinated and tetracoordinated tin(IV) compounds for theNMR spectra assignment. R=CH3–,

CH3CH2CH2CH2– (CH𝛼, CH𝛽, CH𝛾, CH𝛿) or C

6H5– (CHo, CHm, CHp).

Table 1: 1H NMR data of compounds 1–5.

Compound numbering 1CDCl32

CDCl33

CD3OD4

CDCl3H11 8.13 (s, 1H) [58] 7.91 (s, 1H) [52] 8.33 (s, 1H) [70] 8.34 (s, 1H)H17 7.63 (s, 1H) 7.60 (s, 1H) 7.08 (s, 1H) 7.48 (s, 1H)H5 7.54 (d, 1H) [2.4] 7.51 (d, 1H) [2.7] 7.63 (d, 1H) [2.4] 7.35 (d, 1H) [2.4]H3 6.85 (d, 1H) [2.4] 6.76 (d, 1H) [2.7] 7.07 (d, 1H) [2.5] 7.03 (d, 1H) [2.4]H19 6.80 (s, 1H) 6.73 (s, 1H) 6.52 (s, 1H) 6.73 (s, 1H)H12 4.43 (m, 1H) 4.43 (m, 1H) 4.59 (m, 1H) 4.14 (m, 1H)

H14 3.39–3.25(m, 2H)3.47–3.44

3.11–3.07 (m, 2H)3.27–3.16(m, 2H)

3.31–3.15(m, 2H)

H𝛾 1.73–1.51(m, 4H)1.27–1.28(m, 6H)

H𝛼 1.4–1.3 (m, 4H) 1.27–1.28 (m, 6H)

H𝛽 1.4–1.3 (m, 4H) 1.53(m, 6H)

H𝛿 0.92 (t, 3H) [7.3]0.79 (t, 3H) [7.3] 0.80 (t, 9H) [7.3]

Ho 7.87–7.82(m, 4H)

Hm 7.58–7.29(m, 4H)

Hp 7.58–7.29(m, 4H)H8, H10t-butyl CH3

1.37 (s, 9H)1.28 (s, 9H)

1.37 (s, 9H)1.25 (s, 9H)

1.47 (s, 9H)1.30 (s, 9H)

1.41 (s, 9H)1.28 (s, 9H)

CH3-Sn0.64 (s, 6H),0.56 (s, 6H)

Data obtained at 500MHz. Chemical shifts in ppm with respect to TMS; coupling constants in hertz, 𝑛𝐽(1H–1H) and 𝑛𝐽(1H–119/117Sn) between brackets.s: singlet; d: doublet; t: triplet; m: complex pattern. Assignment base in 1D and 2D NMR studies.


Table 2: 13C and 119Sn NMR data of compounds 1–5.

Compound numbering 1CDCl32

CDCl33

CD3OD4

CDCl35

Solid stateC11 174.33 174.54 177.66 167.57 166.6C13 173.72 173.72 175.79 175.62 176.6C2 166.59 167.0 168.61 158.13 157.55C1 141.29 140.96 143.61 140.00 aC4 139.04 138.64 142.00 136.67 aC6 135.70 135.67 134.63 134.09 aC5 133.19 133.08 132.97 127.16 aC17 131.08 (b) 131.30 (b) 132.64 (b) 131.98 (b) —C3 129.49 129.47 129.95 126.24 aC19 119.78 (b) 119.84 (b) 118.00 (b) 123.69 (b) 120.2C15 116.61 116.51 119.66 117.98 117.5C12 67.18 67.42 68.56 72.02 64.0C7 35.27 35.19 35.45 35.08 34.68C9 34.06 33.93 34.17 34.16 33.86C14 33.97 33.90 (b) 33.98 29.50 (b) 29.5C8 31.23 31.10 30.56 31.54 31.0C10 29.44 29.36 29.47 29.50 29.2

CH31.23, 0.933[653/648]

C𝛽

27.00 [38]26.85 [n.o.] 28.07 [24]

C𝛾

26.74 [91]26.56 [92] 27.02 [72/70]

C𝛼

22.26 [599]22.20 [599] 17.73 [435/415]

C𝛿

13.5913.39 13.66

Ci142.67 [n.o.]141.27 [n.o.] a

Co137.78 [53]137.32 [53] a

Cm130.54 [87]130.23 [83] a

Cp132.12 [n.o.]131.64 [16] a

119Sn −162.16CDCl3−197.58CDCl3

−369CD3OD

39.44CDCl3

No soluble119SnSolid state −169.50 −196.68 −455.87 −112.59 −122.09

Chemical shifts in ppm with respect to TMS; 119Sn chemical shifts in ppm with respect to (CH3)4Sn;𝑛𝐽(13C–119/117Sn) coupling constants between square

brackets. n.o.: not observed.a: Unambiguous assignment of this resonance peak was not reached because there are multiple broad signals included in the range 143–127 ppm.

The 1𝐽(13C–117/119Sn) coupling constant values are ofmajor importance in the estimation of the coordinationmodeof the tin atom.The values of 1𝐽(in solution) can be related tothe tin-coordination number.Thus these values are a qualita-tive evidence of the organotin(IV) compound structure [26–28]. Pentacoordinated organotin(IV) ions show 1𝐽 values

between 450–610Hz, while tetracoordinated organotin(IV)ions show values in the range 325–440Hz [18].

The 1𝐽 coupling constants for compounds 1 and 2 suggesta pentacoordinated nature in solution. For compound 3 the1𝐽 coupling constants are not observed. For compound 4 the1𝐽 values are 415 and 435Hz, suggesting a four-coordinated


S. aureus P. mirabilis S. typhimurium

P. aeruginosa S. dysenteriae S. typhi

E. coli S. marcescens K. pneumoniae

1

2

34

5

1

2

3 4

5

1

2

3

4

5

1

2

3 4

5

1

2

3 4

5

12

3 4

5

1

2

3

4

5

12

3

4

5

1

2

34

5

(1) Compound1

(2) Compound 2

(3) Compound 3

(4) Kanamycin

(5) Chloranphenicol

(1) Compound1

(2) Compound 2

(3) Compound 3

(4) Kanamycin

(5) Chloranphenicol

(1) Compound1

(2) Compound 2

(3) Compound 3

(4) Kanamycin

(5) Chloranphenicol

Figure 5: Photographs of the antimicrobial activities of compounds 1, 2, and 3 against S. aureus, P. mirabilis, S. typhimurium, P. aeruginosa,S. dysenteriae, and S. typhi, showing their inhibition zone.

structure in solution. The 2𝐽(13C–117/119Sn) = 72/70Hz alsosuggests a tetrahedral geometry for 4.

The correct assignment of 13C NMR resonances of then-butyl group in 2 is determined by the coupling constants𝑛𝐽 (13C–117/119Sn). Compound 2 displays a resonance peak

for the n-butyl C𝛼 at 21-22 ppm with two very close couplingsignals.This observation provides additional evidence for themagnetic equivalence of the butyl moieties. The same crite-rion is followed in the assignment of 13C NMR resonances ofthe 𝑛-butyl group in 4. Themagnetic equivalence of the butylmoieties is concluded from the spectra.

In order to provide further evidence for the proposedstructures of the complexes in solution, 119Sn NMR spectraare analyzed. The 119Sn chemical shifts are extremely depen-dent on the coordination number for tin and the nature ofthe groups directly coordinated to the metal. The chemicalshift values for compounds 1–3 are within the expected rangefor pentacoordinated tin ions with a single resonance peak insolution. There are not changes in the solid state spectra ascould be appreciated by the chemical shifts observed in thecorresponding solid 119Sn NMR spectra. Thus, the structural

composition in the solid state is retained in solution forcompounds 1, 2, and 3.119Sn NMR spectrum of compound 4 exhibits a single

resonance in solution, with a chemical shift of 39.44 ppm. Inthe solid state, the chemical shift observed is characteristic ofa five-coordinated compound. This evidence suggests that inthe solid state inter- or intramolecular interactions could beresponsible of the increase in coordination number.

No 119Sn resonance could be observed for compound 5 insolution, due to its limited solubility. In addition the chemicalshift observed in the 119Sn NMR spectrum in the solid statesuggests the tetracoordinated nature of 5. Despite the Lewisacidity that a phenyl group could induce in the tin atom [29],this is very low as this compound appears unable to extent itscoordination sphere.

3.4. Microbial Activities. Organotin(IV) cations with bio-logical active ligands are a major research debt for thescientific efforts in the search of new metal-based drugs,but little work is available on the bactericidal properties oforganotin(IV) derivatives of amino acids in the literature. In


S. aureus P. mirabilis S. typhimurium

P. aeruginosa S. dysenteriae S. typhi

E. coli S. marcescens K. pneumoniae

12

34

1

2

3

4

1 2

34

12

34

12

3

4

1 2

34

12

34

1 2

34

12

34(1) Compound4

(2) Compound 5

(3) Vancomycin

(4) Chloramphenicol

(1) Compound4

(2) Compound 5

(3) Vancomycin

(4) Chloramphenicol

(1) Compound4

(2) Compound 5

(3) Vancomycin

(4) Chloramphenicol

Figure 6: Photographs of the antimicrobial activities of compounds 4 and 5 against S. aureus, P. mirabilis, S. typhimurium, P. aeruginosa, S.dysenteriae, and S. typhi, showing their inhibition zone.

Table 3: Antimicrobial activity of organotin(IV) compounds 1–5.

Strain Compound1 2 3 4 5

Staphylococcus aureus + − − ++ +++Proteus mirabilis RTX337 + + − − −Pseudomona aeruginosa + − − − −Salmonella typhi − + − − −Salmonella typhimurium − + − − −Escherichia coli 933 − + − − −Klebsiella − + − − −Serratia marcescens − − − − −Shigella dysenteriae − − − − +

particular, organotin derivatives of amino acids containingN-heterocycles bonded to the 𝛼-carbon should be studied inmore detail because of the well-known role of the histidineresidue binding properties. In particular it is importantto study the histidine binding properties to triorganotincompounds in order to provide evidence for importantmechanisms of biological activities [30].

In order to study the potential biological properties ofthe synthesized compounds, the bactericidal properties arestudied.

The degree of effectiveness was measured by determin-ing the diameters of the zone of inhibition caused by thecompound. The biological activity was then classified in 4categories on the bases of their diameter of growth inhibition:(+++) most effective, (++) moderate effective, (+) slightlyeffective, and (−) noneffective.

Compound 1 is slightly effective against both Gram-positive andGram-negative bacteria; 2 ismoderately effectiveagainst Gram-negative bacteria; 3 does not show antibacterialactivity at all.These results are comparable to related pentaco-ordinated tin(IV) compounds with Schiff bases derived fromamino acids reported in the literature [2].

Compounds 4 and 5 are moderate effective and mosteffective, respectively, against Staphylococcus aureus strains(Gram-positive). Results are presented in Table 3 and Figures5 and 6.

Thus the results clearly indicate that pentacoordinatedtin(IV) compounds of Schiff bases derived from L-histidinehave exhibited moderate to minimal bactericidal propertieswhile tetracoordinated tin(IV) compounds have presented


high activity against the Gram-positive methicillin-resistantS. aureus. Even more, compound 5 as observed in Figure 6is more active when compared with standard referencesvancomycin and chloramphenicol against the same bac-teria under identical experimental conditions. These arevery promising results in particular for the triphenyltin(IV)derivative.

It has been described that triorganotin compounds aresignificantly more biocidally active than other classes [30],statement that is true based on the results of this work.

4. Conclusions

Five novel tin(IV) compounds have been synthesized. Thecompounds are coordinated to a histidine analogue. Withthe help of various physicochemical techniques, the structureof the newly synthesized compounds has been proposed(Figure 1). It has been spectroscopically demonstrated thatthe Schiff base ligand derived from L-histidine and 3,5-di-tert-butyl-2-hydroxybenzaldehyde coordinates to tin(IV) ina tridentate and monodentate manner producing pentacoor-dinated and tetracoordinated tin(IV) compounds.

Amino acids are very difficult ligands to work withdue to their many donor groups and reduced solubility innonpolar solvents. Nevertheless it was possible to isolate purecompounds. The selection of the ligand, a biologically activeamino acid, has producedmetal-ligand combined effects thatmay result in an important improvement in the activity of theresulting coordination compounds.

The triphenyltin(IV) complex 5 has been found to bemost active against the Gram-positive methicillin-resistant S.aureus.

With these results, it is important to stress the need ofmore research in the synthesis, isolation, and characterizationof new organotin(IV) cations with biologically active ligands,in an effort to obtain important structure-activity relation-ships.

Acknowledgment

Ariadna Garza-Ortiz expresses gratitude to UniversidadAutonoma Metropolitana-Xochimilco for the posdoctoralfellowship.

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Research Article Novel Organotin(IV) Schiff Base Complexes with Histidine Derivatives ...downloads.hindawi.com/journals/bca/2013/502713.pdf · 2019-07-31 · logical importance. In