Synthesis, Characterization, Reactivity, Catalytic Activity, and Antiamoebic Activity of Vanadium(V) Complexes of ICL670 (Deferasirox) and a Related Ligand

Article abstract of DOI:10.1002/ejic.201501336

The reactions of [V^IVO(acac)₂] (acac = acetylacetonato) with two ONO tridentate ligands, 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (H₂L¹, I) and 3,5-bis(2-hydroxyphenyl)-1-phenyl-1,2,4-triazole

Full text of DOI:10.1002/ejic.201501336

DOI: 10.1002/ejic.201501336
Full Paper
Anticancer Complexes
Synthesis, Characterization, Reactivity, Catalytic Activity, and
Antiamoebic Activity of Vanadium(V) Complexes of ICL670
(Deferasirox) and a Related Ligand
Mannar R. Maurya,*[a] Bithika Sarkar,[a] Fernando Avecilla,[b] Saba Tariq,[c] Amir Azam,[c] and
Isabel Correia[d]
Abstract: The reactions of [VIVO(acac)2] (acac = acetylacet- together with 4,4′-bipyridyl). The oxidative bromination of thym-
onato) with two ONO tridentate ligands, 4-[3,5-bis(2-hydroxy- ol, catalyzed by these complexes, in the presence of KBr and
phenyl)-1,2,4-triazol-1-yl]benzoic acid (H2L1, I) and 3,5-bis(2- HClO4 with H2O2 as an oxidant, gives 2-bromothymol, 4-bromo-
hydroxyphenyl)-1-phenyl-1,2,4-triazole (H2L2, II) in methanol thymol, and 2,4-dibromothymol. The amounts of the catalyst,
lead to the formation of the oxidovanadium(V) complexes oxidant, KBr, HClO4, and the solvent were optimized for the
[VVO(μ-L1)(OMe)]2 (1) and [VVO(μ-L2)(OMe)]2 (2). In the presence maximum conversion of thymol. Both ligands and all complexes
of KOH/CsOH, they give the corresponding dioxidovanadium(V) were tested in vitro for antiamoebic activity against the
complexes. The isolated complexes K(H2O)[VVO2(L1)] (3), HM1:IMSS strain of Entamoeba histolytica by a microdilution
K(H2O)[VVO2(L2)]
(4),
Cs(H2O)[VVO2(L1)]
(5),
and method. The complexes are more potent amoebicidal agents
Cs(H2O)[VVO2(L2)] (6) along with 1 and 2 have been character- than the standard drug metronidazole. Toxicity studies against
ized by various spectroscopic techniques (FTIR; UV/Vis; H, 13C, a human cervical cancer cell line (HeLa) also confirm that these
1
and 51V NMR), elemental analysis, thermal studies, MALDI-TOF compounds are less cytotoxic than metronidazole.
MS analysis, and single-crystal analysis of 1a (complex 1 grown
Introduction
years.[5–8] In VHPOs, the vanadium centers bind covalently to
the Nε atoms of imidazole rings in the active sites of en-
zymes.[9,10] Therefore, we have selected 4-[3,5-bis(2-hydroxy-
phenyl)-1,2,4-triazol-1-yl]benzoic acid (ICL670, H2L1), and 3,5-
bis(2-hydroxyphenyl)-1-phenyl-1,2,4-triazole (H2L2, Scheme 1)
and prepared their vanadium(V) complexes. The obtained com-
plexes are able to model the structural features of VHPOs and
are also functional models, owing to their catalytic activity in
the oxidative bromination of thymol by H2O2.
4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic
acid
(ICL670), commonly known as deferasirox, is a promising drug
approved for the oral treatment of transfusional iron overload
in patients suffering from chronic anemia, including ꢀ-thalasse-
mia.[1] The complexing behavior of deferasirox and related li-
gands towards FeII and FeIII ions, their stability, redox properties,
and catalytic potential for Fenton reactions in biological media
have been investigated recently.[2]
Another relevant field based on vanadium chemistry is the
biological/medicinal potential of vanadium compounds.[11]
Their antiamoebic activity against Entamoeba histolytica[12] and
antitrypanosomal activity against Trypanosoma cruzi[13] have
been established in addition to other therapeutic applica-
tions.[11] E. histolytica, an aerobic parasitic protozoan, causes
life-threatening amoebiasis, a contagious disease of the human
gastrointestinal tract. According to the World Health Organiza-
tion, this disease causes approximately 110000 deaths and af-
fects almost 500 million people annually.[14,15] In amoebiasis,
the protozoan affects all body organs, destroys human tissue,
and leads to diseases such as hemorrhagic colitis and extra in-
testinal abscesses.[16] The most effective drug for amoebiasis is
metronidazole (MNZ).[17] However, in the last two decades, it
has been reported that MNZ is mutagenic towards bacteria,
causes tumors in rodents, and presents toxic effects such as
genotoxicity, gastric mucus irritation, and spermatoid dam-
age.[18] Therefore, new, effective antiamoebic agents that have
greater potency and efficacy with lower toxicity are required.
The dibasic tridentate ONO functionalities of deferasirox and
related ligands with a triazole group have high potential for the
design of structural models of vanadate-dependent haloperox-
idase enzymes (VHPOs).[3,4] Structural models of VHPOs and
their use as functional mimics have attracted the attention of
researchers and found tremendous growth over the past few
[a] Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee
247667, India
E-mail: rkmanfcy@iitr.ac.in
www.iitr.ac.in/~CY/rkmanfcy
[b] Department of Chemistry, Jamia Millia Islamia, Jamia Nagar,
New Delhi 100025, India
[c] Departamento de Química Fundamental, Universidade da Coruña,
Campus de A Zapateira, 15071 A Coruña, Spain
[d] Centro de Química Estrutural, Instituto Superior Técnico, Universidade de
Lisboa,
Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejic.201501336.
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Scheme 1. Overview of the ligands and complexes described in this work.
In recent decades, there has been a remarkable growth in cessful. Complex
1
instead crystallized as [VVO(μ-L1)-
research into the synthesis of nitrogen-containing heterocyclic (OMe)]2·4,4′-bipy (1a, 4,4′-bipy = 4,4′-bipyridine), in which a
derivatives. Ring systems containing 1,2,4-triazoles have at- 4,4′-bipy molecule is weakly associated with 1. All of the com-
tracted considerable scientific interest because of their varied plexes are soluble in N,N-dimethylformamide (DMF) and di-
chemical properties, synthetic versatility, and pharmacological methyl sulfoxide (DMSO) and partially soluble in methanol and
activities, such as antibacterial,[19] antifungal[20] antitubercu- acetonitrile. The structures of the complexes described in this
lar,[21] anti-inflammatory,[22] anticancer,[23] anticonvulsant,[24] an- work are presented in Scheme 1 along with ligands. The struc-
tiviral,[25] and antidepressant[26] properties. Several drugs in the tural formula of each complex is based on elemental analysis,
market contain the 1,2,4-triazole moiety, for example, astriaz- thermal, and spectroscopic (IR; UV/Vis; 1H, 13C, and 51V NMR)
olam[27] and etizolam.[28] The promising antiamoebic activity of data as well as single-crystal X-ray analysis for 1a.
the 1,2,4-triazole scaffold has also been reported recently.[29]
For these reasons and to further explore the biological activity Thermal Analysis
of vanadium complexes, we studied the antiamoebic and cyto-
The thermal stability of the monomeric complexes 3, 4, 5, and
toxic activity of monooxidovanadium(V) and dioxidovana-
6 was studied under an oxygen atmosphere. The complexes
dium(V) complexes of H2L1 and H2L2, and the results are re-
lose mass above 110 °C that is roughly equal to one water
ported herein.
molecule indicating the presence of weekly coordinated water.
As the temperature increases further, complex 3 decomposes
exothermically in one step, whereas the others (4, 5, and 6)
take two or three overlapping steps and form MVO3 (M = K or
Cs) as the final product. Complexes 1 and 2 are relatively more
stable (up to ca. 310 °C) and only exhibit partial mass loss. A
Results and Discussion
The reactions of [VIVO(acac)2] (acac = acetylacetonato) with
H2L1 (I) and H2L1 (II) in 1:1 molar ratios in methanol under reflux
followed by aerial oxidation yield the dinuclear oxidovana-
dium(V) complexes [VVO(μ-L1)(OMe)]2 (1) and [VVO(μ-
L2)(OMe)]2 (2), respectively. The dropwise addition of a methan-
olic solution of KOH or CsOH to a methanol solution of these
complexes gradually leads to the formation of the correspond-
ing VVO2 complexes K(H2O)[VVO2(L1)] (3) and K(H2O)[VVO2(L2)]
(4) or Cs(H2O)[VVO2(L1)] (5) and Cs(H2O)[VVO2(L2)] (6). The syn-
thetic procedures are summarized in Equations (1), (2), and (3)
for H2L1 as the representative ligand.
further increment in temperature leads to their decomposition
to form V2O5 at ca. 400 °C. Further details of this study are
presented in Table S1 and Figures S1 and S2 in the Supporting
Information.
MALDI-TOF MS Analysis
MALDI-TOF MS analysis was performed to ascertain the exis-
tence of the proposed dimeric species of 1 and 2. The MALDI-
TOF MS analysis showed molecular ion peaks at m/z = 876.15
(calcd. 876.06) and 788.12 (calcd. 788.08) for 1 and 2 (Figures S3
and S4), respectively. These peaks are generated after the elimi-
nation of two weakly coordinated OMe groups from the metal
centers in 1 and 2.
2[VIVO(acac)2] + 2H2L1 + 2MeOH + 1/2O2 →
2[VVO(μ-L1)(OMe)]2 + 4Hacac + H2O (1)
[VVO(μ-L1)(OMe)]2 + 2KOH + 2H2O →
2K(H2O)[VVO2(L1)] + 2MeOH (2)
[VVO(μ-L1)(OMe)]2 + 2CsOH + 2H2O →
Crystal Structure of [VVO(μ–L1)(OMe)]2·4,4′-bipy (1a)
2Cs(H2O)[VVO2(L1)] + 2MeOH (3)
Compound 1a crystallized from methanol as black blocks, and
Efforts to prepare a dinuclear complex connected through an ORTEP representation is depicted in Figure 1. The asymmet-
the two distinct mononuclear units present in 1 were unsuc- ric unit of 1a contains half of the dinuclear complex and half a
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4,4′-bipy molecule. Selected bond lengths and angles are listed (L1) in a [VVO(μ-OMe)2VVO] unit with an anti-coplanar configura-
in Table 1.
tion.[30] Each vanadium center is six-coordinate in a distorted
octahedral geometry: ligand L1 is bound through the triazole N
atom [V1–N1 2.118(4) Å] and the two phenolic O atoms, one of
which acts as a terminal ligand [V1–O2, 1.825(4) Å] and the
other acts as a bridge [V1–O1 1.924(4) Å]; one terminal oxygen
atom [V1–O3 1.593(4) Å] and one methoxy O atom [V1–O1M
1.790(4) Å] complete the coordination sphere. The V–μ-
Ophenolate bonds trans to the oxido groups are significantly
longer [V1–O1#1 2.409(4) Å] than the others. The triazole group
(C7, C8, N1, N2, N3) and one of the phenolate rings (C9, C10,
C11, C12, C13, C14, O2) are coplanar [mean deviation from
plane 0.0288(44) Å], and the other phenolate ring (C1, C2, C3,
C4, C5, C6, O1), which acts as a bridge, forms a torsion angle
of 26.98(17)° with the previous one. The vanadium atom is dis-
placed towards the apical oxido ligand from the equatorial
plane defined by the two Ophenolate, one Ntriazole, and Omethoxy
atoms by 0.3001(19) Å [mean deviation from plane O1M–O2–
N1–O1, 0.0976(19) Å]. The V=O bond is characteristic of oxido-
type O atoms with strong π bonding.[31] The V–V separation of
3.521(19) Å is similar to those reported for other compounds.[32]
Intermolecular hydrogen bonds exit between the protonated
Ocarboxyl and N4,4′-bipy atoms along the structure (see Table 2).
These hydrogen bonds determine the molecular structure in
which alternate 4,4′-bipy groups and dinuclear complexes form
chains. The chains are packed as sandwich structures between
4,4′-bipy groups and dinuclear complexes, which are in contact
through CH–π and van der Waals interactions (Figure 2).
Figure 1. ORTEP plot of 1a (CCDC-1437168). All non-hydrogen atoms are rep-
resented by 50 % probability ellipsoids. Hydrogen atoms and 4,4′-bipy mol-
ecule are omitted for clarity. Symmetry transformation used to generate
equivalent atoms: #1 –x + 1, –y + 1, –z + 1.
Table 2. Hydrogen bonds in the 1a.[a]
D–H···A
d(D–H)
d(H···A)
d(D···A)
<(DHA)
167.7
O(5)–H(5O)···N(4)#3
1.00
1.67
2.658(6)
Table 1. Bond lengths [Å] and angles [°] for 1a.[a]
[a] Symmetry transformation used to generate equivalent atoms: #3 –x + 2,
–y, –z.
Bond
1a
V(1)–O(1)
V(1)–O(1M)
V(1)–O(2)
V(1)–O(3)
V(1)–N(1)
V(1)–O(1)#1
1.924(4)
1.790(4)
1.825(4)
1.593(4)
2.118(4)
2.409(4)
Angle
1a
O(3)–V(1)–O(1M)
O(3)–V(1)–O(2)
O(1M)–V(1)–O(2)
O(3)–V(1)–O(1)
O(1M)–V(1)–O(1)
O(2)–V(1)–O(1)
O(3)–V(1)–N(1)
O(1M)–V(1)–N(1)
O(2)–V(1)–N(1)
O(1)–V(1)–N(1)
O(3)–V(1)–O(1)#1
O(1M)–V(1)–O(1)#1
O(2)–V(1)–O(1)#1
O(1)–V(1)–O(1)#1
N(1)–V(1)–O(1)#1
99.40(18)
105.8(2)
100.00(17)
97.91(18)
91.39(16)
151.49(18)
92.23(18)
166.91(17)
82.41(17)
81.02(16)
169.31(17)
84.08(15)
83.41(16)
71.79(16)
83.43(15)
Figure 2. Crystal packing of 1a. The hydrogen bonds that are shown in
dashed blue lines form the chains. The sandwich structures formed by two
4,4′-bipy groups and one dinuclear complex can be seen in the center of the
image.
IR Spectroscopy Study
A partial list of IR spectroscopic data of the ligands and com-
plexes is presented in Table 3. Two strong bands at ν = 1618
˜
and 912 cm–1 for I and at ν = 1624 and 938 cm–1 for II are
˜
assigned to ν(C=N) and ν(N–N) stretching, respectively. A batho-
chromic shift of ν(C=N) of 15–24 cm–1 in the spectra of all com-
plexes indicates the coordination of the vanadium center
[a] Symmetry transformation used to generate equivalent atoms: #1 –x + 1,
–y + 1, –z + 1.
The structure of 1a contains one dinuclear complex grown through the nitrogen atom of the azomethine group. This is
by a symmetry operation, consisting of a tridentate ONO ligand further supported by the shift of the ν(N–N) stretch to higher
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wavenumbers, owing to reduced repulsion between the lone and 304 nm for II, which are assigned to ꢁ → ꢁ*, π → π*, and
pairs of adjacent nitrogen atoms. The ν(C=O) band for the carb- n → π* transitions, respectively. These bands are also observed
oxylic acid in ligand I appears at ν = 1692 cm–1 and is slightly in the spectra of the complexes with slight shifts in their fre-
˜
affected in the corresponding spectra of complexes. The broad quency (Figure S5). Additionally, the spectra of all of the com-
band at ν ≈ 3266 cm–1 might be assigned to ν(O–H) stretching plexes display a medium intensity band at λ ≈ 350–362 nm
˜
owing to the presence of coordinated water. This band pre- (Table 4), which can be attributed to ligand-to-metal charge
vented the unequivocal identification of the coordination of the transfer (LMCT) from the lone pair of the pπ orbitals of the
phenolic oxygen atom.
phenolate oxygen atoms to vacant d orbitals of the vanadium
atoms.
Table 3. IR spectroscopic data [cm–1] of ligands and complexes.
Complexes 1 and 2 also show the presence of intense bands
at λ = 567 and 527 nm, respectively. The VO3+ ion has a d0
configuration (V5+) and, therefore, no d–d transitions are ex-
pected. The high molar extinction coefficient of these bands
suggests LMCT character. This is consistent with observations
from other researchers, who found LMCT bands in the visible
range at λ = 475–550[34] and 550–800 nm[35] in oxovanadium(V)
complexes and assigned them to LMCT transitions from phenol-
ate and alkoxide oxygen atoms to empty vanadium d orbitals.
Therefore, we assign these two bands for 1 and 2 to LMCT
transitions from the pπ orbitals of the phenolate and methoxy
oxygen atoms to the empty d orbitals of the d0 vanadium cen-
ters.
ν(–C=N–)
ν(–N–N–)
ν(V=O)/(VO2)
H2L1 (I)
1618
1624
1605
1604
1605
1600
1603
1608
912
938
–
–
973
968
924/882
936/923
926/886
930/905
H2L2 (II)
[VVO(μ-L1)(OMe)]2 (1)
[VVO(μ-L2)(OMe)]2 (2)
K(H2O)[VVO2(L1)] (3)
K(H2O)[VVO2(L2)] (4)
Cs(H2O)[VVO2(L1)] (5)
Cs(H2O)[VVO2(L2)] (6)
1019
1022
1019
1029
1016
1026
The VVO complexes 1 and 2 exhibit strong but relatively
broad bands at ν = 973 and 970 cm–1, respectively, for ν(V=O)
˜
stretching. The broadness of this band suggests a slight asym-
metry in the dinuclear complexes. The presence of two such
sharp bands in the spectra of the VVO2 complexes 3–6 in the
ν = 882–936 cm–1 region for the νsym(O=V=O) and νasym(O=V=
1H NMR Spectroscopy Study
˜
O) modes reinforces the assignment of a cis-[VVO2] structure in
The 1H NMR spectra of the ligands and complexes in [D6]DMSO
were recorded, and the relevant spectroscopic data are col-
these complexes.[33]
1
lected in Table 5. The H NMR spectra of H2L2 (II) and two of
Electronic Spectroscopy Study
its complexes (2 and 4) are presented in Figure 3. Two broad
The UV/Vis absorption spectra of the ligands exhibit three signals for the phenolic OH groups at δ = 10.51 (s, 1 H) and
bands at λ = 205, 270, and 309 nm for I and at λ = 207, 239, 11.44 (s, 1 H) ppm in the spectrum of I and at δ = 10.90 (s, 1
Table 4. UV/Vis spectroscopic data of ligands and complexes obtained in methanol.
λmax [nm] (ε, M )
–1 cm–1
H2L1 (I)
309 (5.7 × 103), 270 (1.8 × 104), 205 (3.4 × 104)
H2L2 (II)
304 (1.2 × 104), 239 (3.3 × 104), 207 (4.4 × 104)
[VVO(μ-L1)(OMe)]2 (1)
[VVO(μ-L2)(OMe)]2 (2)
K(H2O)[VVO2(L1)] (3)
K(H2O)[VVO2(L2)] (4)
Cs(H2O)[VVO2(L1)] (5)
Cs(H2O)[VVO2(L2)] (6)
567, 362 (1.4 × 103), 306 (1.4 × 104), 233 (5.0 × 104), 210 (6.0 × 104)
527, 352 (2.4 × 103), 305 (2.4 × 104), 238 (6.7 × 104), 208 (9.6 × 104)
350 (1.4 × 103), 307 (1.6 × 104), 228 (5.2 × 104), 207 (5.7 × 104)
354 (1.4 × 103), 306 (1.4 × 104), 233 (4.9 × 104), 210 (6.0 × 104)
353 (1.5 × 103), 303 (1.5 × 104), 237 (4.2 × 104), 207 (5.6 × 104)
356 (1.4 × 103), 307 (1.6 × 104), 228 (5.2 × 104), 207 (5.7 × 104)
Table 5. 1H NMR chemical shifts[a] [ppm] of ligands and complexes in [D6]DMSO.
–COOH
–OH
–OMe
Ar-H
H2L1 (I)
12.00 (s, 1 H)
10.51 (s, 1 H),
11.44 (s, 1 H)
6.91 (d, 1 H), 7.02 (m, 3 H), 7.08 (m, 2 H), 7.44 (d,1 H), 7.65 (d, 2 H),
7.85 (d, 2 H), 8.06 (d, 1 H)
6.82 (d, 2 H), 7.36b(t, 1 H), 7.62 (m, 5 H), 7.819 (m, 3 H), 8.00 (s, 1 H)
6.78 (d,1 H), 6.97 (m, 4 H), 7.46 (m, 2 H), 7.83, 7.87 (m, 2 H), 8.11
(s, 1 H), 8.21 (d, 2 H)
7.04 (m, 3 H), 7.46 (m, 3 H), 7.87 (m, 3 H), 8.19 (m, 3 H)
6.93 (d, 1 H), 6.99 (t, 1 H), 7.02 (m, 2 H), 7.37 (t, 1 H), 7.48 (m, 6 H),
8.04 (d, 1 H)
6.62 (m, 2 H), 6.84 (m, 4 H), 6.9 (s, 1 H), 7.5 (m, 5 H), 8.08 (s, 1 H)
6.75 (m, 3 H), 6.95 (t, 1 H), 7.01 (m, 2 H), 7.21 (m, 3 H), 7.37 (t, 2 H),
8.04 (d, 1 H)
[VVO(μ-L1)(OMe)]2 (1)
K(H2O)[VVO2(L1)] (3)
12.93 (s, 1 H)
13.51 (s, 1 H)
4.25 (s, 3 H)
Cs(H2O)[VVO2(L1)] (5)
H2L2 (II)
13.54 (s, 1 H)
10.90 (s, 1 H),
10.07 (s, 1 H)
[VVO(μ-L2)(OMe)]2 (2)
K(H2O)[VVO2(L2)] (4)
4.25 (s, 3 H)
Cs(H2O)[VVO2(L2)] (6)
6.68 (m, 1 H), 7.01 (t, 1 H), 7.36(d, 2 H), 7.44(d, 2 H), 7.66 (m, 5 H),
8.05 (s, 1 H)
[a] The letters given in parentheses indicate the signal multiplicity: s = singlet, d = doublet, t = triplet, and m = multiplet.
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H) and 10.07 (s, 1 H) ppm in the spectrum of II are absent in 13C NMR Spectroscopy Study
the spectra of the complexes; therefore, the spectra confirm the
The 13C NMR spectra of the ligands and complexes in [D6]DMSO
were recorded to further confirm the coordination modes of
the ligands and the structures of the complexes. The relevant
spectroscopic data are collected in Table 6; the 13C NMR spectra
of H2L2 and its corresponding complexes are presented in Fig-
ure S6. The chemical shifts of the carbon atoms in the vicinity of
the coordinating atoms [coordination-induced shifts, see ref.[36]
(Δδ); C1/C1′, C2/C2′, and C7/C7′ in Table 6] undergo downfield
shifts. The signals of the aromatic carbon atoms appear in the
expected region in the spectra of the ligands and complexes
with slight shifts in their positions. The signal for the carboxyl
group (–COOH) appears well within the expected range in the
spectra of ligands I and the respective complexes.
coordination of the phenolate oxygen atoms to the metal ions.
The signals of the aromatic protons appear in the expected
region for the ligands and complexes with slight shifts in their
positions. A signal due to the proton of the carboxyl group
(–COOH) appears at δ = 12.00 ppm in the spectrum of I and at
δ = 12.90–13.10 ppm in the spectra of corresponding com-
plexes. The methyl protons of the methoxido groups of 1 and
2 resonate at δ = 4.25 ppm.
51V NMR Spectral Study
Further characterization of the complexes was achieved
through 51V NMR spectroscopy. The chemical shifts obtained
for each complex in MeOH and DMSO are listed in Table 7, and
the spectra are shown in Figures S7 and S8. The spectra of the
complexes derived from H2L1 (1, 3, and 5) in MeOH show two
resonances in an approximate ratio of 30:70 at δ = –545 and
–550 ppm, respectively, which probably correspond to two iso-
mers of [VVO2(L1)(MeOH)]. The chemical shifts are in the usual
range for tridentate ONO ligands.[37] For the complexes derived
from H2L2 in MeOH, either one (for 2) or more species (for 4
and 6) are detected by 51V NMR spectroscopy; these species
correspond to the same type of complexes as those for H2L1 as
Figure 3. 1H NMR spectra of ligand H2L2 and complexes [VO(μ-L2)(OMe)]2 (2)
and K(H2O)[VVO2(L2)] (4) in [D6]DMSO. The peaks due to solvent/H2O have
been identified by asterisks.
Table 6. 13C NMR chemical shifts [ppm] of ligands and complexes in [D6]DMSO.
C1/C1′
C7/C7′
C2/C2′
Other aromatic carbon atoms
H2L1 (I)
119.7
126.3
(6.6)
125.3
(5.6)
125.4
(5.71)
119.6
125.7
(6.1)
156.9
161.6
(4.7)
163.2
(6.3)
162.9
(6.0)
156.3
164.7
(8.4)
164.1
167.5
(3.4)
175.5
(11.4)
174.9
(10.8)
159.5
167.5
(8.0)
167.1, 134.3, 130.7, 130.4, 123.4, 123.0, 119.0, 117.2
172.6, 134.6, 132.3, 130.8, 129.2, 128.6, 123.6, 118.9, 117.9, 114.8
[VVO(μ-L1)(OMe)]2 (1)
(Δδ)[a]
K(H2O)[VVO2(L1)] (3)
(Δδ)
167.3, 134.2, 129.8, 132.2, 123.4, 123.7, 120.0, 117.3
Cs(H2O) [VVO2(L1)] (5)
(Δδ)
167.2, 134.3, 130.7, 126.5, 123.4, 118.7, 119.1, 117.8, 116.2, 114.6
H2L2 (II)
131.3, 129.2, 128.7, 126.6, 123.7, 119.2, 116.0
152.5, 148.0, 145.9, 142.6, 133.4, 131.2, 130.7, 129.2, 127.1, 124.5
[VVO(μ-L2)(OMe)]2 (2)
(Δδ)
K(H2O)[VVO2(L2)] (4)
(Δδ)
127.4
(7.8)
127.6
(8.0)
162.6
(6.3)
161.2
(4.9)
170.2
(10.7)
170.8
(11.3)
132.3, 130.2, 129.2, 126.6, 122.8, 119.4, 117.4
Cs(H2O)[VVO2(L2)] (6)
(Δδ)
151.2, 138.1, 131.2, 128.2, 123.5, 119.4, 117.3, 116.2, 114.2
[a] Δδ = [δ(complex) – δ(free ligand)].
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Table 7. 51V NMR chemical shifts [ppm] of the complexes.
MeOH (%)
DMSO (%)
1
2
3
4
5
6
–545 (30), –549 (70)
–550 (100)
–545 (30), –549 (70)
–541 (5), –546 (5), –563 (10), –574 (80)
–545 (10), –550 (90)
–493 (100)
–456 (5), –534 (15), –568 (30), –585 (50)
–469 (25), –495 (30), –519 (25), –560 (20)
–447 (40), –535 (30), –565 (30)
–467 (30), –559 (40), –582 (30)
–544 (100)
–542 (10), –550 (20), –552 (70)
well as VV complexes with different numbers of OMe molecules,
as has been observed for other VV complexes in alcohols.[37]
In DMSO, the linewidths at half-height are much larger, and
either one strong resonance (for 1 and 6) or several are ob-
served. The ones at
δ ≈ –550 ppm are assigned to
[VVO2(L)(DMSO)],[38] and those at δ = –535 ppm are tentatively
assigned to species containing H2O instead of DMSO in the
coordination sphere. All resonances are within the expected
range for VO2 complexes with mixed O/N donor sets.[39,40]
Reactivity of the Complexes
Reactivity of Oxidovanadium(V) Complexes with H2O2
The reactivity of the VVO complexes 1 and 2 in methanol with
H2O2 was monitored by UV/Vis spectroscopy. The progressive
addition of a 2 × 10–2
M M solu-
H2O2 solution to a 1.32 × 10–4
tion of 1 in MeOH (25 mL) caused the flattening of the LMCT
band at λ = 353 nm (Figure 4, a). After the addition of a total
of 1.4 mL of H2O2, the charge-transfer (CT) band disappeared,
and the shoulders at λ ≈ 300 and 280 nm developed into two
bands. Additionally, the LMCT band at λ = 566 nm in the visible
range also disappeared upon the dropwise addition of
3.94 × 10–2
M
H2O2 to a 1.54 × 10–3
M
solution of 1 in MeOH
(25 mL; see the inset in Figure 4, a). These changes suggest
the in situ generation of oxidoperoxidovanadium(V) species in
solution. Similar observations were made for 2 in MeOH (see
Figure 4, b).
The reactivity of the mononuclear complexes 3, 4, 5, and 6
with H2O2 was also evaluated by UV/Vis spectroscopy, and simi-
lar changes were observed: the intensity of the charge-transfer
band at λ ≈ 350 nm decreased slowly (see inset of Figure 5, a
and b), and a weak shoulder at λ ≈ 300 nm developed upon
the addition of H2O2 (Figure 5, a and b). Additionally, the inten-
sity of the bands at λ = 236 and 207 nm increased. Again, these
changes suggest the generation of oxidoperoxidovanadium(V)
species in solution.
Figure 4. (a) Spectral changes observed during the reaction of 1 with H2O2.
The spectra were recorded upon the dropwise addition of a 2 × 10–2
H2O2
solution to a 1.32 × 10–4
solution of 1 in MeOH (25 mL). The inset shows
the spectral changes for the CT band of 1 during the dropwise addition of
M
M
3.94 × 10–2
M M solution of 1 in MeOH (25 mL). (b)
H2O2 to a 1.54 × 10–3
Spectral changes observed during the titration of [VO(μ-L2)(OMe)]2 with
H2O2. The spectra were recorded upon the dropwise addition of
1.97 × 10–2
M
H2O2 to a 1.06 × 10–4
M
solution of 2 in MeOH. The inset shows
the spectral changes for the CT band of [VO(μ-L2)(OMe)]2 during the drop-
wise addition of 5.9 × 10–2 H2O2 to a 2.1 × 10–3 solution of 2 in MeOH.
M
All these observations are consistent with the formation of
oxidoperoxidovanadium(V) complexes. Usually, side-on oxi- and –673 ppm. The addition of 2 equiv. of H2O2 led to the
doperoxidovanadate complexes exhibit a weak absorption increase of the intensity of these two peaks, and the disappear-
band (ε ≈ 102–103
M
–1 cm–1) as the lowest-energy identifiable ance of the peaks assigned to the VVO2 complexes. For 6, no
charge-transfer feature. In some cases, a shoulder or an addi- changes were observed even after the addition of 4 equiv. of
tional weak peak is observable.[41]
H2O2 (see Figure S9). The two peaks have been assigned to
diperoxidovanadate(V) species.
Evidence of the formation of a peroxidovanadate complex
was found for 1 in DMSO, (see Figure 6); the addition of H2O2
To obtain further insights into the reactivity of the complexes
towards H2O2, 51V NMR measurements were performed (Fig-
ures S9 and S10). Upon the addition of 1 equiv. of H2O2 to 2 m
M
solutions of the complexes in MeOH, the resonances at δ ≈ produced a new resonance at δ = –564 ppm, at the expense of
–550 ppm decreased, and two new peaks appeared at δ ≈ –653 the resonance at δ = –492 ppm.
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Catalytic Oxidative Bromination of Thymol
The oxidative bromination of thymol catalyzed by 6 in the pres-
ence of KBr, 70 % aqueous HClO4, and 30 % aqueous H2O2 in
aqueous media led to the formation of 2-bromothymol, 4-
bromothymol, and 2,4-dibromothymol (Scheme 2). Among
these products, 2,4-dibromothymol was found in the highest
yields, possibly because of the further bromination of the
monobromo product(s). The identities of the obtained products
were confirmed by GC–MS and 1H NMR spectroscopy after their
separation and by comparison with literature data.[42,43]
Scheme 2. Products of the oxidative bromination of thymol (2-Brth = 2-
bromothymol, 4-Brth = 4-bromothymol, 2,4-dBrth = 2,4-dibromothymol).
To obtain the maximum yield of brominated products, sev-
eral parameters, that is, the amount of catalyst, H2O2, KBr, and
HClO4, were varied at room temperature with 6 as a representa-
tive catalyst. Thus, for 0.010 mol (1.5 g) of thymol, three differ-
ent amounts of catalyst (0.0010, 0.0020, and 0.0030 g), H2O2
(0.010, 0.020, and 0.030 mol), KBr (0.010, 0.020, and 0.030 mol),
and HClO4 (0.010, 0.020, and 0.030 mol) were added to water
(20 mL), and the reactions were performed at room tempera-
ture for 2 h.
Figure 5. (a) Spectral changes observed during the reactivity of
K(H2O)[VVO2(L1)] with H2O2. The spectra were recorded upon the dropwise
addition of 1.35 × 10–2
M
H2O2 solution to a 1.29 × 10–3
M
solution of 3 in
MeOH (25 mL). The inset shows the spectral changes for the CT band of 3
during the dropwise addition of 1.40 × 10–2 H2O2 to a 2.14 × 10–3
solu-
M
M
The conversion of thymol obtained in the different assays
and the selectivity of the different brominated products under
particular conditions are summarized in Table 8. It is clear from
the data presented that the best reaction conditions to maxi-
mize the oxidative bromination (99 % conversion) of thymol are
catalyst (0.0010 g), H2O2 (2.3 g, 0.020 mol), KBr (2.3 g,
tion of 3 in MeOH. (b) Spectral changes observed during the titration of
K(H2O)[VVO2(L2)] with H2O2. The spectra were recorded upon the dropwise
addition of 0.7 mL of 1.47 × 10–2
M M solution of 4 in
H2O2 to a 3.3 × 10–3
MeOH (25 mL). The inset shows the spectral changes of the CT band of 4
during the dropwise addition of 1.29 × 10–2
M M solu-
H2O2 to a 1.76 × 10–3
tion of 4 in MeOH (25 mL).
Figure 6. 51V NMR spectra of solutions of 1 (2 m
M) in DMSO (with 5 % D2O) with increasing amounts of H2O2 (0.02 M); the concentration of H2O2 in each
sample is indicated.
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Table 8. Conversion of thymol (for 1.5 g, 0.010 mol), turnover frequency (TOF), and product selectivity with 6 as a catalyst precursor for 2 h of reaction time
under different reaction conditions.
Entry
Catalyst [g (mol)]
H2O2 [g (mol)]
KBr [g (mol)]
HClO4 [g (mol)]
Conversion [%] TOF [h–1
]
2-Brth
4-Brth
2,4-dBrth
1
2
3
4
5
6
7
0.0010 (1.8 × 10–6
0.0020 (3.6 × 10–6
0.0030 (5.3 × 10–6
0.0010 (1.8 × 10–6
0.0010 (1.8 × 10–6
0.0010 (1.8 × 10–6
0.0010 (1.8 × 10–6
0.0010 (1.8 × 10–6
0.0010 (1.8 × 10–6
blank
)
)
)
)
)
)
)
)
)
1.1 (0.010)
1.1 (0.010)
1.1 (0.010)
2.3 (0.020)
3.4 (0.030)
2.3 (0.020)
2.3 (0.020)
2.3 (0.020)
2.3 (0.020)
2.3 (0.020)
1.2 (0.010)
1.2 (0.010)
1.2 (0.010)
1.2 (0.010)
1.2 (0.010)
1.2 (0.020)
1.2 (0.010)
2.3 (0.020)
3.6 (0.030)
2.3 (0.020)
1.4 (0.010)
1.4 (0.010)
1.4 (0.010)
1.4 (0.010)
1.4 (0.010)
2.8 (0.020)
4.3 (0.030)
4.3 (0.030)
4.3 (0.030)
4.3 (0.030)
38
40
41
69
70
75
88
99
99
43
950
975
13
12
13.5
14
11
13
10.2
6
5
85
87
85
86
86
65
81
21
7
2
1
1
0
2
22
8.7
73
88
61
1000
1725
1750
1875
2200
2475
2475
8[a]
9
10
20.7
26
[a] Optimized reaction condition.
0.020 mol), and HClO4 (4.3 g, 0.030 mol) in water (20 mL; thymol/KBr/H2O2 ratios of 0.048:1:1:1 for 100 m
M
of thymol at
Table 8, Entry 8). Under these conditions, the selectivity ob- pH 1.[42] These results suggest that the complexes are intact
served follows the order 2,4-dibromothymol (73 %) > 4-bromo- during the catalytic cycle; therefore, the conversion of thymol
thymol (21 %) > 2-bromothymol (6 %).
is enhanced and the selectivity of the products is altered.
The amount of catalyst does not seem to influence much the
reaction outcome (see Table 8, Entries 1–3). Also, 10 mmol of
HClO4 is enough to obtain high conversions (Table 8, Entry 7);
thus, the reaction also does not seem dependent on this rea-
gent. On the other hand, KBr and the oxidant H2O2 impact the
conversion and have an interesting role on the selectivity of
different products. Mainly, two monobrominated products with
high selectivity (up to 87 %) for 4-bromothymol are obtained
at substrate/H2O2/KBr = 1:1:1, although the overall conversion
was low. Increasing the amount of KBr improved the conversion
but resulted in the formation of a considerable amount of the
dibrominated product, 2,4-dibromothymol, at the expense of 4-
bromothymol.
Under the optimized reaction conditions (Table 8, Entry 8),
the effects of different solvent systems on the catalytic activity
of 6 and the selectivity were also studied. The conversion of
thymol is highest in H2O and H2O/MeCN (99 %), although more
than 90 % conversion was obtained for all solvent systems eval-
uated (Table 9). The selectivity order is 2,4-dibromothymol > 4-
bromothymol > 2-bromothymol.
Table 10. Conversion of thymol (for 1.5 g, 0.010 mol), TOF, and product select-
ivity for different catalysts precursors over 2 h of reaction time under the
optimized reaction conditions.[a]
Conv. [%] TOF [h–1
]
2-Brth 2-Brth 2,4-dBrth
[VVO(μ-L1)(OMe)] (1)
[VVO(μ-L2)(OMe)] (2)
K(H2O)[VVO2(L1)] (3)
K(H2O)[VVO2(L2)] (4)
Cs(H2O)[VVO2(L1)] (5)
Cs(H2O)[VVO2(L2)] (6)
95
94
97
96
99
98
2375
2350
2425
2400
2475
2450
16
13
11
14
8
18
16
19
21
14
16
65
72
68
60
75
72
9
[a] Reaction conditions: catalyst (0.0010 g), H2O2 (0.020 mol, 2.3 g), KBr
(0.020 mol, 2.3 g), HClO4 (0.030 mol, 4.3 g), H2O (20 mL).
The catalytic abilities of these complexes compare well with
that of the vanadium complex [VVO(OMe)(MeOH)(L)] {H2L =
6,6′-[2-(pyridine-2-yl)ethylazanediyl]bis(methylene)bis(2,4-di-
tert-butylphenol); the optimized reaction conditions were: sub-
strate/H2O2/KBr/HClO4 1:2:2:2 for 0.010 mol of thymol}, for
which 99 % conversion was obtained with 57 % selectivity to-
wards 2,4-dibromothymol, 37 % towards 4-bromothymol, and
the rest towards 2-bromothymol.[43] Dioxidomolybdenum(VI)
complexes of Schiff base ligands derived from 8-formyl-7-
hydroxy-4-methylcoumarin and hydrazides showed 94–99 %
conversion[44] with almost the same order of selectivity for the
different products.
Table 9. Solvent effects on the conversion of thymol and selectivity of prod-
ucts for catalyst 6.[a]
Solvent
Conversion [%]
TOF [h–1
]
2-Brth
4-Brth 2,4-dBrth
Water
99
93
94
94
99
91
2475
2325
2375
2350
2475
2275
6
9
2
4
2
1
21
17
18
22
20
27
73
70
72
73
78
62
H2O/CH2Cl2
H2O/CHCl3
H2O/MeOH
H2O/MeCN
H2O/hexane
Antiamoebic Activity
Preliminary experiments were performed to determine the in
vitro antiamoebic activity of ligands H2L1 and H2L2 and their
vanadium complexes against the HM1:IMSS strain of E. histolyt-
ica by the microdilution method. Their 50 % inhibitory concen-
[a] Reaction conditions: catalyst (0.0010 g), H2O2 (0.020 mol, 2.3 g), KBr
(0.020 mol, 2.3 g), HClO4 (0.030 mol, 4.3 g).
The other complexes tested under the optimized reaction tration values (IC50) are reported in Table 11 with that of the
conditions showed almost the same conversion and selectivity widely used antiamoebic drug metronidazole, which showed
(Table 10). A blank reaction without catalyst under the same an IC50 of 1.8 0.01 μ
M in our experiments. The results were
conditions (as in Table 8, Entry 10) gave 48 % conversion. V2O5 estimated as the percentage of growth inhibition compared
under the above optimized reaction conditions resulted in 75 % with the untreated controls and plotted as probit values as a
conversion. Conte et al. reported 88 % conversion with NH4VO3 function of the drug concentration. The IC50 and 95 % confi-
as the catalyst at NH4VO3/thymol/KBr/H2O2 ratios of 0.048:1:1:2 dence limits were interpolated in the corresponding dose–re-
for 100 m
M
of thymol at pH 1 and 82 % conversion at NH4VO3/ sponse curves. All of the synthesized complexes showed prom-
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ising antiamoebic activity with IC50 values in the range 0.14– The above results show that there is no significant reduction
1.45 μM. The data shows that both ligands have low potency to in cell viability of HeLa cells upon treatment with the above-
inhibit the proliferation of E. histolytica. However, complexation mentioned compounds. Thus, these compounds are not signifi-
with VV resulted in compounds with very promising activities. cantly cytotoxic at the concentration necessary to have anti-
Among the synthesized metal complexes 1–6, the highest level amoebic activity (or double of it).
of activity was exhibited by 1 (IC50 of 0.14 0.01) followed by
the others in the order 4 > 5 > 2 > 6 > 3. Thus, all metal
complexes were more potent amoebicidal agents than the
Conclusions
standard drug metronidazole (IC50 of 1.8 0.01) and their re-
Dinuclear oxidovanadium(V) complexes [VVO(μ-L1)(OMe)]2 (1)
spective ligands; therefore, the complexation to the metal cen-
and [VVO(μ-L2)(OMe)]2 (2) with deferasirox {4-[3,5-bis(2-hydroxy-
ter enhances the activity of the ligand. This may be explained
phenyl)-1,2,4-triazol-1-yl]benzoic acid} or its unsubstituted de-
by the Tweedy theory,[45] that is, that the chelation favors the
rivative and their potassium and cesium salts of dioxidovana-
permeation of the complexes through the lipid layer of the cell
dium(V) analogs, that is, K(H2O)[VVO2(L1)] (3), K(H2O)[VVO2(L2)]
membrane.
(4), Cs(H2O)[VVO2(L1)] (5), and Cs(H2O)[VVO2(L2)] (6), have been
prepared and characterized. The crystal structure of 1·4,4′-bipy-
ridyl (1a) confirmed the coordination of the ONO ligand to the
vanadium ion through the nitrogen atom and the two phenolic
oxygen atoms. These complexes are potential catalysts for the
oxidative bromination of thymol in the presence of KBr and
HClO4 with H2O2 as the oxidant to give 2-bromothymol, 4-bro-
mothymol, and 2,4-dibromothymol. Thus, they are considered
as functional models of vanadium-dependent haloperoxidases.
These complexes have also been screened against the
HM1:1MSS strain of E. histolytica; the IC50 values of the metal
complexes are significantly lower than that of metronidazole.
These complexes are also less cytotoxic against human cervical
(HeLa) cancer cell line than metronidazole; therefore, they may
be promising drugs for the treatment of amoebiasis.
Table 11. Antiamoebic activity of ligands and oxidovanadium(V) complexes of
N-substituted triazole derivatives against the HM1:IMSS strain of E. histolytica.
IC50 [μM]
I
II
1
2
3
4
5
6
9.38(3)
11.26(2)
0.14(1)
1.13(1)
1.45(2)
0.32(4)
0.82(1)
1.32(2)
1.80(1)
MNZ
Cell Viability Assay
The cytotoxicities of the compounds against human cervical
cancer (HeLa) cells were accessed through a 3-(4,5-dimethylthi-
azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.[46] As
presented in Table 12, cells treated with 2, 3, 4, and 6 at their
IC50 values showed more than 90 % cell viability, whereas cells
treated with 1 and 5 resulted in viability values of 89.2 and
89.6 %, respectively. Similar results were seen when the cells
were treated at double their IC50 values. A slight increase in cell
viability was usually observed if the incubation was increased
from 48 to 72 h for most compounds. However, doubling of the
concentration did not always result in decreased cell viability.
Experimental Section
Materials, Instrumentation, and Physical measurements: Analyt-
ical reagent-grade V2O5 (Loba Chemie, India), acetylacetone, hydra-
zine hydrate, thymol (Himedia, New Delhi), and 30 % aqueous H2O2,
(Rankem, India) were used as received. Other chemicals and sol-
vents were of analytical reagent grade. The ligands H2L1, H2L2,[2] and
[VIVO(acac)2][47] were prepared according to the methods reported
previously.
The elemental analyses of the compounds were performed with an
Elementar Vario-El-III instrument. The IR spectra were recorded with
samples as KBr pellets with a Nicolet NEXUS Aligent 1100 series
FTIR spectrometer. The electronic spectra of the ligands and com-
plexes in MeOH were recorded with a Shimadzu 2450 UV/Vis spec-
trophotometer. The 1H and 13C NMR spectra of the ligands and
complexes and the 51V NMR spectra of the vanadium(V) complexes
were recorded with a Bruker Avance III 400 MHz spectrometer with
common acquisition parameters. The 51V NMR spectra were re-
corded with the following acquisition parameters: spectral width
3960 ppm, acquisition time 39 ms, line broadening 100 Hz, dwell
time 1.200, frequency 105 mHz, free induction decay (FID) resolu-
tion 13 Hz, receiver gain 2050, and number of scans > 1500. The
51V NMR spectra were recorded with samples in MeOH and DMSO
containing 5–10 % of deuterated solvent, and the 51V chemical
shifts (δV) are referenced to neat VVOCl3 as an internal standard. The
Table 12. Effect on cell viability of HeLa cells in response to 1–6 at their IC50
values (and double their IC50 values) as assessed by MTT assay.
Concentration [μ
M]
48 h
87
72 h
89
1
1
2
2
3
3
4
4
5
5
6
6
MNZ
MNZ
0.14
0.28
1.13
2.26
1.45
2.90
0.32
0.64
0.82
1.64
1.32
2.64
1.8
7
3
4
5
2
2
4
2
3
3
3
3
1
2
1
1
3
4
2
1
3
2
4
2
2
2
1
2
89
94
84
88
83
89
93
88
86
93
92
98
99
94
94
96
93
85
94
96
90
82
91
94
96
97
1
chemical shifts of the H and 13C NMR spectra are quoted relative
to tetramethylsilane (TMS) as an internal standard. The thermogravi-
metric analyses of the complexes were obtained under an oxygen
atmosphere with a TG Stanton Redcroft STA 780 instrument. The
MALDI-TOF mass spectra were measured with a Bruker Ultra-
3.6
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fleXtreme-TN MALDI-TOF/TOF spectrometer with 2-(4′-hydroxy-
benzeneazo)benzoic acid (HABA) as the matrix. A Shimadzu 2010
plus gas chromatograph fitted with an Rtx-1 capillary column
(30 m × 0.25 mm × 0.25 μm) and a flame ionization detector was
used to analyze the catalytic reaction products. The identities of the
products were confirmed by GC–MS with a Perkin–Elmer Clarus 500
complexes as catalysts. In a typical reaction, thymol (1.5 g, 0.010
mol), 30 % aqueous H2O2 (2.3 g, 0.020 mol), 70 % HClO4 (4.3 g,
0.030 mol), and KBr (2.3 g, 0.020 mol) were dissolved in water
(20 mL) at room temperature. The catalyst (0.0010 g) was added to
the reaction mixture, which was then stirred for 2 h. The obtained
brominated products were analyzed quantitatively by gas chroma-
instrument through the comparison of the fragments of each prod- tography, and the identities of the products were confirmed by GC–
1
uct with the available library. The percent conversion of the sub- MS and H NMR spectroscopy.
strate and the selectivity of the products were calculated from the
In vitro Antiamoebic Assay: All of the synthesized compounds
GC data by using the formulas presented elsewhere.
were screened for in vitro antiamoebic activity against the
X-ray Crystal Structure Determination: The three-dimensional X-
ray data of 1a were collected with a Bruker Kappa Apex CCD diffrac-
tometer at 102(2) K by the φ-ω scan method. The reflections were
measured from a hemisphere of data collected from frames that
covered 0.3° in ω. A total of 32055 measured reflections were cor-
rected for Lorentz and polarization effects and for absorption by
multiscan methods based on symmetry-equivalent and repeated
reflections. Of the total, 2412 independent reflections exceeded the
significance level (|F|/σ|F|) > 4.0. After the data collection, a multis-
can absorption correction (SADABS)[48] was applied, and the struc-
ture was solved by direct methods and refined by full-matrix least-
squares techniques on F2 with the SHELX suite of programs.[49] The
hydrogen atoms were included in calculated position and refined
in a riding mode, except the hydrogen atom of O(5), which was
located in the difference Fourier map and fixed to an oxygen atom.
The refinements were performed with allowance for the thermal
anisotropy of all non-hydrogen atoms. A final difference Fourier
map showed no residual density in the crystal (0.687 and
–0.554 e Å–3). A weighting scheme w = 1/[σ2(Fo2) + (0.112400P)2 +
0.000000P] was used in the latter stages of the refinement. Further
details of the crystal structure determination are given in Table 13.
CCDC 1437168 (for 1a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
HM1:IMSS strain of E. histolytica by the microdilution method. E.
histolytica trophozoites were cultured in culture tubes with Dia-
mond TYIS-33 growth medium. The tested compounds (1 mg) were
dissolved in DMSO (40 μL, the level at which no inhibition of
amoeba occurs).[50,51] Stock solutions (1 mg/mL) of the compounds
were prepared freshly before use. Twofold serial dilutions were
made in the wells of 96-well microliter plates (costar). Each test
included metronidazole as a standard amoebicidal drug, control
wells (culture medium plus amoebae), and a blank (culture medium
only). All experiments were performed in triplicate at each concen-
tration level and repeated three times. The amoeba suspension was
prepared from a confluent culture: the medium was poured off at
37 °C, fresh medium (5 mL) was added, and the culture tube was
cooled with ice to detach the organisms from the side of flask.
The number of amoeba per mL was estimated with the help of a
haemocytometer with trypan blue exclusion to confirm the viability.
The suspension was diluted to 105 organisms per mL by the addi-
tion of fresh medium, and this suspension (170 μL) was added to
the test and control wells in the plate so that the wells were com-
pletely filled (total volume, 340 μL). An inoculum of 1.7 × 104 organ-
isms/well was chosen so that confluent, but not excessive growth,
occurred in the control wells. The plate was sealed and gassed for
10 min with nitrogen before incubation at 37 °C for 72 h. After
incubation, the growth of the amoebae in the plate was checked
with a low-power microscope. The culture medium was removed
through the inversion of the plate and gentle shaking. The plate
was then washed immediately with sodium chloride solution
(0.9 %) at 37 °C. This procedure was completed quickly, and the
plate was not cooled to prevent the detachment of amoeba. The
plate was allowed to dry at room temperature, and the amoebae
were fixed with chilled methanol and stained with aqueous eosin
(0.5 %) for 15 min after they dried. The stained plate was washed
once with tap water and twice with distilled water and then allowed
Table 13. Crystal data and structure refinement details for 1a.
1a
Formula
Formula weight
T [K]
C54H40N8O12V2
1094.82
102(2)
Wavelength [Å]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
0.71073
triclinic
P1
¯
9.3660(18)
10.013(2)
12.987(3)
88.059(14)
89.482(15)
89.682(16)
1217.1(4)
1
to dry. A portion (200 μL) of 0.1
N sodium hydroxide solution was
added to each well to dissolve the protein and release the dye. The
optical density of the resulting solution in each well was deter-
mined at λ = 490 nm with a microplate reader. The percentage
inhibition of amoebal growth was calculated from the optical densi-
ties of the control and test wells and plotted against the logarithm
of the dose of the drug tested. Linear regression analysis was used
to determine the best fit line from which the IC50 value was found.
Α [°]
ꢀ [°]
Γ [°]
V [Å3]
Z
F(000)
562
1.494
0.460
1.57 to 26.45
0.2065
0.15 × 0.08 × 0.06
0.971
0.0787
0.2418
0.687 and –0.554
Dcalcd. [g cm–3
]
μ [mm–1
θ [°]
]
Cell Viability Assay: The cytotoxicity of the compounds against
HeLa cells was checked through an MTT assay.[46] HeLa cells (4000
cells/well) were plated in 96-well tissue culture plates in triplicate
with compounds. Each compound was added at two different con-
centrations: their E. histolytica IC50 value and double it. Cells treated
with DMSO were used as the control. The cells were incubated for
two different time periods (48 and 72 h), and the cell viability was
accessed after these time intervals. The absorbance values were
measured at λ = 570 nm.
Rint
Crystal size [mm3]
Goodness-of-fit on F2
[a]
R1 [I > 2σ(I)]
[b]
wR2 (all data)
Largest difference peak and hole [e Å–3
]
[a] R1 = Σ||Fo| – |Fc||/Σ|Fo|. [b] wR2 = {Σ[w(||Fo|2 – |Fc|2|)2]|/Σ[w(Fo2)2]}1/2
.
Catalytic Reaction – Oxidative Bromination of Thymol: The oxi-
[VVO(μ-L1)(OMe)]2 (1): A solution of H2L1 (0.37 g, 0.0010 mol) was
dative bromination of thymol was performed with the synthesized prepared in hot absolute methanol (15 mL) and then filtered. A
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solution of [VIVO(acac)2] (0.26 g, 0.0010 mol) in methanol (10 mL)
was added to the above solution with stirring. After 6 h under re-
flux, the clear solution was reduced to 10 mL and stored in a refrig-
erator (ca. 5 °C). Gradually, a black solid precipitated. The solid was
collected by filtration, washed with methanol and then petroleum
ether (b.p. ca. 60 °C), and dried in a desiccator over silica gel, yield
0.654 g (69.7 %). C44H32N6O12V2 (938.11): calcd. C 56.30, H 3.44, N
8.95; found C 55.9, H 3.7, N 8.9.
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[VVO(μ-L2)(OMe)]2 (2): The black complex 2 was prepared by fol-
lowing the method outlined for 1 with H2L2 instead of H2L1, yield
0.613 g (72.1 %). C42H32N6O8V2 (850.12): calcd. C 59.30, H 3.79, N
9.88; found C 59.3, H 3.9, N 10.0.
[4]
[5]
[6]
[7]
[8]
K(H2O)[VVO2(L1)] (3): A solution of KOH (0.11 g, 0.0020 mol) in
methanol (15 mL) was added slowly to a solution of 1 (0.50 g,
0.00053 mol) in methanol (150 mL) with stirring. The obtained or-
ange solution was allowed to oxidize aerially at room temperature.
After 2 d, the solution was yellow. After the solvent volume was
reduced to ca. 10 mL, the solution was kept for 12 h at room tem-
perature. The yellow solid was collected by filtration, washed with
methanol, and dried in a desiccator over silica gel, yield 0.22 g
(42.8 %). C21H15KN3O7V (511.00): calcd. C 49.32, H 2.96, N 8.22;
found C 49.0, H 3.5, N 8.1.
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K(H2O)[VVO2(L2)] (4): The yellow complex 4 was prepared from 2
by the procedure outlined for 3, yield 0.24 g (51.8 %). C20H15KN3O5V
(467.01): calcd. C 51.39, H 3.23, N 8.99; found C 51.7, H 3.1, N 9.5.
Cs(H2O)[VVO2(L1)] (5): A solution of CsOH (0.33 g, 0.0020 mol) in
methanol (15 mL) was added slowly with stirring to a solution of 1
(0.50 g, 0.00053 mol) in methanol (150 mL). The obtained dark or-
ange solution was left at room temperature for slow aerial oxid-
ation. After 2 d, the solution became yellow. After the volume was
reduced to ca. 10 mL, the solution was kept at room temperature
for 12 h and a yellow solid separated. The solid was collected by
filtration, washed with methanol, and dried in a desiccator over
silica gel, yield 0.27 g (46.2 %). C21H15CsN3O7V (604.94): calcd. C
41.68, H 2.50, N 6.94; found C 41.8, H 2.8, N 7.4.
[9]
[10]
Cs(H2O)[VVO2(L2)] (6): Complex 6 was prepared similarly to 5 from
2, yield 0.29 g (51.1 %). C20H15CsN3O5V (560.95): calcd. C 42.80, H
2.69, N 7.49; found C 43.3, H 3.0, N 7.9.
[11]
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Reaction of [VVO(μ-L1)(OMe)]2 (1) with 4,4′-Bipyridyl: Complex
1 (0.50 g, 0.00053 mol) was dissolved in methanol (50 mL), and 4,4′-
bipyridyl (0.078 g, 0.00050 mol) was added. The reaction mixture
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solution was cooled and then kept at room temperature for slow
evaporation. Black crystal blocks of 1a separated slowly within a
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Acknowledgments
M. R. M. thanks the Science and Engineering Research Board
(SERB), Government of India, New Delhi for financial support of
the work (EMR/2014/000529). B. S. is thankful to Indian Institute
of Technology (IIT) Roorkee for awarding an MHRD fellowship.
I. C. acknowledges the Portuguese Fundação para a Ciência e a
Tecnologia (FCT) for an Investigador FCT contract and the IST-
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Received: November 17, 2015
Published Online: February 25, 2016
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