2-, 3-, and 4-(1-Oxo-1H-2,3-dihydroisoindol-2-yl)benzoic acids and their corresponding organotin carboxylates: Synthesis, characterization, fluorescent, and biological activities

Article abstract of DOI:10.1016/j.bmcl.2010.08.034

Three novel organotin complexes with general formula Sn(OH)(bz) ₂L (bz = benzyl, HL = 2-, 3-, or 4-(1-oxo-1H-2,3-dihydroisoindol-2- yl)benzoic acid) and one of their ligands were prepared and characterized. In vitro antifungal and antibacterial

Full text of DOI:10.1016/j.bmcl.2010.08.034

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5649–5652
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-, 3-, and 4-(1-Oxo-1H-2,3-dihydroisoindol-2-yl)benzoic acids and their
corresponding organotin carboxylates: Synthesis, characterization, fluorescent,
and biological activities
b,
Shuang-Lian Cai a, Yong Chen a, , Wen-Xia Sun b, , Hui Li a, , Yun Chen a, , Shi-Shan Yuan
*
*
a College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
b The Medical College of Hunan Normal University, Changsha, Hunan 410013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three novel organotin complexes with general formula Sn(OH)(bz)2L (bz = benzyl, HL = 2-, 3-, or 4-(1-
oxo-1H-2,3-dihydroisoindol-2-yl)benzoic acid) and one of their ligands were prepared and characterized.
In vitro antifungal and antibacterial activities of these complexes and ligands were investigated with the
representative strains of Candida albicans, Staphylococcus aureus, Escherichia coli, and Pseudomonas
aeruginosa. Their fluorescence properties have also been discussed.
Received 5 May 2010
Revised 24 July 2010
Accepted 6 August 2010
Available online 11 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Organotin carboxylate
Synthesis
Antibacterial activity
Antifungal activity
Fluorescence
Heterocyclic compounds containing the phthalimidine (isoin-
dolin-1-one) skeleton are being paid more and more attention
due to their fascinating properties and potential applications in
many fields, especially in biology and medical science.1 The recent
elaboration has proven that the phthalimidino group plays a key
role in the pharmacological activity of correlated synthetic and
natural compounds.2 The new phthalimidine derivative with un-
ique biological activity might be a precursor of efficacious drug
for therapeutic and prophylactic use, such as antipsychotics, hypo-
lipidemic, and antimicrobial.3 In the last decades, many new
N- and C-substituted phthalimidine derivatives have been synthe-
sized and tested for their diverse biological activity.4 Although the
majority of synthetic N-substituted derivatives are N-alkylphtha-
limidines, and most of them display no antifungal activity.1–4 The
relatively less regarded N-arylphthalimidines might also be an
alternative strategy in designing potent agents for medical use, in
which the electronic delocalization in N-arylphthalimidines will
be bound to affect the stability of the phthalimidino ring which
is closely related to the bioactivity of this kind of compound.2,5
Moreover, many substituents such as carboxyl and hydroxyl them-
selves might be able to endow the compound with a broader spec-
trum of biological activity.6 Thus, a further study regarding the
synthesis, bioeffect and structure–activity relationship of this kind
of compound is essential. The combination of functionals from dif-
ferent kinds of compounds with extensive bioactivities could often
be helpful for good selectivity and stronger activity as well as low-
er toxicity. Thus, an organotin complex containing phthalimidino
group can improve the bioactivity of phthalimidines in view of
the special bioactivity widely existed in a variety of organotin com-
pound. However, to the best of our knowledge, no example of this
kind of compound has been reported until now.
Herein, as a part of our ongoing research projects, we report the
synthesis and characterization of 3-(1-oxo-1H-2,3-dihydroisoin-
dol-2-yl)benzoic acid (1, mHpba, positional isomer of our
previously reported 2- and 4-(1-oxo-1H-2,3-dihydroisoindol-2-
yl)benzoic acid (oHpba 2 and pHbpa 3, respectively))7 and three
correlated organotin carboxylates with general formula
Sn(OH)(bz)2L (4, 5, and 6, bz = benzyl, HL = mHpba, oHpba, and
pHpba, respectively). The latter are the first examples of organotin
complex with phthalimidine derivative. The fluorescent and bio-
logical activities of all these six compounds have been investigated.
According to the synthetic scheme described in Scheme 1, com-
pounds 4, 5, and 6 were prepared by the one-step reaction of dib-
enzyltin chloride and the corresponding sodium salt of the
phthalimidinobenzoic acids 1–3 in an ethanol/dimethylformamide
(2:1) mixture with moderate yield.9,10 Both of the two kinds of
* Corresponding authors. Tel.: +86 731 88822275; fax: +86 731 88713642 (Y.C.);
tel.: +86 731 88912458; fax: +86 731 88912429 (S.-S.Y.).
E-mail addresses: cnchenyun@yahoo.com.cn (Y. Chen), yuanshishan@yahoo.
com.cn (S.-S. Yuan).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.034

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S.-L. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5649–5652
Scheme 1. Synthetic method for compounds 1–6: (a) EtOH, 90 °C; (b) NaOH; (c) Sn, H2O, toluene, 123 °C; (d) EtOH/DMF, 50 °C.
reactants were prepared by the reported methods in the litera-
ture.11–13
appear as a singlet in 1H NMR of related free ligands at ca. d
5 ppm.7,8 In addition, the existence of the hydroxyl hydrogen atom
in the three complexes are confirmed by the singlet in the region of
d 1.24–3.27.
Although an attempt to obtain single crystals of compounds 1
and 4–6 for single-crystal X-ray diffraction was not successful,
their molecular structure has been elucidated by elemental analy-
ses, 1H NMR, IR, and mass spectra.14–17 The results of elemental
analyses are in good agreement with the proposed formulates.
The molecular ion peak at m/z 253 and one set of fragments in
the mass spectrum of 1 are fully consistent with its molecular
structure as drawn. The IR spectrum of 1 showed a broad band at
3421 cmÀ1 assigned to v(O–H), and the medium band at 3062
cmÀ1 ascribed to the C–H stretching of the aromatic ring. The
bands of the antisymmetric and symmetric stretching vibrations
In complexes, the
D
v value of 160–210 cmÀ1 indicated the dif-
ference of the two O atoms of the carboxyl group with chelating
bidentate coordination mode. Meanwhile, the big unsymmetrical
phthalimidino carboxylate group7 tend to hamper the rotation of
the two benzyl groups, and it inevitably lead to the large chemi-
cal-shift difference between the methylene protons with magneti-
cally non-equivalent as above mentioned. And vice versa, the IR
and NMR data suggested that there is no symmetry plane (r) in
these organotin molecules. Obviously, the inversion center (i) and
4n-fold improper axis (S4n) of rotation cannot exist in these mole-
cules. Therefore, the organotin carboxylate molecules have no type
of symmetry whatever, and are chiral molecules. Whereas, it
would be beyond the scope of this study to assign the chiral Sn(IV)
centers as R or S, since the stereoisomers have not been separated
into enantiomers.
of methylene C–H bond are observed at 2906 and 2827 cmÀ1
,
respectively. The broad band around 2538 cmÀ1 indicated the pres-
ence of strong hydrogen bond interaction.18 The characteristic
strong absorption of the stretching vibration of lactam carbonyl
was redshifted towards 1633 cmÀ1 due to the conjugation between
the benzene ring, carbonyl group, and an sp2-hybridized nitrogen.7
The free carboxyl group are clearly present at 1695 (vs, v(C@O)),
In order to study the bioactivity of this kind of ligand and their
organotin carboxylates, their in vitro antifungal and antibacterial
activities have been evaluated by the minimum inhibition concen-
tration (MIC) test using the doubling dilution technique against
fungus Candida albicans, Gram-positive bacteria Staphylococcus
aureus, and Gram-negative bacteria Escherichia coli and Pseudomo-
nas aeruginosa. The results are summarized in Table 1. As revealed
from these data, all the above mentioned six compounds were
found to be not only active against these bacteria corresponds well
with that of the reported N-substituted phthalimidins, but also to
be active against fungi which is infrequent for this kind of com-
pound.6 Moreover, the organotin carboxylates 4–6 display a great
improvement in antibacterial and antifungal activity upon their
corresponding phthalimidine derivatives 1–3. It is also worth men-
tioning that the inhibition efficiency, in cases both of phthalimi-
dine ligands and of organotin carboxylates, is dependent
somewhat on the substitution position of the carboxylate group
on its N-connected benzene ring. Among which, the compounds
1 and 4 with the substituent carboxylate group on the meta-posi-
1385 (s, O–H bend), 1257 (s, v(C–O)) cmÀ1 19
Bands at 1587,
.
1491, and 1444 cmÀ1 are attributed to the skeleton vibration of
aromatic ring, and the meta-disubstitution pattern on benzene ring
was confirmed by the peaks at 758 (s) and 685 (m) cmÀ1 (C–H out-
of-plane bend).20 The most significant change in IR spectra from
the ligands 1–3 to their organotin carboxylates 4–6 mainly are
embodied in the following three aspects: (1) the disappearance
of strong absorption at ca. 1700 cmÀ1 corresponding to v(C@O) of
carboxyl group; (2) the presence of obvious absorption at ca.
1545 for vasym(COO), 550 cmÀ1 for Sn–C and 450 cmÀ1 for Sn–
O;21 (3) the appropriate blue shift (ca. 20 cmÀ1) of v(C@O) of the
lactam carbonyl group in complex compared to that of 1. These
changes clearly indicated the deprotonation and participation of
the carboxyl group in the complexation process with Sn(IV) cation.
The
D
v[vasym(COO) À vsym(COO)] in the range 160–210 cmÀ1 sug-
gested the chelating bidentate coordination mode of the carboxyl
group in these three organotin complexes.21,22 As a result, the
Sn(IV) center is coordinated by two C atoms from two benzyl
groups and three O atoms from one carboxyl and one hydroxyl
group, forming a distorted trigonal bipyramidal geometry. This
mode is also proven by the 1H NMR spectroscopic data, in which
the most fascinating character is the coupling pattern and chemical
shift related to the bridging methylene protons. Because of the lack
of a plane of symmetry in the molecule, the methylenes of two
benzyl groups as well as the relevant protons are stereochemically
and magnetically non-equivalent. Large chemical-shift differences
were observed between these methylene protons. Complex 5 gives
typical two AX patterns for two groups of bridge C6H5CH2Sn pro-
tons at d 2.03–2.29 and 2.66–3.03, which arise as an AB system
and an AX system in 4 (d 2.58 and 2.68–2.86) and 6 (d 2.61 and
2.79–2.99). The diagnostic signal of the resonance of bridging
methylene protons of the phthalimidino group is represented by
an AB system at ca. d 6.54–6.72 the three complexes, which often
Table 1
In vitro antifungal and antibacterial activities as the minimum inhibition concentra-
tion (MIC) values (mg/mL)a for compounds 1–6
Compounds
E.c.b
P.a.c
S.a.d
C.a.e
1
2
3
4
5
6
0.625
2.5
1.25
0.0625
0.125
0.125
0.625
1.25
0.625
0.125
0.125
0.125
1.25
2.5
1.25
0.0625
0.0625
0.0625
0.625
1.25
1.25
0.125
0.125
0.125
a
b
c
Values are means of three experiments.
E.c. = Escherichia coli.
P.a. = Pseudomonas aeruginosa.
S.a. = Staphylococcus aureus.
C.a. = Candida albicans.
d
e

S.-L. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5649–5652
5651
6. Breytenbach, J. C.; Van Dyk, S.; Van den Heever, I.; Allin, S. M.; Hodkinson, C. C.;
Northfield, C. J.; Page, M. I. Bioorg. Med. Chem. Lett. 2000, 10, 1629.
7. Chen, Y.; Li, H.; Cai, S. Chem. Commun. 2009, 5392.
tion are found to be more active than the others, while the ligand 2
with the carboxylate group on the ortho-position exhibit lowest
activity in three ligands, and its organotin carboxylate 5 display
the same activity as 6 whose carboxylate group is on the para-
position.
The substituent position can also strongly influence the fluores-
cence of the phthalimidine derivatives. Distinctly unlike its posi-
tion isomers 2 and 3 which emits intense fluorescence around
408 nm (in DMF), ligand 1 exhibits only a very weak emission at
455 nm with a large redshift of 47 nm.8 While the emission spectra
of its organotin carboxylate 4 (in the solid state at room tempera-
8. Li, H.; Chen, Y.; Ying, S.-M.; Zhang, J.; Liu, H. J. Mol. Struct. 2009, 936, 137.
9. Chemicals and reagents were purchased commercially and used as received.
Thin-layer chromatography (TLC) analyses were conducted with silica gel-
coated plate (from Qingdao Ocean Chemicals). C, H, and N-microanalyses were
carried out with a Vario EL III elemental analyzer. Melting point of compound 1
was determined using a Beijing Taike XT-4 microscopy melting point apparatus
and was reported uncorrected. The IR spectra were recorded as KBr discs on a
Nicolet Magna 750 FT-IR spectrometer. 1H NMR spectrum was obtained at
room temperature on Varian INOVA-400 spectrometer, and the chemical shift
scale (ppm) is based on internal standard tetramethylsilane. LC–MS analyses
were performed using a Waters Micromass ZQ-4000 spectrometer. Fluorescent
analyses were carried out with an F-2500 fluorescence spectrophotometer with
the slit widths of excitation and emission at 10.0 nm.
ture) shows this ligand-centered (LC, n–p p–p
* and/or *) emission
at 451 nm as a very strong peak with a shoulder peak at 425 nm.
Simultaneously, it also exhibits two new strong emissions at 471
and 526 nm which may be assigned as ligand-to-metal charge
transfer (LMCT) or metal-to-ligand charge transfer (MLCT).23 The
emission spectra of organotin carboxylate 6 is quite similar to that
of 4 except the significant enhancement of the yellow-green emis-
sion at 525 nm which may come from a higher conjugation of the
ligand 3 than that of 4.7 However, complex 5 displays the only fluo-
rescence maximum at 409 nm which is attributed to its ligand 2
just with an obvious enhancement. It could be envisioned that
these remarkable and unique fluorescent property of phthalimi-
dine derivatives might be useful in exploiting some sensory and
diagnostic applications.
In conclusion, this Letter describes the preparation and charac-
terization of a new N-substituted phthalimidine and three organo-
tin carboxylates as the first examples of organotin complex of
phthalimidine derivatives with broad spectrum resistance and
great improved antibacterial and antifungal activity upon their
corresponding phthalimidine derivatives. The substitution position
of the carboxylate group on their N-connected benzene ring
strongly influenced the bioactivity and fluorescent activities of
both the ligands and the organotin carboxylates.
10. Synthesis of 4, 5, and 6: Related ligand 1, 2, or 3 (0.0405 g, 0.16 mmol) and
sodium hydroxide (0.040 g, 1.0 mmol) were successively added to a mixture of
dibenzyltin chloride (0.2976 g, 0.80 mmol) in EtOH/DMF solution (4:1, 30 mL).
The reactant mixture was violently stirred for 2 h at 60–80 °C. Then, the
resulting mixture was cooled down to room temperature followed by filtration.
The residue for 4 and 6 were washed with EtOAc and acetone for four times
and dried for 1 h under vacuum at about 60 °C to give the compounds 4
(0.043 g) and 6 as pale yellow solid (0.035 g) with the yield of 47% and 38%,
respectively. On the other hand, the filtrate for 5 was concentrated by rotary
evaporation followed by standing at room temperature for 3 days to produce
compound 5 as white crystal (0.027 g, 30%). Mp: >300 °C. Anal. Calcd for
C
29H25NO4Sn: C, 60.94; N, 2.45; H, 4.41. Found for 4: C, 69.75; N, 2.40; H, 4.31.
Found for 5: C, 70.22; N, 2.38; H, 4.27. Found for 6: C, 70.31; N, 2.34; H, 4.25.
11. Synthesis of 1: Ortho-phthalaldehyde (OPA) (0.685 g, 5.0 mmol) was added to a
stirred solution of meta-aminobenzoic acid (0.670 g, 5.0 mmol) in the mixture
of acetone (10 mL) and deionized water (50 mL). The reactant mixture was
refluxed for 3 h at about 110 °C. After the completion of the reaction (TLC, 4:1
EtOAc/MeOH), the resulting mixture was cooled down to room temperature
followed by filtration, and the residue was wished with water,
extracted with EtOAc. Then, recrystallized from EtOH and dried under
vacuum to give the compound 1 as brownish black solid (0.7080 g, 56%).
Mp: 182 °C. Anal. Calcd for C15H11NO3: C, 71.13; N, 5.53; H, 4.38. Found: C,
70.39; N, 5.45; H, 4.29.
12. (a) Zuman, P. Chem. Rev. 2004, 104, 3217; (b) DoMinh, T.; Johnson, A. L.; Jones, J.
E., ; Senise, P. P., Jr. J. Org. Chem. 1977, 42, 4217.
13. Sissido, K.; Takeda, Y.; Kinngawa, Z. J. Am. Chem. Soc. 1961, 83, 538.
14. Compound 1: IR (KBr pellets): 3421 (m, br), 3062 (m), 2906 (m), 2827 (m),
2619 (m), 2538 (m, br), 1695 (vs), 1633 (s),1587 (s), 1491 (m), 1444 (s), 1385
(s), 1296 (s), 1257 (s), 1225 (s), 1159 (m), 1120 (m), 1080 (m), 997 (w), 945 (w),
912 (w), 816 (w), 758 (s), 685 (m), 567 (w) cmÀ1 1H NMR (DMSO-d6,
;
400 MHz): d 5.10 (s, 2H, ArCH2N), 7.69–7.71 (m, 2H, Ar-H4, 6), 7.55–7.60 (m,
2H, Ar-H7), 7.81 (d, J = 7.6 Hz, 2H, Ar-H5,13), 8.16 (d, J = 8.0 Hz, 1H, Ar-H14),
8.53 (s, 1H, Ar-H10), 12.94 (s, br, 1H, COOH). ES-MS (70 eV, m/z): 253 ([M+]),
236, 225, 207, 178, 148, 132, 117, 105, 89, 76, 65, 44.
Acknowledgments
This work forms a part of the SIT Project of Hunan University
(2009125), and was financially supported by the Open-End Fund
of Main Precise Instrument of Hunan University (104080 and
104082). The authors thank Yi Wang (Fudan University) for HRMS
measurements and useful discussions.
15. Compound 4: IR (KBr pellets): 3575 (w, br), 3055 (w), 3022 (m), 2920 (w), 2864
(w), 2000–1700 (vw), 1653 (s), 1595 (s), 1545 (s), 1489 (s), 1448 (s), 1385 (s),
1257 (m), 1205 (m), 1107 (m), 1053 (m), 1028 (m), 1001 (w), 947 (w), 904 (m),
800 (m), 758 (vs), 696 (vs), 627 (s), 584 (m), 553 (s), 449 (m) cmÀ1 1H NMR
;
(CDCl3, 400 MHz): d 2.58 (AB system, J = 12.8 Hz, 2H, ArCH2Sn), 2.68 and 2.86
(AX system, J = 11.6 Hz, 2H, ArCH2Sn), 1.24 (s, 1H, Sn(OH), 6.72 (AB system,
J = 8.0 Hz, 2H, ArCH2N), 6.82–7.40 (m, 18H, Ar-H).
References and notes
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2924 (w), 2878 (w), 2000–1700 (vw), 1662 (s), 1599 (s), 1545 (s), 1491 (s),
1450 (m), 1414 (s), 1358 (vs), 1254 (w), 1209 (m), 1180 (w), 1155 (w), 1107
(m), 1055 (m), 1030 (w), 999 (w), 972 (w), 904 (w), 839 (w), 758 (vs), 698 (vs),
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