Synthesis, crystal and calculated structure, and biological activity of 2-((6-bromo-2-methoxyquinolin-3-yl) (phenyl)methyl)-2,3,7,7a-tetrahydro-3a,6- epoxyisoindol-1(6H)-one

Article abstract of DOI:10.1007/s10870-011-0245-x

The title compound, C₂₅H₂₁BrN₂O ₃, was synthesized and structurally characterized by elemental analysis, IR, MS, ¹H NMR and single crystal X-ray diffraction. The crystal is of orthorhombic system, space group Pbca with a = 11.706(2) A, b = 18.038(4) A, c = 20.369(4) A, α = 90.00°, β = 90.00°, γ = 90.00°, V = 4301.0(15) A³, Z = 8, Dc = 1.474 g/cm³, F (000) = 1952.0, μ(MoKα) = 1.941 mm ^-1, the final R₁ = 0.0670 and wR₂ = 0.2319 for reflections with I > 2σ(I). The crystal structure is stabilized by un-classical hydrogen-bonding C-H...O forming a threedimensional network. The optimized geometric bond lengths and bond angles obtained by using density functional theory have been compared with X-ray diffraction values. In addition, the preliminary biological test showed that the title compound had anti-Mycobacterium phlei 1180 activity. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s10870-011-0245-x

J Chem Crystallogr (2012) 42:318–322
DOI 10.1007/s10870-011-0245-x
ORIGINAL PAPER
Synthesis, Crystal and Calculated Structure, and Biological
Activity of 2-((6-Bromo-2-methoxyquinolin-3-yl) (phenyl)methyl)-
2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-1(6H)-one
•
Yue-Fei Bai Lei Yuan Yu Chen
•
•
•
Li-Juan Wang Chao Wang Tie-Min Sun
•
Received: 18 May 2011 / Accepted: 3 December 2011 / Published online: 14 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The title compound, C25H21BrN2O3, was syn-
thesized and structurally characterized by elemental analysis,
1
IR, MS, H NMR and single crystal X-ray diffraction. The
Introduction
Tuberculosis (TB) infection (Mycobacterium tuberculosis)
has become a serious worldwide problem, infecting in
synergy with human immunodeficiency virus (HIV)
infection. The overall incidence of TB in HIV-positive
patients is 50 times than that of the rate for HIV-negative
individuals. Especially, it is worsen by the emergence of
drug-resistant, multi-drug-resistant TB (MDR-TB) and
recently developed extensive drug-resistant tuberculosis
(XDR-TB).There is thus an urgent need to develop rela-
tively inexpensive new drugs to treat this deadly disease
[1]. TMC-207 has been completed Phase II clinical trial
and will be marked in 2012, acting at a new targeting
proton pump of adenosine triphosphate (ATP) synthase [2].
It exhibits excellent activity and high selectivity, long term
of drug potency and no obvious toxicity. Much more
importantly, TMC-207 can exhibit superior activity against
MDR-TB and XDR-TB with no cross-resistance to current
TB drugs [3]. Based on the features of the afore-mentioned,
TMC-207 is used as the lead compound, and entirely-new
quinoline compounds are designed and synthesized. The
title compound is one of these compounds. In order to
determinate the molecular structure and spatial absolute
conformation, the single crystal was grown and tested by
X-ray single-crystal diffraction. In addition, it is well
known that DFT has become the dominant and accurate
computational tools for dealing with natural organic mol-
ecules [4]. The organic molecular structure of the title
compound in the ground state was optimized by a DFT
method. Furthermore, preliminary pharmacological activ-
ity was screened.
crystal is of orthorhombic system, space group Pbca with
˚
˚
˚
a = 11.706(2) A, b = 18.038(4) A, c = 20.369(4) A, a =
3
˚
90.00°, b = 90.00°, c = 90.00°, V = 4301.0(15) A ,
Z = 8, Dc = 1.474 g/cm3, F (000) = 1952.0, l(MoKa) =
1.941 mm-1, the final R1 = 0.0670 and wR2 = 0.2319 for
reflectionswithI [ 2r(I).Thecrystalstructureisstabilizedby
un-classical hydrogen-bonding C–HÁÁÁO forming a three-
dimensional network. The optimized geometric bond lengths
and bond angles obtained by using density functional theory
have been compared with X-ray diffraction values. In addi-
tion, the preliminary biological test showed that the title
compound had anti-Mycobacterium phlei 1180 activity.
Keywords Synthesis Á X-ray diffraction Á DFT Á
Biological activity
Y.-F. Bai Á L. Yuan Á C. Wang Á T.-M. Sun (&)
Key Laboratory of Original New Drug Design & Discovery
Ministry of Education, School of Pharmaceutical Engineering,
Shenyang Pharmaceutical University, Shenyang 110016,
People’s Republic of China
e-mail: suntiemin@126.com
Y. Chen
School of Vocational and Technical, Shenyang Pharmaceutical
University, Shenyang 110026, People’s Republic of China
L.-J. Wang
State Key Laboratory of Supramolecular Structure
and Materials, Jilin University, Changchun 130012,
People’s Republic of China
123

J Chem Crystallogr (2012) 42:318–322
Experimental
319
(0.51 g, 0.001 mmol) prepared according to literature
method [1] and K2CO3 (0.69 g, 0.005 mmol) in DMF was
stirred for 6 h at 50 °C. The reaction mixture was diluted
with water (60.0 ml). The resulting precipitate was collected
by filtration, washed several times with cold water, and dried
to afford white powder (0.44 g, 86.2% yield). mp
162–164 °C. IR (KBr pellets)/cm-1: 1693(C=O), 1623,
Reagents and Techniques
The melting point was determined by means of a Gal-
lenkamp apparatus. The infrared spectrum was recorded on
a Perkin Elmer one FT-IR spectrograph with KBr pellets.
By means of an ARX-300 MHz spectrometer, in combi-
nation with tetramethylsilane (TMS) as internal standard,
the 1H NMR spectra was recorded. For elemental analysis,
we used combustion gas chromatography method and these
analyses were performed on a Hewlett-Packard 185 CHN
analyzer. Mass spectrometry (MS): Hewlett-Packard 1100
LC/MSD spectrometer (Hewlett-Packard, USA). The
homogeneity of the synthesized compounds was controlled
by thin-layer chromatography (TLC) using TLC aluminum
sheets with silica gel F254 (Merck). Spots were visualized
by ultraviolet (UV) light or iodine. All commercially
available solvents and reagents were used without further
purification.
1
1600, 1464(ArH), 1256, 1011(C–O). H NMR (300 MHz,
CDCl3) d: 1.59–1.69(m, 1H, COCH); 2.51–2.29(m, 1H,
COCHCH2-a); 2.26–2.32(d, 1H, J = 13.5 Hz, COCHCH2-
b); 3.45–3.49(d, 1H, NCH2-a); 3.67–3.84(d, 1H, NCH2-b);
5.20–5.21(m, 1H, CH2CH); 6.30–6.32(d, J = 10.5 Hz, 1H,
CH=CH); 6.39–6.41(dd, J = 10.5 Hz, J = 3.0 Hz, 1H,
CH=CH); 3.85(s, 3H, OCH3); 6.85(s, 1H, ArCH); 7.28–
7.31(m, 1H, C6H5-H4); 7.33–7.34(m, 2H, C6H5-H3,H5);
7.78–7.79(d, 2H, C6H5-H2,H6); 7.35(s, 1H, quinoline ring-
H7); 7.37(m, 1H, quinoline ring-H2); 7.64(m, 1H, quinoline
ring-H3); 7.73(m, 1H, quinoline ring-H6); ESI–MS, m/z =
477.1 [M ? H]?, 478.1 [M ? 2]?. Anal. calcd for C25H21
BrN2O3: C, 62.90; H, 4.43; N, 5.87%. Found: C, 62.94; H,
4.40; N, 5.90% (Scheme 1).
Molecular structure of the title compound in the ground state
was optimized by a basis of density functional theory (DFT)
method using Becke’s three parameter hybrid exchange-
correlation functional (B3LYP) with a 6-31G(d) basis set [5].
Molecular geometries were fully optimized by Berny’s opti-
mization algorithm using redundant internal coordinates. The
entire set of computation was performed using the GAUSSIAN
09WTM software [6]. An extensive search for low energy
conformations on potential energy surfaces (PES) of compound
was carried out and minimum energy conformation was re-
optimized at DFT/B3LYP/6-31G(d) without symmetry con-
straints. For large and flexible molecules, the PES contains
many local minima corresponding to different relative orien-
tations of the functional groups in the molecule. The compu-
tational molecular structure was shown by the animation option
of the Gauss-View5.0TM graphical interface [7].
Single Crystal X-ray Diffraction
The white powder was dissolved in acetonitrile/methanol
mixed solvents = 1:1. After slowly evaporating the solvents
several days, a suitable single crystal was mounted on the top
of a glass fiber and performed on a Bruker P4 diffractometer
equipped with a graphite-monochromatic MoKa radiation
˚
(k = 0.71073 A) by using an x scan mode at 295(2) K. The
structure was solved by direct methods with SHELXS-97
program [8] and expanded by Fourier technique. The non-
hydrogen atoms were refined anisotropically. The hydrogen
atoms bound to carbon were determined with theoretical
calculations and those attached to nitrogen and oxygen were
determined with successive difference Fourier syntheses.
The structure was refined by full-matrix Least-squares
techniques on F2 with SHELXL-97 [9]. The final cycle of
refinement with reflections corresponding to the criterion
I [ 2r(I) led to final discrepancy factors R1 = 0.0670
and wR2 = 0.2319 (w = 1/[r2 (Fo2) ? (0.1778P)2 ?
0.7563P]) where P = (Fo2 ? 2Fc2)/3. All calculations
Synthesis of 2-((6-Bromo-2-methoxyquinolin-3-yl)
(phenyl)methyl)-2,3,7,7a-tetrahydro-3a,6-
epoxyisoindol-1(6H)-one
A solution of N-((6-bromo-2-methoxyquinolin-3-yl) (phe-
nyl) methyl)-3-chloro-N-(furan-2-yl-methyl) propanamide
Scheme 1 Synthetic route of
the title compound
O
Cl
O
N
O
O
Br
Br
K2CO3/DMF
50
N
O
N
O
N
123

320
J Chem Crystallogr (2012) 42:318–322
Determining the Minimal Inhibitory Concentration
were performed using the Crystal Structure crystallographic
software package except for the refinement. The crystal data
and the refinement results are given in Table 1. The molec-
ular structure and packing diagram of the title compound are
shown in Figs. 1, 2 respectively. The un-classical hydrogen-
A series of broth tubes containing diluted chemical syn-
thetic compounds concentrations were prepared and inoc-
ulated with a 48 h liquid culture of Mycobacterium phlei
1180. Then the tubes were incubated at 37 °C for 20 h. The
minimal inhibitory concentration (MIC) was defined as the
lowest concentration that prevented the mycobacterial
growth. In vitro activity of the title compound in
1.0 mg mL-1 against M. phlei 1180, MIC (mg mL-1) is 40
with rifampicin as a standard drug (MIC = 10.0) for
comparison of anti-tuberculosis results and its inhibition
against other strains is under test.
˚
bond geometry (A, °) in title compound is also showed in
Table 2. The fractional atomic coordinates of both mole-
cules of the asymmetric unit and their detailed geometry
have been deposited to Cambridge Crystallographic Data
Centre (CCDC-802877) as a supplementary publication.
Geometry Optimization
The calculated molecular structure of the title compound and
its numbering scheme are shown in Fig. 3 in accordance with
the atom numbering given in Fig. 1 respectively. The global
energy minimum obtained by DFT of the structure optimi-
zation is -3872.1643389 Hartree (-24.30 9 105 kcal
mol-1). The optimized structural parameters of the title
compound calculated using B3LYP functional at a
6-31G(d) basis set are listed and compared with X-ray dif-
fraction values in Table 3.
Results and Discussion
All the bond lengths in the compound are typical and
similar to our reported compounds [10, 11]. There are four
C–HÁÁÁO hydrogen bonds suggested by SHELXL-97
(Table 2). Three of them are intermolecular C(3)–
Fig. 1 Molecular structure of the title compound, displacement
ellipsoids is drawn at the 30% probability level
i
ii
˚
H(3)ÁÁÁO(2) = 3.282 (7) A, C(13)–H(13)ÁÁÁO(2) = 3.305
Fig. 2 A packing diagram of
the title compound
123

J Chem Crystallogr (2012) 42:318–322
321
Table 1 Crystal data and refinement details for the title compound
CCDC deposition number
Formula
802877
25H21BrN2O3
C
Formula weight
Crystal size (mm)
Temperature (K)
Crystal color
477.34
0.32 9 0.23 9 0.20
295(2)
Colorless
Orthorhombic
Pbca
Crystal system
Space group
˚
a (A)
11.706 (2)
18.038 (4)
20.369 (4)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
90
90
3
˚
Volume (A )
4301.0 (15)
8
Z
Dcalc (g cm-3
)
1.474
Absorption coefficient (mm-1
)
1.941
F (000)
1952.0
Fig. 3 Atom numberings and optimized structure of the title
compound from B3LYP/6-31G(d) calculation
Theta range for data collection
Index ranges
3.02–25.10
-13 B h B 13, -21
B k B 21, -24 B l B 24
Data/restraints/parameters
Reflections collected/unique
R (int)
3719/0/281
29289/3719
0.062
Table 3 Comparison of the optimized and experimental geometric
parameters of the title compound
X-ray
DFT
Refinement method
Full-matrix least-squares
on F2
Bond lengths
Br(1)–C(2)
Goodness of fit ref
Data completeness
0.950
1.863(5)
1.353(5)
1.439(6)
1.211(6)
1.454(6)
1.451(7)
1.301(6)
1.370(6)
1.358(6)
1.462(6)
1.482(5)
1.303(9)
1.521(6)
1.496(7)
1.489(10)
1.492(7)
1.567(6)
1.526(7)
1.495(6)
119.7(4)
118.1(4)
112.1(5)
117.8(4)
1.91436
0.972
O(1)–C(9)
1.35047
1.43084
1.22072
1.44564
1.44003
1.30776
1.36742
1.37941
1.46376
1.46736
1.33837
1.52840
1.51792
1.52782
1.51647
1.56442
1.54663
1.52997
119.79411
118.65129
121.55458
118.18635
Final R indices[I [ 2r(I)]
R indices (all data)
R1 = 0.0670, wR2 = 0.2004
R1 = 0.0984, wR2 = 0.2319
0.413 and -1.126
O(1)–C(10)
O(2)–C(19)
O(3)–C(21)
O(3)–C(24)
N(1)–C(9)
-3
)
˚
Largest diff. peak and hole (eA
N(1)–C(6)
˚
Table 2 Un-classical hydrogen-bond geometrical parameters (A, °)
of the title compound
N(2)–C(19)
N(2)–C(17)
N(2)–C(18)
C(22)–C(23)
C(19)–C(20)
C(21)–C(22)
C(23)–C(24)
C(18)–C(21)
C(20)–C(21)
C(20)–C(25)
C(14)–C(17)
C(1)–C(2)–Br(1)
C(3)–C(2)–Br(1)
C(1)–C(2)–C(3)
C(9)–N(1)–C(6)
D–HÁÁÁA
D–H
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
C(7)–H(7)ÁÁÁO(3)
0.95
0.95
0.95
0.95
2.57
2.42
2.44
2.34
3.492 (6)
3.282 (7)
3.305 (6)
3.321 (6)
165
151
152
173
C(3)–H(3)ÁÁÁO(2)i
C(13)–H(13)ÁÁÁO(2)ii
C(18)–H(18A)ÁÁÁO(2)ii
Symmetry codes: (i) -x, -y ? 1, -z ? 2; (ii) x - 1/2, -y ? 3/2,
-z ? 2
ii
˚
˚
(6) A and C(18)–H(18A)ÁÁÁO(2) = 3.321 (6) A, symmetry
code ((i) -x, -y ? 1, -z ? 2; (ii) x - 1/2, -y ? 3/2,
-z ? 2). The other is intramolecular hydrogen bonds
˚
C(7)–H(7)ÁÁÁO(3) = 3.492 (6) A. As hydrogen-bond
donors, it always carries the strong O–H group and N–H
group, however, the weak C–H group has been recognized
123

322
J Chem Crystallogr (2012) 42:318–322
Supplementary Material
Table 3 continued
X-ray
DFT
117.17083
Crystallographic data for the structure reported in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no.
CCDC-802877. Copies of available material can be
obtained, free of charge, on application to the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
C(9)–O(1)–C(10)
N(1)–C(9)–O(1)
117.2(4)
119.7(4)
108.6(4)
115.0(4)
110.6(3)
110.7(3)
101.8(3)
125.5(4)
98.9(4)
119.79223
107.58768
114.99431
110.04975
112.46330
102.26771
125.19782
100.11284
100.43940
N(2)–C(19)–C(20)
O(1)–C(9)–C(8)
N(2)–C(17)–C(14)
N(2)–C(17)–C(8)
N(2)–C(18)–C(21)
O(2)–C(19)–N(2)
O(3)–C(21)–C(20)
O(3)–C(24)–C(25)
Torsion angles
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