Synthesis, crystal, computational study and in vitro anti-tuberculosis activity of N-(furan-2-yl-methyl)-N-(phenyl(quinolin-3-yl)methyl) acetamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2011.08.033

A one-pot synthesis of N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)- N-(furan-2-yl-methyl)-2-morpholinoacetamide (1) and N-((6-bromo-2- methoxyquinolin-3-yl)(phenyl)methyl)-N-(furan-2-yl-methyl)-2-adamantylacetamide (2) was achieved in good yield fo

Full text of DOI:10.1016/j.molstruc.2011.08.033

Journal of Molecular Structure 1005 (2011) 113–120
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, crystal, computational study and in vitro anti-tuberculosis activity
of N-(furan-2-yl-methyl)-N-(phenyl(quinolin-3-yl)methyl) acetamide derivatives
Yuefei Bai a, Lijuan Wang b, Yu Chen c, Lei Yuan a, Wei Xu d, Tiemin Sun a,
⇑
a Key Laboratory of Original New Drug Design & Discovery Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University,
Shenyang 110016, PR China
b State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, PR China
c School of Vocational and Technical, Shenyang Pharmaceutical University, Shenyang 110026, PR China
d School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2011
Received in revised form 15 August 2011
Accepted 16 August 2011
Available online 31 August 2011
A one-pot synthesis of N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)-N-(furan-2-yl-methyl)-
2-morpholinoacetamide (1) and N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)-N-(furan-2-
yl-methyl)-2-adamantylacetamide (2) was achieved in good yield for the first time. Compounds 1 and
2ꢀH2O were characterized by single crystal X-ray diffraction in solid state. The structures of two new
derivatives have been confirmed by typical spectroscopic techniques, namely IR, 1H and 13C NMR. The
optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT)
have been compared with X-ray diffraction values. The experimental molecular structures are well repro-
duced by the computation. The geometrical parameters of the title compounds are similar to those of
some reported derivatives. In addition, in vitro anti-tuberculosis activities of derivatives 1 and 2 were also
investigated.
Keywords:
One-pot synthesis
X-ray diffraction
DFT calculations
Molecular structure
Diarylquinoline
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
selective and less toxic anti-tuberculosis drugs, we have published
some good results from our medicinal chemistry research of
Most quinoline derivatives are of considerable interest in the
field of agriculture, food, additives, materials, polymers, physical
and environmental chemistry [1–6]. It is also an accepted pharma-
cophore and represents an important synthetic precursor in drug
discovery. At the same time, some quinoline derivatives have po-
tent anti-tumor, anti-bacterial, anti-ulcer, anti-platelet aggregation
[7–10], anti-inflammatory activities and especially show good
activity against mycobacterial growth [11]. It is estimated that
approximately eight million people developed active tuberculosis
(TB) in 2004 with two million death. The prevailing situation is
even worse for a continuous increase in the number of immune-
compromised patients living with HIV who are more prone to TB
and other bacterial infections [12]. As a result, TB has been in-
creased substantially on a worldwide basis over the past decade,
but no TB-specific drugs have been discovered in the past 40 years.
A Phase II clinical trial of anti-tubercular TMC-207 has been
completed and expected to be marketed in 2012 if approved.
TMC-207 acts on a new target at proton pump of adenosine tri-
phosphate (ATP) synthase [13]. With regard to developing potent,
diarylquinoline derivatives, such as N-[(6-bromo-2-methoxy-
3-quinolyl)-phenylmethyl]-2-morpholino-N-(1-phenylethyl) acet-
amide [14], N-((6-bromine-2-methoxylquinoline-3-yl)benzyl)-
3-morpholine-N-(naphthalene-1-yl)propionamide
[15]
and
N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl) amide deri-
vatives [16]. According to literature survey, mefloquine, a well
known anti-malarial drug, was identified as an agent with rela-
tively potent activity against nonreplicating persistent TB (NRP-
TB). There are data suggestive of an ATPase target for meflo-
quine-based compounds. A remarkable similarity of mefloquine
to TMC-207 was found when it was superimposed with TMC-
207. Mao et al. [17] replaced hydroxyl group with CAN double
bond and obtained derivative I whose anti-TB activity is better
than or equal to that of mefloquine while demonstrating signifi-
cantly less toxicity at a receptor, cellular, and animal level. Consid-
ering the acid amide-enol tautomerization, we replaced hydroxyl
with acid amide (Scheme 1). At the same time, furan, morpholine
and adamantine are also good moiety with anti-tuberculosis activ-
ity. We introduced morpholine to form hydrogen bonds with Glu-
61 in the c-subunit of ATP synthase and prevent proton transport
that is an essential step in the synthesis of ATP [17]. Meanwhile
adamantine is incorporated to get better lipophilicity and higher
selectivity. On the basis of the aforementioned features,
⇑
Corresponding author. Tel./fax: +86 24 23986398.
E-mail address: suntiemin@126.com (T. Sun).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.08.033

114
Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
and are commercially available. For TLC analysis, pre-coated plates
of silica gel 60 F254 were used. Spots were visualized with UV light
and iodide vapors.
To a stirred solution of 1-(6-bromo-2-methoxyquinolin-3-yl)-
N-(furan-2-yl-methyl)-1-phenylmethanamine (0.630 g, 1.5 mmol)
preparated according to the modified literature method [25] and
dry triethylamine (0.455 g, 0.15 mmol) in dry DMF (20 mL) at
ꢁ20 °C was added 2-chloroacetyl chloride (0.178 g, 1.575 mmol)
diluted with 5 mL dry DMF under nitrogen atmosphere until no
starting material could be detected via TLC. With no further purifi-
cation necessary, then morpholine (0.131 g, 1.5 mmol) and tetra-
butylammonium iodide (0.055 g, 0.15 mmol) were added to the
above solution. After stirring for 7 h at 60 °C, the reaction mixture
was quenched with water then extracted with chloroform. The
resulting organic phase was then dried over anhydrous magnesium
sulfate, concentrated at reduced pressure and the residue was sep-
arated by flash column chromatography (50% ethyl acetate in hex-
ane) for purification, obtaining a white powder 0.562 g in a yield of
68.2%, m.p. 217–219 °C (Scheme 2).
Scheme 1. The proposed design idea of TMC-207 derivatives.
IR(KBr pellets)/cmꢁ1: 2928, 2852(NCH2), 1649(C@O), 1623,
1598, 1465(ArH), 1257, 1010, 1111(CAO).
N-((6-bromo-2-methoxyquinolin-3-yl) (phenyl)methyl)-N-(furan-
2-yl-methyl)-2-morpholinoacetamide (1) and N-((6-bromo-
2-methoxyquinolin-3-yl) (phenyl)methyl)-N-(furan-2-yl-methyl)-
2-adamantylacetamide (2) were synthesized in one- pot method,
instead of other common stepwise synthesis [18], and confirmed
by spectroscopy techniques. The syntheses of the derivatives 1
and 2 have never been reported before. In addition, the organic
molecular structures of the two derivatives in the ground state
were optimized by a DFT method. It is well known that DFT has be-
come the dominant and accurate computational tools for dealing
with natural organic molecules [19]. The computation is valuable
for providing insight into diarylquinoline derivatives with potent
anti-tuberculosis activity.
1H NMR (500 MHz, CDCl3) d: 2.47–2.57(m, 4H, 2ꢂNCH2); 3.28
(d, 1H, J = 13.5 Hz, COC H2-b); 3.42(d, 1H, J = 13.5 Hz, COCH2-a);
3.44–3.47(m, 4H, 2ꢂOCH2); 3.89(s, 3H, OCH3); 4.12(d, J = 15.5 Hz,
1H, NCH2); 4.94(d, J = 15.5 Hz, 1H, NCH2); 5.75(s, 1H, furan-H20);
6.02(s, 1H, furan-H21); 7.05(s, 1H, ArCH); 7.13–7.14(m, 2H,
C6H5-H2, H6); 7.26–7.28(m, 1H, C6H5-H4); 7.35–7.37(m, 2H,
C6H5-H3, H5); 7.37(s, 1H, quinoline ring-H7); 7.38–7.39(m, 1H,
quinoline ring-H2); 7.64–7.65(m, 1H, quinoline ring-H3); 7.68(s,
1H, furan-H22); 7.72–7.73(m, 1H, quinoline ring-H6).
13C NMR (125 MHz, CDCl3) d:170.4, 160.4, 150.1, 144.7, 141.8,
137.3, 136.7, 133.0, 129.6, 129.4, 128.8, 128.5, 128.3, 128.1,
127.7, 126.4, 125.9, 117.4, 110.3, 110.2, 62.2, 57.3, 40.7, 53.9,
53.6, 53.6, 66.5, 66.5.
2. Experimental and computational details
MS (ESI(+)): m/z 550.2 [M+H]+, 552.2 [M+2+H]+. Anal. calc. for
C
28H28BrN3O4: C, 61.10; H, 5.13; N, 7.63. Found: C, 61.09; H,
2.1. Experimental
5.15; N, 7.65.
The melting points were determined using a Gallenkamp appa-
ratus. By using a Perkin Elmer one FT-IR spectrograph with KBr pal-
lets, the IR spectra of the two derivatives were recorded in the
range of 4000–400 cmꢁ1 region. With the Bruker NMR spectrome-
ter, using tetramethylsilane (TMS) as internal standard and CDCl3
as solvent, the 1H and 13C NMR spectra were recorded. Combustion
gas chromatography method was used for elemental analysis, and
these analyses were performed on a Hewlett–Packard 185 CHN
analyzer. Mass spectrometry (MS): Hewlett–Packard 1100
LC/MSD spectrometer (Hewlett–Packard, USA); X-ray spectra of
the selected crystal 1 with dimensions of 0.25 ꢂ 0.22 ꢂ 0.13 mm
and 2ꢀH2O with dimensions of 0.32 ꢂ 0.24 ꢂ 0.22 mm were
recorded by Bruker P4 X-diffractometer. Data were collected by
2.3. N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)-N-(furan-
2-yl-methyl)-2-adamantylace-tamide (2)
In the similar manner as described above, derivative 2 was ob-
tained as a white solid (0.9765 g, 65.1%), m.p. 252–255 °C.
IR (KBr pellets)/cmꢁ1: 3432(NH), 2902, 2847(adamantyl group),
1650(C@O), 1625, 1601, 1464(ArH), 1254, 1013(CAO).
1H NMR (500 MHz, CDCl3) d: 1.51–2.09(m, 15H, adamantyl
group); 3.46(d, 1H, J = 13.5 Hz, COCH2-b); 3.74(d, 1H, J = 13.5 Hz,
COCH2-a); 3.96(s, 3H, OCH3); 4.09(d, J = 15.5 Hz, 1H, NCH2);
5.00(d, J = 15.5 Hz, 1H, NCH2); 5.70(s, 1H, furan-H20); 6.03(s, 1H,
furan-H19); 7.09(s, 1H, ArCH); 7.15–7.16(m, 2H, C6H5-H2, H6);
7.30–7.32(m, 1H, C6H5-H4); 7.39–7.41(m, 2H, C6H5-H3, H5);
7.39(s, 1H, quinoline ring-H7); 7.40–7.41(m, 1H, quinoline ring-
H2); 7.64–7.65(m, 1H, quinoline ring-H3); 7.68(s, 1H, furan-
H18); 7.72–7.73(m, 1H, quinoline ring-H6).
using graphite monochromated MoK
a radiation (k = 0.71073 Å)
at 293 K. For 1 and 2ꢀH2O, data collection: APEX2 [20]; cell refine-
ment: SAINT [21]; program used to solve structure: SHELXS-97
[22]; program used to refine structure, calculate the hydrogen
bonds and draw molecular figures: SHELXTL-97 [23]; program
used to measure centroid-centroid distance: Mercury 2.3 [24].
13C NMR (125 MHz, CDCl3) d: 170.4, 160.3, 150.1, 144.7, 142.0,
137.7, 136.7, 133.2, 129.7, 129.5, 128.7, 128.6, 128.3, 128.2,
127.8, 126.4, 126.0, 117.5, 110.6, 110.2, 58.5, 54.0, 53.9, 40.7,
51.1, 42.0, 41.9, 41.8, 36.5, 36.5, 36.5, 29.4, 29.4, 29.4.
MS (ESI(+)): m/z 614.2 [M+H]+, 615.2 [M+2]+. Anal. calcd for
C34H36BrN3O3: C, 66.45; H, 5.90; N, 6.84. Found: C, 66.42; H,
5.94; N, 6.90.
2.2. Preparation of N-((6-bromo-2-methoxyquinolin-3-yl) (phenyl)
methyl)-N-(furan-2-yl-methyl)-2-morpholinoacetamide (1)
Triethylamine and dimethylformamide (DMF) (Aldrich, Co. Ltd.)
were purchased and used after dehydrated with molecular sieves
4 Å. Morpholine, tetrabutylammonium iodide (TBAI), 1-adaman-
tanamine hydrochloride and 2-chloroacetyl chloride (Wako Co.
Ltd.) were purchased. All the reagents were of analytical grade
2.4. Computational methods
Molecular structures of the two new derivatives 1 and 2 in the
ground state were optimized by DFT method using Becke’s three

Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
115
Scheme 2. A one-pot synthesis of novel derivatives 1 and 2.
parameter hybrid exchange-correlation functional in conjunction
with a 6-31++Gꢃꢃ basis set [26]. Molecular geometries were fully
optimized by Berny’s optimization algorithm using redundant
internal coordinates. The entire set of computation was performed
using the GAUSSIAN 09W™ software [27]. An extensive search for
low energy conformations on potential energy surfaces (PES) of
compounds was carried out and minimum energy conformations
were re-optimized at DFT/B3LYP/6-31++Gꢃꢃ without symmetry
constraints. For large and flexible molecules, the PES contains
many local minima corresponding to different relative orientations
of the functional groups in the molecules. The calculated results at
the same level show that there are no imaginary frequencies for
both derivatives, indicating that both of them are equilibrium
geometries. The computational molecular structures were shown
by the animation option of the Gauss-View5.0™ graphical interface
[28].
est concentration that prevented the mycobacterial growth and
their inhibition against other strains is under test.
3. Results and discussion
3.1. Crystal structure determination of derivatives 1 and 2ꢀH2O
The crystals of 1 and 2ꢀH2O were grown from slow evaporation
of water/ethanol mixed solvent at ambient conditions. Derivative 1
is in monoclinic crystal system with C 2/c space group, unit cells
a = 32.666(6) Å, b = 10.737(2) Å, c = 17.161(3) Å. While 2ꢀH2O is in
trigonal crystal system, R-3 space group with one additional free
water molecule, unit cells a = 34.5748(12) Å, b = 34.5748(12) Å,
c = 13.4496(4) Å. The crystallographic and refinement data of 1
and 2ꢀH2O are shown in Table 1.
3.2. Crystal structure descriptions of 1 and 2ꢀH2O
2.5. Determining the minimal inhibitory concentration (MIC)
In the molecular structure 1: The bond lengths Br(1)AC(1)
(1.881 Å) and C(9)AO(1) (1.357 Å) are characteristics of single
bond. C(23)AO(2) (1.217 Å) is characteristics of the bond length
in a carbonyl group. The bond angle C(6)AC(1)ABr(1) is 121.1°.
The bond length C(23)AN(2) is 1.367 Å. The bond angles
A series of broth tubes containing diluted chemical synthetic
compound concentrations were prepared and inoculated with a
48 h liquid culture of Mycobacterium phlei 1180. Then the tubes
were incubated at 37 °C for 20 h. The MIC was defined as the low-
Table 1
Crystal data and refinement details for 1 and 2ꢀH2O.
Derivatives
1
2ꢀH2O
Empirical formula
Formula weight
Crystal size
Crystal color
Crystal system
Space group
a (Å)
C
28H28BrN3O4
C34H36BrN3O3ꢀH2O
550.43
632.58
0.25 ꢂ 0.22 ꢂ 0.13
Colorless
Monoclinic
C 2/c
32.666(6)
10.737(2)
17.161(3)
90.00
0.32 ꢂ 0.24 ꢂ 0.22
Colorless
Trigonal
R-3
34.5748(12)
34.5748(12)
13.4496(4)
90.00
b (Å)
c (Å)
a
(°)
b (°)
120.43(3)
90.00
5190(2)
8
90.00
120.00
13923.8(8)
18
c
(°)
V (Åꢁ3
)
Z
Theta range for data collection (°)
Limiting indices
Reflections collected/unique
Refined parameters/restraints
Goodness of Fit on F2
R1, wR2
3.11–25.01
1.66–25.02
ꢁ38 6 h 6 38, ꢁ12 6 k 6 12, ꢁ20 6 l 6 20
ꢁ41 6 h 6 27, ꢁ41 6 k 6 40, ꢁ15 6 l 6 16
20,083/4574 (Rint = 0.0391)
326/0
26,541/5430 (Rint = 0.0623)
394/19
1.054
0.0649, 0.2270
0.998
0.937
0.0577, 0.1926
0.997
Data completeness
Data/restraints/parameters
Max. and min. transmission
4574/0/326
0.8102 and 0.6731
0.495 and ꢁ0.783
5430/19/394
0.7402 and 0.6810
0.320 and ꢁ0.862
Largest diff. peak and hole (eÅꢁ3
)

116
Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
O(2)AC(23)AN(2)and O(2)AC(23)AC(24) are 121.8° and 119.3°
respectively. The morpholine system exists in a twisted chair-like
conformation and the bond angles indicate sp3 hybridization nat-
ure of those atoms. The torsion angles C(8)AC(9)AN(1)AC(4) and
C(20)AC(19)AO(4)AC(22) are ꢁ1.1° and ꢁ1.2°, which means that
substituted quinoline and furan remain almost planar individually.
The dihedral angle between passing through the atoms of substi-
tuted quinoline and benzene planes is 99.1°. It is almost perpendic-
ular with respect to one another. The dihedral angle between
passing through the atoms of substituted quinoline and furan
planes is 15.1 l°. It is generally parallel to one another. Moreover,
the systems of morpholine and benzene are inclined to one
another.
We have analyzed the hydrogen bond interactions in the molec-
ular crystal structure 1, 2ꢀH2O and their geometry and details of
interactions in the structures are listed in the Table 2. No conven-
tional hydrogen bonds were found at 293(2)K for 1. The weak
intermolecular hydrogen bond C(22)AH(22)ꢀꢀꢀO(2)i (i = ꢁx, ꢁy +
2, ꢁz) is observed, as is shown. In addition to the interactions
Fig. 2. The molecular structure with atom-numbering scheme of derivative 2ꢀH2O
displacement ellipsoids are drawn at the 30% probability level.
described above, the crystal can be stabilized by weak
p-stacking
interactions between the planes of the -electron systems of
p
the two positions. The bond length C(23)AN(2) is 1.351 Å. The
bond angle C(6)AC(1)ABr(1) is 120.2°. The bond angles
O(3)AC(23)AN(2) and O(3)AC(23)AC(24) are 122.0° and 120.1°
respectively. The bond angles of amantadine system also indicate
sp3 hybridization nature of those atoms. The torsion angles
C(8)AC(9)AN(1)AC(4) and (20)AC(21)AO(2)AC(18) are ꢁ0.7°,
0.2° respectively. The dihedral angle between passing through
the atoms of substituted quinoline and benzene planes is 69.6°.
The dihedral angle between passing through the atoms of substi-
tuted quinoline and furan planes is 27.3°. While the dihedral angles
between phenyl and substituted quinolinyl groups in related struc-
ture TMC-207 is 97.4°, naphthalenyl and substituted quinolinyl
groups are nearly coplanar [14]. At the same time, there is a
strong intermolecular hydrogen bond O(1W)AH(1W)ꢀꢀꢀO(1W)ii,
O(1W0)AH(1W)ꢀꢀꢀO(1W’)ii (ii = x ꢁ y + 2/3, x + 1/3, ꢁz + 1/3). and
C(7)AH(7)ꢀꢀꢀO(3)iii (iii = x ꢁ y + 2/3, x + 1/3, ꢁz + 4/3) is also
observed in the crystal packing (Table 2).
substituted quinoline and furan with a ring centroid-centroid dis-
tance of 3.819 Å [30]. The two-dimensional layer structure is
formed in the crystal packing from Fig. 3. Interestingly, the crystal
packing of molecule 1 is a C(28)AH(28A)ꢀꢀꢀ
p intramolecular contact
with a short HꢀꢀꢀX distance of 2.786 Å calculated by Mercury 2.3
[24] and they are in a nearly perpendicular orientation, which
brought about the peculiar packing motif (X is the center of the
benzene ring) [30].
Similarly, in the molecular structure 2ꢀH2O: the free water
molecule has two positions owing to the crystallographic disorder
of O(1W) and O(1W0). Each of them has 50% occupancy over
Table 2
Hydrogen bond geometry (Å, °) for crystal 1 and 2ꢀH2O.
DAHꢀꢀꢀA
Crystal 1
d(DAH)
d(HꢀꢀꢀA)
d(DꢀꢀꢀA)
<(DHA)
165.9
C(22)AH(22)ꢀꢀꢀO(2)i
Crystal 2ꢀH2O
0.93
2.52
3.428(9)
The crystal with a ring centroid-centroid distance of 4.199 Å be-
tween substituted quinoline and furan plane is indicative of a weak
O(1 W)AH(1 WA)ꢀꢀꢀO(1 W)ii
O(1 W)AH(1 WB)ꢀꢀꢀN(3)
O(1 W0)AH(1WC)ꢀꢀꢀO(1W0)ii
O(1W0)AH(1WD)ꢀꢀꢀN(3)
C(7)AH(7)ꢀꢀꢀO(3)iii
0.87
0.87
0.87
0.89
0.93
0.97
2.05
2.14
1.87
2.31
2.42
2.50
2.77(2)
138.8
147.1
164.9
127.8
147.3
139.5
p-stacking stabilization. Those interactions are fairly important in
2.913(18)
2.719(12)
2.936(12)
3.240(4)
3.298(5)
view of the stability of the crystal structure. The three-dimensional
supramolecular network structure is assembled by the hydrogen
bond interactions (Fig. 4).
As is above described, these two derivatives are analogous to
some previously reported compounds [13–16,29,31]. All of them
belong to diarylquinoline with the comprising of 3-benzyl-6-
bromo-2-methoxyquinoline and amido chain. The maximum
difference in experimental bond lengths between these two deriv-
atives is the furan group. It can be attributed to steric repulsion.
C(24)AH(24B)ꢀꢀꢀO(2)
Symmetry codes: (i) ꢁx, ꢁy + 2, ꢁz; (ii) x ꢁ y + 2/3, x + 1/3, ꢁz + 1/3; (iii) x ꢁ y + 2/3,
x + 1/3, ꢁz + 4/3.
3.3. Geometry optimization
The calculated molecular structures of 1, 2 and their numbering
scheme are shown in Figs. 5 and 6, in accordance with the atom
numbering given in Figs. 1 and 2 respectively. The global energy
minimum obtained by DFT calculations of the structure optimiza-
tion for
1
and
2
are
–
4120.770849 Hartree (ꢁ25.86 ꢂ
105 kcal molꢁ1) and – 4279.0657667 Hartree (ꢁ26.85 ꢂ 105 kcal
molꢁ1) respectively. The optimized structural parameters of 1 and
2 calculated using B3LYP functional with a 6-31++Gꢃꢃ basis set are
listed and compared with X-ray diffraction values in Table 3.
The corresponding distances of C(23)AN(2) in the optimized
geometry of two molecules are 1.378 Å and 1.382 Å, respectively.
As expected, most of the calculated bond lengths for the two deriv-
atives are slightly larger than the X-ray values. For the optimized
Fig. 1. The molecular structure with atom-numbering scheme of derivative
1
displacement ellipsoids is drawn at the 30% probability level.

Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
117
Fig. 3. Crystal packing structure of 1.
Fig. 4. Crystal packing structure of 2ꢀH2O.
geometry of 1 in the ground state with C1 symmetry, the calcu-
lated bond lengths and bond angles deviate from the X-ray values
by 0.09 Å at C(21)AC(22) and 2.7° at O(2)–C(23)–C(24), respec-
tively. In contrast, the optimized geometry of 2 in the ground state
with C1 symmetry shows a maximum difference from the X-ray
values in bond lengths and bond angles of 0.09 Å at C(19)AC(20)
and 2.2° at C(8)AC(17)AC(14), respectively.
These deviations may be partly due to the fact that the theoret-
ical optimization for a single molecule is obtained in the gas phase
(in vacuo) without any intermolecular interactions. However the
experimental data are measured at very low temperature in the so-
lid phase where it can undergo intermolecular and crystal packing
effects interactions holding the molecules together as stated above,
so the molecular rotations were restricted.
In addition, the optimized structure predicts boat conformation
as the preferential one to morpholinyl group for 1. At the same
time, the optimized conformations of furan group are also slight
different from X-ray data for 1 and 2ꢀH2O respectively. The
difference also exists in structure of 4-[(2-{[(2-furylmethyl)-
imino]methyl}-4-methoxyphenoxy)methyl]benzonitrile [32].
The conformations of investigated molecules are mainly
restrained by hydrogen bonds and electrostatic interactions. In

118
Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
Fig. 5. Atom numbering and optimized structure of 1 from B3LYP/6-31++Gꢃꢃ calculation.
Fig. 6. Atom numbering and optimized structure of 2 from B3LYP/6-31++Gꢃꢃ calculation.
crystals, there are both intramolecular and intermolecular electro-
static interactions. While in the optimized single molecule, the
intermolecular interactions are absent, and the intramolecular
ones are stronger than those in crystals. The variations of intermo-
lecular interactions from crystal to single molecules should be
responsible for the above described geometry differences. The
observed disagreement between computation and experiment
could be a consequence of the anharmonicity and the general
tendency that quantum chemical methods overestimate the force
constants at the exact equilibrium geometry.
if a compound with a certain pharmacological or biological activity
has properties that would make it a likely orally active drug in
humans. The rule is important for drug development where phar-
macologically active lead structure is optimized step wise for
increased activity and selectivity, as well as drug like properties
as described. The rule states that in general an orally active drug
has not more than 5 hydrogen bond donors, and not more than
10 hydrogen acceptors, a molecular weight under 500 and the par-
tition coefficient c logP less than 5 [33]. The two derivatives fall
well in the range, but their molecular weight values and the high
lipophilicity of derivative 2 (clogP = 6.10) violate Lipinski’s Rule
of Five, which may limit its therapeutic potential (Table 4). In the
case of anti-tubercular activity studies, although both were found
biologically active, the unsatisfactory result is that both showed
lower inhibitory activities than the standard drugs. In addition to
the above stated, we assume that steric factor should account for
the weak activity of derivative 2. Adamantyl group is rigid and
3.4. Anti-tuberculosis activity
To qualify as a drug candidate, a new molecule has to be ana-
lyzed for the parameters set by Lipinski’s rule of five using Osiris
property explorer (www.organic-chemistry.org). Lipinski’s rule of
five is a rule of thumb to evaluate drug likeliness or to determine

Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
119
Table 3
Selected experimental and calculated geometry parameters for crystal 1 and 2ꢀH2O.
Bond distances (Å)
Exp. (1)
Cal.
Dif.
Bond distance (Å)
Exp. (2ꢀH2O)
Cal.
1.907
Dif.
0.02
Br(1)AC(1)
C(1)AC(2)
C(2)AC(3)
C(3)AC(4)
C(4)AC(5)
C(5)AC(6)
C(1)AC(6)
C(5)AC(7)
C(7)AC(8)
1.881
1.399
1.361
1.416
1.416
1.413
1.357
1.417
1.361
1.436
1.294
1.357
1.438
1.518
1.521
1.382
1.399
1.366
1.345
1.388
1.394
1.475
1.476
1.497
1.345
1.362
1.275
1.434
1.332
1.367
1.217
1.516
1.451
1.907
0.03
C(1)ABr(1)
C(1)AC(2)
C(2)AC(3)
C(3)AC(4)
C(4)AC(5)
C(5)AC(6)
C(1)AC(6)
C(5)AC(7)
C(7)AC(8)
1.887
1.401
1.353
1.430
1.405
1.399
1.359
1.433
1.357
1.437
1.304
1.343
1.441
1.513
1.527
1.386
1.392
1.374
1.363
1.390
1.382
1.485
1.469
1.478
1.376
1.380
1.309
1.344
1.405
1.351
1.223
1.529
1.458
1.412
1.381
1.417
1.426
1.416
1.377
1.423
1.371
1.440
1.308
1.353
1.437
1.527
1.534
1.405
1.394
1.399
1.395
1.400
1.399
1.477
1.480
1.498
1.375
1.365
1.363
1.435
1.366
1.378
1.229
1.538
1.447
0.01
0.02
0.00
0.01
0.00
0.02
0.01
0.01
0.00
0.01
0.00
0.00
0.01
0.01
0.02
ꢁ0.01
0.03
0.05
0.01
0.01
0.00
0.00
0.00
0.03
0.00
0.09
0.00
0.03
0.01
0.01
0.02
0.00
1.412
1.381
1.417
1.426
1.417
1.377
1.423
1.371
1.440
1.308
1.353
1.437
1.527
1.535
1.405
1.395
1.399
1.395
1.400
1.399
1.475
1.478
1.499
1.375
1.365
1.363
1.435
1.366
1.382
1.227
1.546
1.451
0.01
0.03
ꢁ0.01
0.02
0.02
0.02
ꢁ0.01
0.01
0.00
0.00
0.01
0.00
0.01
0.01
0.02
0.00
0.03
0.03
0.01
0.02
ꢁ0.01
0.01
0.02
0.00
ꢁ0.02
0.05
0.09
ꢁ0.04
0.03
0.00
0.02
ꢁ0.01
C(8)AC(9)
C(9)AN(1)
C(9)AO(1)
C(8)AC(9)
C(9)AN(1)
C(9)AO(1)
C(10)AO(1)
C(8)AC(11)
C(11)AC(12)
C(12)AC(13)
C(13)AC(14)
C(14)AC(15)
C(15)AC(16)
C(16)AC(17)
C(17)AC(12)
C(11)AN(2)
C(18)AN(2)
C(18)AC(19)
C(19)AO(4)
C(22)AO(4)
C(21)AC(22)
C(20)AC(21)
C(19)AC(20)
C(23)AN(2)
C(23)AO(2)
C(23)AC(24)
C(24)AN(3)
C(10)AO(1)
C(8)AC(17)
C(14)AC(17)
C(13)AC(14)
C(12)AC(13)
C(11)AC(12)
C(11)AC(16)
C(15)AC(16)
C(14)AC(15)
C(17)AN(2)
C(22)AN(2)
C(21)AC(22)
C(21)AO(2)
C(18)AO(2)
C(18)AC(19)
C(19)AC(20)
C(20)AC(21)
C(23)AN(2)
C(23)AO(3)
C(23)AC(24)
C(24)AN(3)
Bond angle (°)
Exp. ‘(1)
Cal.
Dif.
Bond angle (°)
Exp. (2ꢀH2O)
Cal.
Dif.
C(6)AC(1)ABr(1)
N(1)AC(9)AC(8)
C(19)AO(4)AC(22)
O(1)AC(9)AC(8)
C(8)AC(11)AC(12)
O(2)AC(23)AC(24)
O(2)AC(23)AN(2)
121.1
125.9
107.3
114.3
113.8
119.3
121.8
119.7
124.9
107.4
115.4
113.5
122.0
120.7
ꢁ1.4
ꢁ1.0
0.1
C(6)AC(1)ABr(1)
N(1)AC(9)AC(8)
C(21)AO(2)AC(18)
O(1)AC(9)AC(8)
C(8)AC(17)AC(14)
O(3)AC(23)AC(24)
O(3)AC(23)AN(2)
120.2
125.1
105.8
114.6
115.7
120.1
122.0
119.7
124.9
107.4
115.5
113.5
122.2
120.5
ꢁ0.5
ꢁ0.2
1.6
1.1
0.9
ꢁ0.3
ꢁ2.2
2.7
2.1
ꢁ1.1
ꢁ1.5
structures. Hence, the computed results with only reasonable devi-
ations from the experimental values seem feasible. The structural
elucidation obtained by this paper could further contribute to
understanding molecular structures of the diarylquinoline deriva-
tives and especially discovering better anti-tubercular inhibitors.
Table 4
Anti-tubercular activity and pharmacological parameters for bioavailability of the
derivatives (M. phlei 1180).
Entry No.
MIC (mg mLꢁ1
)
clogP
Drug likeliness
Drug score
1
2
140
210
4.22
6.10
1.57
1.29
0.40
0.15
Standard: isoniazid 8 mg mLꢁ1, rifampicin 10 mg mLꢁ1. All compounds tested at
concentration of 1.0 mg mLꢁ1
.
Supplementary material
The supplementary crystallographic data for the two new deriv-
atives reported in this paper have been deposited with the
Cambridge Crystallography Data Centre, 12 Union road, Cambridge
CB22 1EZ, UK (Fax: +44 1223 336 033; E-mail: deposit@ccdc.ca-
m.ac.uk or http://www.ccdc.cam.ac.uk) and are available free of
charge on request quoting the deposition number CCDC 814136,
CCDC 815289 for 1 and 2ꢀH2O respectively.
large in contrast with morpholinyl group. As a result, it might be
difficult to penetrate mycobacterial cell wall barrier to reach the
active site.
4. Conclusions
With the goal of developing better anti-tuberculosis drugs, we
synthesized two new diarylquinoline derivatives by a one-pot
method. The molecular structures of 1 and 2ꢀH2O were determined
by single crystal X-ray method. In spite of the aforementioned
slightly conformational discrepancies, the optimized geometric
bond lengths and bond angles obtained by using DFT are generally
closer to X-ray diffraction values, which supports the solid-state
Acknowledgements
The authors gratefully acknowledge the College of Experimental
Center of Testing Science of Jilin University for the X-ray data col-
lection and School of Pharmaceutical Engineering, Shenyang
Pharmaceutical University for providing research facilities.

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Y. Bai et al. / Journal of Molecular Structure 1005 (2011) 113–120
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