Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2019.04.050

Three quinazolin-4-ylamino derivatives containing phenylbenzenesulfonamides (7a-7c)were synthesized by reacting (E)-N'-(2-cyanophenyl)-N,N-dimethyl formamidine (6)with different 4-amino-N-(phenyl)benzenesulfonamides (4a-4c)and characterized by different techniques such as HRMS, IR, ¹H NMR and ¹³C NMR spectroscopy. The structural properties were further examined by single crystal X-ray diffraction method. The X-ray data shows that compounds 7a and 7c contain two molecules and 7b contains one molecule in the asymmetric unit. Comparison of conformation of two distinct molecules, “A” and “B”, in the asymmetric unit of 7a and 7c were studied with the aid of reported literature. The in vitro antiproliferative activity of the compounds was tested against two breast cancer cell lines (MDA-MB-231 and MCF7). Compound 7b observed as a highest potent candidate against MDA-MB-231with IC₅₀ of 5.44 μg/mL. Antimicrobial activity was also screened against bacterial and fungal strains. Compound 7a with chloro substitution was observed as the most potent candidate against the Gram-negative bacterial strains, whereas the compounds showed no significant activity against the fungal strain.

Full text of DOI:10.1016/j.molstruc.2019.04.050

Journal of Molecular Structure 1190 (2019) 29e36
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis, characterization, crystal structures and biological screening
of 4-amino quinazoline sulfonamide derivatives
,
A. Sunil Kumar a, Jyothi Kudva a *, Manu Lahtinen b, Anssi Peuronen c, Rajitha Sadashiva d,
Damodara Naral e
a Department of Chemistry, St Joseph Engineering College, Mangaluru, 575028, India
b
€
€
Department of Chemistry, University of Jyvaskyla, P.O. Box 35, FI-40014 JY, Finland
c Department of Chemistry, University of Turku, FI-20014, Turku, Finland
d Sigma-Aldrich Chemical Pvt. Ltd, Bommasandra, Bengaluru, 560100, India
e Department of Chemistry, Canara Engineering College, Mangaluru, 574219, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three quinazolin-4-ylamino derivatives containing phenylbenzenesulfonamides (7a-7c) were synthe-
sized by reacting (E)-N'-(2-cyanophenyl)-N,N-dimethyl formamidine (6) with different 4-amino-N-
(phenyl)benzenesulfonamides (4a-4c) and characterized by different techniques such as HRMS, IR, 1H
NMR and 13C NMR spectroscopy. The structural properties were further examined by single crystal X-ray
diffraction method. The X-ray data shows that compounds 7a and 7c contain two molecules and 7b
contains one molecule in the asymmetric unit. Comparison of conformation of two distinct molecules,
“A” and “B”, in the asymmetric unit of 7a and 7c were studied with the aid of reported literature. The
in vitro antiproliferative activity of the compounds was tested against two breast cancer cell lines (MDA-
MB-231 and MCF7). Compound 7b observed as a highest potent candidate against MDA-MB-231with IC50
Received 5 October 2018
Received in revised form
30 March 2019
Accepted 11 April 2019
Available online 16 April 2019
Keywords:
X-ray-diffraction
Quinazoline-sulfonamide
Crystal structure
Antimicrobial
of 5.44 mg/mL. Antimicrobial activity was also screened against bacterial and fungal strains. Compound
7a with chloro substitution was observed as the most potent candidate against the Gram-negative
bacterial strains, whereas the compounds showed no significant activity against the fungal strain.
© 2019 Published by Elsevier B.V.
Antiproliferative activity
1. Introduction
Sulfonamides act as inhibitors of folic acid synthesis in the living
system which assists in the flourishing condition of bacteria [14].
The biological activity of a variety of quinazoline derivatives
depends on the nature and the position of the substituent group in
their framework. Out of the broadly identified substitution pattern,
4-aminoquinazolines and their N-anilino derivatives were found to
be effective especially as anticancer agents [1,2]. The literature re-
ports also have explained the broad range biological potential of
quinazolinone and quinazoline derivatives in antitubercular [3],
antimicrobial [4,5], antimalarial [6], anticonvulsant [7], antiviral
[8], anti-inflammatory [9], antidiabetic [10] and many other bio-
logical activities. Therefore, the synthesis of 4-aminoquinazolines
has attracted broad attention in recent years [11]. On the other
hand, sulfonamides and their different derivatives are broadly used
in medicine due to their pharmacological properties such as anti-
bacterial activity [12,13].
The existence of donor and acceptor atoms in sulfonamide de-
rivatives helps them to participate in the arrangement of different
hydrogen bond networks. Earlier studies show that this property
enables them to form different polymorphic [15,16] as well as co-
crystal structures [17,18]. Therefore, the sulfonamide derivatives
have more significance not only in the field of studying their bio-
logical application but also their crystal features as well. Our pre-
vious work explained the crystal structure, hydrogen bonding and
molecular contacts of quinazoline scaffold containing oxazole and
fluorophenyl sulfonamide derivatives [19,20]. This work focused on
the quinazoline scaffold containing phenyl sulfonamide derivatives.
The synthesized derivatives were characterized by the HRMS, IR, 1H
NMR, 13C NMR and elemental analysis. The lattice parameters, bond
angles, bond lengths, dihedral angles, torsion angles, hydrogen
bonding (HB) and intermolecular interactions of the grown crystals
were obtained by single crystal X-ray diffraction (XRD). Anti-
proliferative, antibacterial and antifungal activities were also
screened to verify the potency of the compounds.
* Corresponding author.
E-mail address: jyothik@sjec.ac.in (J. Kudva).
https://doi.org/10.1016/j.molstruc.2019.04.050
0022-2860/© 2019 Published by Elsevier B.V.

30
A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
2. Experimental
2.2.1. Synthesis of 4-(acetylamino)benzene-1-sulfonyl chloride(2)
from acetanilide (1)
2.1. Materials and methods
Acetanilide (1) (10 g, 0.074 mol) was stirred in a minimum
quantity of chloroform and cooled to 0 ꢀC. Excess of chlorosulfonic
acid (50 mL, 0.74 mol) was added to the cooled solution under
stirring. The reaction temperature was maintained between 0 and
5 ꢀC during the addition. After the completion of the reaction,
mixture was slowly added to crushed ice to neutralize the excess of
acid and the solid was collected by filtration and dried [28].
The melting points (uncorrected) of targeted quinazoline sul-
fonamide derivatives were determined with DIGITAL MELTING
POINT APPARATUS EQ 730 (EQUIPTRONICS) using an open capillary
tube with the heating rate of 10 ꢀC/min. HRMS (High-resolution
mass spectra) were recorded on an Agilent 6520 (QTOF) ESI-HRMS
instrument. Infrared spectra were recorded in a Shimadzu FT-IR
spectrometer using KBr pellets. 1H (400 MHz) and 13C (100 MHz)
NMR spectra were recorded on a Bruker Avance (AC 80) instrument
in DMSO‑d6 using tetramethylsilane (TMS) as an internal standard.
2.2.2. Synthesis of sulfonamide intermediates (4a-4c)
Synthesis of the precursor sulfonamides 4a- 4c was achieved by
treating 0.01 mol of substituted aromatic amines (3a-3c) with
0.015 mol of 4-(acetylamino)benzene sulfonylchloride (2) in
0.03 mol of pyridine at room temperature (RT) for 8 h. Reaction
progress was monitored by TLC (with hexane: EtOAc (1:1) mixture
as eluent. Excess pyridine was neutralized with diluted HCl solution
and the product was isolated by filtration. The hydrolysis of the
above product was carried out by refluxing it with concentrated
HCl in ethanol for 4 h. The clear solution was cooled and neutralized
by ammonium hydroxide solution. The solid precipitated was
filtered and dried at 50e55 ꢀC (Scheme 1).
The chemical shift values (d) were recorded in parts per million
(ppm). All synthesis reactions were monitored by thin layer chro-
matography (TLC) using aluminium TLC plate, silica gel coated with
fluorescent indicator F254(Merck). The C, H, N and S elemental
analysis was performed using Thermo Finnigan Elemental Micro
Analyser.
2.1.1. Structural determination by single crystal X-ray diffraction
studies
Single crystal structure data of 7a, 7b and 7c were collected by
Agilent/Rigaku SuperNova diffractometer, equipped with Eos de-
2.2.3. Synthesis of N,N-dimethylformamidine intermediate (6)
The N,N-dimethylformamidine intermediate (6) was obtained
by heating 0.01 mol of 2-aminobenzonitrile (5) with 0.015 mol of
dimethylformamide-dimethylacetal (DMF-DMA) at 90 ꢀC in DMF
solvent [29]. The product was precipitated by diluting with water
and isolated by filtration.
tector, using multilayer optics monochromated Mo
Ka
(l
¼ 0.71073 Å) radiation and processed with CrysAlisPro(v.
1.171.38.43c) [21]. The structures were solved (direct methods) and
refined within Olex2(v. 1.2.10) [22] program package using SHELXS
[23] and SHELXL [24] programs. All non-hydrogen atoms were
anisotropically refined. CeH hydrogen atoms were calculated to
their ideal positions and refined using a riding model with Uiso
parameters 1.2e1.5 times larger to their respective host atoms.
OeH and NeH hydrogen atoms were located from the difference
density map and refined without any restraints. The crystal lattices
of structures of compounds 7a and 7c contain spherical voids that
contribute to ca. 1% of the unit cell volume (calculated using Mer-
cury [25] contact surface with 1.2 Å probe radius and 0.7 Å grid
spacing). These voids did not, however, show any residual electron
density and thus were not considered to include any solvent
molecules.
2.2.4. Synthesis of 4-amino quinazoline derivatives (7a-7c)
The target quinazoline derivatives (7a-7c) were obtained by
refluxing 0.01 mol of intermediate 6 with 0.011 mol of synthesized
sulfonamides (4a-4c) in acetic acid. The products were isolated by
filtration [19].
2.2.4.1. N-(4-Chlorophenyl)-4-[(quinazolin-4-yl)amino]benzene-1-
sulfonamide (7a). Yield 74%; mp: 243e245 ꢀC; IR (KBr, cmꢁ1): 3378
(NeH), 1621 (C]N), 1322 (SO2 asym), 1150 (SO2 sym); 1H NMR
(400 MHz, DMSO‑d6):
d
¼ 10.32 (s, 1H, SO2NeH), 9.99 (s, 1H, NeH),
8.63 (s, 1H, Ar), 8.48e8.50 (d, J ¼ 8.4 Hz, 1H, Ar), 8.05e8.07 (d, 2H,
Ar), 7.81e7.84 (t, 1H, Ar), 7.76e7.78 (d, J ¼ 8.4 Hz, 1H, Ar), 7.71e7.73
(d, 2H, Ar), 7.59e7.62 (t, 1H, Ar), 7.23e7.25 (d, 2H, Ar),
2.1.2. Antiproliferative studies
The compounds (7a-7c) were tested for their in vitro anti-
proliferative activity against two breast cancer cell lines MDA-MB-
231 and MCF7 by MTT assay [26]. Compounds screened at seven
7.07e7.09 ppm (d, 2H, Ar); 13C NMR (100 MHz, DMSO):
d
¼ 157.3,
154.0, 149.8, 143.5, 136.8, 133.3, 132.7, 129.0, 127.9, 127.9, 127.5,
126.5, 123.0, 121.4, 121.2, 115.2 ppm; HRMS (ESI) m/z calcd:
411.0683 [MþH]þ, found 411.0681; Anal. calcd for C20H15N4SO2Cl
(%): C 58.46; H 3.68; N 13.64; S 7.80, found: C 58.38; H 3.58; N
13.69; S 7.74.
different concentrations (1.0, 6.25, 12.5, 25, 50, 100 and 500
mg/mL)
along with Cisplatin, used as a reference standard. The concentra-
tion required for 50% inhibition of cell viability (IC50
) was
calculated.
2.1.3. Antimicrobial studies
2.2.4.2. N-(4-Fluorophenyl)-4-[(quinazolin-4-yl)amino]benzene-1-
sulfonamide (7b). Yield 94%; mp: 276e278 ꢀC; IR (KBr, cmꢁ1): 3386
(NeH), 1622 (C]N), 1330 (SO2 asym), 1153 (SO2 sym); 1H NMR
The compounds 7a-7c were also screened for their in vitro
antibacterial activity against two representative Gram-positive
bacterial strains Bacillus subtilis and Staphylococcus aureus; two
Gram-negative bacterial species Escherichia coli and Pseudomonas
aeruginosa and a fungal strain Aspergillus niger by broth dilution
method [27]. Ciprofloxacin and Fluconazole were used as reference
drugs in terms of minimum inhibitory concentration (MIC).
(400 MHz, DMSO‑d6):
d
¼ 10.45 (s, 1H, SO2NeH), 10.06 (s, 1H, NeH),
8.69 (s, 1H, Ar), 8.55e8.57 (d, 1H, Ar), 8.13e8.15 (d, 2H, Ar),
7.87e7.91 (t, 1H, Ar), 7.82e7.84 (d, 1H, J ¼ 8 Hz, Ar), 7.77e7.79 (d,
2H, Ar), 7.65e7.67 (t, 1H, Ar), 7.29e7.31 (d,1H, Ar), 7.24e7.27 (t, 1H,
Ar), 7.09e7.13 ppm (m,1H, Ar); 13C NMR (100 MHz, DMSO):
d
¼ 157.2, 153.9, 152.4, 149.6, 144.2, 137.0, 133.3, 129.2, 128.2, 127.9,
2.2. Synthesis
126.5, 121.2, 121.0, 119.2, 116.4, 115.7 ppm; HRMS (ESI) m/z calcd:
395.0972 [MþH]þ, found 395.0968; Anal. calcd for C20H15N4SO2F
(%): C 60.90, H 3.83, N 14.20, S 8.13, found: C 60.78, H 3.72, N 14.13, S
8.18.
The synthetic routes are shown in Scheme 1 and the molecules
were synthesized based on available procedures.

A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
31
Scheme 1. Synthesis of compounds 7a-7c. Reagents and conditions: i) ClSO3H/CHCl3, RT, 12 h; ii) Pyridine/CHCl3, RT, 8 h; iii) HCl/Ethanol, 75e80 ꢀC, 4 h; iv) DMF-DMA/DMF, 90 ꢀC,
3e4 h; v) Acetic acid, 100 ꢀC, 3e4 h.
2.2.4.3. N-(4-methylphenyl)-4-[(quinazolin-4-yl)amino]benzene-1-
sulfonamide (7c). Yield 91%; mp: 243e245 ꢀC; IR (KBr, cmꢁ1): 3361
(NH), 1624 (C]N), 1313 (SO2 asym), 1150 (SO2 sym); 1H NMR
molecular composition of the compounds was assigned on the
basis of IR, 1H NMR and 13C NMR spectroscopy. The IR spectra of
final compounds 7a, 7b and 7c show absorption bands with me-
dium to strong intensities as follows: the range of 3369e3386 cmꢁ1
is assigned for NeH stretching frequency and high intense bands in
the ranges 1313e1330 and 1150-1153 cmꢁ1 for asymmetric and
symmetric stretching modes of O]S]O group (Fig. 1 and Fig. S2).
The quinazoline ring protons are observed at the downfield
region and among that, pyrimidine proton (H1) manifest the
(400 MHz, DMSO‑d6):
d
¼ 10.07 (s, 1H, SO2NeH), 10.02 (s, 1H, NeH),
8.68 (s. 1H, Ar), 8.54e8.56 (d, 1H, Ar), 8.09e8.11 (d, 2H, Ar),
7.81e7.87 (m, 2H, Ar), 7.76e7.78 (d, 2H, Ar), 7.64e7.67 (t, 1H, Ar),
7.03 (s, 4H, Ar), 2.17 ppm (s, 3H, eCH3); 13C NMR (100 MHz, DMSO):
d
¼ 157.3, 154.0, 149.7, 143.2, 135.2, 133.2, 133.2, 133.1, 129.5, 127.8,
126.5, 122.99, 121.1, 120.4, 115.2, 20.25 ppm; HRMS (ESI) m/z calcd:
391.1223 [MþH]þ, found 391.1228; Anal. calcd for C21H18N4SO2 (%):
C 64.60, H 4.65, N 14.35, S 8.21, found: C 64.64, H 4.58, N 14.42, S
8.10.
highest chemical shift value among the other aromatic protons (
d
8.63e8.69 ppm) (Fig. 2). The aromatic protons ortho to the NH
group are observed in the upfield region. This shielding effect is due
to the electron cloud around the ortho protons produced by the
electron-rich amino group. The aromatic protons ortho to the SO2
group were observed at more deshielding region due to the elec-
tron withdrawing nature of sulfonyl group. The two NeH protons
(Ha & Hb) can be seen as two broad peaks in the downfield region.
Since the sulfonamide NH (Hb) protons are more acidic compared
to phenyl NH (Ha) protons and thereby can be observed in the most
deshielded region [31]. The characteristic peaks in the 13C NMR
spectra also support the conformation of the synthesized com-
pounds. The carbon atoms bonded to the functional groups and
heteroatoms have shown a slight variation in the chemical shift
values. The 13C NMR spectra of carbon atoms, which are directly
bonded to the nitrogen atom, show up in the more deshielded re-
gion compared to other phenyl carbon atoms. C1 and C8 carbons in
the diazine ring (ring b) bonded to two nitrogen atoms emerge in
the most deshielded region154 and 157 ppm, respectively, due to
the less electron charge density around these atoms. The chemical
shift value for the carbon bonded to the electronegative fluorine
atom, in compound 7b, is observed at 152.44 ppm.
3. Results and discussion
3.1. Synthesis
In the present work, we have synthesized three N-(quinazolin-
4-yl)sulfonamide derivatives by condensing different aryl sulfon-
amides with (E)-N'-(2-cyanophenyl)-N,N-dimethylformamidine. It
is assumed that the synthesized aromatic amine first attacks on the
carbon of the N,N-dimethylamine following an ejection of N,N-
dimethylamine [29]. The intermediate aromatic amidine then un-
dergoes cyclization into a quinazoline frame in which the endocy-
clic and exocyclic nitrogen atoms interchange their place via
Dimroth
rearrangement
to
obtain
the
expected
4-
anilinoquinazoline (Scheme 1). The attack of an amine into the
cyano group is impossible in practice without a probable catalytic
action of an acid [30].
3.2. Spectral analysis
The primary characterization of the compounds included
measuring of melting point, elemental analysis and mass spectra.
The HRMS results have displayed (Mþ1) peak as a major peak. The
3.3. Single crystal XRD studies
The solid-state structures of compounds 7a-7c were determined

32
A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
Fig. 1. IR spectrum of N-(4-Chlorophenyl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide (7a).
aniline moiety. This orientation seems to be typical for anilino-
quinazoles with secondary amine as the linker as it is most likely
sterically favored. On the other hand, the quinazoline moiety in
molecule A is nearly coplanar (7.5ꢀ tilt angle) with the backbone
whereas in B it is tilted away from the plane by ~34ꢀ. Comparison of
the relevant geometrical parameters of the sulfonamide environ-
ment indicates that they are consistent with several other sulfon-
amides and sulfanilamides reported e.g. by Lahtinen et al.,
Pervolich et al. and Parkin et al. [34e36]. Similar molecular con-
formations can be exemplified for instance by the crystal structures
of
N-[4-(phenylsulfamoyl)phenyl]benzamide
[34],
3-(((4-
acetamidophenyl)sulfonyl)amino)benzoic acid [37] and 4-amino-
N-(3-chloro-4-methylphenyl) benzenesulfonamide [38]; dihedral
angles shown in ESI Table S1.
The solid-state structures of secondary sulfonamides have the
tendency of showing an abundance of intermolecular hydrogen
bonds (HB) [35,38,39]. Indeed, the most noticeable intermolecular
interactions in 7a are the hydrogen bonds between the amino
group of the 4-anilinoquinazoline and sulfonamide S]O and the
sulfonamide NeH and quinazoline N groups (see hydrogen bonding
parameters in Table 2). These constitute several different hydrogen
bonding networks with two examples illustrated in Fig. 2. Addi-
Fig. 2. Atom numbering of core unit to assign the 1H and 13C NMR values of com-
pounds 7a, 7b and 7c.
by single crystal X-ray diffraction (see Table 1 for crystallographic
data). Single crystals of all three compounds were obtained by
dissolving each of the highly pure compound (100 mg) in 15e20 mL
of acetone at 35e40 ꢀC. The clear solution was allowed for crystal
growth by slow evaporation of the solvent without any disruption.
Compound 7a crystallizes in a monoclinic space group P21/n
with two molecules, “A” and “B”, in the asymmetric unit and eight
in the unit cell altogether (Fig. 2). The orientation of the sulfon-
amide functionality in both A and B molecules is consistent with
the observation that the staggered geometry is preferred in the
solid state structures of unhindered sulfonamides [32] although the
eclipsed conformer has been addressed as the global energy min-
imum in the gas phase [33]. Molecules A and B both show the
twisting of the 4-chlorophenyl group (ring d in Fig. 2) in a way that
the NeH hydrogens of the sulfonamide and the anilinoquinazole
face toward the same side of the central aryl ring (ring c in Fig. 2).
However, in molecule B the 4-chlorophenyl group shows a higher
degree of rotation away from the arylsulfonamide group (See ESI
Fig. S8). The quinazoline moieties in each of the unique molecules
in the asymmetric unit show major similarities but also small dif-
ferences regarding their orientation in respect to the aryl sulfon-
amide backbone. In both distinct molecules the quinazoline unit
shows anti orientation in respect to the C(6)eH atom and the
tional significant intermolecular contacts include two distinct p-p
dimers which are formed between the aromatic quinazoline groups
with respective inter-quinazole distances of 3.54 and 3.57 Å (see ESI
Fig. S8).
Interestingly, the solid state structure of the methyl derivative
7c is isostructural with 7a and shows nearly identical crystallo-
graphic unit cell parameters and molecular packing (Table 1,
Table 2, Fig. 3d). The isostructurality is most likely due to the similar
sizes of the CH3e and Clegroups and the lack of eagerness of these
groups to engage in any significant attractive intermolecular in-
teractions. Since the structural interpretation made for the struc-
ture 7a is similarly valid for 7c, no further analysis is presented for
7c. The crystal structure of the fluorine derivative 7b was solved
and refined in space group P21/c with one molecule in the asym-
metric unit and four in the unit cell. The molecular geometry of 7b
resembles that of the “B” molecules in the structures of 7a and 7c
and there by shows conventional dihedral angles with analogous
sulfonamides, as discussed above. Since only one conformer is
observed in 7b, the molecular packing in the lattice is different to
7a and 7c. This is manifested for example by the formation of linear

A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
33
Table 1
Crystallographic structure and refinement data for compounds 7a-7c.
Parameters
7a
7b
7c
CCDC No.
1857204
C20H15ClN4O2S
410.87
1563909
C20H15FN4O2S
394.42
293.00(2)
Monoclinic
P21/c
8.2860(4)
13.6797(4)
16.7470(8)
90
99.669(5)
90
1857205
C21H18N4O2S
390.45
120.00(10)
Monoclinic
P21/n
16.6600(4)
13.3798(2)
18.1035(4)
90
107.919(2)
90
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
a/Å
120.00(10)
Monoclinic
P21/n
16.5427(3)
13.1893(2)
18.1771(3)
90
108.0859(18)
90
3770.05(11)
8
b/Å
c/Å
ꢀ
ꢀ
ꢀ
/
a
/
b
/
g
Volume/Å3
Z
1871.30(14)
4
1.4
3839.67(15)
8
1.351
rcalcg/cm3
1.448
0.338
m
/mmꢁ1
0.207
0.193
F(000)
1696
816
1632
Crystal size/mm3
Radiation
0.30 ꢂ 0.30 ꢂ 0.20
0.3 ꢂ 0.24 ꢂ 0.23
0.35 ꢂ 0.30 ꢂ 0.30
MoKa
(
l
¼ 0.71073)
MoK
a
(l
¼ 0.71073)
MoK
a
(l
¼ 0.71073)
2
Q
range for data collection/ꢀ
4.006 to 51.998
4.934 to 51.994
3.854 to 52.000
Index ranges
ꢁ18 ꢃ h ꢃ 20, ꢁ15 ꢃ k ꢃ 16,-18 ꢃ l ꢃ 22
ꢁ10 ꢃ h ꢃ 10, ꢁ16 ꢃ k ꢃ 16,-20 ꢃ l ꢃ 20
ꢁ20 ꢃ h ꢃ 19, ꢁ15 ꢃ k ꢃ 16,-16 ꢃ l ꢃ 22
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
13608
20021
13976
7360 [Rint ¼ 0.0285, Rsigma ¼ 0.0515]
7360/0/521
1.032
3667 [Rint ¼ 0.0321, Rsigma ¼ 0.0208]
3667/0/261
1.058
7534 [Rint ¼ 0.0283, Rsigma ¼ 0.0555]
7534/0/523
1.030
Final R indexes [I ꢄ 2
s
(I)]
R1 ¼ 0.0413, wR2 ¼ 0.0915
R1 ¼ 0.0544, wR2 ¼ 0.1002
0.30/-0.52
R1 ¼ 0.0425, wR2 ¼ 0.1081
R1 ¼ 0.0505, wR2 ¼ 0.1137
0.19/-0.25
R1 ¼ 0.0448, wR2 ¼ 0.0994
R1 ¼ 0.0609, wR2 ¼ 0.1102
0.39/-0.45
Final R indexes [all data]
Largest diff. peak/hole/e Åꢁ3
chains of molecules in the direction of the crystallographic c-axis by
NeH/N hydrogen bonds (Fig. 4b). The NeH/O]S hydrogen
bonding pattern seems similar to 7a/7c when viewed perpendic-
ular to the plane formed by the HB network (Fig. 4c). View along the
1D HB chain, however, shows that with a single conformer in case
of 7b a network with two alternating molecules is formed, whereas
in 7a and 7c a four-fold helical HB-network is observed (Fig. 4d).
The quinazoline p-p dimer is found also in 7b, but it shows slipped
geometry with fairly short quinazoline inter-planar distance of
3.25 Å.
3.4. Biological evaluation
3.4.1. Antiproliferative activity
The synthesized compounds (7a-7c) were tested for their
in vitro antiproliferative activity against two cancer cell lines (MDA-
MB-231 and MCF7) and the results were summarized in Table 3.
The tested compounds exhibited a remarkable cytotoxicity against
MDA-MB-231 cell line. Among these compounds, electronegative
fluoro substituted compound 7b has shown the most potent ac-
tivity with IC50 of 5.44 mg/mL and the activity observed was more
Table 2
Hydrogen bond parameters derived from the solid state structure of 7a-7c.
7a
D
H
A
d(DeH)/Å
0.88(2)
0.85(2)
0.85(2)
0.91(3)
d(HeA)/Å
2.28(2)
2.07(2)
2.21(2)
2.00(3)
d(DeA)/Å
3.143(2)
2.912(2)
3.027(2)
2.907(3)
DeHeA/ꢀ
164(2)
172(2)
162(2)
178(3)
N3A
N4A
N3B
N4B
H3A
H4A
H3B
H4B
O1Ba
N1Bb
O1A
N1Ac
7b
D
H
A
d(DeH)/Å
d(HeA)/Å
d(DeA)/Å
DeHeA/ꢀ
N3
N4
H3
H4
O1d
N1e
0.81(2)
0.81(2)
2.23(2)
2.13(2)
2.993(2)
2.927(2)
156(2)
168.3(19)
7c
D
H
A
d(DeH)/Å
d(HeA)/Å
d(DeA)/Å
DeHeA/ꢀ
N3A
N4A
N3B
N4B
H3A
H4A
H3B
H4B
O1Ba
N1Bb
O1A
0.86(2)
0.89(2)
0.82(2)
0.87(3)
2.32(2)
2.07(2)
2.24(2)
2.06(3)
3.151(2)
2.944(3)
3.032(2)
2.926(3)
162(2)
169(2)
163(2)
173(2)
N1Ac
a
-1/2 þ X,1/2-Y,1/2 þ Z.
b
c
1-X,1-Y,1-Z.
1/2-X,1/2 þ Y,1/2-Z.
2-X,-1/2 þ Y,1/2-Z
þX,1/2-Y,-1/2 þ Z.
d
e

34
A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
Fig. 3. a) Illustration of the asymmetric unit of structure of 7a with distinct molecules labelled “A” and “B” (ellipsoids presented at 30% probability level). Atomic labels are shown
for molecule A. b), and c) Examples of the different intermolecular NeH/O¼Sand NeH/N hydrogen bond networks formed in the crystal lattice of 7a. d) Overlay of crystal lattices
(view along a-axis) of the structure of 7a (orange) and 7c (blue).
than the standard drug Cisplatin (IC50 ¼ 5.61
and methyl (7c) derivatives exhibited moderate inhibitory activities
with IC50 of 17.83 and 19.56 g/mL respectively. The tested com-
pounds have not shown any significant cytotoxicity against MCF7
cell line even at higher concentrations (IC50 > 500 g/mL). The
structural evaluation of similar compounds from the literature
revealed that the fluoro substituted quinazoline derivatives have
been reported to possess an excellent range of antiproliferative
activities. It was observed from the reports that, the fluorophenyl
substitution at 4-aminoquinazoline ring can enhance the anti-
cancer activity [40,41].
m
g/mL). Chloro (7a)
Gram-positive bacterial species. Compound 7c with methyl sub-
stitution showed less toxicity profile against all the tested bacte-
rial strains. The replacement of the methyl group with halo
substitutions enhanced the activity. Compounds 7a and 7b
showed a moderate to good activity against the Gram-negative
bacterial strains (E. coli and P. aeruginosa). It is significant that 4-
chloro derivative 7a was found to be more active against Gram-
negative bacteria than Ciprofloxacin, which is a known antimi-
crobial drug. The compound 7a also showed moderate activity
against the tested Gram-positive bacteria. Therefore, compound
7a can be considered as a potent antibacterial candidate against
the Gram-negative bacteria. The antibacterial activity of com-
pounds is mainly due to the presence of sulfonamide moiety and
the synthesized phenylsulfonamide derivatives were observed as
less active compared to heterocyclic sulfa drugs [42,43]. The
compounds were also tested against a fungal strain A. niger, but
did not show any remarkable activity. They were active only at
m
m
3.4.2. Antimicrobial activity
The in vitro antibacterial activity was tested against two Gram-
positive (B. subtilis and S. aureus) and two Gram-negative (E. coli
and P. aeruginosa) bacterial strains by broth dilution method. The
results are displayed in Table 4. The compounds showed toxic
effects against all the tested bacterial strains and the toxicity is
more pronounced against Gram-negative bacterial strains than
higher concentration (MIC 50
drug Fluconazole.
mg/mL) compared to the standard

A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
35
Fig. 4. a) Illustration of the asymmetric unit of structure of 7bwith atomic labels shown (ellipsoids presented at 30% probability level). b) and c) Examples of the different
intermolecular NeH/N and NeH/O]S hydrogen bond networks found in the crystal lattice of 7b. d) Comparison between the H/O]S hydrogen bond networks observed in 7a
and 7b.
Table 3
Table 4
In vitro antiproliferative activity studies of compound 7a-7c.
Antimicrobial activity studies of compound 7a-7c.
Comp. No.
R
Antiproliferative activity (IC50 in
g/mL)
Comp. No.
Antimicrobial activity, MIC in mg/mL
m
Gram-positive
Bacteria
Gram-negative
bacteria
Fungal strain
MDA-MB-231
MCF7
7a
7b
7c
Cisplatin
4-Cl
4-F
4-CH3
e
17.83
5.44
19.56
5.61
>500
>500
>500
6.78
B. Sa
S. Ab
E. Cc
P. Ad
A. Ne
7a
7b
7c
12.5
50
25
NT
2.0
NT
6.25
12.5
6.25
NT
2.0
NT
1.6
6.25
50
NT
4.0
NT
3.12
3.12
50
NT
2.0
NT
50
50
50
NT
NT
4.0
Cisplatin
Ciprofloxacin
Fluconazole
4. Conclusion
‘NT’ Indicates not tested; a, B. subtilis, b. S. aureus, c, E. coli, d, P. aeruginosa, e. A.
niger.
Three novel quinazoline derivatives containing phenyl-
sulfonamide moiety were synthesized and single crystals of each
compound were grown by a slow evaporation method in acetone.
X-ray single crystal structures were succesfully determined for all
three quinazoline derivates. Compounds 7a and 7c showed to be
isostructural whereas the fluoro derivative 7b manifested clearly
different molecular packing and hydrogen bond network in the
crystal lattice. Even though the molecular packing scheme between
7a/7c and 7b proved to be different, the three compounds exhibited
only two different types of molecular conformations: two types (A
and B) in case of 7a and 7c and type B in case of 7b. The in vitro
anticancer activity of the compounds was tested against two breast
cancer cell lines (MDA-MB-231 and MCF7). The fluoro derivative 7b
displayed excellent activity against MDA-MB-231 with IC50 value of
5.44 mg/mL, which was more than the standard drug Cisplatin.
Compound 7a with chloro substitution revealed the highest anti-
microbial activity against the Gram-negative bacterial strain, E. coli

36
A. Sunil Kumar et al. / Journal of Molecular Structure 1190 (2019) 29e36
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Acknowledgements
The authors are gratefully acknowledge the financial support
provided by VGST-K-FIST (L1)/2017, GRD No. 557 and the Academy
of Finland (Project No. 277250 and 315911).
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