Synthesis, characterization, crystal structure, Hirshfeld interaction and bio-evaluation studies of 4-amino quinazoline sulfonamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2018.04.055

In the present work, two new potentially active quinazolin-4-yl-aminobenzenesulfonamide derivatives, N-(5-methyl-1,2-oxazol-3-yl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide (4a) and N-(3,4-dimethyl-1,2-oxazol-5-yl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide (4b), were synthesized and the structures were confirmed by different spectroscopic techniques like FT-IR, ¹H NMR, ¹³C NMR, HRMS and elemental analysis. The crystal structures were solved by single crystal X-ray diffraction (XRD) studies. The single crystal XRD studies revealed that the compound 4a crystallized in monoclinic crystal system in P 2₁/n space group with Z = 4 and compound 4b crystallized in triclinic crystal system in P-1 space group with Z = 2. The XRD study has explained the intramolecular interactions of the title compounds. The thermal behaviour was determined with the aid of differential scanning calorimetry (DSC) and thermogravimetry-differential thermal analysis (TG-DTA). Further, the Hirshfeld surface analysis with finger plots and the electrostatic potential map has shown the nature of interactions and percentage contribution from each individual intermolecular contact of these title compounds. The H?H interactions have maximum contributions and C?H, O?H and N?H also have shown major contributions to the total area of the surface. In vitro antimicrobial activity studies have disclosed that the compound 4b exhibited a moderate antibacterial activity against B. Subtilis and E. Coli strains and excellent activity against the fungal strain, A. Niger. In vitro anticancer activity of the compounds 4a and 4b was also screened against MCF 7 and MDA-MB-231 breast cancer cell lines and revealed that there is no significant effect of substitution on biological activity for the synthesized compounds.

Full text of DOI:10.1016/j.molstruc.2018.04.055

Accepted Manuscript
Synthesis, characterization, crystal structure, Hirshfeld interaction and bio-evaluation
studies of 4-amino quinazoline sulfonamide derivatives
A. Sunil Kumar, Jyothi Kudva, S. Madan Kumar, U. Vishwanatha, Vasantha Kumar,
Damodara Naral
PII:
S0022-2860(18)30497-6
10.1016/j.molstruc.2018.04.055
MOLSTR 25128
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 16 January 2018
Revised Date: 13 April 2018
Accepted Date: 13 April 2018
Please cite this article as: A. Sunil Kumar, J. Kudva, S. Madan Kumar, U. Vishwanatha, V. Kumar, D.
Naral, Synthesis, characterization, crystal structure, Hirshfeld interaction and bio-evaluation studies
of 4-amino quinazoline sulfonamide derivatives, Journal of Molecular Structure (2018), doi: 10.1016/
j.molstruc.2018.04.055.
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ACCEPTED MANUSCRIPT
Synthesis, Characterization, Crystal structure, Hirshfeld
interaction and Bio-evaluation studies of 4-amino
quinazoline sulfonamide derivatives
Sunil Kumar Aa, Jyothi Kudvaa,*, Madan Kumar Sb, Vishwanatha Uc, Vasantha
Kumard, Damodara Narale
aDepartment of Chemistry, St Joseph Engineering College, Mangaluru, 575028,
India.
bDST-PURSE Lab, Mangalagangotri, Mangalore University, Mangaluru, 574199,
India.
cSDM Centre for Research in Ayurveda and Allied Sciences, Udupi, 574118, India.
dDepartment of Chemistry, Sri Dharmasthala Manjunatheshwara College
(Autonomous) Ujire-574240, India.
eDepartment of Chemistry, Canara Engineering College, Mangaluru, 574219, India.
*Corresponding author’s email: jyothikudva@gmail.com
Graphical Abstract

Journal of Molecular Structure
Manuscript Draft
ACCEPTED MANUSCRIPT
Manuscript Number: MOLSTRUC-D-18-00267
Title: Synthesis, Characterization, Crystal structure, Hirshfeld interaction and Bio-evaluation studies
of 4-amino quinazoline sulfonamide derivatives
Article Type: Research Paper
Keywords: Quinazoline-Sulfonamide, Single crystal XRD, TG-DTA, Hirshfeld interactions,
Antimicrobial, Cytotoxicity.
1

Manuscript
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ACCEPTED MANUSCRIPT
Synthesis, Characterization, Crystal structure, Hirshfeld
interaction and Bio-evaluation studies of 4-amino quinazoline
sulfonamide derivatives
Sunil Kumar Aa, Jyothi Kudvaa,*, Madan Kumar Sb, Vishwanatha Uc, Vasantha Kumard, Damodara
Narale
aDepartment of Chemistry, St Joseph Engineering College, Mangaluru, 575028, India.
bDST-PURSE Lab, Mangalagangotri, Mangalore University, Mangaluru, 574199, India.
cSDM Centre for Research in Ayurveda and Allied Sciences, Udupi, 574118, India.
dDepartment of Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous)
Ujire-574240, India.
eDepartment of Chemistry, Canara Engineering College, Mangaluru, 574219, India.
*Corresponding author’s email: jyothikudva@gmail.com
ABSTRACT
In the present work, two new potentially active quinazolin-4-yl-aminobenzenesulfonamide
derivatives, N-(5-methyl-1,2-oxazol-3-yl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide
(4a) and N-(3,4-dimethyl-1,2-oxazol-5-yl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide
(4b), were synthesized and the structures were confirmed by different spectroscopic
1
techniques like FT-IR, H NMR, 13C NMR, HRMS and elemental analysis. The crystal
structures were solved by single crystal X-ray diffraction (XRD) studies. The single crystal
XRD studies revealed that the compound 4a crystallized in monoclinic crystal system in P 21/n
space group with Z = 4 and compound 4b crystallized in triclinic crystal system in P-1 space
group with Z = 2. The XRD study has explained the intramolecular interactions of the title
compounds. The thermal behaviour was determined with the aid of differential scanning
calorimetry (DSC) and thermogravimetry-differential thermal analysis (TG-DTA). Further, the
Hirshfeld surface analysis with finger plots and the electrostatic potential map has shown the
nature of interactions and percentage contribution from each individual intermolecular contact
of these title compounds. The H···H interactions have maximum contributions and C···H,
O···H and N···H also have shown major contributions to the total area of the surface. In vitro
antimicrobial activity studies have disclosed that the compound 4b exhibited a moderate
antibacterial activity against B. Subtilis and E. Coli strains and excellent activity against the
2

fungal strain, A. Niger. In vitro anticancer activity of the compounds 4a and 4b was also
screened against MCF 7 and MDA-MB-231 breast cancer cell lines and revealed that there is
no significant effect of substitution on biological activity for the synthesized compounds.
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Keywords: Quinazoline-Sulfonamide, Single crystal XRD, TG-DTA, Hirshfeld interactions,
Antimicrobial, Cytotoxicity.
1. Introduction
Quinazolines are representing a vital molecular scaffold among heterocyclic compounds and
they exhibit a wide variety of pharmacological properties [1]. The literature reports have
explained the broad range biological potential of quinazoline derivatives such as antimicrobial,
anticancer, antitubercular, antimalarial and antifungal etc [2-6]. It is now believed that the
biological activity of a variety of quinazoline derivatives depends on the nature and the
position of the substituent group in their framework. Among the identified substitution pattern,
4-aminoquinazolines and its N-anilino derivatives were known to be effective and highly
selective inhibitors of Tyrosine Kinase [7]. On the other hand, the sulfonamide derivatives are
pharmacologically important due to their wide applications as antibacterial agent [8].
Quinazoline-4-sulfonamide derivatives represent an important class of medicinally active
compounds which are extensively used as antibacterial agents. These hybrid molecules contain
a planar heterocyclic quinazoline ring with a benzenesulfonamide moiety at the 4th position.
The introduction of an amino group at the 4th position will act as a hydrogen bond donor,
which is an essential feature for the activity [9]. Based on the above inference, we have
synthesized two 4-amino quinazoline sulfonamide derivatives containing five-membered
oxazole ring. The target compounds 4a and 4b were synthesized based on the available
procedures and were well characterized by the FT-IR, 1H NMR, 13C NMR, DSC, TG-DTA and
elemental analysis. The HRMS results have shown peaks (M+1), (M+2) and (M+Na) as major
peaks. The lattice parameters, bond angles, bond lengths, torsion angles, dihedral angles,
hydrogen bonding and intermolecular interactions of the crystals were acquired from single
crystal X-ray diffraction (XRD) technique. The percentage of intercontacts contributing to the
Hirshfeld surface in the crystal structure of the compounds was quantized using Hirshfeld
surfaces computational analyses with 2D fingerprints. The compounds were also screened for
its antimicrobial activity studies. The in vitro anticancer activity was screened on two breast
cancer cell lines, MCF 7 (Michigan Cancer Foundation 7) and MDA-MB 231(M. D.
Anderson-Metastasis Breast cancer-231).
[Scheme 1]
3

2. Experimental
2.1. Materials and Methods
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The melting points of all these synthesized compounds were measured in an open capillary
tube and uncorrected. Infrared spectra were recorded in a Shimadzu FT-IR spectrometer using
1
KBr pellets. H (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. The chemical shifts recorded in δ ppm (parts per million). High-resolution mass
spectra (HRMS) were recorded on an Agilent 6520 (QTOF) ESI-HRMS instrument. The DSC-
TG/DTA of compounds has been recorded by using SDT Q600 thermal analyzer. All reactions
were monitored by thin layer chromatography (TLC) using aluminium TLC plate, silica gel
coated with fluorescent indicator F254 (Merck). The C, H, N and S elemental analysis was
performed in Thermo Finnigan Elemental Micro Analyzer.
2.1.1. Structural determination by single crystal X-ray diffraction studies
A single crystal of the compounds 4a and 4b with dimensions of 0.21 x 0.23 x 0.24 mm each
was chosen for X-ray diffraction studies. The X-ray intensity data were collected at a
temperature of 296 K on a Rigaku Saturn 724 diffractometer using graphite monochromated
Mo-Kα radiation. A complete data set was processed using CrystalClear [10]. The structure
was solved by direct methods and refined by full-matrix least squares method on F2 using
SHELXS and SHELXL programs [11]. The geometrical calculations were carried out using the
program PLATON [12]. The molecular and packing diagrams were generated using the
software MERCURY [13]. The ORTEP [14] of the molecule with thermal ellipsoids were
generated. Crystallographic data for the compounds 4a and 4b have been deposited at
Cambridge Crystallographic Data Centre as supplementary publication number CCDC
1563907 and 1563908. Copies of this information may be obtained free of charge via external
link www.ccdc.cam.ac.uk/conts/retrieving.html.
2.1.2. Hirshfeld interactions
The intercontacts observed in the crystal structure of the compound were quantized using
Hirshfeld surfaces computational analyses. This analysis is used to spot the intermolecular
interactions including H···H, C···H, O···H, N···H, N···C, C···C contacts. The red coloured
spots on the Hirshfeld surface indicate the intercontacts involved in the intermolecular
interactions [15, 16]. The contacts with distances equal to the sum of the van der Waals radii
are represented as white and the contacts with distances shorter and longer than van der Waals
radii are represented as red and blue, respectively [17]. The dark-red spots on the dnorm surface
arise as a result of the short interatomic contacts, i.e., strong hydrogen bonds, while the other
intermolecular interactions appear as light-red spots. The 2D fingerprint plots (FP) calculate
the relative contributions of intermolecular interactions observed in crystal packing. The 2D-
4

fingerprint plots are used to plot intercontacts with respect to di and de, where di is the closest
internal distance from a given point on the Hirshfeld surface and de is the closest external
contacts. The electrostatic potential surfaces are plotted with the red region, which is a
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negative electrostatic potential (hydrogen acceptors) and blue region, which is a positive
electrostatic potential (hydrogen donor) [18-20].
2.1.3. Antimicrobial studies
Compounds 4a and 4b were screened for their in-vitro antibacterial activity against two
representative Gram-positive bacteria species Bacillus subtilis and Staphylococcus aureus; two
Gram-negative bacterial strains Pseudomonas aeruginosa and Escherichia coli and a fungal
strain Aspergillus niger by broth dilution method [21]. Ciprofloxacin and Fluconazole were
used as reference drugs in terms of minimum inhibitory concentration (MIC). Brain Heart
Infusion (BHI) broth was used as medium and the samples were tested at ten different
concentrations ranging from 0.2 ꢀg/mL to 100 ꢀg/mL concentrations. The drugs were
dissolved in minimum amount of DMSO. 5 ꢀL organisms were taken out from the stock and
diluted it with 2 mL of BHI broth. 200 ꢀL of the above-diluted suspension was added equally
to each tube containing drug of different concentrations. The tubes were incubated for 24 h at
o
37 C in the incubator and checked for the microbial growth. If the broth became turbid or a
layer of cells formed at the bottom, then bacterial growth has occurred. For facultative
anaerobes, tubes were incubated at 37 °C for 48-72 h in the CO2 atmosphere.
2.1.4. Anticancer studies
Compounds 4a and 4b were also tested for their tumor cell killing proficiency against two
breast cancer cells such as MCF 7 and MDA-MB-231 at different concentrations by MTT (3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay method [22]. The cells
were seeded (3,000 to 10,000 cells /well) onto a 96 well titer plate containing DMEM
(Dulbecco's Modified Eagle's Medium) High Glucose H-21 media supplemented with 10%
FBS (Fetal Bovine Serum), containing Penicillin-Streptomycin and L-Glutamine and
o
incubated at 37 C and 5% CO2 for 24 h. The drugs were dissolved in a minimum
concentration of DMSO and added suitable serum-free medium to make different test
concentrations. After 24 h, drugs of different concentrations were added to the wells and
incubated for 48 h. MTT solution was prepared by dissolving 5 mg/mL of PBS buffer and
added 20 µL to each well after 48 h and further incubated for 4 h. The media was removed
after 4 h and added DMSO (100 µL) to the well to dissolve the reduced formazan crystals. The
absorbance was recorded using multiwell plate reader FluoSTAR Omega, BMG Labtech at
540 nm (or 540 nm with reference to 630 nm). The percentage viable cells were calculated
using the formula:
5

% of viable cells = [(Test sample-blank) / (Control-blank)] x 100.
2.2. Synthesis
The synthetic routes are shown in Scheme 1 and the compounds were synthesized based on
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available procedures [23-25].
2.2.1. Synthesis of N'-(2-cyanophenyl)-N,N-dimethylimidoformamide (2)
The compound 2 was synthesized by heating 2-aminobenzonitrile with a methylating agent,
o
N,N-dimethylformamide dimethyl acetal (DMF-DMA) at 90 C in presence of DMF as a
solvent. The clear reaction mixture was added to cold water to precipitate the product and the
isolation of the product was done by filtration.
0
Yield, 80.4%; m.p. 64-66 C; IR, (KBr, cm-1): 2912(aromatic C-H), 2800(C-H aliphatic),
1
2212(-CN), 1629(C=N), 1583, 1552(C-C), 1367(-CH3). H NMR (dmso-d6) δ: 7.91[s, 1H, -
N=C-H], 7.57-7.59[d, 1H, J=8Hz, Ar-H], 7.45-7.49[t, 1H, Ar-H], 7.11-7.13[d, 1H, J=8Hz, Ar-
13
H], 6.98-7.02[t, 1H, Ar-H], 3.06[s, 3H, N-CH3], 2.98[s, 3H, N-CH3). C NMR (dmso-d6) δ:
155.01, 154.77, 133.66, 132.92, 121.54, 118.96, 118.60, 105.63, 33.95. ESI-MS (m/z):
196.0851(M+Na). Anal. calcd (%) for C10H11N3: C, 69.34; H, 6.40; N, 24.26, Found: C, 69.38;
H, 6.38; N, 24.32.
2.2.2. Synthesis of N-(5-methyl-1,2-oxazol-3-yl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide
(4a)
The intermediate 2 was refluxed with sulfamethoxazole, a commercially available sulfa drug
in acetic acid for 3 h. The reaction mixture became a clear solution in the beginning and
started precipitating the product after 10 min. The product was filtered and washed with water
to remove inorganic impurities. The product was recrystallized with acetone.
o
Yield: 76%; m.p. 240-242 C; IR (KBr, cm-1): 3373, 3103(N-H), 3034(aromatic C-H stretch),
1622(C=N), 1315(asy. SO2), 1147(sym. SO2). 1H NMR (dmso-d6) δ: 10.16[s, 1H, NH], 8.66[s,
1H, Ar-H], 8.51[s, 1H, Ar-H], 8.08-8.10[d, 2H, J=8Hz, Ar-H], 7.82-7.87[t, 4H, Ar-H], 7.65-
13
7.67[d, 1H, J=4.8Hz, Ar-H], 6.15[s, 1H, oxazole], 2.28[s, 1H, -CH3]. C NMR (dmso-d6) δ:
162.2, 158.2, 154.9, 153.6, 149.7, 144.6, 133.5, 132.4(2), 127.6, 127.3, 125.9, 122.2, 120.2(2),
116.3, 104.4, 10.92. ESI-MS (m/z): 382.0974(M+1). Anal. calcd (%) for C18H15N5SO3: C,
56.68; H, 3.96; N, 18.36; S, 8.41. Found: C, 56.72; H, 3.92; N, 18.42; S, 8.46.
2.2.3. Synthesis of N-(3,4-dimethyl-1,2-oxazol-5-yl)-4-[(quinazolin-4-yl)amino]benzene-1-
sulfonamide (4b)
A mixture of compound 2 and sulfisoxazole was refluxed in acetic acid for 3 h to form the
compound 4b. The product was not precipitated and therefore added to cold water to
precipitate it and isolated by filtration. The crude product was recrystallized with acetone.
o
Yield: 74%; m.p. 213-215 C; IR (KBr, cm-1): 3414, 3107(N-H), 2931(aromatic C-H stretch),
1
1660(C=N), 1330(asy. SO2), 1142(sym. SO2). H NMR (dmso-d6) δ: 10.16[d, 1H, N-H],
6

8.66[s, 1H, Ar-H], 8.52-8.54[d, 1H, Ar-H], 8.11-8.13[d, 2H, Ar-H], 7.72-7.87[m, 4H, Ar-H],
13
7.61-7.65[t, 1H, Ar-H], 2.03[s, 3H, -CH3], 1.62[s, 3H, -CH3]. C NMR (dmso-d6) δ: 161.3,
157.4, 155.7, 153.9, 149.5, 143.8, 133.7, 133.4, 127.7, 127.4(2), 126.6, 123.0, 121.3(2), 115.2,
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104.7, 10.29, 5.90. ESI-MS (m/z): 396.1136(M+1). Anal. calcd (%) for C19H17N5SO3: C,
57.71; H, 4.33; N, 17.71; S, 8.11. Found: C, 57.76; H, 4.28; N, 17.67; S, 8.17.
3. Results and discussion
3.1. FT- IR spectroscopy
The IR spectrum of intermediate compound 2 has shown stretching vibrations at 2912 cm-1 (C-
H aromatic), 2800 cm-1 (C-H aliphatic), 2212 cm-1 (nitrile), 1629 cm-1 (C=N) and 1282 cm-1
(C-N). The IR absorption bands of compounds 4a and 4b contain some characteristic
stretching vibrations for N-H, C=N, and SO2 groups. The bands at 3414-3373 cm-1 are
assigned to N-H stretching mode of amino group attached to the quinazoline ring. The bands at
3107-3103 cm-1 are assigned to the N-H stretching vibrations of SO2N-H. The SO2 asymmetric
and symmetric vibrations appear in the range 1330-1332 cm-1 and 1142-1143 cm-1
respectively. Strong bands were observed in the range 1660-1662 cm-1 corresponding to C=N
stretching vibration.
3.2. NMR spectroscopy
The formation of intermediate 2 was also confirmed with the aid of NMR spectroscopy. Two
singlet peaks were observed with six protons at δ 2.98 and 3.06 ppm in the 1H NMR spectrum
corresponding to N(CH3)2 protons and a singlet peak at δ 7.91 ppm for the imine proton (H-
C=N) have confirmed the formation of the product.
The atom numbering for interpreting the NMR data is shown in Fig. 1. The 1H NMR spectrum
of compound 4a has shown a singlet peak at δ 2.28 ppm corresponding to -CH3 group in the
oxazole ring. A singlet peak observed at δ 6.15 ppm corresponding to the oxazole ring proton.
These two peaks confirmed the presence of 5-methyl-1,2-oxazol-3-yl ring in the structure. The
pyrimidine proton (H1) in the quinazoline ring resonates in the downfield at δ 8.66 ppm. The
N-H (Ha) proton attached to the quinazoline ring (Fig. 1) is less acidic compared to
sulfonamide (Hb) proton and appears at upfield than Hb proton. Therefore the broad peak
observed at δ 10.16 ppm was corresponding to the N-H group proton (Ha). These protons
(H1and Ha) confirmed the formation of 4-amino quinazoline ring. Similarly, the compound 4b
has shown two peaks at δ 1.62 and 2.03 ppm, corresponding to 3,4-dimethyl-1,2-oxazol-5-yl
methyl protons and the pyrimidine proton (H1) in the quinazoline ring of compound 4b
resonates at δ 8.71 ppm. The above observations have confirmed the presence of oxazole and
quinazoline rings in the molecule. The N-H group proton (Ha) bonded to the quinazoline ring
1
in compound 4b resonates as a broad peak at δ 10.16 ppm [26]. The H NMR spectrum of
sulfonamide N-H proton bonded to the heterocyclic ring has been reported at downfield
7

compared to the N-H bonded to homocyclic ring. The sulfonamide N-H proton bonded to
nitrogen and oxygen heterocyclic rings was reported at 11.0 and 10.90 ppm respectively [27,
28], whereas the N-H proton bonded to the homocyclic ring has reported at 7.72 ppm [29]. But
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the N-H protons of sulfonamide group (Hb) were not observed in the H NMR spectra of
1
compounds 4a and 4b. It may be due to the presence of moisture in the DMSO-d6 NMR
solvent. A broad peak was observed in the 1H NMR spectra of compounds 4a and 4b at δ 3.6
ppm may be due to the NH proton merged with water protons.
[Figure 1]
The 13C NMR spectrum of intermediate 2 has shown characteristic peaks at δ 33.9 for (CH3)2
group, 118.6 ppm for nitrile (C≡N) group and 155.0 ppm for imine (N=C) group carbons
confirmed the structure. The 13C NMR spectrum of compound 4a has shown two peaks at
154.95 and 162.23 ppm corresponding to quinazoline ring carbon atoms (C1 and C8). The
oxazole ring carbon signals were observed between 100-155 ppm and the methyl carbon peak
was observed at δ 10.92 ppm have confirmed the formation of the product. The compound 4b
has shown similar observations in the 13C spectrum, in which the two methyl carbon peaks
were observed at δ 5.90 and 10.29 ppm [30].
3.3. TG/DTA and DSC analysis
In the TG-DTA analyses, the samples were analyzed between the temperatures 27 and 800 °C
at a heating rate of 10 oC/min. The TG/DTA and DSC curves of compound 4a are shown
in Fig. 2a and Fig. 2b respectively. The typical DTA and DSC curves of the compound 4a have
shown two exothermic decomposition processes and the peak temperatures of the first and
second decomposition stages were observed at 278.37 and 655.73 °C respectively. In TGA
graph, the corresponding decomposition was observed between 258-343 ºC and 559-756 ºC
respectively.
[Figure 2a] & [Figure 2b]
The compound 4b has shown quite different thermal behaviour from that of compound 4a. The
TG/DTA and DSC curves of compound 4b are given in Fig. 3a and Fig. 3b respectively. The
DTA and DSC curves of compound 4b indicate that the compound has shown only one
o
exothermic decomposition peak and the peak temperature was observed at 238.04 C. The
corresponding decomposition was observed in the TGA curve between 226-356 °C. The above
results indicate that the thermal stability of compound 4a is higher than that of compound 4b.
o
The decomposition process of the compounds 4a and 4b was started at above 200 C. This
reveals that the crystals are free from moisture [31]. No phase transition was observed till the
compound melts and the sharpness of the peaks indicates a good degree of crystalline quality
and purity of the crystal [32, 33].
[Figure 3a] & [Figure 3b]
8

3.4. Single crystal XRD studies
The X-ray diffraction studies have confirmed the structures of 4a and 4b, which were also
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established by the NMR and other spectroscopic data. The details of the crystal structure and
data refinement of the compounds 4a and 4b are given in Table 1. The list of important bond
lengths and bond angles of the non-hydrogen atoms of the analyzed compounds are given in
Table 2. The ORTEP diagram of the molecules 4a and 4b are represented in Fig. 4 and Fig. 5
respectively.
[Table 1] & [Table 2]
The single crystal X-ray diffraction structure analysis of the compound 4a revealed that the
compound crystallized in monoclinic system under the space group P 21/n, with cell
parameters a = 11.1904(6) Å, b =13.8698(4) Å, c =12.3722(6) Å, α = 90o β =115.431(6)0, γ =
90o and Z = 4 with unit volume 1734.20(16) Å3. The molecular structure contains oxazole
(Cg1: O3/N5/C15-C17), phenyl (Cg4: C9-C14) and quinazoline (Cg5: N1-N2/C1-C8) rings.
The quinazoline ring makes dihedral angles of 89.91(9)0 and 28.22(7)0 with oxazole and
phenyl rings respectively. The dihedral angle between oxazole and phenyl ring is 85.99(11)0.
The compound exhibits intramolecular hydrogen bonds of type C(13)-H(13)...O(1), C(14)-
H(14)...N(1) and C(16)-H(16)...O(1). In the crystal structure, molecules are connected through
N(3)-H(3)...O(1), N(4)-H(4)...N(2), C(1)-H(1)...O(2) and C(6)-H(6)...O(1) intermolecular
hydrogen bond. In addition, molecules are stabilized with the intermolecular contacts of type
C(18)-H(18C)...Cg(2) (distance = 3.724(3) Å) and Cg(2)…Cg(2) (distance =3.6940(11) Å)
(Table 7), where H(18C) is one of the hydrogen atoms attached to the C(18) carbon atom and
Cg2 is the centroid (Cg2: N1/C1/N2/C2/C7/C8) of the ring.
[Figure 4] & [Figure 5]
The compound 4b crystallizes in triclinic system under the space group P-1, with cell
parameters a = 9.0499(2) Å, b = 9.6900(3) Å, c = 11.9206(3) Å, α = 111.660(3)0, β =
110.090(2)0, γ = 92.064(2)0 and Z = 2 with unit volume 896.42(5) Å3. In compound 4b, the
quinazoline ring (Cg5: N1-N2/C1-C8) makes dihedral angles of 56.11(8)0 and 12.86(7)0 with
oxazole (Cg1: O3/N5/C15-C17) and phenyl (Cg4: C9-C14) rings respectively. The dihedral
angle between Cg1 and Cg4 is 56.43(9)0. The compound shows intramolecular hydrogen
bonds of type C(13)-H(13)...O(1) and C(14)-H(14)...N(1). The molecules are connected
through N(3)-H(3)...N(5), N(4)-H(4)...N(2) and C(11)-H(11)...O(2), intermolecular hydrogen
bonds. In addition, an intermolecular contact of type C(18)-H(18B)...Cg(2) (distance =
3.423(2) Å), Cg2…Cg2 (distance = 3.6282(10) Å) and Cg4…Cg2 (distance = 3.6283(10) )
were also observed (Table 3). The bond lengths and bond angles of the two compounds agree
with the standard values and are comparable to related structure [33-36].
[Table 3]
9

3.5. Hirshfeld interactions
The intercontacts were quantified using visualization of the Hirshfeld surfaces and 2D
fingerprint plots. Fig. 6 and Fig. 7 have shown the dnorm mapped on Hirshfeld surface for the
ACCEPTED MANUSCRIPT
visualization of the intercontacts of the compounds 4a and 4b respectively. The dnorm mapping
indicates that strong hydrogen bond interactions, such as C-H...O, C-H...N are seen as a bright
red area in the Hirshfeld surfaces.
[Figure 6] & [Figure 7]
3.5.1. Hirshfeld surface analysis of the compound 4a
The intercontacts in compound 4a were found to be HꢀꢀꢀH (31.9 %), CꢀꢀꢀH (23.8 %), OꢀꢀꢀH
(20.1 %), NꢀꢀꢀH (13.9 %), NꢀꢀꢀC (3.6 %), CꢀꢀꢀC (3.0 %), OꢀꢀꢀO (1.7 %), NꢀꢀꢀN (1.0 %), OꢀꢀꢀN
(0.5 %) and OꢀꢀꢀC (0.4 %). The 2D fingerprint plots of these intercontacts are shown in Fig. 8.
The major contributions are from H…H and C...H when compared to other intercontacts. This
supports that van der Waals forces influence the stabilization of the packing in compound 4a
[37]. The other two major contributions from OꢀꢀꢀH and NꢀꢀꢀH are due to the intermolecular
hydrogen bonding between the molecules. The electrostatic potential mapped on Hirshfeld
surface (different orientation) with ±0.030 au for compound 4a as shown in Fig. 9.
[Figure 8] & [Figure 9]
3.5.2. Hirshfeld surface analysis of the compound 4b
The intercontacts in compound 4b were found to be HꢀꢀꢀH (39.3 %), OꢀꢀꢀH (21.3 %), NꢀꢀꢀH
(15.6 %), CꢀꢀꢀH (9.8 %), CꢀꢀꢀC (8.0 %), NꢀꢀꢀC (2.9 %), OꢀꢀꢀC (2.0 %), OꢀꢀꢀN (0.6 %), NꢀꢀꢀN
(0.3 %), and SꢀꢀꢀC (0.1 %). The 2D fingerprint plots of these intercontacts are shown in Fig.
10. The major contributions are from HꢀꢀꢀH, OꢀꢀꢀH and NꢀꢀꢀH when compared to other inter
contacts. The electrostatic potential over Hirshfeld surface has shown in Fig. 11. The
percentage of various intermolecular contacts contributing to Hirshfeld surface in compounds
4a and 4b as shown in Table 4.
[Figure 10] & [Figure 11]
[Table 4]
3.6. Biological evaluation
3.6.1. Antimicrobial
In vitro antimicrobial activity studies were carried out by broth dilution method and the results
are summarized in Table 5. The MIC results of both compounds 4a and 4b revealed that
sulfisoxazole derivative (compound 4b) is more potent than sulfamethoxazole (compound 4a)
derivative. The compound 4b has shown a moderate antibacterial activity against all tested
organisms. It also exhibited an enhanced antifungal activity against A. Niger than that of
standard drug Fluconazole. The structural evaluation of similar compounds from the literature
revealed that the two subunits: quinazoline ring and the sulfonamide moiety have been
10

reported to possess an excellent range of antimicrobial activities. It was observed from the
reports that, substitution at 2nd and 3rd positions or presence of halogen atoms at 6th and 8th
positions of quinazoline ring can enhance the antimicrobial activity [39]. But compounds 4a
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and 4b have shown less antimicrobial activity than halo substituted quinazoline derivatives as
well as sulfonamide-Schiff base derivatives [40-42].
[Table 5]
3.6.2. Anticancer
The in vitro anticancer activity of compounds 4a and 4b was screened on two breast cancer
cell lines, MCF 7 and MDA-MB-231 by MTT assay method. The percentage cell viability at
seven different concentrations (1, 6.25, 12.5, 25, 50, 100 and 500 ꢀg/mL) was tested and the
results at 500 ꢀg/mL concentration were displayed in Table 6. The compounds have not shown
any remarkable anticancer activity in both cancer cell lines even at higher concentrations. The
activity was less than the other reported 4-aminoquinazoline derivatives [43]. It was observed
from the literature that, thiazole or indazole ring bonded to sulfonamide moiety in 4-
aminoquinazoline-sulfonamide derivatives have given better cytotoxic activity against MDA-
MB-231, but the activity decreased when these rings were replaced with oxazole ring [44].
Substituents at positions 6 and 7 or phenyl ring substitution at 3rd position in the quinazoline
ring have also shown better activity in 4-amino quinazoline derivatives [43, 45]. Therefore the
less potency of compounds 4a and 4b is may be due to the presence of oxazole ring in SO2-
NH- group.
[Table 6]
4. Conclusions
Two novel quinazoline derivatives containing sulfonamide moiety were synthesized with
significant yield and single crystals were grown by a slow evaporation method using acetone
1
13
as solvent. The compounds were characterized by FT-IR, H NMR, C NMR, HRMS, DSC,
TG/DTA and elemental analysis. Both the compounds were thermally stable and the thermal
stability of compound 4b was higher than that of compound 4a. The molecular structure of
these compounds was determined by single crystal XRD studies. The compound 4a
crystallized in monoclinic crystal system with P 21/n space group and compound 4b
crystallized in triclinic crystal system with P-1 space group. The compounds exhibited
intramolecular hydrogen bonds with type C-H...O and C-H...N and the molecules are
connected through N-H...O, N-H...N and C-H...O intermolecular hydrogen bonds. In addition,
short contact with types C-H...π and π… π also help in crystal stabilization. The crystal and
molecular structure of the compound were stabilized by weak intramolecular interactions and
the contribution of these intercontacts was also analyzed by visualizing Hirshfeld surface. The
intermolecular contacts HꢀꢀꢀH and CꢀꢀꢀH have shown major contribution towards Hirshfeld
11

surface in compounds 4a and 4b. This indicates that van der Waals forces exert a significant
influence on the stabilization of the packing in both the compounds. Compounds 4a and 4b
have shown less antimicrobial activity than reported quinazoline and sulfonamide derivatives.
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Also, compounds 4a and 4b are less potent against the breast cancer cell lines may be due to
the presence of oxazole ring.
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15

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Scheme 1. The synthesis of target quinazoline derivatives (4a and 4b).
Figures and Tables
Fig. 1. Atom numbering for interpreting the NMR data.
Fig. 2a. TGA-DTA curves of compound 4a.
16

ACCEPTED MANUSCRIPT
Fig. 2b. DSC curve of compound 4a
Fig. 3a. TGA-DTA curves of compound 4b.
Fig. 3b. DSC curve of compound 4b
17

Table 1
Crystal data and structure refinement details for compounds 4a and 4b.
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Parameter
4a
4b
CCDC number
1563907
C18 H15N5SO3
381.41
1563908
Empirical formula
Formula weight
C19
H17
N
5
SO3
395.43
293(2)
Temperature (K)
Wavelength (Kα,Å)
Crystal system, space group
293(2)
0.71075
0.71075
Monoclinic, P 21/n
Triclinic, P-1
a = 11.1904(6) Å
b = 13.8698(4) Å
c = 12.3722(6) Å
Unit cell dimensions
= 90 0
α
115.431(6)0
β =
= 90 0
γ
1734.20(16)
4, 1.461
Volume Å3
1734.20(16)
4, 1.461
896.42(5)
2, 1.465
Z, Calculated density (Mg/m3)
Absorption coefficient (m/m)
0.218
0.213
F(000)
792
872
Crystal size mm
Theta range for data collection (0)
0.21 x 0.23 x 0.24
2.5 to 27.1
-14≤ h ≤ 13,
0.21 x 0.23 x 0.24
2.0 to 27.1
-11≤ h ≤ 11,
-17 ≤ k ≤ 17,
-12 ≤ k ≤ 10,
Limiting indices
-14≤ l ≤15
-15 ≤ l ≤ 15
Reflections collected / unique [R(int)]
Refinement method
20115/3799 [0.045]
10272/3898 [0.025]
Full-matrix least-
squares on F2
3363 / 0 / 245
0.0443
Full-matrix least-
squares on F2
3898 / 0 / 259
0.0396
Data / restraints / parameters
R value
Goodness-of-fit on F2
Largest diff. peak and hole (e. Å-3)
1.05
1.05
0.28 and −0.32
0.38 and −0.30
18

Table 2
Important bond angles and bond lengths of compounds 4a and 4b.
ACCEPTED MANUSCRIPT
Parameter
Bond angles (0)
O1-S1-O2
4a
4b
118.37(9)
105.40(9)
107.81(8)
109.42(9)
106.16(8)
117.60(2)
123.10(2)
112.50(2)
104.00(2)
109.70(2)
109.20(2)
--
120.43(8)
104.01(8)
107.55(8)
110.22(8)
106.03(8)
116.40(1)
124.80(2)
--
O2-S1-N4
O1-S1-C12
O2-S1-C12
N4-S1-C12
N3-C9-C10
N3-C9-C14
N5-C15-C16
O3-N5-C15
O3-C17-C16
N5-O3-C17
N5-C17-C16
O3-C15-C16
N5-O3-C15
O3-N5-C17
--
--
--
112.0(2)
111.0(1)
107.4(1)
105.8(1)
--
--
--
Bond lengths (Å)
N4─C15
S1─C12
N3─C9
O3─N5
S1─N4
S1─O2
S1─O1
C15─N5
O3─C15
1.395(3)
1.756(2)
1.413(2)
1.412(3)
1.620(1)
1.424(2)
1.433(1)
1.300(3)
--
1.393(2)
1.758(2)
1.404(3)
1.413(2)
1.650(1)
1.429(1)
1.426(1)
--
1.353(2)
Fig. 4. The molecular structure of the compound 4a, showing the atomic numbering system.
Displacement ellipsoids are drawn at the 50% probability.
19

ACCEPTED MANUSCRIPT
Fig. 5. The molecular structure of the compound 4b, showing the atomic numbering system.
Displacement ellipsoids are drawn at the 50% probability.
Table 3
Intermolecular and intramolecular interactions of compounds 4a and 4b.
Comp.
No.
D-H/...A/Cg
D-H
H/X...A/Cg D....A/Cg
D-
Symmetry codes
H/X...A/Cg
(Å)
(Å)
(Å)
(0)
C13-H13...O1
C14-H14...N1
C16-H16...O1
N3-H3...O1
N4-H4...N2
C1-H1...O2
C6-H6...O1
0.93
0.93
0.93
0.86
0.86
0.93
0.93
0.96
2.52
2.29
2.56
2.37
2.09
2.32
2.49
2.83
2.898(2)
2.815(3)
3.023(2)
3.133(2)
2.896(3)
3.080(3)
3.243(3)
3.581(3)
104
115
--
--
111
149
157
139
138
135
--
-1/2+x,1/2-y,-1/2+z
-1/2+x,1/2-y,1/2+z
1/2+x,1/2-y,-1/2+z
-1/2+x,1/2-y,-1/2+z
3/2-x,-1/2+y, -1/2-z
4a
C18-
H(18C)...Cg2
C13-H13...O1
0.93
0.93
2.50
2.23
2.884(2)
2.833(2)
3.458(2)
105
122
--
C14-H14...N1
N3-H3...N5
N4-H4...N2
--
0.86
2.62
166
x,-1+y,z
x,y,-1+z
4b
0.84(2)
2.09(2)
2.9092(1
9)
163(2)
C11-H11...O2
0.93
0.96
2.810(1)
2.84
3.3043(1
9)
158
120
1-x,1-y,-z
-x,2-y,-z
C18-
3.423(2)
H(18B)...Cg2
20

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Fig. 6. dnorm mapped on Hirshfeld surface for the visualization of the intercontacts of the
compound 4a.
Fig. 7. dnorm mapped on Hirshfeld surface for the visualization of the intercontacts of the
compound 4b.
21

ACCEPTED MANUSCRIPT
Fig. 8. Two-dimensional fingerprint plot analysis of compound 4a. (a) all interactions, (b) H
H contacts, (c) C H contacts, (d) O H contacts, (e) N H contacts, (f) N C contacts, (g) C
C contacts, (h) O O contacts and (i) N N contacts.
Fig. 9. Electrostatic potential of compound 4a mapped on Hirshfeld surface (different
orientation) with ±0.030 au.
22

ACCEPTED MANUSCRIPT
Fig. 10. Two-dimensional fingerprint plot analysis of compound 4b. (a) all interactions, (b) H
H contacts, (c) O H contacts, (d) N H contacts, (e) C H contacts, (f) C C contacts, (g) N
C contacts, (h) O C contacts and (i) O N contacts.
Fig. 11. Electrostatic potential of compound 4b mapped on Hirshfeld surface (different
orientation) with ±0.030 au.
Table 4
Percentage of various intermolecular contacts contributing to Hirshfeld surface in compounds
4a and 4b.
Intercontacts
HꢀꢀꢀH CꢀꢀꢀH OꢀꢀꢀH NꢀꢀꢀH CꢀꢀꢀC NꢀꢀꢀC OꢀꢀꢀO NꢀꢀꢀN OꢀꢀꢀC
31.9 23.8 20.1 13.9 3.0 3.6 1.7 1.0 0.4
%
4a
4b
Contribution
Intercontacts HꢀꢀꢀH CꢀꢀꢀH OꢀꢀꢀH NꢀꢀꢀH CꢀꢀꢀC NꢀꢀꢀC OꢀꢀꢀN NꢀꢀꢀN OꢀꢀꢀC
%
39.3
9.8
21.3
15.6
8.0
2.9
0.6
0.3
2.0
Contribution
23

Table 5
Antimicrobial activity study results of compounds 4a and 4b.
Comp. No.
MIC (µg/mL)
ACCEPTED MANUSCRIPT
Gram +ve bacteria
Gram –ve bacteria
Fungus
A. N*
25
B. S*
50
S. A*
12.5
6.25
2.0
P. A*
25
E. C*
6.25
3.12
2.0
4a
3.12
2.0
6.25
4
6.25
NT
4b
Ciprofloxacin
Fluconazole
NT
NT
NT
NT
8.0
* B.S: Bacillus Subtilis, S.A: Staphylococcus Aureus, P.A: Pseudomonas Aeruginosa, E.C:
Escherichia Coli and A.N: Aspergillus Niger, NT: Not tested.
Table 6
Anticancer activity study results of compounds 4a and 4b.
Comp. No. Percentage cell viability at 500 µg/mL concentration (%)
MDA-MB-231
MCF 7
52.07
55.14
3. 12
70.82
80.40
15.26
4a
4b
Cisplatin
24

ACCEPTED MANUSCRIPT
Synthesis, Characterization, Crystal structure, Hirshfeld
interaction and Bio-evaluation studies of 4-amino
quinazoline sulfonamide derivatives
Sunil Kumar Aa, Jyothi Kudvaa,*, Madan Kumar Sb, Vishwanatha Uc, Vasantha
Kumard, Damodara Narale
aDepartment of Chemistry, St Joseph Engineering College, Mangaluru, 575028,
India.
bDST-PURSE Lab, Mangalagangotri, Mangalore University, Mangaluru, 574199,
India.
cSDM Centre for Research in Ayurveda and Allied Sciences, Udupi, 574118, India.
dDepartment of Chemistry, Sri Dharmasthala Manjunatheshwara College
(Autonomous) Ujire-574240, India.
eDepartment of Chemistry, Canara Engineering College, Mangaluru, 574219, India.
*Corresponding author’s email: jyothikudva@gmail.com
Highlights
•
•
•
•
4-aminoquinazoline-sulfonamide derivatives (4a & 4b) synthesized and characterized.
Single crystal XRD studies revealed the structures of compounds 4a & 4b.
Nature of intermolecular contacts was studied by Hirshfeld surface analysis.
In vitro antimicrobial and anticancer activity studies were performed.