Supramolecular architecture in sulfonylurea, sulfonyldiurea and sulfonyltriurea drugs: Synthesis, X-ray structure and Hirshfeld surface analysis

Article abstract of DOI:10.1016/j.molstruc.2021.130158

Sulfonylureas provide a useful motif for carrying donor and acceptor sites capable of hydrogen bonding. These are a prominent class of therapeutic agents in the pharmaceutical industry. However, the use of aryl sulfonyl oligomers in drug discovery, supramolecular chemistry and crystal engineering are unexplored. This motivated us to design, synthesize and understand the structural features of aryl sulfonylurea oligomers (n = 1–3). Here, we report the synthesis and spectroscopic characterization details such as ¹H NMR, ¹³C NMR, mass spectrometry and single-crystal X-ray diffraction analysis for three sulfonylurea oligomer derivatives. Further, the molecular packing analysis of three derivatives reveals the significance of N[sbnd]H…O and C[sbnd]H…O intra and intermolecular hydrogen bonding. These hydrogen bonding contacts enable the sulfonylurea derivatives to form 2D framework/architecture. We quantify various intermolecular interactions in these derivatives by Hirshfeld analysis and 2D fingerprint plots. We have performed in-silico docking studies against Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) to rationalize the binding affinity of title compounds.

Full text of DOI:10.1016/j.molstruc.2021.130158

Journal of Molecular Structure 1233 (2021) 130158
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Supramolecular architecture in sulfonylurea, sulfonyldiurea and
sulfonyltriurea drugs: Synthesis, X-ray structure and Hirshfeld surface
analysis
Amarjyoti Das Mahapatraa, Althaf Shaika, Vijay Thiruvenkatamb, Bhaskar Dattaa,b,∗
a Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India-382355
b Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India-382355
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfonylureas provide a useful motif for carrying donor and acceptor sites capable of hydrogen bond-
ing. These are a prominent class of therapeutic agents in the pharmaceutical industry. However, the use
of aryl sulfonyl oligomers in drug discovery, supramolecular chemistry and crystal engineering are unex-
plored. This motivated us to design, synthesize and understand the structural features of aryl sulfonylurea
oligomers (n = 1–3). Here, we report the synthesis and spectroscopic characterization details such as
1H NMR, 13 C NMR, mass spectrometry and single-crystal X-ray diffraction analysis for three sulfonylurea
oligomer derivatives. Further, the molecular packing analysis of three derivatives reveals the significance
Received 4 November 2020
Revised 2 February 2021
Accepted 16 February 2021
Available online 23 February 2021
Keywords:
Sulfonylurea
Sulfonyldiurea
–
–
of N H…O and C H…O intra and intermolecular hydrogen bonding. These hydrogen bonding contacts
enable the sulfonylurea derivatives to form 2D framework/architecture. We quantify various intermolec-
ular interactions in these derivatives by Hirshfeld analysis and 2D fingerprint plots. We have performed
in-silico docking studies against Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) to rationalize
the binding affinity of title compounds.
Sulfonyltriurea
Crystal structure
Hirshfeld surface
2D fingerprint plot analysis
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
may be broadly categorized into components of analysis and syn-
thesis. Crystal engineering also provides an effective route to im-
Weak non-covalent interactions such as hydrogen bonding [1],
metal-ligand coordination [2], π-π stacking [3], hydrophobic, ionic,
and van der Waals forces [4] enable mobility in biological struc-
tures and are the energetic cornerstones for biomolecular interac-
tion [5]. These interactions form the basis of critical processes oc-
curring in living systems. Biomolecular interactions have provided
inspiration for the design of synthetic supramolecular constructs
with diverse applications [5-7]. Most drug-receptor interactions in
medicinal chemistry operate in a supramolecular framework. Ma-
terials based on supramolecular design find application in a variety
of domains such as drug delivery, imaging, diagnostic methods and
regenerative medicine [8]. In crystal engineering, the supramolec-
ular chemist aims to design and control packing arrangements to
obtain specific crystal size, shape and crystalline form with specific
properties [5, 9]. Crystal engineering now encompasses many as-
pects of solid-state intermolecular interactions, rationalisation and
control of structures, as well as the synthesis of distinctive molec-
ular building blocks and crystalline materials. Engineered crystals
proving solubility, dissolution rates and bioavailability of poorly
soluble drugs [10]. Active pharmaceutical ingredients (APIs) are ex-
tremely valuable materials and pharmaceutical co-crystallization
plays a significant role in API formulation in the context of drug
development and delivery [11]. Crystalline API’s are preferred ow-
ing to their ease of isolation, rejection of impurities inherent to the
crystallization process and the physico-chemical stability afforded
by crystalline solid state [12]. API’s can exist in several polymor-
phic, solvated and/or hydrated forms and they provide an opportu-
nity in pharmaceutical research to scrutinize and identify the sta-
bility of different polymorphs of each potential new drug [12-14].
Bioisosteric replacement approach is widely used in medici-
nal chemistry and in the drug discovery process to attenuate the
toxicity and/or improve the pharmacokinetic profile of biologically
active molecules [15]. Sulfonylurea is one such group, used as a
surrogate for amides, ureas, thioureas, nitrosoureas, carbamates,
and sulfonamides in the bioisosteric replacement process [16]. Sul-
fonylureas are an eminent class of oral antidiabetic agents widely
used for the management of Type 2 diabetes mellitus (T2DM) [17].
These compounds exert their hypoglycaemic effects by stimulating
insulin secretion from the pancreatic β-cell and have been success-
fully used to treat non-insulin dependent diabetes mellitus [17, 18].
∗
Corresponding author at: Discipline of Chemistry & Biological Engineering, In-
dian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382355 India.
E-mail address: bdatta@iitgn.ac.in (B. Datta).
https://doi.org/10.1016/j.molstruc.2021.130158
0022-2860/© 2021 Elsevier B.V. All rights reserved.

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Fig. 1. Structure of (A) N-((4-methoxyphenyl)carbamoyl)−4-methylbenzenesulfonamide (B) N-(((4-methoxyphenyl)carbamoyl)carbamoyl)−4-methylbenzenesulfonamide (C)
N-((((4-methoxyphenyl)carbamoyl)carbamoyl)carbamoyl)−4-methylbenzenesulfonamide.
Literature reports have described a range of other medicinal ap-
plications of sulfonylureas such as zinc metalloenzyme modulators
[19], human carbonic anhydrase II inhibitor [20], inhibitor of in-
terleukin (IL)−1β activity [21, 22], anticancer activity [23-25], 5-
lipoxygenase inhibitors [26] and antimicrobial agents [27, 28]. The
presence of donor and acceptor moieties in sulfonylurea groups fa-
cilitates their participation in various non-covalent interactions es-
netic resonance (NMR) spectra were recorded on a 500 MHz
Bruker Instrument using tetramethylsilane (TMS) as an internal
reference. Chemical shifts were measured in ppm (δ) relative to
TMS (0.00 ppm). Coupling constants (J) are reported in Hertz (Hz).
Multiplicity of resonance peaks are indicated as singlet (s), doublet
(d), triplet (t), quartet (q) and multiplet (m). Mass spectra were
measured by LC-MS on a Waters SYNAPT-G2S-S using the elec-
trospray ionization technique. Progress of the reactions was mon-
itored by thin-layer chromatography (TLC) analysis on silica gel
plates.
–
pecially hydrogen bonding (N H…O). Such interactions can con-
tribute to crystal packing, stability of polymorphs and solvato-
morphs, and co-crystallization. Accordingly, synthetic methodology
and structural properties of sulfonylureas has attracted attention
for several years. As part of our work we have reported the syn-
thesis of oligomeric sulfonylurea products (n = 1 and 3) and high-
lighted their biological applications [29]. Based on their applicabil-
ity as a unique scaffold in medicinal chemistry, we were motivated
to learning more about the structural details of the molecules.
In this work, we report the comparative analysis of structural
properties and packing features in three sulfonylurea derivatives,
namely sulfonylurea (A), sulfonyldiurea (B) and sulfonyltriurea (C)
molecules (Fig. 1). Also, we have generated Hirshfeld surface and
2D fingerprint plots for these three derivatives to assess the appli-
cable molecular interactions and their contribution towards overall
crystal packing.
2.2. General procedure for the synthesis of sulfonylurea (A) and
sulfonyltriurea (C)
Compounds A and C were synthesized according to the reported
method [37]. Briefly, sulfonyl chloride (2.4 mmol) was stirred in
pyridine (5.0 mmol) for 5 min. The resulting solution was added
to a mixture of sodium cyanate (3.9 mmol) in acetonitrile (10 mL)
and allowed to stir at room temperature for 4 h. Aniline derivatives
(4.4 mmol) were added to the reaction mixture and stirred for an-
other 1 h at the same temperature. The resulting reaction mixture
was poured on crushed ice-cold water and acidified with dilute
HCl (pH 5–6). The aqueous layer was extracted with ethyl acetate
and was washed with brine and dried over anhydrous sodium sul-
phate (Na2SO4). The ethyl acetate layer was concentrated under re-
duced pressure, and the solid residue was purified by flash column
chromatography using ethyl acetate and hexane as mobile phase.
N-((4-methoxyphenyl)carbamoyl)−4-methylbenzenesulfonamide
(A)
The distinctive structural differences between A, B, and C led
us to explore their effects on a specific protein target. We based
our preliminary investigation on the well-known anti-malarial sul-
fonylurea molecule glyburide. Malaria continues to affect public
health worldwide and remain dominant in resource-poor tropical
and subtropical regions [30, 31]. Resistance of antiparasitic drugs
demands the development of new classes of cost-effective anti-
malarial drugs [31-33]. Plasmodium falciparum (Pf) prolyl-tRNA syn-
thetase (ProRS) has been recognized as one of the few chemical-
genetically validated drug targets for malaria [31, 34]. While sev-
eral drugs have been developed for the treatment of malaria, the
search for suitable inhibitors of Pf ProRS continues to persist. In
particular, halofuginone and its analogues are associated with tox-
icity related to Homo sapiens (Hs) ProRS inhibition [31, 35, 36].
Recently, Hewitt and co-workers have developed glyburide and
TCMDC-124506 as selective allosteric inhibitors of prolyl-tRNA syn-
thetase with IC50 values 34 μM and 74 μM respectively [31]. In
search of new scaffolds for Pf ProRS, we have performed in sil-
ico docking studies for comparing sulfonylurea, sulfonyldiurea and
sulfonyltriurea. Our results show that these sulfonylurea oligomers
offer promising potential for the development of a new class al-
losteric inhibitor of Pf ProRS.
The title compound was synthesized as described above and
obtained as white solid powder, yield 48%, 1H NMR (DMSO–d6,
500 MHz): δ 8.62 (s, 1H, NH), 7.84 (d, 2H, J = 8), 7.40 (d, 2H,
J = 8), 7.25 (d, 2H, J = 8.5), 6.83 (d, 2H, J = 9), 3.69 (s, 3H,
OCH3), 2.39 (s, 3H, CH3); 13C NMR (DMSO-d6, 126 MHz): δ 155.65,
150.63, 143.84, 138.27, 131.72, 129.80, 127.82, 121.20, 114.40, 55.64,
21.49; MS (ESI): m/z calculated: 321.0904 [M + H]+ and observed:
321.0903 [M + H]+.
N-((((4-methoxyphenyl)carbamoyl)carbamoyl)carbamoyl)−4-
methylbenzenesulfonamide (C)
The title compound was synthesized as described above and
obtained as white solid powder, yield 24%, 1H NMR (DMSO–d6,
500 MHz): δ10.01 (s, 1H, NH), 9.84 (s, 1H, NH), 9.51 (s, 1H, NH),
7.87 (d, 2H, J = 8), 7.44 (d, 2H, J = 8), 7.37(d, 2H, J = 8.5), 6.91 (d,
2H, J = 9), 3.73 (s, 3H, OCH3), 2.41 (s, 3H, CH3); 13C NMR (DMSO–
d6, 126 MHz): δ 156.25, 152.31, 151.01, 150.07, 144.64, 137.07,
130.73, 129.99, 128.18, 121.99, 114.57, 55.69, 21.53; MS (ESI): m/z
calculated: 407.1020 [M + H]+ and observed: 407.1027 [M + H]+.
2. Experimental section
2.1. Materials and methods
2.3. General procedure for the synthesis of sulfonyldiurea (B)
Chemicals were procured from Sigma Aldrich or Merck or Alfa
Aesar. Solvents were obtained from Merck Chemicals or SDFCL or
FINAR and were used without further purification. Nuclear mag-
A
mixture of sulfonyl isocyanate (1.5 mmol) and N-
monosubstituted urea (1 mmol) was taken in a dry round bottom
flask and refluxed at 100 °C for 60 min. The progress of the
2

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Table 1
X-ray diffraction data collection, refinement and structure solution details for compound A, B and C.
Data collection parameters
Compound A
30H32N4O8S2
Compound B
Compound C
Chemical formula
C
C16H17N3O5S
C17H18N4O6S
Molecular weight
640.72
363.38
406.41
Crystal system, space group
Temperature (K)
Triclinic, P-1
Orthorhombic, Pbca
Monoclinic, P21
273
293
273
˚
a, b, c (A)
9.7390 (14), 9.8883 (14), 16.541 (3)
10.208 (2), 15.865 (3), 21.164 (4)
5.177 (2), 30.656 (12), 5.909 (2)
α, β, γ (°)
96.557 (5), 90.077 (4), 100.361 (4)
90, 90, 90
90, 101.73 (2), 90
918.2 (6)
3
˚
V (A )
1556.3 (4)
2
3427.5 (11)
8
Z
2
Radiation type
Mo Kα
Mo Kα
Mo Kα
μ (mm−1)
0.23
0.22
0.22
Crystal size (mm)
Diffractometer
0.20 × 0.10 × 0.10
Bruker D8-Quest
19,961, 7826, 3771
0.28 × 0.06 × 0.03
Bruker D8-Quest
19,801, 4385, 2529
0.26 × 0.18 × 0.03
Bruker D8-Quest
8876, 6138, 4683
No. of measured, independent and
observed [I > 2σ(I)] reflections
Rint
0.064
0.091
0.028
−1
˚
(sin θ/λ)max (A
)
0.673
0.675
0.781
R[F2 > 2σ(F2)], wR(F2), S
0.061, 0.207, 0.97
7826
0.073, 0.184, 1.06
4385
0.045, 0.146, 0.88
6138
No. of reflections
No. of parameters
401
236
267
−3
˚
ꢀρmax, ꢀρmin (e A
)
0.45, −0.39
2,026,187
0.20, −0.30
2,026,188
0.19, −0.25
2,026,189
CCDC
Table 2
˚
Hydrogen-bond geometry (A, °) in compound A, B and C.
Compound A
˚
˚
A(A)
˚
•••
•••
•••
•••
A(°)
D—H
A
D—H (A)
H
D
A (A)
D—H
•••
•••
N1—H1
N2—H2
O2A
O3A
0.86
0.86
0.86
0.86
0.93
1.97
2.08
2.05
2.08
2.64
2.826 (3)
2.910 (3)
2.867 (3)
2.865 (3)
3.286 (4)
170.5
161.8
158.9
151.9
126.8
i
•••
N1A—H1A
O2
•••
i
N2A—H2AB
C2A-H2AA…O1ii
O3
Symmetry codes: (i) x − 1, y, z ii) 1-x, 1-y, -z [Symmetry codes are taken from Res file after commanding HTAB in SHELX].
Compound B
˚
˚
˚
•••
•••
•••
•••
D—H A(°)
D—H
A
D—H (A)
H
A (A)
D
A (A)
•••
•••
•••
•••
N1—H1
N2—H2
N3—H4
N3—H4
O4
O2
O2
O3
0.73 (3)
0.86
1.97 (3)
2.09
2.568 (4)
2.921 (3)
3.315 (4)
3.116 (4)
139 (3)
i
i
i
161.7
0.81 (4)
0.81 (4)
2.50 (3)
2.40 (4)
136 (3)
149 (3)
Symmetry codes: (i) x + 1/2, −y + 1/2, −z + 1
Compound C
˚
˚
˚
•••
•••
•••
•••
D—H A(°)
D—H
A
D—H (A)
H
A (A)
D
A (A)
i
•••
•••
•••
N5—H1
N3—H4
N3—H4
O2
O3
O4
0.87 (5)
0.85 (4)
0.85 (4)
0.86
2.08 (5)
2.00 (4)
2.62 (4)
2.63
2.927 (4)
2.694 (3)
3.184 (4)
3.177 (4)
3.067 (4)
2.624 (4)
3.180 (4)
3.165 (5)
165 (5)
138 (3)
125 (3)
122.5
ii
i
•••
•••
N4—H4A
O3
O5
iii
N4—H4A
0.86
2.35
141.5
•••
N2—H5
N2—H5
C16—H16
O4
0.91 (6)
0.91 (6)
0.93
1.90 (6)
2.58 (5)
2.34
135 (5)
124 (4)
147.2
i
•••
O5
iv
•••
O4
Symmetry codes: (i) x + 1, y, z; (ii) x − 1, y, z; (iii) x + 1, y, z + 1; (iv) x − 1, y, z − 1.
reaction was monitored using TLC. After completion of reaction,
the reaction mixture was allowed to cool to room temperature
and resulting white solid residue was further purified by flash
chromatography to afford desired compound B.
2.4. Crystallization condition
We used slow solvent evaporation method to harvest all the
crystals at room temperature. Each compound was dissolved in
minimum amount of acetone followed by addition of a suitable
amount of hexane before allowing for solvent evaporation in a
dust-free environment. Good quality crystals were subjected to
single-crystal X-ray diffraction analysis (Tables 1 and 2).
N-(((4-methoxyphenyl)carbamoyl)carbamoyl)−4-
methylbenzenesulfonamide (B)
The title compound was synthesized as described above and
obtained as white solid powder, yield 72%, 1H NMR (DMSO–d6,
500 MHz): δ 9.30 (s, 1H, NH), 9.20 (s, 1H, NH), 7.88 (d, 2H, J = 8.5),
7.46 (d, 2H, J = 8), 7.34(d, 2H, J = 9), 6.89 (d, 2H, J = 9), 3.73 (s, 3H,
OCH3), 2.42 (s, 3H, CH3); 13C NMR (DMSO–d6, 126 MHz): δ 156.27,
151.63, 150.46, 144.89, 136.77, 130.62, 130.13, 128.14, 122.16, 114.53,
55.69, 21.56; MS (ESI): m/z calculated: 364.0962 [M + H]+ and ob-
served: 364.0957 [M + H]+.
2.5. SCXRD data collection, structure solution and refinement
Suitable crystals were picked for data collection. The details
of data collection and structure refinement are summarized in
Tables 1 and 2. Single crystal X-ray diffraction data for the good
3

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Scheme 1. General synthetic scheme for the synthesis of sulfonylurea and sulfonyltriurea (A) and Sulfonyldiurea (B).
quality crystals were recorded on a Bruker D8-Quest diffractometer
3. Results and discussion
˚
with a PHOTON detector equipped with a Mo Kα (ʎ = 0.71073 A)
source. The atomic structure was solved by direct methods with
SHELXS-97 and refined by the full matrix least square meth-
ods on F2 utilizing the SHELXL-2014. All the non-hydrogen atoms
were refined anisotropically. All hydrogens were placed in geo-
metrically idealized positions and constructed to ride on their
3.1. Chemical synthesis
Sulfonylurea and sulfonyltriurea were synthesized according to
reported method [30] from commercially available sulfonyl chlo-
ride and amines at room temperature (Scheme 1, A). Sulfonyldiurea
was synthesized from corresponding N-monosubstituted urea and
p-Toluenesulfonyl isocyanate at 100 °C (Scheme 1, B).
˚
˚
–
–
parent N or C atoms, with N H = 0.86 A, C H = 0.93 A and
Uiso(H) = 1.2 Ueq(N,C), for the aromatic and amine hydrogens,
˚
– –
and with C C H = 0.96 A and Uiso(H) = 1.5 Ueq(C) for methyl
H atoms. Bruker SHELXTL was used to generate molecular graphics
and Mercury CSD 4.0.0 was used to generate packing diagrams.
3.2. Crystal structure and molecular packing
Molecular structure of N-((4-methoxyphenyl)carbamoyl)−4-
methylbenzenesulfonamide (A)
Sulfonylureas are known to readily self-assemble to homod-
2.6. Hirshfeld surface and 2D fingerprint plot analysis
imers.
A “head to-head” hydrogen bonding pattern of diaryl
sulfonylurea molecule has been reported by Kim and cowork-
ers [41]. They observed that “head to-head” pattern of sulfony-
lurea affords a better crystal packing based on suitable π-π in-
teractions and steric effects. We observed a similar pattern of
“head to-head” arrangement of sulfonylurea-A. Thirunahari and
coworkers have reported crystal polymorphism of the anti-diabetic
drug Tolbutamide (TB) [42]. They have observed that TB crys-
tallizes in four polymorphic forms, which differ in their mode
of packing and in molecular conformation. However, they ex-
hibit a similar hydrogen bonding synthon namely the urea tape
motif. The crystal structure of A was solved and refined in tri-
clinic space group P −1. ORTEP diagram for compound-A with
the atom labelling is shown in Fig. 2. The asymmetric unit
of N-((4-methoxyphenyl)carbamoyl)−4-methylbenzenesulfonamide
(compound-A) contains two independent molecules (molecule 1
The molecular packing of aryl sulfonylurea oligomers was stud-
ied by employing the Hirshfeld surface (HS) and 2D Fingerprint
plot analysis using Crystal Explorer 3.1 software [38, 39]. The crys-
tallographic information (CIF) files were used as input file to gener-
ate Hirshfeld surfaces. The HS was mapped over curvedness, shape
index, and dnorm were studied for all three compounds [40]. On
dnorm surface was mapped using red-white-blue colour scheme:
Where red, white, blue regions represent closer, exactly equal and
longer contacts than the sum of van der Waals radii. Shape index
and curvedness were generated to examine π… π interactions in
the three derivatives. 2D fingerprint plots were used to represent
the relative contribution of each contact towards overall crystal
packing.
–
and 1A) connected via a pair of N H…O hydrogen bonds (graphs
set notation: R22(10)). Compound-A exists in l- conformation,
where the 4-methoxy phenyl ring is in parallel orientation with
torsional angle of −179.5° (C8-N2-C7-N1) with respect to sulfony-
lurea motif while the 4-methyl phenyl group is in perpendicular
orientation 60.9° (C1-S1-N1-C7) with respect to sulfonylurea motif.
The sulfonylurea motif in molecule 1 and 1A was found to be in
planar conformation with torsional angles of −174.6° (S1-N1-C7-
N2) and 175.4°(S002-N1A-C7A-N2A) respectively.
2.7. Molecular docking studies
Crystal structure of prolyl-tRNA synthetase from plasmodium
falciparum in complex with glyburide (PDB ID: 5IFU) was ac-
quired from the Protein Data Bank (PDB, https://www.rcsb.org/).
The prolyl-tRNA synthetase enzyme was prepared and mini-
mized using the protein preparation wizard tool of Glide software
(Schrödinger, LLC, New York, NY, USA) applying OPLS- 2005 force
field. Molecule Builder tool of Maestro 9.8 was used to prepare
designed molecules and glyburide, then all the ligands were min-
imized using LigPrep module of Schrödinger suite applying force
field OPLS-2005. Finally, we carried out Glide extra precision (XP)
docking of sulfonylurea oligomer derivatives into the active site of
the enzyme prolyl-tRNA synthetase. Standard parameters and pro-
tocol as included in Glide was followed during protein and ligand
preparation and docking studies.
The molecular packing in compound A is primarily stabilized by
–
intermolecular N H…O hydrogen bonds involving the sulfonylurea
motif (Fig. 3). These interactions extended along a single direction
forming a 1D framework. Further, crystal packing is also stabilized
by weak C3-H3…O1A and C2A-H2AA…O1 hydrogen bonding in-
teractions between 4-methyl phenyl ring and sulfonyl oxygen of
neighbouring molecule. These interactions extended along ac plane
and contributing in formation of the 2D framework in compound
A.
4

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Fig. 4. ORTEP diagram of compound-B with displacement ellipsoids drawn at the
50% probability. Intramolecular hydrogen bonding is represented as dotted lines
(graph set representation of intramolecular hydrogen bonding: S11(6)).
and N3-H4…O2 intermolecular hydrogen bonding (graph set
representation of intermolecular hydrogen bonding: R21(6)) be-
tween sulfonyl oxygen and sulfonyldiurea motif from neighbouring
molecule (Fig. 5).
Fig. 2. ORTEP diagram of compound-A with displacement ellipsoids drawn at the
N-((((4-methoxyphenyl)carbamoyl)carbamoyl)carbamoyl)−4-
methylbenzenesulfonamide (C)
50% probability. Hydrogen bonding is represented as dotted lines.
The crystal structure of sulfonyltriurea (C) was solved and
refined in monoclinic space group P21. ORTEP diagram for
compound-C with the atom labelling is shown in Fig. 6. Compound
C exists in l- conformation, where 4-methoxy phenyl ring is in a
parallel orientation with torsional angle of −172.2° (C13-N2-C12-
N3) with respect to sulfonylurea motif and 4-methyl phenyl group
is in perpendicular orientation 63.0° (C1-S1-N5-C10) with respect
to the sulfonylurea motif. Compound C forms one intramolecular
N-(((4-methoxyphenyl)carbamoyl)carbamoyl)−4-
methylbenzenesulfonamide (B)
The crystal structure of sulfonyldiurea (B) was solved and re-
fined in orthorhombic space group Pbca. ORTEP diagram for the
compound-B with the atom labelling is shown in Fig. 4. The asym-
metric unit of compound-B contains one molecule. Compound B
exits in l-conformation where 4-methoxy phenyl ring is in a par-
allel orientation with torsional angle of −175.8° (C10-N3-C8-N2)
with respect to sulfonyldiurea motif while the 4-methyl phenyl
ring is in orientation −63.2° (C1-S1-N1-C7) with respect to sul-
fonyldiurea motif. Compound-B forms one intramolecular hydrogen
–
hydrogen bonding through N H…O interaction (graphs set nota-
tion: S11(6)).
Compound-C is also stabilized primarily by intermolecular
–
N H…O hydrogen bonding involving sulfonyltriurea motif. A pair
bond through the N H…O route (graphs set notation: S11(6)).
of intramolecular hydrogen-bonding motif through N3-H4…O3
(graph set representation of intramolecular hydrogen bonding:
S11(6)) and N2-H5…O4 interactions (graph set representation of
intramolecular hydrogen bonding: S11(6)) plays a crucial role in
inducing planarity in sulfonyltriurea. We also observed six mem-
bered hydrogen-bonding ring motifs through N3-H4…O4 and N4-
H4A…O3 (graph set representations of intermolecular hydrogen
–
The molecular packing in compound-B is mainly stabilized
–
by intermolecular N H…O hydrogen bonds involving the sul-
fonyldiurea motif. We observed a six membered ring motif stabi-
lized through N1-H1…O4 intramolecular hydrogen bonds (graph
set representation of intramolecular hydrogen bonding: S11(6)).
Another six membered motif was observed through N2-H2…O2
–
–
Fig. 3. Crystal packing diagram of compound-A, viewed down along crystallographic ‘b’ axis. N H…O and C H…O interactions are highlighted as dotted line with atom
labelling.
5

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
˚
somewhat shorter than typical C-S single bond length (C-S: 1.82 A)
[43]. The S-N bond lengths in sulfonylurea (S1-N1), sulfonyldiurea
(S1-N1) and sulfonyltriurea (S1-N5) are 1.646 (3), 1.631(3), 1.666
(3) respectively. The S-O bond lengths in sulfonylurea (S1-O1 and
S1-O2), sulfonyldiurea (S1-O1 and S1-O2) and sulfonyltriurea (S1-
O1 and S1-O2) are 1.422 (2) and 1.426 (2), 1.426 (2) and 1.425
–
(2), 1.418 (3) and 1.437 (2) respectively. The C O bond length in
–
sulfonylurea (C7-O3) is 1.225 (4). The C O bond lengths in sul-
fonyldiurea (C7-O3 and C8-O4) are 1.212 (4) and 1.224 (4) respec-
–
tively. The C O bond lengths in sulfonyltriurea (C10-O3, C11-O4
and C12-O5) are 1.215 (3), 1.228 (4), 1.217 (4) respectively.
3.3. Hirshfeld surface and fingerprint plot analysis
Hirshfeld surface was generated for three compounds and en-
abled scrutiny of various intermolecular contacts in crystal packing
(Fig. 8). The dnorm, shape index and curvedness were mapped in
the range of −0.602 to −1.590, −1.00 to 1.00, and −4.00 to 0.40,
respectively, for all the compounds. Deep red spots on the dnorm
–
surface of A, B and C indicates the prominent feature of N H…O
˚
(1.97–2.08 A) intermolecular interaction integral to the sulfony-
Fig. 5. Crystal packing diagram of compound-B, viewed down along crystallo-
lurea motif.
graphic ‘a’ axis.
–
In compound C, apart from N H…O interactions, additional
–
weak C H…O interaction on the dnorm surface was also visualized
as light red spots. Further, to understand the effect of number of
urea motif on π…π interaction, we examined the shape index and
curvedness of sulfonylurea oligomeric products. The shape index
of compound A and B showed no sign of complementary blue and
red triangles on the Hirshfeld surface, confirming the absence of
π…π (C…C) interactions in these two derivatives. Interestingly, in
sulfonyltriurea, shape index showed complementary blue and red
spots over urea and aryl groups. Further, curvedness of compound
C showed flat region in the same area, confirming the presence of
weak π…π stacking.
Additionally, two-dimensional (2D) fingerprint plots were gen-
erated using de versus di values from Hirshfeld surface (Fig. 9).
It is understood that H…H, O…H, and C…H, contacts are play-
ing prominent role in molecular packing [44-48]. The O…H/H…O
contact are represented as a pair of sharp spikes with minimum
Fig. 6. ORTEP diagram of compound-C with displacement ellipsoids drawn at the
50% probability. Intramolecular hydrogen bonding is represented as dotted lines
(graph set representation of intramolecular hydrogen bonding: S11(6)).
bonding: R22(10) and R22(6) respectively) interactions between
two neighboring sulfonyltriurea units.
˚
di + de values of ≈ 1.95 A in sulfonylurea oligomers (A, B and C).
Further, crystal packing is stabilized by C16-H16…O4 hydrogen
bonds between 4-methoxy phenyl ring and the carbonyl oxygen of
sulfonyltriurea from the neighboring molecule (Fig. 7). These in-
teractions extended along bc plane giving 2D hydrogen bonding
framework.
This confirms the presence of strong O…H/H…O hydrogen bonding
in sulfonylurea oligomeric products.
Further, C…H/H…C interactions appear as chicken wing-shaped
˚
structure with minimum di + de values of ≈ 2.85, 3.15 and 2.95 A
in A, B and C respectively, have its place to weak and medium
hydrogen bonding. The relative contribution of O…H, N…H, and
C…H, interactions in sulfonylurea derivatives were also studied
from 2D intercontacts.
The C-S bond lengths in sulfonylurea (C1-S1), sulfonyldiurea
(C1-S1) and sulfonyltriurea (C1-S1) are 1.763 (3), 1.748 (3), and
˚
1.760 (4) A respectively, which indicates that C-S bond lengths are
–
–
Fig. 7. a) Crystal packing diagram of compound-C, viewed down along crystallographic ‘a’ axis; b) highlighting C H…O and N H…O interactions.
6

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Fig. 8. Hirshfeld surface of sulfonylurea oligomers (compound A, B and C) mapped over dnorm, shape index and curvedness.
Fig. 9. 2D fingerprint plots for the compound A, B and C.
Fig. 10. Relative contribution of all non-covalent interaction in crystal packing of compound A, B and C.
Due to its dimeric nature, compound A showed a slightly higher
Further, compound B has maximum C…C contact contribution
of 4.1% followed by 2.7% and 1.8% for compound A and C, respec-
tively. On the other hand, compound C showed a higher percentage
of C…O contact (4.3%) as compared to compound A and B having
lower contributions of the similar contacts 1.5% and 3.1%, respec-
tively. Comparable N…H contacts of 2.3%, 2% and 1.9% were ob-
served for compounds A, B and C, respectively.
percentage of H…H (40.5%) contacts when compared to compound
B (40%) and C (37.8%) (Fig. 10). Compound A also showed a higher
percentage of C…H contact (23.1%) as compared to compounds
B and C having lower contributions of the similar contacts 14.9%
and 16.9%, respectively. On the other hand, compound B showed a
greater percentage of O…H contact (32.3%) as compared to com-
pound A and C having lower contributions of the similar contacts
29.7% and 30.3%, respectively.
7

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Table 3
Docking scores of sulfonylurea-oligomer compounds.
Sulfonylurea Oligomers
Design
R/R1
SU
SDU
STU
1
CH3/H
−8.1
−7.8
−7.4
−6.8
−8.3
−8.1
−7.6
−7.0
−7.1
−9.0
−9.0
−8.6
−7.8
7.9
−8.2
−8.2
−7.6
−6.6
−8.3
−8.6
−7.4
−7.9
−7.2
−8.6
−9.7
−9.5
2
CH3/CH3
CH3/Isopropyl
CH3/Tertbutyl
CH3/CF3
CH3/F
−7.4
−5.6
−6.5
−7.8
−9.0
−7.6
−7.1
−7.1
−8.6
−9.2
−9.1
3
4
5
6
7
CH3/Cl
8
CH3/Br
9
CH3/OCH3
t-butyl/CF3
CF3/CF3
10
11
12
CF3/F
Glyburide
Fig. 11. 2D binding interactions of design compound 6 (A) Sulfonylurea (SU), (B) Sulfonyldiurea (SDU), (C) Sulfonyltriurea (STU) and (D) glyburide. Hydrogen bonding inter-
actions are shown as purple coloured dotted arrows.
3.4. Molecular docking
respectively. Molecules A, B and C formed similar pattern of hy-
drogen bonding interactions with important amino acid residues
such as Glu404, Tyr266, Arg514 and Thr402. These compounds also
shared most of the important residues that glyburide shared in
the allosteric site of Pf prolyl-tRNA synthetase. The docking scores
of A, B and C with Pfprolyl-tRNA synthetase are similar with one
another and to the glyburide. Interestingly, substitution patterns
on the sulfonylurea oligomeric compounds clearly influences their
binding with the enzyme. In particular, the docking scores of sul-
fonyltriureas of two designs 11 and 12 appear quite promising for
their potential inhibitory activity. Our in silico studies suggest that
sulfonylurea oligomers can be explored for the optimization and
development of potential lead candidates against Plasmodium falci-
parum (Pf) prolyl-tRNA synthetase.
The binding interactions and binding affinity of sulfonylurea
oligomers towards prolyl-tRNA synthetase were evaluated by in
silico molecular docking studies. One of the well-known sulfony-
lurea molecules, glyburide motivated us to screen sulfonylurea
oligomer compounds against prolyl-tRNA synthetase through in sil-
ico studies. Glyburide has been reported to be absent from the
enzyme active site and instead preferring to bind at allosteric
–
–
site of prolyl-tRNA synthetase [31]. The urea unit (-NH CO NH)
of glyburide was observed to form hydrogen bonds to Glu404
and Tyr266. It formed hydrophobic interactions with surrounding
residues Tyr266, Arg514, Tyr746, Ser263, and Asn470. The sulfox-
ide group (-SO2-) of glyburide molecule was found to form a weak
hydrogen bond with Arg514. Glide docking scores of selected com-
pounds are represented in Table 3. The molecules used comprise
substitutions at two phenyl rings that are mainly responsible for
their inhibitory activity. 2D binding interactions and 3D binding
poses of sulfonylurea oligomeric compounds in the active site of
Pf prolyl-tRNA synthetase are shown in figure Fig. 11 and Fig 12
3.5. Conclusions
In summary, sulfonylurea, sulfonyldiurea and sulfonyltriurea
derivatives have been successfully synthesized and characterized
using spectroscopic methods and SCXRD. Our study identifies that
8

A.D. Mahapatra, A. Shaik, V. Thiruvenkatam et al.
Journal of Molecular Structure 1233 (2021) 130158
Fig. 12. Superimposed binding poses of designed compounds 9 (A) and 5 (B). Hydrogen bonding interactions are shown in dotted red lines. Sulfonylurea, sulfonyldiurea,
sulfonyltriurea and glyburide molecules are represented in red, plum, orange and green colours respectively. Amino acid residues and compounds are shown in stick and,
ball and stick representations respectively.
compound A crystallizes as the Triclinic with space group P −1,
compound B crystallizes as Orthorhombic, with space group P bca
and compound C crystallizes as the Monoclinic, with space group
P 21. Asymmetric unit of compound A contains two independent
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130158.
–
molecules (molecule 1 and 1a) connected via pair of N H…O hy-
drogen bonds (graphs set notation: R22(10)). On the other hand,
the asymmetric unit of compound B and C contains one molecule.
–
Compound B and C are stabilized by intramolecular N H…O and
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