X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak non-covalent interactions, chemotherapeutic activities and QM/MM binding energy

Article abstract of DOI:10.1080/07391102.2020.1840443

A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with a known closely related structure has been performed to delineate the effect of halogen substituents and the role of weak intermolecular interactions in

Full text of DOI:10.1080/07391102.2020.1840443

Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
X-ray and theoretical investigation of (Z)-3-
(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-
(4-bromobenzyl)isothioureas: an exploration
involving weak non-covalent interactions,
chemotherapeutic activities and QM/MM binding
energy
Fatmah A. M. Al-Omary , Nikhila Chowdary Gude , Lamees S. Al-Rasheed ,
Hamad N. Alkahtani , Hanan M. Hassan , Ebtehal S. Al-Abdullah , Ali A. El-
Emam , M. Judith Percino & Subbiah Thamotharan
To cite this article: Fatmah A. M. Al-Omary , Nikhila Chowdary Gude , Lamees S. Al-Rasheed ,
Hamad N. Alkahtani , Hanan M. Hassan , Ebtehal S. Al-Abdullah , Ali A. El-Emam , M. Judith
Percino & Subbiah Thamotharan (2020): X-ray and theoretical investigation of (Z)-3-(adamantan-1-
yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak
non-covalent interactions, chemotherapeutic activities and QM/MM binding energy, Journal of
Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2020.1840443
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2020.1840443
X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-
chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak
non-covalent interactions, chemotherapeutic activities and QM/MM
binding energy
Fatmah A. M. Al-Omarya, Nikhila Chowdary Gudeb, Lamees S. Al-Rasheeda, Hamad N. Alkahtania, Hanan M.
Hassanc, Ebtehal S. Al-Abdullaha, Ali A. El-Emamd, M. Judith Percinoe and Subbiah Thamotharanb
b
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Biomolecular Crystallography
Laboratory, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, India;
cDepartment of Pharmacology and Biochemistry, College of Pharmacy, Delta University for Science and Technology, Mansoura, Dakahliya,
d
e
ꢀ
Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Unidad de Polımeros y
ꢀ
ꢀ
ꢀ
ꢀ
Electronica Organica, Instituto de Ciencias, Benemerita Universidad Autonoma de Puebla, San Pedro Zacachimalpa, Puebla-C.P, Mexico
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
Received 24 July 2020
Accepted 18 October 2020
A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with
a known closely related structure has been performed to delineate the effect of halogen substituents
and the role of weak intermolecular interactions in their supramolecular architectures. The adaman-
tane-isothiourea hybrid derivatives used in the present study are (Z)-3-(Adamantan-1-yl)-S-(4-bromo-
benzyl)-1-phenylisothiourea (1), C24H27BrN2S and (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-(3-
chlorophenyl)isothiourea (2), C24H26BrClN2S, characterized by X-ray crystallography. The X-ray struc-
tures revealed that the molecular conformation of 1 and 2 are different and stabilized by intramolecu-
lar C–HꢀꢀꢀN interactions. In addition, a short intramolecular HꢀꢀꢀH contact is formed in 2. The Hirshfeld
surface analysis was used to delineate the nature of different intermolecular interactions and their con-
tributions toward crystal packing. The quantitative analysis of strengths of molecular dimers existed in
1 and 2 has been performed using the PIXEL method. The electrostatic potential map clearly revealed
nature and strength of r-holes at Br and Cl atoms. The topological analysis was used to characterize
the nature and the strength of various intermolecular interactions including the type I BrꢀꢀꢀBr contact.
Interestingly, all the H–H bonding observed in 1 and 2 show closed-shell in nature. Further, an in-vitro
antimicrobial activity studies suggest that the title compounds exhibited potent antibacterial activity
against all the tested Gram-positive bacterial strains and Gram-negative Escherichia coli. Compound 2
showed marked anti-proliferative activity against MCF-7 and HeLa cell lines.
KEYWORDS
Adamantane; isothiourea;
sphingosine kinase 1
inhibitor; PIXEL; QTAIM;
QM/MM; difference
fingerprint plot
1. Introduction
et al., 2005). Antitumor activity was reported for some ada-
mantane derivatives. The synthetic retinoid CD437 was discov-
ered as a potent inducer of apoptosis in human head and neck
squamous cell carcinoma (Sun et al., 2002), and the adaman-
tane-based anticancer drug Opaganib (ABC294640) was
recently approved for the treatment of patients with advanced
solid tumors (Britten et al., 2017). In addition, several adaman-
tane-based derivatives were recognized as potent bactericidal
(Al-Abdullah et al., 2014; El-Emam et al., 2013; Kadi et al.,
2010), fungicidal (Omar et al., 2010) and anti-protozoal (Kaiser
et al., 2007; Kelly et al., 2001) agents.
The adamantyl cage is frequently found as a core scaffold in
several drugs (Guy & Graciela, 2010; Liu et al., 2011; Wanka
et al., 2013). The chemotherapeutic potency of adamantane
derivatives was early explored after the development of aman-
tadine (Davies et al., 1964; Wendel et al., 1966) and rimanta-
dine (Wingfield et al., 1969) as effective therapies against
Influenza A viral infections. Tromantadine, an adamantane-
based analogue was further developed as antiviral drug for
the treatment of skin infection caused by herpes simplex virus
(HSV) (Rosenthal et al., 1982). Various adamantane-based
derivatives were also reported to exhibit marked anti-HIV
activity (Balzarini et al., 2007; Burstein et al., 1999; El-Emam
et al., 2004). The adamantane-ethylenediamine derivative
SQ109 was approved as efficient therapy against drug-suscep-
On the other hand, thiourea and isothiourea derivatives
were proved to possess diverse chemotherapeutic activities
including antiviral (Ahgren et al., 1995; Kang et al., 2009;
Osmond & Fatih, 2006), anticancer (Hu et al., 2017; Huang
tible and drug-resistant Mycobacterium tuberculosis strains (Jia et al., 2016; Lain et al., 2008; Miroslawa et al., 2015), anti-
CONTACT Subbiah Thamotharan
thamu@scbt.sastra.edu
Biomolecular Crystallography Laboratory, Department of Bioinformatics, School of Chemical and
Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2020.1840443.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
F. A. M. AL-OMARY ET AL.
tuberculosis (Joshi et al., 2016) and antimalarial (Verlinden APEX-II CCDC diffractometer. The structures were solved by
et al., 2011) activities.
the direct methods using the SHELXS-2014 program
(Sheldrick 2015) and refined with full-matrix least-squares
minimization on F2 using SHELXL 2018/3 (Sheldrick 2015).
The structure solution and refinement were conducted with
the WinGX suite (Farrugia, 2012) using shelx program. All the
non-hydrogen atoms were refined anisotropically. The pres-
ence of amine H atoms was confirmed from difference
Fourier maps. Further, all the H atoms were placed in calcu-
lated geometrical positions with C–H ¼ 0.93–0.98 Å and
N–H ¼ 0.86 Å and Uiso(H)¼1.2Ueq(C). The crystal packing dia-
grams were drawn using the program Mercury 3.8 (Macrae
et al., 2008).
In view of the previously reported observations and as a
continuation of an ongoing researches on the structural and
biological properties of adamantane-based derivatives (Al-
Wahaibi et al. 2018; El-Emam et al., 2020), we report herein
the synthesis, preliminary antimicrobial and anti-proliferative
activities of two adamantane-linked isothiourea derivatives. A
closely related reported structure of (Z)-3-(adamantan-1-yl)-1-
(3-chlorophenyl)-S-benzylisothiourea has also been included
to understand the role of halogen substituents on the con-
formation and crystal packing. Various theoretical tools
including Hirshfeld surface, Bader’s quantum theory of
atoms-in-molecules (QTAIM), molecular electrostatic potential
and energy frameworks have been used to primarily analyze
the nature and the strength of weak non-covalent interac-
tions and their roles in the solid state structures of the title
compounds. We also demonstrate the in vitro antimicrobial
activity of the title compounds against selective Gram-posi-
tive and Gram-negative bacterial pathogenic strains and an
important fungal pathogen Candida albicans. Further, the
in vitro anti-proliferative activity of the title compounds was
assessed against five different human tumor cell lines and
activities were compared with anticancer drug Doxorubicin.
To corroborate the anti-proliferative activity, we also present
the molecular docking analysis to see the binding potential
of the title compounds against sphingosine kinase 1 (SPHK1)
target. This target is well known for cancer and inflammatory
diseases (Kunkel et al., 2013).
2.3. Hirshfeld surface analysis
The Hirshfeld surfaces and their associated 2 D fingerprint
plots were produced using CrystalExplorer-17.5 program
(Turner et al., 2017). The difference fingerprint plots were
obtained for different pairs of structures 1–3 as outlined in
the literature (Carter et al., 2017).The energy frameworks for
structures 1–3 were constructed with B3LYP/6-31G(d,p) level
of theory (Mackenzie et al., 2017).
2.4. PIXEL energy analysis
Final refined coordinates of 1 and 2 were used after normal-
izing the distances involving H atoms. These distances were
moved to typical neutron diffraction values (C–H ¼ 1.083 Å
and N–H ¼ 1.009 Å). The PIXELC code (Gavezzotti, 2002, 2003,
2005) within the Coulomb–London–Pauli (CLP) program
(Gavezzotti, 2011) was used to calculate the lattice energies
for crystal structures and intermolecular interaction energies
for dimers. The single point energy calculation was per-
formed to obtain the electron density of the monomers of 1
2. Materials and methods
2.1. Synthesis and crystallization
The adamantyl isothiourea derivatives 1 and 2 were synthe-
sized via condensation of 1-adamantylamine A with phenyl
isothiocyanate or 3-chlorophenyl isothiocyanate to yield the
corresponding 1-(adamantan-1-yl)-3-arylthiourea derivatives
B (Al-Wahaibi et al., 2016) and C (Al-Omary et al., 2017),
which were reacted with 4-bromobenzyl bromide in the
presence of potassium carbonate to yield the target com-
pounds 1 and 2 (Scheme 1).
ꢁꢁ
and 2 at MP2/6-31G level of theory using Gaussian09 pro-
gram (Frisch et al. 2013).
4-Bromobenzyl bromide (500 mg, 2.0 mmol) and anhyd-
rous potassium carbonate (277 mg, 2.0 mmol) were added to
a solution of compounds B or C (2.0 mmol), in acetone
(10 mL), and the mixture was heated under reflux with stir-
ring for 3 h. The solvent was then distilled off in vacuo and
the residue was washed with water, dried and crystallized
from ethanol to yield target compounds 1 or 2. Pure single
crystals for X-ray diffraction were obtained by slow evapor-
ation of a solution of compounds in EtOH/CHCl3 (1:1, v/v) at
room temperature. The 1H, 13C and ESI-MS data are pre-
sented in supplementary section.
2.5. Topological analysis of electron density
Various topological properties for intra and intermolecular
interactions in 1 and 2 at the bond critical points (BCPs)
were calculated at the crystal structure geometry with
M062X-D3/cc-pVTZ level of theory using AIMALL package
(Keith, 2019). The dissociation energies for non-covalent
interactions were calculated using EML empirical scoring
scheme (Espinosa et al., 1998). The closed-shell nature of
non-covalent interactions was assessed using the positive
ꢂVðrÞ
2
value of Laplacian of the electron density (r q(r) > 0), j
j
GðrÞ
< 1 and total electronic energy density H(r) > 0 (Gatti,
2005). Further, the hydrogen bonds were differentiated from
van der Waals interactions using Koch–Popelier rule 4 (KP-4
2.2. Single crystal X-ray diffraction (SCXRD) analysis
The X-ray intensity data were collected at room temperature
(293 K) for single crystals of compounds 1 and 2 on a Bruker rule) as mentioned earlier (Koch & Popelier, 1995).

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
Scheme 1. The synthetic pathway for compounds 1 and 2.
mechanical (MM) level with OPLS_2005 force field. This
hybrid QM/MM-PBSA energy minimization (without any con-
straints) was carried using the Qsite module (Murphy et al.,
2.6. Molecular electrostatic potential surface
map (MESP)
The wave functions were calculated for the normalized X-ray
geometries of 1 and 2 using the program Gaussian09 with
M062X-D3/cc-pVTZ level of theory. The molecular electro-
static potential surface map (MESP) was drawn using the
WFA-SAS program (Bulat et al., 2010).
€
2000) present in the Schrodinger suite 2019-4 as described
earlier (Sathya & Thamotharan, 2015). The binding energy of
the ligand was calculated by
Ebind ¼ Ecomplex–Ereceptor–Eligand
2.7. Molecular docking and hybrid QM/MM-PBSA
energy analysis
3. Results and discussion
In the present work, we explored the roles of different weak
non-covalent interactions in two adamantane-isothiourea
hybrid derivatives and the conformational variations of these
molecular derivatives due to halogenated phenyl substitu-
ents. The qualitative and quantitative analyses of non-cova-
lent interactions present in them are discussed in detail.
All the molecular docking simulation was performed with
€
€
Schrodinger suite 2019-4 (Schrodinger, LLC, New York, NY,
2019). The molecular docking analysis was carried out using
the 3 D structure of human sphingosine kinase 1 (SPHK1).
One of the subunits of SPHK1 was (PDB id: 4V24 and chain
A) used for molecular docking analysis. The missing residues
from the loop region were modelled with SWISS MODEL ser-
ver (Waterhouse et al., 2018). The resultant model was pre-
pared for docking analysis using protein prep wizard module
(Madhavi Sastry et al., 2013) in which bond order and add-
ition of H atoms were done followed by the energy mini-
mization using OPLS3e force field (Roos et al., 2019). The
location of the control inhibitor PF-543 (PDB Ligand ID: GYR)
was used to generate the receptor grid box. The control
inhibitor and the title compounds (1 and 2) and their closely
related structure 3 were prepared using ligprep module
using OPLS3e force field. Initially, the glide XP docking
(Friesner et al., 2006) was carried out for all the four mole-
cules including control inhibitor. Then, the predicted geom-
etry from the glide XP docking was subsequently used for
the QM/MM calculation. In the QM/MM calculation, the lig-
and molecules were treated at the quantum mechanical
3.1. Molecular and crystal structure
The molecular structures of 1 and 2 that differ with respect to
the chlorine substituent on C16 (ring A). In closely-related
reported structure namely (Z)-3-(adamantan-1-yl)-1-(3-chloro-
phenyl)-S-benzylisothiourea (3), the bromine substituent is
absent (El-Emam et al., 2017). The compound 1 crystallizes in
the triclinic P-1 space group with two crystallographically inde-
pendent molecules in the asymmetric unit. These two mole-
cules superimpose very well with the rmsd value of 0.11 Å. The
compound 2 crystallizes in the monoclinic C2/c space group
with one molecule in the asymmetric unit. The thermal ellips-
oidal plots of compounds 1 and 2 are illustrated in Figure 1.
Crystal data and refinement parameters for crystals 1 and 2
are presented in Table 1. The selected torsion angles which
describe the molecular conformation of 1 and 2 and its related
ꢁ
(QM) level with B3LYP/LACVP level of theory and the pro-
tein receptor molecule was treated at the molecular structure 3 are summarized in Table 2. From this table, we can

4
F. A. M. AL-OMARY ET AL.
Figure 1. Thermal ellipsoidal representation of (a) molecule of A (left) and molecule of B (right), (b) compound 2 and (c) structural superimposition diagram reveal
conformational change on the methylene phenyl group in molecule 2 (colour code: green (1- mol A), grey (1-mol B), orange (2) and purple (3).
Table 1. Crystal data and refinement parameters for compounds 1 and 2.
1
2
Crystal data
Chemical formula
Mr
C24H27BrN2S
455.44
Triclinic, P-1
293 (2)
11.2886(4), 13.2292(5), 15.3746(6)
78.724(2), 78.227(2), 73.034(1)
C24H26BrClN2S
489.89
Monoclinic, C2/c
293 (2)
33.5576(12), 10.1353(3), 13.7469(5)
90, 107.895(3), 90
Crystal system, space group
Temperature (K)
a, b, c (Å)
a, b, c (ꢃ)
V (Å3)
2127.11(14)
4449.3(3)
Z
4
4
Radiation type
Mo Ka (k ¼ 0.71073)
Cu Ka (k ¼ 1.54184)
m (mmꢂ1
)
2.04
4.59
qCalc (g cmꢂ3
)
1.422
0.41 ꢄ 0.31 ꢄ 0.23
1.463
0.39 ꢄ 0.21 ꢄ 0.15
Crystal size (mmꢂ3
Data collection
Diffractometer
)
Bruker APEX-II CCD diffractometer
Bruker APEX-II CCD diffractometer
Absorption correction
Tmin, Tmax
No. of measured, independent and observed [I > 2r (I)] reflections
Multi-scan
0.889, 0.907
55365, 16121, 9531
0.069
Multi-scan
0.821, 0.913
14968, 4066, 3191
0.049
Rint
(sin h/k)max (Åꢂ1
)
0.771
0.603
Refinement
R[F2 > 2r(F2)], wR(F2), S
Number of reflections
Number of parameters
H-atom treatment
Dqmax, Dqmin (e Å-3)
CCDC No.
0.050, 0.087, 1.00
16121
505
0.046, 0.127, 1.05
4066
262
H-atom parameters constrained
0.50, ꢂ0.63
H-atom parameters constrained
0.59, ꢂ0.54
1906757
1896968
see that the torsion angles s1–5 are comparable in 1 (if enantio- molecules (Figure 1(c)). Four fused six-membered rings consti-
merically related molecule A used) and 3. Another two torsion tute the adamantane moiety and the Cremer and Pople puck-
angles s4 and s5 which define the rotation of methylene phe- ering parameters (Cremer & Pople, 1975) indicates that each of
nyl moiety are different in molecule 2 compared to other these six-membered ring exhibits chair conformation as

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
Table 2. List of selected torsion angles for 1–3.
¼ 1.7–2.0 Å, which belongs to BrꢀꢀꢀBr contacts appeared
only in molecule A (i.e. positive) and the areas in blue beyond
de ¼ di ¼ 2.0 Å (i.e. negative) in molecule B. This feature
suggests that the BrꢀꢀꢀBr contacts only appear in molecule A
even though the contribution of these contacts are similar in
both molecules A and B.
Compound
s1
s2
s3
s4
s5
1-Mol A
1-Mol B
2
3
4.4 (1)
ꢂ2.6 (1)
ꢂ0.9 (1)
ꢂ7.6 (1)
ꢂ169.3 (1) ꢂ177.4 (1) ꢂ114.5 (1)
59.9 (1)
ꢂ57.5 (1)
ꢂ170.3 (1)
ꢂ62.6 (1)
171.5 (1)
175.4 (1)
171.3 (1)
178.3 (1)
179.1 (1)
174.5 (1)
113.5 (1)
10.6 (1)
104.9 (1)
The definition of torsion angles with respect to atomic numbering in 1 (mol-
ecule A): s1, C1A-N1A-C11-N2A; s2, N1A-C11A-N2A-C12A; s3, C1A-N1A-C11A-
S1A; s4, N1A-C11A-S1A-C18A; s5, C11A-S1A-C18A-C19A.
Introducing chlorine substituent on C16 atom (i.e. com-
pound 2) in compound 1, the relative contribution of two
inter-contacts (HꢀꢀꢀH and HꢀꢀꢀC) are significantly changed. The
former contact is reduced and contributes 49.7%, while the
contribution of the latter contact is increased and it is being
20.5% towards the crystal packing of 2 compared to 1. Due
to presence of Cl substituent, intermolecular HꢀꢀꢀCl contacts
appeared beyond deþdi ¼ 3.1 Å which is slightly longer (by
0.15 Å) than the sum of the vdW radii of H and Cl atoms.
Difference fingerprint plots of 1A-2 and 1B-2 pairs look simi-
lar (Figure 3). However, these plots highlight some interest-
ing features. For instance, the red areas in the shortest
distance regions correspond to intermolecular HꢀꢀꢀH contacts
which are intense in both molecules A and B of 1. Similarly,
the blue areas are more intense in 2 which are mostly associ-
ated with intermolecular HꢀꢀꢀC and BrꢀꢀꢀC contacts. This fea-
ture indicates that the halogen bond of the type BrꢀꢀꢀC is not
appeared. An intense red line located beyond (deþdi¼4.0 Å)
which also belongs to long range BrꢀꢀꢀBr contacts in molecule
B of 1 (1B-2 pair).
Removing bromine substituent on C22 atom (compound 3)
in compound 2, the relative contribution of various inter-con-
tacts appears to be very similar to that of compound 1. In
compound 3, intermolecular HꢀꢀꢀCl contact contributes 12.4%
which is comparable to its counterpart HꢀꢀꢀBr contacts
(10–10.6%) in 1. Through the relative contribution of different
intermolecular interactions are comparable, the difference fin-
gerprint plots clearly reveal the presence of HꢀꢀꢀCl and HꢀꢀꢀBr
contacts in 1 and 3. The intense blue areas around (de ¼ 1.1 Å
and di ¼ 1.7 Å) which correspond to HꢀꢀꢀCl contacts in 3,
observed in related adamantane structures (Al-Wahaibi et al.
2018; El-Emam et al., 2017; 2020).
In 1-3, the molecular conformation is found to be stabi-
lized with two intramolecular C–HꢀꢀꢀN (involving two protons
of adamantane and N2 of thiourea moiety) except in mol-
ecule 2 wherein only one intramolecular C–HꢀꢀꢀN interaction.
As mentioned earlier, the methylene phenyl group has differ-
ent conformation in 2 and this conformation is further stabi-
lized by a short intramolecular HꢀꢀꢀH contact with a distance
of 1.928 Å. The topological analysis confirms the existence of
intramolecular C–HꢀꢀꢀN interaction and the short HꢀꢀꢀH con-
tact in 2.
3.2. 2 D-fingerprint plots analysis
The intermolecular interactions in 1 and 2 and their closely
related structure 3 described qualitatively based on the
Hirshfeld surface (HS) and 2 D-fingerprint plots to demon-
strate the roles of halogen substituents. The red spots on the
HS show the short intermolecular contacts and these con-
tacts could be important for stabilization of the crystal struc-
tures. In molecule A of 1, three most prominent interactions
such as Br1AꢀꢀꢀBr1A short contact, C21A–H211ꢀꢀꢀS1B and
C18A–H181ꢀꢀꢀC17A show relatively intense red areas on the
HS compared to
a
pair of short H71ꢀꢀꢀH241 and
a
C24B–H242ꢀꢀꢀC19A contacts (Figure 2(a)). In molecule B of 1,
the C21A–H211ꢀꢀꢀS1B interaction displays intense red spot
compared to a short H52ꢀꢀꢀH102, C24B–H242ꢀꢀꢀC19A and another pairs of red spikes near to HꢀꢀꢀCl contact correspond
C23B –H 232ꢀꢀꢀS1A interactions (Figure 2(b)). In 2, small and to HꢀꢀꢀBr contacts which appear only in 1. Difference finger-
less intense red spots are seen for C8–H8ꢀꢀꢀBr1, print plots of 2–3 pair demonstrate existence of BrꢀꢀꢀC and
HꢀꢀꢀBr contacts (intense red areas) in 2 and intermolecular
HꢀꢀꢀH and HꢀꢀꢀCl contacts are more intense (blue areas) in 3.
C15–H15ꢀꢀꢀC23,
H5ꢀꢀꢀH8
and
C24ꢀꢀꢀC24
interactions
(Figure 2(c)).
2D-fingerprint plots were obtained to analyze the relative
contribution of different intermolecular interactions. In 1, the
relative contribution of different inter-contacts is comparable
for molecules A and B. The intermolecular HꢀꢀꢀH contacts
occupy the 2/3 (64.7 to 67.6%) of the total HS area and the
shortest distance of these contacts are located around 2.2 Å.
The next major contribution (13.4% in molecule A and 12.6%
in molecule B) comes from HꢀꢀꢀC contacts. The intermolecular
HꢀꢀꢀBr interactions offer 10 and 10.6% for molecules A and B
to the total HS area, respectively. It is to be noted that the
HꢀꢀꢀS contacts assist 6.4% to the molecule A and 4.5% to the
molecule B. The halogen bond (BrꢀꢀꢀC(p)) and homo halogens
contact (BrꢀꢀꢀBr) aid 2.4% and 1% for molecule A. The
corresponding values are 2.6% and 0.8% in molecule B.
The difference fingerprint plot for molecules A and B reveals
3.3. Molecular electrostatic potential surface
map (MESP)
From the MESP plot for molecule A of 1 (Figure 4(a)) we can
see that the most positive electrostatic potentials observed
on the surface of NH group (Vs,max ¼ 33.8 kcal molꢂ1), the
protons of the bromophenyl ring and methylene group
(Vs,max ¼ 20 kca molꢂ1). The protons of the phenyl group
show moderate positive electrostatic potentials as compared
to protons of the adamantane core. The most negative elec-
trostatic potentials observed for N2A (Vs,min ¼ 26.3 kcal
molꢂ1) and S1A (Vs,min ¼ ꢂ21.0 kcal molꢂ1). Interestingly, the
MESP plot also reveals the presence of r-hole at Br atom
with Vs,max ¼ 10.8 kcal molꢂ1 and a characteristic negative
an interesting difference between these two molecules belt around Br atom suggesting the anisotropic distribution
(Figure 3). The more intense red line located around de ¼ di of electron density around this atom. The negative belt of Br

6
F. A. M. AL-OMARY ET AL.
Figure 2. Hirshfeld surface is mapped over the normalized distance (dnorm) (a) two different views of molecule A of 1, (b) molecule B of 1 and (c) two different
views of molecule of 2. The red areas on the HS showing the short contacts observed in the crystal structures of 1 and 2.
atom acts an acceptors sites for the formation of HꢀꢀꢀBr inter- through M8AB; Figure 7) in the solid state. As can be seen
actions. Molecule B of 1 is also showing similar electrostatic from Table 3, some of the dimers formed by self-association
potential surface (Figure 4(b)). The structure of 2 shows simi- of molecules of A or molecules of B become more stronger
lar positive and negative electrostatic potentials as observed
than the dimers formed by molecules of A and B.
for 1 (Figure 4(c)). In contrast, the protons of the adaman-
The intermolecular interaction energies for the dimers
tane core have moderate positive electrostatic potentials formed by molecules of A ranging from ꢂ15.9 to ꢂ0.2 kcal
compared to 1. The chlorine shows weak positive electro- molꢂ1. Motif M1A stabilizes by intermolecular C–HꢀꢀꢀN hydro-
static potential with the Vs,max value of 0.03 kcal molꢂ1 and
gen bond, C–Brꢀꢀp halogen bond and a short HꢀꢀꢀH contact
this feature suggesting that the chlorine in 2 is less likely to
be participated in intermolecular interactions.
with the separation of 2.14 Å resulting in the formation of
compact dimeric motif. The inversion-related molecules of A
form the motif M2A stabilizes with a C–HꢀꢀꢀC(p) interaction
(involving H181 and C17A). A short HꢀꢀꢀH contact observed
between neighbouring adamantane moieties produces the
motif M3A. The dispersion energies are contributing more
towards the stabilization of these three dimers and the corre-
sponding energy component being in the range of 58-72%.
A short homo BrꢀꢀꢀBr contact stabilizes the dimer M4A. This
contact adopts type I trans geometry as described in the lit-
3.4. Molecular dimeric pairs in 1 and 2
The intermolecular interactions existing in dimeric pairs of 1
and 2 are summarized in Table 3 along with interaction ener-
gies for these dimers. Crystal packing 1 and 2 can be
described as columnar packing. In 2, adamantane moieties
are in close proximity.
In 1, there are two molecules in the asymmetric unit as erature (Al-Wahaibi et al., 2019).
As observed for molecule A, molecule B also produces
three self-associated dimers involving symmetry-related mol-
ecules of B (Figure 6). The intermolecular interaction energies
mentioned earlier. The dimeric motifs were identified separ-
ately for molecule A with its symmetry related partners
(motifs designated as M1A, M2A, M3A and M4A; Figure 5),
molecule
B
with its symmetry equivalent molecule for these dimers are ranging from ꢂ15.5 to ꢂ2.9 kcal molꢂ1
.
(motifs: M1B, M2B and M3B; Figure 6) and between molecule The dimer M1B is very similar to dimer M1A. However, the
A with symmetry-related molecules of B (Motifs: M1AB C–HꢀꢀꢀN, C–Brꢀꢀp halogen bond formed at longer distance as

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
Figure 3. Difference fingerprint plots (red areas are positive and blue areas are negative) for different pairs of compounds 1–3.
Figure 4. MESP plots of (a) molecule A of 1, (b) molecule B of 1 and (c) molecule of 2. Colour scales (in kcal molꢂ1): red: >15; yellow: <15 > 0; green: <0> ꢂ15;
blue: > ꢂ15.
compared to M1A. An extensive number of short HꢀꢀꢀH con- M2AB dimer stabilizes is very similar to that of M1AB dimer.
tacts which are responsible for the formation of M1B dimer. This M2AB dimer formed by C–HꢀꢀꢀS and short
The dimer M2B is generated by intermolecular C–HꢀꢀꢀC(p) Csp3–HꢀꢀꢀH–Csp3 and Nsp3–HꢀꢀꢀH–Csp2 contacts. The
interaction involving adamantane and phenyl rings. The M3B N–HꢀꢀꢀC(p) interaction is not established as in M1AB instead a
is also very similar to that of dimer M3A in which the adja- Nsp3–HꢀꢀꢀH–Csp2 contact formed. The stability of dimer
cent adamantane moieties are interconnected by the HꢀꢀꢀH M3AB is ꢅ three-fold weaker than the first two dimers (M1AB
contact. The HꢀꢀꢀH contact was established longer than the and M2AB) and stabilized by intermolecular C–HꢀꢀꢀC(p) and
sum of the vdW radii.
a short HꢀꢀꢀH contact. One of the protons of the adaman-
Molecules of A and B interact with each other in the solid tane core is acting as a donor for the intermolecular
state resulting in the formation of eight dimers (Figure 7). C–Hꢀꢀꢀp interaction (M4AB) with the p-hole (Cg2) of the bro-
The interaction energies for these dimers are ranging from mophenyl ring. The next two dimers (M5AB and M6AB) sta-
ꢂ11.9 to ꢂ2.1 kcal molꢂ1. All these dimers are substantially bilize with intermolecular C–HꢀꢀꢀBr interactions. In both
directed by dispersion energy component and the contribu- cases, the protons of the adamantane moiety involved as
tion of this energy being in the range 64–79% towards sta- donors. It is important to note that least stable dimers
bilization. The crystallographically independent molecules of (M7AB and M8AB
)
formed by short HꢀꢀꢀH contacts of
A and B in the asymmetric unit formed a stable dimer (M1AB
)
Csp2–HꢀꢀꢀH–Csp3 type.
and stabilized by C–HꢀꢀꢀS, N–HꢀꢀꢀC(p) and two short
The molecular dimers of 2 are primarily dispersive in
Csp3–HꢀꢀꢀH–Csp3 and Csp2–HꢀꢀꢀH–Csp2 contacts. The way nature with the dispersion energy component contributes

8
F. A. M. AL-OMARY ET AL.
Table 3. Geometrical parameters for intermolecular interactions exist in different dimers of 1 and 2 and the intermolecular interaction energies for these dimers
(in kcal molꢂ1).
Motif
CD
Symmetry operator
Important interactions
Geometry (Å, ꢃ) HꢀꢀꢀA//D-HꢀꢀꢀA
ECoul
Epol
Edisp
Erep
Etot
Compound 1
M1A
M2A
5.040
–x, –y þ 1, –z þ 1
C23A–H231ꢀꢀꢀN2A
C23A–H231ꢀꢀꢀC13A
C22A–Br1AꢀꢀꢀCg1
H241ꢀꢀꢀH71
2.63/156
2.86/119
3.991 (2)/98.01(1)
2.14
2.61/163
3.04/110
2.39
–6.0
–3.5
–24.0
17.6
–15.9
9.190
–x þ 1, –y þ 1, –z þ 1
C18A–H181ꢀꢀꢀC17A
C18A–H181ꢀꢀꢀS1A
H161ꢀꢀꢀH201
–6.9
–3.6
–14.5
16.3
–8.7
M3A
M4A
M1B
13.116
12.880
5.194
–x, –y þ 1, –z
–x, –y, –z
–x þ 1, –y, –z
H31ꢀꢀꢀH42
2.34
–1.2
–0.5
–4.6
–0.6
–0.4
–2.7
–4.7
–2.0
–22.1
4.0
2.7
13.9
–2.6
–0.2
–15.5
C22A–Br1AꢀꢀꢀBr1A–C22A
H103ꢀꢀꢀH142
3.488 (1)/169.2 (1)
2.34
2.34
H73ꢀꢀꢀH132
H74ꢀꢀꢀH202
2.34
C22B–Br1BꢀꢀꢀCg1
C4B–H43ꢀꢀꢀC15B
C10B–H104ꢀꢀꢀH82
C21A–H211ꢀꢀꢀS1B
N1A–H11ꢀꢀꢀC17B
H102ꢀꢀꢀH52
4.220 (1)/100.2(1)
2.97/127
2.427
2.68/148
2.78/169
2.13
2.36
2.82/161
2.29
2.24
2.72/160
2.31
2.71/139
2.97, 139
3.11, 142
2.24
M2B
M3B
M1AB
11.289
11.380
7.522
x–1, y, z
–x, –y, –z
x, y, z
–0.9
–0.8
–5.4
–0.5
–0.4
–2.0
–5.7
–4.3
–15.1
3.0
2.7
11.5
–4.1
–2.9
–11.9
H201ꢀꢀꢀH172
M2AB
M3AB
7.819
8.683
x, y þ 1, z
C23B–H232ꢀꢀꢀS1A
H12ꢀꢀꢀH161
–4.5
–1.0
–2.4
–0.8
–14.2
–6.1
9.9
3.5
–11.2
–4.4
H103ꢀꢀꢀH51
–x þ 1, –y, –z þ 1
C24B–H242ꢀꢀꢀC19A
H242ꢀꢀꢀH181
M4AB
M5AB
M6AB
M7AB
M8AB
9.980
x–1, y þ 1, z
C9A–H92ꢀꢀꢀCg2
C2B–H23ꢀꢀꢀBr1A
C2A–H22ꢀꢀꢀBr1B
H152ꢀꢀꢀH41
–0.9
–1.1
–0.8
–0.8
–0.6
–0.4
–0.4
–0.3
–0.4
–0.3
–4.8
–3.4
–2.9
–3.2
–2.8
2.9
2.5
1.6
2.2
1.5
–3.1
–2.5
–2.4
–2.2
–2.1
10.261
10.173
11.877
11.630
–x, –y, –z þ 1
–x þ 1, –y, –z
–x þ 1, –y þ 1, –z
–x, –y þ 1, –z þ 1
H151ꢀꢀꢀH44
2.37
Compound 2
M1
M2
M3
M4
6.107
–x þ 1, –y þ 1, –z þ 1
–x þ 1, –y, –z þ 1
–x þ 1, y, –z þ 3/2
–x þ 1, y, –z þ 1/2
C6–H62ꢀꢀꢀBr1
C23–H23ꢀꢀꢀC17
C24ꢀꢀꢀC24
3.04/125
2.89/147
3.377 (1)
2.98/147
2.66/141
2.77/165
3.04/173
2.12
–4.1
–4.3
–2.9
–3.0
–1.9
–2.0
–1.4
–2.2
–14.7
–13.0
–12.6
–14.3
8.6
9.0
7.0
–12.1
–10.3
–9.8
7.264
8.395
7.845
C14–H14ꢀꢀꢀS1
C15–H15ꢀꢀꢀCg2
C2–H21ꢀꢀꢀCg1
C24–H24ꢀꢀꢀC15
C5–H5ꢀꢀꢀH8–C8
C3–H3ꢀꢀꢀH42–C4
C8–H8ꢀꢀꢀBr1
10.2
–9.3
M5
M6
M7
M8
M9
8.110
9.014
12.778
15.922
16.077
x, –y þ 1, z–1/2
–1.7
–1.0
–1.3
–0.6
–0.7
–0.9
–0.6
–0.7
–0.5
–0.4
–9.1
–5.0
–5.9
–3.6
–2.6
3.9
1.6
3.5
2.7
2.0
–7.7
–5.0
–4.4
–2.0
–1.7
x, –y, z þ 1/2
–x þ 1/2, y þ 1/2, –z þ 1/2
–x þ 1/2, –y þ 3/2, –z þ 1
x þ 1/2, –y þ 1/2, z þ 1/2
2.29
2.90/132
Cg1 and Cg2 are the centroid of the phenyl and bromophenyl rings, respectively. CD, centroid-to-centroid distance of the respective molecular pair.
Figure 5. Self-association of molecule A with its symmetry equivalents in 1.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
9
Figure 6. Self-association of molecule B with its symmetry equivalents in 1.
Figure 7. Molecular dimers formed between molecules A and B and their symmetry equivalents in 1.
ranging from 67 to 78% towards the stabilization of these and these dimers combine to generate a sequence of
dimers (Table 3 and Figure 8). The most stabilized dimer in 2 ꢀꢀꢀM2ꢀꢀꢀM8ꢀꢀꢀM2ꢀꢀꢀM8ꢀꢀꢀ (Figure 9(a)). In this sequence, ada-
(motif M1) which forms by an intermolecular C–HꢀꢀꢀBr inter- mantane moieties of M2 dimers interact with each other via
action in which one of protons of the adamantane moiety a short HꢀꢀꢀH contact with the distance of 2.29 Å (motif M8).
acts as a donor. A compact dimer (motif M2) consists of
Molecular dimer (motif M3) supports by a stacking inter-
an intermolecular C–HꢀꢀꢀC(p) interaction in which proton of action between symmetry-related bromophenyl rings in an
the bromophenyl ring is involved as a donor, while C off-set mode with the distance of 4.161(2) Å. The shortest
atom of the chlorophenyl ring as an acceptor. The CꢀꢀꢀC contact (involving symmetry-related C24 atoms) is
adjacent M2 dimers are further interconnected via motif M8 3.377(1) Å between these two rings. The molecular pair

10
F. A. M. AL-OMARY ET AL.
Figure 8. Molecular dimers in 2.
Figure 9. (a) The chain formed by alternate M2 and M8 motifs and (b) Molecular chain formed by motifs M4 and M3 in an alternate manner in the crystal of 2.
(motif M4) is stabilized by intermolecular C–HꢀꢀꢀS interaction molecules of 2 into a helical chain which runs parallel to the
and further supported by the C–Hꢀꢀꢀp (centroid of bromo- c axis. The least stable dimers (motifs M7 and M8) in 2 form
phenyl ring) interaction. The adjacent M4 dimers interlink via by short HꢀꢀꢀH contacts which establish less than 2.4 Å. The
motif M3. This alternate dimeric arrangement generates a adjacent adamantane moieties are interconnected by these
supramolecular 1 D-chain which runs parallel to the crystallo- HꢀꢀꢀH contacts. Similar interactions involving adamantane
graphic c axis (Figure 9(b)). A weak and a lengthy C–HꢀꢀꢀC(p) moieties in non-electrostatic origin have been reported (Al-
(involving H24 and C15; motif M6) interaction links the Wahaibi et al. 2018; El-Emam et al., 2020).

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
11
Table 4. Lattice energy (in kcal molꢂ1) for crystals 1–3.
3.6. Topological analysis
Crystal
ECoul
Epol
Edisp
Erep
Etot
All the dimers observed in 1 were subjected to topological ana-
lysis and the topological properties for the intermolecular inter-
actions which stabilize these dimers are summarized in Table 5.
The molecular graphs are showing the presence of intermolecu-
lar interactions in various dimers of 1 (supporting information
Figures S2–S5). As mentioned earlier, molecule A and its sym-
metry-related molecules generate self-associated dimers involv-
ing molecules A and four such dimers are observed in 1. These
dimers (M1A–M4A) are stabilized by intermolecular C–HꢀꢀꢀN,
C–HꢀꢀꢀC(p), C–HꢀꢀꢀS, C–BrꢀꢀꢀC(p), BrꢀꢀꢀBr and HꢀꢀꢀH interactions. As
can be seen from Table 5, all the intermolecular interactions are
1
2
3
–13.4
–12.4
–8.5
–7.3
–6.8
–4.6
–52.6
–55.7
–47.3
35.2
30.9
23.7
–38.1
–44.1
–36.7
3.5. Energy frameworks
To decipher the functional roles of different non-covalent
interactions in the construction of supramolecular architec-
tures in the solid state, the energy frameworks analysis have
been performed. The lattice energies for crystal structures
1–3 are provided in Table 4. From this table we can see that
compound 2 is more stable than other two. However, the
component of the dispersion energy contributes 72–78%
towards stabilization of these structures.
2
classified as closed shell interactions as determined by (i) r q(r)
> 0; (ii) jꢂGVððrÞrÞj < 1.0 and (iii) H(r) > 0. Further, the KP-4 rule was
employed to differentiate a hydrogen bond from van der Waals
interaction as described in our earlier studies (El-Emam et al.,
2020; Udayakumar et al., 2020). In dimers M1A–M4A, the dissoci-
The crystal structure of 1 can be described as columnar
packing and the molecules of 1 are arrangedꢁin column which
runs parallel to the crystallographic c-axis. The energy frame- ation energies (De) are ranging from 0.5 to 1.5 kcal molꢂ1
.
Moreover, only two intermolecular C23A–H231ꢀꢀꢀN2A and
C18A–H181ꢀꢀꢀC17A interactions are characterized as hydrogen
bonds. It is important to note that the short H241 … H71 (De:
1.5 kcal molꢂ1) contact is found to be strong among interac-
tions in these dimers. We also found that BrꢀꢀꢀBr contact is
slightly stronger than C–HꢀꢀꢀN and C–HꢀꢀꢀC interactions. The
C–BrꢀꢀꢀC(p) halogen bond is a weak interaction among other
interactions observed in these dimers.
In dimers M1B–M3B, an extensive number of short HꢀꢀꢀH
contacts are involved in these dimers in addition to C–HꢀꢀꢀC
and C–BrꢀꢀꢀC(p) interactions. The De values for these interac-
tions range from 0.5 to 1.0 kcal molꢂ1. It is to be noted that
the C–HꢀꢀꢀC interaction is categorized as a van der Waals
interaction based on KP-4 rule. Among interactions in these
dimers, H74ꢀꢀꢀH202 contact is calculated to be strong.
work of 1 is consisting of hexagonal rings and these rings are
fused at sides where the magnitudes of horizontal tubes are
relatively larger (Figure 10(a)). The larger green horizontal
tubes represent motifs M1A (C–HꢀꢀꢀN, C–Hꢀꢀꢀp, C–Brꢀꢀꢀp and
HꢀꢀꢀH contact) and M4A (type I BrꢀꢀꢀBr homo-halogen contact).
It is also noted that two sides of the hexagonal rings (con-
structed from intermolecular C–Hꢀꢀꢀp interaction) are further
connected by a pair of small cylindrical tubes which corres-
pond to intermolecular C–HꢀꢀꢀBr interaction (motif M5AB).
Further, small horizontal tubes (represent intermolecular HꢀꢀꢀH
short contacts; motif M3A) which interconnect the adjacent
hexagonal rings at the large horizontal tubes.
The crystal structure of 2 can be described as a columnar
packing structure. The zigzag layer forms by adamantane moi-
eties emanated from adjacent columns which in turn sand-
wiched between columns. The energy framework of 2 is
consisting of a square box (basic pattern) and the adjacent
square boxes are joined together to build the columnar (lad-
der like) structure. The square box is also consisting of diag-
onal cylindrical tubes. As shown in Figure 10(b), the horizontal
tubes of the square represent intermolecular C–HꢀꢀꢀS and
C–Hꢀꢀꢀp interactions (motif M4). The vertical tubes of the
square correspond to intermolecular C–Hꢀꢀꢀp interaction (motif
M5). Two diagonals also formed within the square topology
and one of the diagonals represent off-set p-stacking
(C24ꢀꢀꢀC24; motif M3) of bromophenyl rings, while another
diagonal generated by intermolecular C–HꢀꢀꢀS (motif M4) inter-
action. A small proportion of the electrostatic contribution is
seen only for the C–HꢀꢀꢀS interaction (zigzag red tubes). It is to
be noted that the adjacent ladders are interconnected by a
central zigzag chain topology. Within the central zigzag chain,
the horizontal tubes correspond to short HꢀꢀꢀH contacts (motif
M7) interlink the adjacent adamantane moieties. The diagonal
green tubes in the central zigzag chain represent intermolecu-
lar C–HꢀꢀꢀBr (motif M9) interaction. The 3 D topology of energy
framework of 3 is very similar to that of crystal 2 (supporting
information Figure S1). Overall, the energy framework analysis
suggests that the crystals 2 and 3 have similar mechanical
properties compared to the crystal 1.
As noted earlier, molecules A and B generate eight dimers
in 1. The De values lie in the range of 0.8–1.6 kcal molꢂ1. The
KP-4 rule suggests that five intermolecular interactions
(C21A–H 211ꢀꢀꢀS1B, N1A–H11ꢀꢀꢀC17B, C23B–H232ꢀꢀꢀS1A,
C24B–H242ꢀꢀꢀC19A and C2B–H23ꢀꢀꢀBr1A) showing the hydro-
gen bonding character. Out of five hydrogen bonds, one of
the C–HꢀꢀS hydrogen bond is relatively stronger. Moreover,
the strength of intermolecular HꢀꢀꢀH contacts is also compar-
able to the strength of other hydrogen bonding interactions.
The topological properties for the intermolecular interac-
tions in 2 are summarized in Table 6. The molecular graphs
confirm the existence of intermolecular interactions in molecu-
lar dimers of 2 (supporting information Figure S6). The inter-
molecular interactions listed in Table 6 are concluded as
closed shell interactions based on the ꢂpVðorÞsitive value of
2
Laplacian of electron density (r q(r) > 0), j GðrÞ j < 1.0 and H(r)
> 0. All the intermolecular interactions are weak and their dis-
sociation energies (De) are ranging from 0.5 to 1.5 kcal molꢂ1
.
Further, the intermolecular C–HꢀꢀꢀBr, C–HꢀꢀꢀS and C–HꢀꢀꢀC(p)
interactions are analyzed based on the KP-4 rule in order to
differentiate between the character of a hydrogen bond and a
van der Waals interaction. Though the De values for two inter-
molecular C–HꢀꢀꢀBr interactions are nearly the same, one of the
C–HꢀꢀꢀBr interactions (C6–H62ꢀꢀꢀBr1) is classified as a hydrogen
bond. Among four C–HꢀꢀꢀC(p) interactions, three of them

12
F. A. M. AL-OMARY ET AL.
Figure 10. Energy frameworks for the crystal structures of (a) 1 and (b) 2 showing dispersion (green cylinders), electrostatic (red cylinders) and total energy (blue
cylinders) components. Energies with magnitudes less than 15 kJ molꢂ1 have been omitted for clarity.
(C23–H23ꢀꢀꢀC17, C15–H15ꢀꢀꢀC23 and C2–H21ꢀꢀꢀC12) are classi-
The results of the antimicrobial screening of compounds
fied as hydrogen bonds. A weak intermolecular C–HꢀꢀꢀS inter- 1, 2 (200 lg/disc), the antibacterial antibiotics Gentamicin
action is also referred as a hydrogen bond. It should be sulphate, Ampicillin trihydrate and the antifungal drug
emphasized that the short H5ꢀꢀꢀH8 contact (Csp3–HꢀꢀꢀH8–Csp3 Clotrimazole (100 lg/disc) are shown in Table 7.
type; De: 1.5 kcal molꢂ1) is relatively strong interaction com-
As seen from Table 7, the results revealed that compounds
1 and 2 exhibited potent antibacterial activity (inhibition zones
ꢆ18 mm) against all the tested Gram-positive bacteria, the
Gram-negative bacteria Escherichia coli, and moderate or weak
activity against Pseudomonas aeruginosa. The inhibitory activ-
ity of the compounds against Candida albicans was generally
lower than their antibacterial activity. Compounds 1 and 2
retained moderate activity compared to Clotrimazole. The val-
pared to other interactions in 2.
3.7. In vitro antibacterial and antifungal activity
The in vitro growth inhibitory activity of the target compounds
1 and 2 against the standard bacterial strains of the American
type culture collection ATCC namely; Staphylococcus aureus
ATCC 6571, Bacillus subtilis ATCC 5256, Micrococcus luteus ATCC
27141 (Gram-positive bacteria), Escherichia coli ATCC 8726,
Pseudomonas aeruginosa ATCC 27853 (Gram-negative bacteria),
and the yeast-like pathogenic fungus Candida albicans MTCC
227 was evaluated. The primary screening was carried out using
€
ues of the MIC in Muller–Hinton broth were in accordance
with the results obtained in the primary screening (Table 7).
3.8. In vitro anti-proliferative activity
€
the semi-quantitative agar-disc diffusion method with Muller- The in vitro anti-proliferative activity of the isothiourea deriv-
Hinton agar medium (Woods & Washington, 1995), followed by atives 1 and 2 was assessed against five human tumour cell
determination of the minimal inhibitory concentration (MIC) for lines namely; PC-3 (human prostate cancer), HEPG-2 (hepato-
the highly active compounds against the same microorganism cellular carcinoma), HCT-116 (colorectal carcinoma), MCF-7
used in the primary screening was carried out using the micro- (mammary gland breast cancer) and HeLa (epithelioid carcin-
€
dilution susceptibility method in Muller-Hinton Broth and oma) using the 3-[4,5-dimethylthiazoyl-2-yl]-2,5-diphenyltetra-
Sabouraud Liquid Medium (National Committee for Clinical zolium bromide (MTT) assay (Berridge Tan, 1993;
Laboratory Standards (NCCLS), 1986). Mosmann, 1983). The results of in vitro anti-proliferative
&

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
13
Table 5. Topological parameters for intermolecular interactions in dimers Table 6. Topological parameters for intermolecular interactions in dimers
of 1.
of 2.
Interaction
M1A
Rij
q(r) r q(r) V(r)
G(r) H(r) jꢂGVðrðÞrÞj De
Interaction
M1
Rij
q(r)
r q(r)
V(r)
G(r) H(r) jꢂGVðrðÞrÞj De
2
2
C23A–H231ꢀꢀꢀN2A 2.656 0.049 0.601
C23A–H231ꢀꢀꢀC13A 2.929 0.041 0.507
C22A–Br1AꢀꢀꢀC14A 4.216 0.029 0.296
–10.0 13.2 3.2
0.76 1.2 C6–H62ꢀꢀꢀBr1
0.74 1.0 M2
0.69 0.5 C23–H23ꢀꢀꢀC17
0.79 1.5 M3
C24ꢀꢀꢀC24
3.078 0.047 0.499
2.957 0.037 0.400
3.409 0.039 0.408
–8.9
–6.3
–6.2
11.2 2.3
8.6 2.3
8.7 2.5
0.79
0.73
0.72
1.1
0.8
0.7
–8.0
–4.2
10.9 2.9
6.2 2.0
H241ꢀꢀꢀH71
2.197 0.058 0.675
–12.1 15.2 3.1
M2A
C18A–H181ꢀꢀꢀC17A 2.893 0.063 0.693
–12.1 15.5 3.4
0.78 1.4 M4
0.78 1.1 C14–H14ꢀꢀꢀS1
0.76 1.1 C15–H15ꢀꢀꢀC23
M5
C18A–H181ꢀꢀꢀS1A
H161ꢀꢀꢀH201
M3A
3.159 0.050 0.541
2.652 0.047 0.550
–9.5
–9.2
12.1 2.6
12.1 2.9
3.001 0.041 0.441
2.733 0.049 0.571
–7.2
–9.5
9.6 2.4
12.5 3.0
0.75
0.76
0.9
1.1
H31ꢀꢀꢀH42
2.427 0.041 0.458
3.492 0.052 0.704
–8.3
10.4 2.1
0.80 1.0 C2–H21ꢀꢀꢀC12
2.990 0.046 0.517
3.141 0.024 0.280
2.170 0.059 0.639
–8.7
–3.9
11.4 2.7
5.8 1.9
0.76
0.68
0.83
0.80
0.78
1.0
0.5
1.5
1.0
1.2
M4A
M6
Br1AꢀꢀꢀBr1A
M1B
H103ꢀꢀꢀH142
H73ꢀꢀꢀH132
H74ꢀꢀꢀH202
Br1BꢀꢀꢀC14B
M2B
–11.6 15.4 3.8
0.75 1.4 C24–H24ꢀꢀꢀC15
M7
2.387 0.036 0.396
2.438 0.039 0.456
2.403 0.040 0.462
4.521 0.028 0.282
–6.8
–7.8
–8.1
–3.9
8.8 2.0
10.1 2.3
10.3 2.2
5.8 1.9
0.77 0.8 C5–H5ꢀꢀꢀH8–C8
–12.3 14.8 2.5
–8.3 10.3 2.0
–10.0 12.7 2.7
0.77 0.9 M8
0.78 1.0 C3–H3ꢀꢀꢀH42–C4 2.342 0.042 0.452
0.68 0.5 M9
C8–H8ꢀꢀꢀBr1
2.919 0.048 0.570
q(r), electron density (e/Å3); r q(r), Laplacian of electron density (e/Å5); V(r),
potential energy density; G(r), kinetic energy density; H(r), total energy dens-
ity; Rij, bond path (Å). De ¼ –0.5ꢄV(r) in kcal molꢂ1 and the values of V(r),
2
C4B–H43ꢀꢀꢀC15B
3.044 0.035 0.366
2.492 0.033 0.364
–6.0
–6.4
8.0 2.0
8.2 1.7
0.75 0.7
0.79 0.8
M3B
H104ꢀꢀꢀH82
M1AB
G(r) and H(r) are expressed in kJ molꢂ1 bohrꢂ3
.
C21A–H 211ꢀꢀꢀS1B 2.704 0.064 0.746
–13.6 17.0 3.4
–7.6 10.2 2.5
–12.4 15.2 2.7
0.80 1.6
9.75 0.9
0.82 1.5
0.75 1.0
N1A–H11ꢀꢀꢀC17B
H102ꢀꢀꢀH52
H201ꢀꢀꢀH172
M2AB
3.004 0.039 0.468
2.169 0.060 0.656
2.638 0.043 0.509
Table 7. Growth inhibition zones and minimal inhibitory concentration (MIC)
of compounds 1, 2 (200 lg/8 mm disc), the broad-spectrum antibacterial
drugs Gentamicin sulphate and ampicillin trihydrate, and the antifungal drug
Clotrimazole (100 lg/8 mm disc) against Staphylococcus aureus ATCC 6571
(SA), Bacillus subtilis ATCC 5256 (BS), Micrococcus luteus ATCC 27141 (ML),
Escherichia coli ATCC 8726 (EC), Pseudomonas aeruginosa ATCC 27853 (PA),
and the yeast-like pathogenic fungus Candida albicans MTCC 227 (CA).
–8.4
11.1 2.8
C23B–H232ꢀꢀꢀS1A
H12ꢀꢀꢀH161
H103ꢀꢀꢀH51
M3AB
2.858 0.049 0.546
2.477 0.041 0.501
2.294 0.051 0.570
–9.3
–8.6
12.1 2.8
11.1 2.5
0.77 1.1
0.77 1.0
0.81 1.3
–10.5 13.0 2.5
C24B–H242ꢀꢀꢀC19A 2.745 0.046 0.528
–9.0
–9.5
11.7 2.7
12.4 2.9
0.77 1.1
0.76 1.1
Diameter of growth inhibition zone (mm)a
H242ꢀꢀꢀH181
M4AB
2.532 0.044 0.564
3.201 0.039 0.471
2.991 0.051 0.532
3.129 0.039 0.404
2.286 0.047 0.519
SA
BS
ML
EC
PA
CA
16
14
C9A–H92ꢀꢀꢀC24B
–7.4
–9.5
–6.8
–9.3
–7.2
10.1 2.7
12.0 2.5
8.9 2.1
11.7 2.4
9.3 2.1
0.73 0.9
0.79 1.1
0.77 0.8
0.79 1.1
0.77 0.9
Compound 1
Compound 2
22 (4)b 26 (1)b 22 (2)b 19 (8)b
14
13
M5AB
20 (2)b 23 (2)b 19 (8)b 19 (8)b
C2B–H23ꢀꢀꢀBr1A
M6AB
Gentamicin sulphate 27 (1)b 26 (2)b 20 (2)b 22 (0.5)b 21 (0.5)b NT
Ampicillin trihydrate 22 (2)b 23 (1)b 20 (2)b 16 (8)b
Clotrimazole NT NT NT NT
18 (8)b
NT
NT
C2A–H22ꢀꢀꢀBr1B
21 (4)b
M7AB
a(–): Inactive (inhibition zone <10 mm).
H152ꢀꢀꢀH41
M8AB
H151ꢀꢀꢀH44
bFigures shown in parentheses represent the MIC values (lg/mL).
NT, Not tested.
2.441 0.037 0.420
q(r), electron density (e/Å3); r q(r), Laplacian of electron density (e/Å5); V(r),
potential energy density; G(r), kinetic energy density; H(r), total energy dens-
ity; Rij, bond path (Å). De ¼ –0.5ꢄV(r) in kcal molꢂ1 and the values of V(r),
2
Table 8. In vitro anti-proliferative activity of compounds 1, 2 and the anti-
cancer drug Doxorubicin towards human prostate cancer (PC-3), hepatocellular
carcinoma (HEPG-2), colorectal carcinoma (HCT-116), mammary gland breast
cancer (MCF-7) and epithelioid carcinoma (HeLa) cell lines.
G(r) and H(r) are expressed in kJ molꢂ1 bohrꢂ3
.
IC50 (mM)a
activity of compounds 1,
2 and the anticancer drug
PC-3
HEPG-2
HCT-116
MCF-7
HeLa
Doxorubicin (Tacar et al., 2013) are shown in Table 8.
The anti-proliferative activity results indicated that compound
2 displayed marked anti-proliferative activity against MCF-7 and
HeLa cell lines with IC50 14.0 and 19.15 mM, respectively, and lower
activity towards PC-3, HEPG-2 and HCT-116 cell lines. The anti-pro-
liferative activity of compound 1 was rather lower than compound
2, it produced moderate activity against MCF-7 cell lines.
Compound 1 38.55 3.4 34.80 1.6 29.99 2.5 22.12 1.66 39.55 2.3
Compound 2 26.20 2.0 26.79 1.9 36.21 2.4 14.0 1.2
Doxorubicin 8.87 0.6 4.50 0.2 5.23 0.3 4.17 0.2
19.15 1.0
5.57 0.4
aIC50 values presented as the mean SD of three separate determina-
tions, p < 0.005.
Table 9. The glide XP docking scores (in kcal molꢂ1) and QM/MM-PBSA bind-
ing energies (Ebind in kcal molꢂ1) for the title compounds, their closely related
compound and control inhibitor.
Compound
Glide XP score
Ebind
3.9. Molecular docking and hybrid QM/MM-PBSA
binding energy analysis
1
2
3
–10.7
–11.1
–10.3
–8.8
–87.8
–66.5
–71.0
–103.3
Control inhibitor (PF-543)
In the present investigation, we explored the inhibitory
potential of the title compounds (1 and 2) and its closely
related compound (3) against human sphingosine kinase 1
(SPHK1). The initial glide XP docking analysis suggests that
compared to the known inhibitor (PF-543). In the glide dock-
ing simulation, the protein receptor was kept rigid and the
all three compounds show similar binding strengths ligand molecule was allowed to be flexible. Therefore, the

14
F. A. M. AL-OMARY ET AL.
Figure 11. Optimized binding poses of the title compounds (a) control inhibitor PF-543, (b) 1, (c) 2, (d) 3 and (e) overlay control inhibitor and structures 1–3 at
the active site of SPHK1.
predicted binding pose (top scored) for each complex was The subtle differences of the inter-contacts in these com-
further optimized using hybrid QM/MM-PBSA approach to
get better binding pose and to calculate more accurate bind-
ing energy for ligands. The binding energy analysis suggests
that the title compounds and their closely related compound
could form stable complex with the target protein (Table 9).
It also suggests that the derivatives with chlorine substitu-
ents (compounds 2 and 3) show relatively weak binding
compared to a derivative with bromine substituent (com-
pound 1). The active site of SPHK1 is primarily constituted by
a set of hydrophobic residues as shown in Figure 11. The
adamantane core is well overlapped at the active site and
one of the key residues Phe 259 makes a p-stacking inter-
action with one of the aromatic rings of ligands 1-3.
pounds were revealed via difference fingerprint plots. Energy
framework analysis indicated that crystals 2 and 3 have simi-
lar mechanical properties compared to crystal 1. The Bader’s
QTAIM framework was used to assess the strength and
nature of non-covalent interactions. The results suggested
that a short HꢀꢀꢀH contacts play an important role in the sta-
bilization of the crystal structures of 1 and 2. Further, we
explored the bioactivities of the title compounds and their
closely related structure using in silico approach including
the molecular docking and mixed mode QM/MM-PBSA
method to study the inhibitory potentials against human
sphingosine kinase 1 (SPHK1) receptor.
Disclosure statement
4. Summary
The authors declare that they have no competing interests.
The X-ray crystallography studies reveal that the molecular
conformation of 1 and 2 different and the molecular con-
formation of 1 and its closely related structure are similar.
The molecular conformation of these molecules stabilized by
intramolecular C–HꢀꢀꢀN interaction. The weak interactions pre-
sent in these compounds have been qualitatively character-
ized using the Hirshfeld surface and its associated 2 D
fingerprint plots to understand the effect of halogen sub-
stituents. The result suggested that Cl was less likely to be
involved in intermolecular interaction and these features
were consistent with the electrostatic potential point of view.
ORCID
Subbiah Thamotharan
http://orcid.org/0000-0003-2758-6649
References
Ahgren, C., Backro, K., Bell, F. W., Cantrell, A. S., Clemens, M., Colacino,
J. M., Deeter, J. B., Engelhardt, J. A., Hogberg, M., & Jaskunas, S. R. &.
(1995). The PETT series, a new class of potent nonnucleoside inhibi-
tors of human immunodeficiency virus type 1 reverse transcriptase.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
15
Antimicrobial Agents and Chemotherapy, 39(6), 1329–1335. https://doi.
org/10.1128/aac.39.6.1329
Medicinal Chemistry, 12(19), 5107–5113. https://doi.org/10.1016/j.bmc.
2004.07.033
Al-Abdullah, E. S., Al-Tuwaijri, H. M., Hassan, H. M., Haiba, M. E., Habib,
E. E., & El-Emam, A. A. (2014). Antimicrobial and hypoglycemic activ-
ities of novel N-Mannich bases derived from 5-(1-adamantyl)-4-substi-
tuted-1,2,4-triazoline-3-thiones. International Journal of Molecular
Sciences, 15(12), 22995–23010. https://doi.org/10.3390/ijms151222995
Al-Omary, F. A. M., Al-Rasheed, L. S., Ghabbour, H. A., & El-Emam, A. A.
(2017). Crystal structure of 1-(adamantan-1-yl)-3-(3-chlorophenyl)th-
El-Emam, A. A., Al-Omary, F. A. M., Al-Rasheed, L. S., Ghabbour, H. A., &
Al-Abdullah, E. S. (2017). Crystal structure of (Z)-3-(adamantan-1-yl)-1-
€
(3-chlorophenyl)-S-benzylisothiourea. Zeitschrift Fur Kristallographie –
New Crystal Structures, 232(3), 453–456.
El-Emam, A. A., Al-Tamimi, A.-M S., Al-Omar, M. A., Alrashood, K. A., &
Habib, E. E. (2013). Synthesis and antimicrobial activity of novel 5-(1-
adamantyl)-2-aminomethyl-4-substituted-1,2,4-triazoline-3-thiones.
European Journal of Medicinal Chemistry, 68, 96–102. https://doi.org/
10.1016/j.ejmech.2013.07.024
€
iourea. Zeitschrift Fur Kristallographie - New Crystal Structures, 232(1),
33–35.
Al-Wahaibi, L. H., Ghabbour, H. A., Mostafa, G. A. E., Al-Mutairi, M. S., & El-Emam, A. A., Saveeth Kumar, E., Janani, K., Al-Wahaibi, L. H., Blacque,
El-Emam, A. A. (2016). Crystal structure of 1-(adamantan-1-yl)-3-phe-
O., El-Awady, M. I., Al-Shaalan, N. H., Percino, J. M., & Thamotharan, S.
(2020). Quantitative assessment of the nature of noncovalent interac-
tions in N-substituted-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amines:
Insights from crystallographic and QTAIM analysis. RSC Advances,
10(17), 9840–9853. https://doi.org/10.1039/D0RA00733A
€
nylthiourea. Zeitschrift Fur Kristallographie - New Crystal Structures,
231(2), 593–595.
Al-Wahaibi, L. H., Santhosh Kumar, N., El-Emam, A. A., Venkataramanan,
N. S., Ghabbour, H. A., Al-Tamimi, A.-M S., Percino, J., & Thamotharan,
S. (2019). Investigation of potential anti-malarial lead candidate 2-(4- Espinosa, E., Molins, E., & Lecomte, C. (1998). Hydrogen bond strengths
fluorobenzylthio)-5-(5-bromothiophen-2-yl)-1,3,4-oxadiazole: Insights
from crystal structure, DFT, QTAIM and hybrid QM/MM binding
revealed by topological analyses of experimentally observed electron
densities. Chemical Physics Letters, 285(3–4), 170–173.
energy analysis. Journal of Molecular Structure., 1175, 230–240. Farrugia, L. (2012). WinGX and ORTEP for windows: An update. Journal
https://doi.org/10.1016/j.molstruc.2018.07.102 of Applied Crystallography, 45(4), 849–854.
Al-Wahaibi, L. H., Sujay, S., Muthu, G. G., El-Emam, A. A., Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R.,
Venkataramanan, N. S., Al-Omary, F. A. M., Ghabbour, H. A., Percino, J.,
& Thamotharan, S. (2018). Theoretical investigations of two adaman-
tane derivatives: A combined X-ray, DFT, QTAIM analysis and molecu-
lar docking. Journal of Molecular Structure, 1159, 233–245. https://doi.
org/10.1016/j.molstruc.2018.01.064
Balzarini, J., Orzeszko, B., Maurin, J. K., & Orzeszko, A. (2007). Synthesis
and anti-HIV studies of 2-adamantyl-substituted thiazolidin-4-ones.
European Journal of Medicinal Chemistry, 42(7), 993–1003. https://doi.
org/10.1016/j.ejmech.2007.01.003
Halgren, T. A., Sanschagrin, P. C., & Mainz, D. T. (2006). Extra precision
glide: Docking and scoring incorporating a model of hydrophobic
enclosure for protein-ligand complexes. Journal of Medicinal
Chemistry, 49(21), 6177–6196. https://doi.org/10.1021/jm051256o
Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A.,
Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., Petersson,
G. A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H. P., Izmaylov, A. F.,
Bloino, J., Zheng, G., Sonnenberg, J. L., Hada, M., … Fox, D. J. (2013).
Gaussian 09, revision D.01. Gaussian, Inc.
Berridge, M. V., & Tan, A. S. (1993). Characterization of the cellular reduc-
tion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
Gatti, C. (2005). Chemical bonding in crystals: New directions. Zeitschrift
Fur Kristallographie., 220, 399–457.
(MTT): Subcellular localization, substrate dependence, and involve- Gavezzotti, A. (2002). Calculation of intermolecular interaction energies
ment of mitochondrial electron transport in MTT reduction. Archives
of Biochemistry and Biophysics, 303(2), 474–482. https://doi.org/10.
1006/abbi.1993.1311
by direct numerical integration over electron densities. I. Electrostatic
and polarization energies in molecular crystals. The Journal of Physical
Chemistry B, 106(16), 4145–4154.
Britten, C. D., Garrett-Mayer, E., Chin, S. H., Shirai, K., Ogretmen, B., Bentz, Gavezzotti, A. (2003). Calculation of intermolecular interaction energies
T. A., Brisendine, A., Anderton, K., Cusack, S. L., Maines, L. W., Zhuang,
Y., Smith, C. D., Thomas, M. B. (2017). phase study of
ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients
by direct numerical integration over electron densities. 2. An
improved polarization model and the evaluation of dispersion and
repulsion energies. The Journal of Physical Chemistry B, 107(10),
2344–2353.
&
A
I
with advanced solid tumors. Clinical Cancer Research
4642–4650. https://doi.org/10.1158/1078-0432.CCR-16-2363
, 23(16),
Gavezzotti, A. (2005). Calculation of lattice energies of organic crystals:
The PIXEL integration method in comparison with more traditional
methods. Z. Kristallogr. - Crystalline Materials, 220(499). https://doi.org/
10.1524/zkri.220.5.499.65063
ꢀ
Bulat, F. A., Toro-Labbe, A., Brinck, T., Murray, J. S., & Politzer, P. (2010).
Quantitative analysis of molecular surfaces: Areas, volumes, electro-
static potentials and average local ionization energies. Journal of
Molecular Modeling, 16(11), 1679–1691. https://doi.org/10.1007/ Gavezzotti, A. (2011). Efficient computer modeling of organic materials.
s00894-010-0692-x
Burstein, M. E., Serbin, A. V., Khakhulina, T. V., Alymova, I. V., Stotskaya,
L. L., Bogdan, O. P., Manukchina, E. E., Jdanov, V. V., Sharova, N. K., &
The atom–atom, Coulomb–London–Pauli (AA-CLP) model for intermo-
lecular electrostatic-polarization, dispersion and repulsion energies.
New Journal of Chemistry, 35(7), 1360–1368.
Bukrinskaya, A. G. (1999). Inhibition of HIV-1 replication by newly Guy, L., & Graciela, A. (2010). Use of the adamantane structure in medi-
developed adamantane-containing polyanionic agents. Antiviral
Research, 41(3), 135–144.
Carter, D. J., Raiteri, P., Barnard, K. R., Gielink, R., Mocerino, M., Skelton,
B. W., Vaughan, J. G., Ogden, M. I., & Rohl, A. L. (2017). Difference
cinal chemistry. Current Medicinal Chemistry, 17, 2967–2978.
Hu, H., Lin, C., Ao, M., Ji, Y., Tang, B., Zhou, X., Fang, M., Zeng, J., & Wu,
Z. (2017). Synthesis and biological evaluation of 1-(2-(adamantane-1-
yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer
agents. RSC Advances, 7(81), 51640–51651.
Hirshfeld fingerprint plots:
A
tool for studying polymorphs.
CrystEngComm, 19(16), 2207–2215.
Huang, X., Huang, R., Liao, Z., Pan, Y., Gou, S., & Wang, H. (2016).
Synthesis and pharmacological evaluation of dehydroabietic acid thio-
urea derivatives containing bisphosphonate moiety as an inducer of
apoptosis. European Journal of Medicinal Chemistry, 108, 381–391.
https://doi.org/10.1016/j.ejmech.2015.12.008
Cremer, D., & Pople, J. A. (1975). General definition of ring puckering
coordinates. Journal of the American Chemical Society, 97(6),
1354–1358.
Davies, W. L., Grunert, R. R., Haff, R. F., McGahen, J. W., Neumayer, E. M.,
Paulshock, M., Watts, J. C., Wood, T. R., Hermann, E. C., & Hoffmann, Jia, L., Tomaszewski, J. E., Hanrahan, C., Coward, L., Noker, P., Gorman, G.,
C. E. (1964). Antiviral activity of 1-adamantanamine (amantadine).
Science (New York, N.Y.).), 144(3620), 862–863. https://doi.org/10.1126/
science.144.3620.862
Nikonenko, B., & Protopopova, M. (2005). Pharmacodynamics and
pharmacokinetics of SQ109, new diamine-based antitubercular
drug. British Journal of Pharmacology, 144(1), 80–87. https://doi.org/
a
El-Emam, A. A., Al-Deeb, O. A., Al-Omar, M., & Lehmann, J. (2004).
10.1038/sj.bjp.0705984
Synthesis, antimicrobial, and anti-HIV-1 activity of certain 5-(1-ada- Joshi, S. D., Dixit, S. R., Kirankumar, M. N., Aminabhavi, T. M., Raju, K. V.
mantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-adamantyl)-3-
substituted aminomethyl-1,3,4-oxadiazoline-2-thiones. Bioorganic
S. N., Narayan, R., Lherbet, C., & Yang, K. S. (2016). Synthesis, antimy-
cobacterial screening and ligand-based molecular docking studies on
&

16
F. A. M. AL-OMARY ET AL.
ꢀ
novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl Omar, K., Geronikaki, A., Zoumpoulakis, P., Camoutsis, C., Sokovic, M.,
ꢀ
ꢀ
ꢂ
Ciric, A., & Glamoclija, J. (2010). Novel 4-thiazolidinone derivatives as
potential antifungal and antibacterial drugs. Bioorganic & Medicinal
Chemistry, 18(1), 426–432. https://doi.org/10.1016/j.bmc.2009.10.041
Osmond, J. D. C., & Fatih, M. U. (2006). Novel broad-spectrum thiourea
non-nucleoside inhibitors for the prevention of mucosal HIV transmis-
sion. Current HIV Research, 4, 329–345.
thiourea moieties. European Journal of Medicinal Chemistry, 107,
133–152. https://doi.org/10.1016/j.ejmech.2015.10.047
Kadi, A. A., Al-Abdullah, E. S., Shehata, I. A., Habib, E. E., Ibrahim, T. M., &
El-Emam, A. A. (2010). Synthesis, antimicrobial and anti-inflammatory
activities of novel 5-(1-adamantyl)-1,3,4-thiadiazole derivatives.
European Journal of Medicinal Chemistry, 45(11), 5006–5011. https://
doi.org/10.1016/j.ejmech.2010.08.007
Kaiser, M., Wittlin, S., Nehrbass-Stuedli, A., Dong, Y., Wang, X., Hemphill,
A., Matile, H., Brun, R., & Vennerstrom, J. L. (2007). Peroxide bond-
dependent antiplasmodial specificity of artemisinin and OZ277
(RBx11160). Antimicrobial Agents and Chemotherapy, 51(8), 2991–2993.
https://doi.org/10.1128/AAC.00225-07
Kang, I.-J., Wang, L.-W., Hsu, S.-J., Lee, C.-C., Lee, Y.-C., Wu, Y.-S., Yueh, A.,
Wang, J.-C., Hsu, T.-A., Chao, Y.-S., & Chern, J.-H. (2009). Design and
efficient synthesis of novel arylthiourea derivatives as potent hepatitis
C virus inhibitors. Bioorganic & Medicinal Chemistry Letters, 19(21),
6063–6068. https://doi.org/10.1016/j.bmcl.2009.09.037
Roos, K., Wu, C., Damm, W., Reboul, M., Stevenson, J. M., Lu, C., Dahlgren,
M. K., Mondal, S., Chen, W., Wang, L., Abel, R., Friesner, R. A., & Harder,
E. D. (2019). OPLS3e: Extending force field coverage for drug-like small
molecules. Journal of Chemical Theory and Computation, 15(3),
1863–1874. https://doi.org/10.1021/acs.jctc.8b01026
Rosenthal, K. S., Sokol, M. S., Ingram, R. L., Subramanian, R., & Fort, R. C.
(1982). Tromantadine: Inhibitor of early and late events in herpes sim-
plex virus replication. Antimicrobial Agents and Chemotherapy, 22(6),
1031–1036. https://doi.org/10.1128/aac.22.6.1031
Sathya, R., & Thamotharan, S. (2015). In silico based virtual screening and
mixed mode QM/MM calculation identifies caffeine scaffold for
designing potential inhibitors for tyrosyl tRNA synthetase of
Mycobacterium tuberculosis. International Journal of Quantum
Chemistry, 115(3), 187–195.
Sheldrick, G. (2015). Crystal structure refinement with SHELXL. Acta
Crystallographica. Section C, Structural Chemistry, 71(Pt 1), 3–8. https://
doi.org/10.1107/S2053229614024218
Sheldrick, G. (2015). SHELXT – Integrated space-group and crystal-struc-
ture determination. Acta Crystallographica. Section A, Foundations and
Advances, 71(Pt 1), 3–8. https://doi.org/10.1107/S2053273314026370
Sun, S.-Y., Yue, P., Chen, X., Hong, W. K., & Lotan, R. (2002). The synthetic
retinoid CD437 selectively induces apoptosis in human lung cancer
cells while sparing normal human lung epithelial cells. Cancer
Research, 62(8), 2430–2436.
Tacar, O., Sriamornsak, P., & Dass, C. R. (2013). Doxorubicin: An update
on anticancer molecular action, toxicity and novel drug delivery sys-
tems. The Journal of Pharmacy and Pharmacology, 65(2), 157–170.
https://doi.org/10.1111/j.2042-7158.2012.01567.x
Keith, T. (2019). AIMAll 19.02.13. TK Gristmill Software.
Kelly, J. M., Quack, G., & Miles, M. M. (2001). In vitro and in vivo activities
of aminoadamantane and aminoalkylcyclohexane derivatives against
Trypanosoma brucei. Antimicrobial Agents and Chemotherapy, 45(5),
1360–1366. https://doi.org/10.1128/AAC.45.5.1360-1366.2001
Koch, U., & Popelier, P. L. A. (1995). Characterization of C-H-O hydrogen
bonds on the basis of the charge density. The Journal of Physical
Chemistry, 99(24), 9747–9754.
Kunkel, G. T., Maceyka, M., Milstien, S., & Spiegel, S. (2013). Targeting the
sphingosine-1-phosphate axis in cancer, inflammation and beyond.
Nature Reviews. Drug Discovery, 12(9), 688–702. https://doi.org/10.1038/
nrd4099
Lain, S., Hollick, J. J., Campbell, J., Staples, O. D., Higgins, M., Aoubala, M.,
McCarthy, A., Appleyard, V., Murray, K. E., Baker, L., Thompson, A.,
Mathers, J., Holland, S. J., Stark, M. J. R., Pass, G., Woods, J., Lane,
D. P., & Westwood, N. J. (2008). Discovery, in vivo activity, and mech-
anism of action of a small-molecule p53 activator. Cancer Cell, 13(5),
454–463. https://doi.org/10.1016/j.ccr.2008.03.004
Liu, J., Obando, D., Liao, V., Lifa, T., & Codd, R. (2011). The many faces of the
adamantyl group in drug design. European Journal of Medicinal Chemistry.,
46(6), 1949–1963. https://doi.org/10.1016/j.ejmech.2011.01.047
Mackenzie, C. F., Spackman, P. R., Jayatilaka, D., & Spackman, M. A.
(2017). CrystalExplorer model energies and energy frameworks:
Extension to metal coordination compounds, organic salts, solvates
and open-shell systems. IUCrJ, 4(Pt 5), 575–587. https://doi.org/10.
1107/S205225251700848X
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P.,
Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J., & Wood,
P. A. (2008). Mercury CSD 2.0 - new features for the visualization and
investigation of crystal structures. Journal of Applied Crystallography,
41(2), 466–470.
Madhavi Sastry, G., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W.
(2013). Protein and ligand preparation: Parameters, protocols, and influence
on virtual screening enrichments. Journal of Computer-Aided Molecular
Design, 27(3), 221–234. https://doi.org/10.1007/s10822-013-9644-8
Miroslawa, K., Anna, R., Zdzislaw, C., & Zygmunt, K. (2015). New benzimi-
dazole-derived isothioureas as potential antileukemic agents – studies
in vitro. Medicinal Chemistry, 11, 364–372.
Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and sur-
vival: Application to proliferation and cytotoxicity assays. Journal of
Immunological Methods, 65(1-2), 55–63.
Murphy, R. B., Philipp, D. M., & Friesner, R. A. (2000). A mixed quantum
mechanics/molecular mechanics (QM/MM) method for large-scale
modeling of chemistry in protein environments. Journal of
Computational Chemistry, 21(16), 1442–1457.
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman,
P. R., Jayatilaka, D., & Spackman, M. A. (2017). CrystalExplorer17.
University of Western Australia.
ꢀ
Udayakumar, M., Ceron, M., Ceballos, P., Percino, M. J., & Thamotharan, S.
(2020). Correlation between structural and optical properties of p-con-
jugated acrylonitrile derivatives: Insights from X-ray, energy frame-
works, TD-DFT and charge density analysis. Journal of Molecular
Structure, 1213, 128174. https://doi.org/10.1016/j.molstruc.2020.128174
Verlinden, B. K., Niemand, J., Snyman, J., Sharma, S. K., Beattie, R. J.,
Woster, P. M., & Birkholtz, L.-M. (2011). Discovery of novel alkylated
(bis)urea and (bis)thiourea polyamine analogues with potent antimal-
arial activities. Journal of Medicinal Chemistry, 54(19), 6624–6633.
https://doi.org/10.1021/jm200463z
Wanka, L., Iqbal, K., & Schreiner, P. R. (2013). The lipophilic bullet hits the
targets: Medicinal chemistry of adamantane derivatives. Chemical
Reviews, 113(5), 3516–3604. https://doi.org/10.1021/cr100264t
Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G.,
Gumienny, R., Heer, F. T., de Beer, T. A. P., Rempfer, C., Bordoli, L.,
Lepore, R., & Schwede, T. (2018). SWISS-MODEL: Homology modelling
of protein structures and complexes. Nucleic Acids Research, 46(W1),
W296–W303. https://doi.org/10.1093/nar/gky427
Wendel, H. A., Snyder, M. T., & Pell, S. (1966). Trial of amantadine in epi-
demic influenza. Clinical Pharmacology and Therapeutics, 7(1), 38–43.
https://doi.org/10.1002/cpt19667138
Wingfield, W. L., Pollack, D., & Grunert, R. R. (1969). Therapeutic efficacy of
amantadine HCl and rimantadine HCl in naturally occurring influenza
A2 respiratory illness in man. The New England Journal of Medicine,
281(11), 579–584. https://doi.org/10.1056/NEJM196909112811102
Woods, G. L., & Washington, J. A. (1995). Antibacterial susceptibility tests:
Dilution and disk diffusion methods. In Murray PR, Baron EJ, Pfaller
MA, Tenover FC, Yolken RH, Eds.,Manual of clinical microbiology (6th
ed., pp. 1327–1341). American Society for Microbiology.
National Committee for Clinical Laboratory Standards (NCCLS). (1986).
Methods for dilution antimicrobial susceptibility tests for bacteria that
grow aerobically: Approved Standard M7-A. NCCLS.