Journal of Molecular Structure 1175 (2019) 230e240

Contents lists available at ScienceDirect

Journal of Molecular Structure

journal homepage: http://www.elsevier.com/locate/molstruc

Investigation of potential anti-malarial lead candidate 2-(4-

fluorobenzylthio)-5-(5-bromothiophen-2-yl)-1,3,4-oxadiazole:
Insights from crystal structure, DFT, QTAIM and hybrid QM/MM
binding energy analysis
Lamya H. Al-Wahaibi a, Nandakumar Santhosh Kumar b, Ali A. El-Emam c,
Natarajan S. Venkataramanan d, Hazem A. Ghabbour c, Abdul-Malek S. Al-Tamimi e,
Judith Percino f, Subbiah Thamotharan b, *
a
Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
b
Biomolecular Crystallography Laboratory, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur
613 401, India
c
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
d
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India
e
Department of Pharmaceutical Chemistry, College of Pharmacy, Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
f
Unidad de Polímeros y Electro
nica, Instituto de Ciencias, Benem


nica Orga
noma de Puebla, Val3-Ecocampus Valsequillo,
erita Universidad Auto
Independencia O2 Sur 50, San Pedro Zacachimalpa, Pue. Mexico

a r t i c l e i n f o a b s t r a c t

Article history: A combined study involving single crystal X-ray diffraction and various theoretical approaches has been
Received 11 May 2018 used to characterize the 2-(4-fluorobenzylthio)-5-(5-bromothiophen-2-yl)-1,3,4-oxadiazole compound.
Received in revised form The crystal structure is primarily stabilized by intermolecular CeH$$$p, CeH/N and CeH/F. A short
27 July 2018
and very rare halogen-halogen contact (Br/F) which adopts type I trans geometry along with the S/S,
Accepted 28 July 2018
N/S contacts, which play an important role in the stabilization of the crystal packing. The importance of
Available online 1 August 2018
these contacts is established through various theoretical approaches such as QTAIM and NBO analysis. A
detailed CSD analysis of Br/F contacts is performed to understand the geometrical preference. A
Keywords:
Oxadiazole
detailed in silico analysis is performed to explore the binding potential of the title compound against the
Thiophene Plasmodium falciparum dihydrofolate reductase (PfDHFR). The results clearly suggest that the title
Hetero-halogen contact compound may be a promising anti-malarial lead candidate by inhibiting the DHFR target and haloge-
DHFR nated fragments of the molecule are important for the stabilization of the protein-ligand complex
Anti-malarial formation.
Hybrid QM/MM © 2018 Elsevier B.V. All rights reserved.

1. Introduction cells [1e3]. On the other hand, another isomer of oxadiazole

namely 1,3,4-oxadiazole performs varieties of biological activities
Oxadiazole is an important aromatic heterocyclic nucleus con- that include anti-bacterial [4e6], anti-fungal [7], anti-malarial [8],
taining two nitrogen and an oxygen atoms. Importantly, two of the anti-tubercular [9e11], anti-cancer [12,13] anti-allergic [14] and
oxadiazole isomers such as 1,2,4-oxadiazole and 1,3,4-oxadiazole analgesic [15] and many other activities. Moreover, some of the
have shown their wide application. Interestingly, two natural currently used drug molecules namely Raltegravir (antiretroviral
products namely phidianidine A and B contain 1,2,4-oxadiazole drug) [16], Zibotentan (anticancer drug) [17], Nesapidil (antihy-
core. These two compounds exhibit cytotoxicity against tumor pertensive agent) [18], Fenadiazole (hypnotic drug) [19] contain
cells and not toxic to normal human epithelial kidney (HEK293) 1,3,4-oxadiazole ring. Two of the antibiotics (ABT-751-oxadiazole
and Furamizole) are also having 1,3,4-oxadiazole nucleus [20,21].
Likewise, thiophene-based derivatives have gained vital impor-
* Corresponding author. tance in materials science and technology because of their multiple
E-mail address: [email protected] (S. Thamotharan).

https://doi.org/10.1016/j.molstruc.2018.07.102
0022-2860/© 2018 Elsevier B.V. All rights reserved.
 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240 231

functional properties such as organic electronics, thin film field- binding potential of the title compound against Plasmodium fal-
effect transistors and solar cells. Especially optical properties of ciparum dihydrofolate reductase (PfDHFR) using various in silico
thiophene based compounds are used to monitor biological events approaches including flexible ligand docking and hybrid QM/MM
involving macromolecules such as protein and DNA [22]. Like procedures. The nature of non-covalent interactions between pro-
oxadiazole, thiophone motif is also used as a building block in many tein and ligand were analyzed using non-covalent interactions
drugs such as Tienilic acid, Methapyrilene, Tiaprofenic acid, (NCI) index tool.
Suprofen, Zileuton and OSI-930 [23]. It is well known that thio-
phene metabolism responsible for the formation of reactive
metabolite which causes toxicity. On the other hand, thiophene has 2. Experimental details
proven to be a potential isostere, resulting in better pharmacoki-
netic and pharmacodynamic profiles of a drug [24]. Moreover, the 2.1. Synthesis and crystallization
introduction of fluorine into biologically active pharmaceuticals
results in improved pharmacological profiles and approximately The title compound was synthesized starting from 5-
15% of all pharmaceuticals contain at least one fluorine atom [25]. bromothiophene-2-carbohydrazide. The outline of the synthesis,
Owing to the above reasons, we have synthesized the title NMR spectra (1H NMR and 13C NMR) and ESI-MS are given in the
compound namely 2-(4-fluorobenzylthio)-5-(5-bromothiophen-2- supplementary section. Briefly, single crystals suitable for X-ray
yl)-1,3,4-oxadiazole, in which both thiophene and 1,3,4-oxadiazole analysis were obtained by slow evaporation of CHCl3:EtOH (1:1;
ring systems along with fluorine atom are incorporated. A search of 5 mL) solution of the title compounds at room temperature to yield
Cambridge Structural Database (CSD) reveals that thiophene con- the crystals as shiny colorless transparent plates.
taining derivatives have been extensively characterized by X-ray
crystallographic method. There are 9335 hits, exists with thiophene
based analogs with both organic and organometallic compounds 2.2. Single crystal X-ray diffraction
nature in the CSD. In the case of 1,2,4-oxadiazole nucleus, 91 hits
were found. There are 663 hits containing 1,3,4-oxadiazole core. The X-ray intensity data of the title compound were collected on
In this work, we present the crystal and molecular structure of a Bruker SMART APEXII CCD diffractometer equipped using
the title compound. The structure of the title compound was fully monochromatic Mo Ka (l ¼ 0.71073 Å) radiation at room temper-
optimized in gas and solvent phases using DFT method (M062X/cc- ature (293 K). Data reduction and cell parameters refinement were
pVTZ with the incorporation of empirical dispersion effect) to carried out using the program SAINT (Bruker AXS, 2014). The ab-
investigate the conformational stability in various phases. More- sorption correction was applied using SADABS (Bruker AXS). The
over, to delineate the optical properties of the title compound, we structure solution was obtained by the SIR92 program [27] and all
measured the UVeVis spectrum and the corresponding spectrum the non-hydrogen atoms were refined anisotropically using the
was also computed using the time dependent DFT (TD-DFT) SHELXL-2014/7 program [28]. All the H atoms were placed in
calculation. Further, various intermolecular interactions existing in idealized geometrical positions (CeH ¼ 0.93e0.97 Å) with
the crystal structures of the title compound were visualized using Uiso(H) ¼ 1.2Ueq(C). In the final cycle of refinement, the title com-
Hirshfeld surface (HS) analysis. The two dimensional fingerprint pound was refined as an inversion twin with an absolute structure
plots (FP) are useful tool to understand the relative contributions of parameter of 0.021(15) [29]. The ORTEP and dimeric packing dia-
various non-bonded contacts that exist in the crystal structure. grams were generated using the program MERCURY [30]. The
Different dimeric motifs formed by various non-bonded in- summary of crystal data and refinement are presented in Table 1.
teractions were identified using PIXEL method. This empirical The energetics of various intermolecular interaction observed in
method provides the breakdown of interaction energies into their the title compound is summarized in Table 2.
Coulombic, polarization, dispersion and repulsion energies for
various dimeric motifs. Furthermore, we have used various theo-
2.3. PIXEL and Hirshfeld surface analysis
retical approaches such as quantum theory of atoms-in-molecules
(QTAIM) and natural bond orbital (NBO) analysis to characterize
To visualize various intermolecular interactions and to quantify
the nature of interactions observed in these dimeric motifs.
the relative contributions of various intermolecular interactions
Interestingly, we observed a short hetero-halogen (Br/F) con-
existed in the crystal structure, we carried out the Hirshfeld surface
tact in the title compound. Recently, a detailed study on the role of
(HS) analysis and the disintegrated 2D fingerprint plots using the
hetero-halogen and homo-halogen interactions in substituted
CrystalExplorer-3.1 package [31]. To evaluate the strengths of
benzanilides has been reported [26]. As shown in Scheme 1, these
various dimers observed in the crystal structure and to identify the
halogen-halogen interactions are geometrically classified as Type I
energetically significant molecular pairs, we performed PIXEL
(cis and trans modes) and Type II modes depending on the values of
calculation [32e34]. This method provided the total energy for the
two halogen angles q1 and q2. We present herein a detailed CSD
molecular pair which was decomposed into the Coulombic, polar-
analysis of intermolecular Br/F contact to understand its
ization, dispersion and repulsion energies. More details of HS
geometrical preferences and the role of such contact towards the
analysis and PIXEL calculation are given in our previous papers
stabilization of the crystal structure. Further, we explored the
[35e38].

Scheme 1. Geometrical preference of Br$$ $ F contacts (X ¼ Br or F) (a) Type I (q1 ¼ q2 ; trans geometry) (b) Type I (q1 ¼ q2 ; cis geometry) and (c) Type II (q1 ¼180 and q2 ¼ 90 ; L-
shaped geometry).
232 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240

Table 1 2.5. In silico docking and mixed mode QM/MM analysis

Crystal data and refinement parameters for the compound.

Formula C13H8BrFN2OS2 To explore the antimalarial potential of the title compound, we

Formula weight 371.24
performed in silico molecular docking against Plasmodium falcipa-
Size (mm3) 0.22  0.18  0.05 rum dihydrofolate reductase (PfDHFR) using the Schro €dinger suite
Crystal system Monoclinic €dinger Release 2016-3, LLC, New York, NY, 2016]. The 3D
[Schro
Space group, Z Pc, 4 structure of the PfDHFR was retrieved from the protein data bank
a (Å) 12.266(2)
b (Å) 4.7260(9)
(http://www.rcsb.org; pdbid: 4DPD). Two standard drugs chloro-
c (Å) 12.616(3) quine and pyrimethamine were used as the control to compare the
a ( ) 90 binding scores. The protein and ligand molecules were prepared as
b ( ) 100.592(5) described earlier [45]. The grid box was constructed based on the
g ( ) 90
position of the dihydrofolic acid (DHF) ligand in the crystal struc-
Temperature (K) 293(2)
Wavelength (Å) 0.71073 ture complex. The flexible ligand docking was performed and the
Density (Mgm3) 1.715 docking score was calculated for these compounds using the Glide
No. of reflections collected 12636 extra precision (Glide XP) scoring scheme implemented in the
No. of unique reflections 2532 Glide module [46]. Further, a mixed mode quantum mechanics/
2qmax ( ) 50
molecular mechanics (QM/MM) approach was used to optimize the
No. of parameters/restraints 182/2
R1, wR2 (I > 2s(I)) 0.041, 0.066 predicted binding modes obtained from the Glide XP docking
Goodness of fit 1.015 method as described earlier [47] with the Qsite module [48]. Briefly,
Drmax, Drmin (eÅ3) 0.284, 0.278 the protein was treated at the MM level and the ligand molecule at
CCDC no. 1814186
the QM level using two different levels of density functional theory
(B3LYP/LACVP* and M06-2X/cc-pVTZ). The protein residues within
6 Å from the ligand were treated flexible and the remaining resi-
2.4. DFT calculations dues were constrained with a force constant of 25 kcal mol1. The
binding energy between protein and ligand complex was calculated
In the present study, constraint free structural optimization of using the following formula
the title molecule (monomer) was performed in the gas phase us-
ing the Gaussian 09 program [39] with M06-2X/cc-pVTZ level of E(bind) ¼ E(complex)-E(protein)-E(ligand)
theory. The empirical dispersion correction proposed by Grimme's
was included [40]. To investigate the solvent (acetonitrile) effect on
the conformation of the title compound, the structure was opti-
mized at the same level of theory as in the gas phase using the 2.6. Non-covalent interactions (NCI) index analysis
conductor-like polarizable continuum model (CPCM) method. The
structural optimization in both gas and solvent phases were ach- To understand the nature of non-covalent interactions between
ieved without any imaginary vibrational frequencies. Further, the protein and ligand molecule, we performed NCI index [49] analysis
interaction energies (Eint) for various molecular pairs at their crystal for the protein-ligand complex using the optimized structure at the
structure geometry were computed using the M06-2X-D3/cc-pVTZ MM/QM [M06-2X/cc-pVTZ] approach. The NCI plot was con-
level of theory. The Eint was corrected for basis set superposition structed from the promolecular approximation and it showed the
error (BSSE) using the counterpoise method [41]. The natural bond relationship between electron density (r) and the reduced density
orbital (NBO) analysis was performed for various molecular pairs at gradient (S). The isosurface was visualized using the PyMOL pro-
their crystal structure geometry. QTAIM analysis was performed to gram [50].
evaluate the strength and existence of intermolecular contacts
using AIMALL package [42].
3. Results and discussion
The time dependent DFT (TD-DFT) calculation was carried out to
simulate the electronic absorption spectrum in the solvent phase
3.1. Description of molecular structure
using Kohn-Sham formalism [43]. The quantitative molecular
electrostatic potentials for the title compound was computed and
The title compound crystallizes in the monoclinic system with
visualized on the 3D surface using the WFA-SAS program [44].
the space group of Pc. Single molecule is observed in the asym-
metric unit. The ORTEP of the title compound is given along with
atom-labelling scheme in Fig. 1. The molecular conformation of the

Table 2
Interaction energy (in kcal mol1) for various molecular pairs in the title compound along with centroid-centroid distance of these molecular pairs. Cg1 is the centroid of the
phenyl ring.

Motifs centroid-centroid distance (Å) Symmetry ECoul Epol Edisp Erep Etot BSSE corrected interaction energy (Eint) Possible Interactions Geometry (Å, )a

Compound (I)
I 4.726 x, ye1, z 3.8 2.2 15.8 10.5 11.3 11.47 C7eH7A$$$p (Cg1) 2.536, 142
II 7.667 x, eyþ2, ze1/2 3.8 1.8 6.7 6.2 6.0 7.65 C9eH9A$$$N2 2.389, 169
N1/S2 3.426(7)
H10A$$$H13A 2.312
III 6.319 x, eyþ1, ze1/2 1.3 0.8 5.0 3.1 4.1 6.63 S1/S2 3.656(3)
IV 12.266 xe1, y, z 1.2 0.3 2.6 1.3 2.8 4.97 C2eH2A$$$F1eC11 2.581, 122
V 13.145 xe1, ye1, z 0.6 0.2 2.3 0.9 2.3 4.79 C2eH2A$$$C12 2.992, 147
VI 15.641 xe1, ey, zþ1/2 1.0 0.2 1.1 1.4 0.9 0.98 C1eBr1/F1eC11 3.062(6), 168
a
Neutron values are given for all DeH$$$A interactions.
 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240 233

CeH$$$p (involving H7A and the centroid of the phenyl ring)

interaction and the resulting interaction energy for this dimer was
found to be 11.3 kcal mol1 (72.5% dispersion contribution). The
second most stabilized molecular pair (motif II) displays the
presence of intermolecular CeH/N interaction (involving H9A and
N2) along with intermolecular N/S (involving N1 and S2) and
H/H interaction (involving H10A and H13A). The interaction en-
ergy for this dimer was calculated to be 6.0 kcal mol1. It is also to
be noted that the electrostatic and dispersion components are
contributing 45.5 and 54.5%, respectively towards the stabilization
of this dimer.
Motif III is formed by an intermolecular S/S (lone pair and
antibonding type of interaction as confirmed by the NBO analysis)
contact and the distance being 3.656(3) Å which is slightly longer
(by 0.06 Å) than the sum of the van der Waals radii of the S atom.
The interaction energy for this motif is 4.1 kcal mol1 with 70.4%
dispersion contribution towards the stabilization. Motif IV is
generated by an intermolecular CeH/F interaction (involving H2A
and F1). This motif is stabilized by 36.6% electrostatic and 63.4%
dispersion energies and the total interaction energy for this dimer
is found to be 2.8 kcal mol1.
Fig. 1. (a) ORTEP diagram of the title compound showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level and (b) Structural su-
Motif V is stabilized by CeH/C interaction (involving H2A and
perimposition of crystal structure (grey) and optimized structures in gas (green) and C12) with an interaction energy of 2.3 kcal mol1. This motif is
solvent phases (orange). stabilized mostly by dispersive in nature (74.2%). It is of interest to
note that there is a short and very rare hetero halogen$$$halogen
contact (Br/F) observed in the title compound with an interaction
title compound could be described as the L-shaped molecule. The energy of 0.9 kcal mol1. This molecular pair is stabilized by
geometrical parameters (bond lengths, angles and torsion angles) almost equal contributions of electrostatic (52.2%) and dispersion
are almost unexceptional indicated by a Mercury Mogul geometry (47.8%) interaction energies.
check [30]. The following bond length and bond angles are flagged
as unusual. The C6¼N2 bond length (observed: 1.262(1) Å; mean 3.3. Hirshfeld surface analysis and 2D fingerprints
value: 1.288(1) Å; z-score: 2.510) and bond angle C4eC5¼N1
(observed: 131.2(8) ; mean value: 129.1(9) ; z-score: 2.229). The The Hirshfeld surface (HS) analysis was performed for the title
thiophene ring is twisted 10.59 out of the mean plane of the 1,3,4- compound as mentioned in our earlier work [35e38]. The relative
oxadiazole ring. The phenyl ring is inclined at an angle of 76.45 and contribution of various intermolecular contacts and the 2D
76.42 with respect to the mean planes of the oxadiazole and thio- decomposed fingerprint plots (FP) for important interactions are
phene rings, respectively. given in Fig. 3. It is important to note that the intermolecular H/H
To understand the nature of the conformational flexibilities of contacts are the major contributing interactions to the Hirshfeld
the title compound, the structure was optimized both in gas and surface area (21.5%). This unusually low contribution is due to the
solvent (acetonitrile) phases. The selected torsion angles that presence of C, N, S, O, Br and F atoms in the title compound and the
describe the overall conformation of the molecule from crystal and interatomic distances between H and H atoms are greater than the
optimized structures compared and presented in Table S1. The sum of their van der Waals radii as evident from the distance,
optimized structures of the title compound in gas and solvent de þ di y 2.4 Å (Fig. 3). It is of interest to note that the intermo-
phases are very similar with the root-mean-square deviation lecular close contacts formed between non-hydrogen atoms are
(RMSD) between them is 0.15 Å (Fig. 1(b)). The RMSD between the found to be 36.2% of the total HS area. The next largest contribu-
X-ray structure and the optimized structure involving non- tions come from both C/H/H/C (11.8%) and N/H/H/N (11.7%)
hydrogen atoms in the gas phase is found be 0.26 Å. The result types of interactions. The former interaction is a representative of
suggests that the thiophene and the phenyl ring are undergoing a intermolecular CeH$$$p interactions and shown as wings on the FP
slight rotational motion (~10 ) in the gas and solvent phases as plot. This interaction is clearly visible on the HS as a red spot which
compared to the X-ray geometry as evident from the torsion angles indicates the presence of a CeH$$$p interaction and the most sta-
listed in Table S1. This slight deviation may be attributed to the bilizing interaction as mentioned in the previous section. The
crystal packing effect. N/H/H/N interactions are shown as a pair spikes with
de þ di y 2.4 Å on the FP and clearly visible on the HS which in-
3.2. Crystal packing and energetics dicates the presence of an intermolecular CeH/N interaction
(motif II) (Fig. 3(c)).
The crystal structure of the title compound is stabilized by The intermolecular Br/H/H/Br and F/H/H/F contacts
intermolecular CeH $$$p, CeH /N, CeH /F, S/S, N/S and a short contribute 9.8 and 5.7%, respectively to the HS area. These two
hetero halogen$$$halogen (Br/F) interactions. Various molecular contacts are not visible on the HS, because of the interatomic dis-
dimers extracted from the crystal structure and their non-covalent tances are larger than the sum of the van der Waals radii of the
bonding strengths were estimated using PIXEL and DFT methods respective interacting atoms. The other notable intermolecular
(Table 2). As shown in Table 2, the interaction energies of various contacts (not visible on the HS) such as S/S, Br/F and S/O con-
molecular pairs calculated by these two methods are comparable. tacts are contributing to the crystal packing and were calculated to
Fig. 2 shows various intermolecular interactions exist in different be 5, 5 and 4.3%, respectively, to the total HS area. However, the
molecular pairs identified from the crystal structure. The most existence of these non-visible interactions on the HS is confirmed
stabilized molecular dimer (motif I) is formed by an intermolecular by QTAIM and NBO analysis and more details are given in the next
234 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240

Fig. 2. Various molecular dimers observed in the crystal structure of the title compound. Dashed lines indicate the intermolecular interactions and motif numbers are shown.

Fig. 3. (a) Two dimensional fingerprint plots obtained by the HS analysis, (b) Relative contributions of various intermolecular contacts and (c) Key intermolecular contacts are
visible on the HS and interacting atoms are labelled.

section. It is worth mentioning that the intermolecular contacts Br/S (1.3%), Br/O (0.7%), N/N (0.4%), N/C (0.4%) and O/H
mostly involve non-hydrogen atoms such as C/C (3.8%), Br/C (0.3%) and these contacts are collectively contributing 25% to the
(3.5), S/C (3.2%), S/N (2.9%), C/O (2.9%), S/H (2.8), F/C (2.8%), total HS area.
 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240 235

3.4. Quantitative molecular electrostatic potential Fig. 4(c). Motif III is formed by S1/S2 and S1/O1 contacts as
noted earlier. The MESP analysis of motif III shown in Fig. 4(d)
Quantitative molecular electrostatic potentials (MESP) are indicates a decrease in positive and negative potentials, which
widely used as a tool to investigate how various intermolecular corroborate the presence of these non-bonded contacts. The other
interactions mutually interplay between molecules. Fig. 4 shows negative values are localized on the bromine and fluorine atoms
the two different orientations of the MESP of the isolated molecule with the values of 6.40 and 17.72 kcal mol1 respectively. These
and the locations of various most positive (shown in black spheres) potentials suggest the formation of a Br/F interaction in the title
and negative potentials (shown in blue spheres) along with their compound.
values, designated as Vs,max and Vs,min, respectively. The most pos-
itive potentials Vs,max values are observed on the hydrogen atoms of
3.5. QTAIM and NBO analysis
thiophene, benzene and methylene groups. The highest Vs,max is
observed on the methylene hydrogen with a value of
We used the Bader's theory of atoms-in-molecules [51]
23.98 kcal mol1, while the hydrogens on thiophene have a Vs,max of
approach and NBO analysis to characterize the strengths of various
23.50 and 23.35 kcal mol1. The least Vs,max on hydrogens are found
intermolecular interactions existing in different motifs of the title
to be on the hydrogen atoms of benzene ring with values of 16.25,
compound in addition to the NBO analysis. The calculated electron
14.56 and 13.97 kcal mol1. This indicates the presence of electronic
density (r), the Laplacian of the electron density (V2r), local po-
effect in the molecule. The most positive potentials observed on the
tential energy density (V), local gradient kinetic energy density (G)
methylene and thiophene hydrogens favor the formation of the
at the bond critical points (BCP's) for the various dimeric pairs
intermolecular interactions. This observation supports the
(motifs I-VI) existing in the crystal structure are provided in
involvement of methylene and thiophene hydrogens (motifs I, IV
Table S2. The local stabilization energy was obtained from the
and V) in the intermolecular interactions. The other positive po-
equation: D. E (int) ¼ V  0.5 at the BCP for the intermolecular
tentials are seen on the hydrogen atoms of methylene and benzene
interactions was calculated as proposed earlier [52]; where D. E(int)
moiety. Again, this is also supporting the involvement of these
is the dissociation energy of the interaction. The selected inter-
atoms in the formation of motifs I and II.
molecular interactions in various dimeric motifs are listed in
The most electronegative potential (Vs,min) is located on the ni-
Table 3. The molecular graphs for these dimeric pairs are presented
trogen atom (N1) of the oxadiazole ring with a value
in Fig. S1. In motif I, there are 8 BCP's observed with the electron
of 35.91 kcal mol1. The negative potentials with
density for these interactions, whose values fall in the range of
values 7.45, 7.61 and 4.37 kcal mol1 are located close to the
0.024e0.049 e. Å3. The strongest interactions are observed be-
two sulfur (S1 and S2) and oxygen (O1) atoms. To understand the
tween atom H7A of the methylene and carbon atoms (C9 and C10)
nature of interactions observed in motifs II and III, we calculated
of the phenyl ring with the D. E(int) value of 1.25 and
MESP for the respective dimers and the results are depicted in
1.33 kcal mol1 and these interactions are representing the inter-
Fig. 4. The increase in negative potential compared to the monomer
molecular CeH$$$p interaction. This molecular dimer is further
clearly suggests that the existence of S2/N1 contact as seen in
stabilized by intermolecular O1/S2, C5/S2, Br1/S1, N2/H7B,

Fig. 4. Molecular electrostatic surface potentials mapped on the electron density isosurface at 0.001 a. u. The Vs,max and Vs,min values are indicated as small spheres. (aeb) Two
different orientations of the title compound (c) S/N contact in motif II and (d) S/S/O contacts in motif III.
236 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240

Table 3 Motif III has two intermolecular BCPs (S2/S1, O1/S1) with the
Selected topological parameters for important interactions observed in the title electron density values in the range of 0.033e0.043 eÅ3 with the
compound. Rij: Bond path (Å), r: electron density (a.u.); V2r: Laplacian of electron
density (a.u.); V: potential energy density (a.u.); G: kinetic energy density (a.u.).
D. E(int) values of 0.89e1.06 kcal mol1. There is a charge transfer
D.E(int): dissociation energy ¼ -V  0.5 (kcal mol1). between the lone pair donor orbital 1 on the sulfur atom (S1) of
thiophene ring of one of the monomers to the anti-bonding orbital
Interacting atoms Rij r V2r V G D.E(int)
S2eC7 of the second monomer with an E(2) value of 0.27 kcal mol1
Motif I suggesting the presence of S2/S1 contact. For the O1/S1 contact,
C10/H7A 2.820 0.047 0.657 0.004251 0.005533 1.33
there is a charge transfer between lone pair orbital 1 on the oxygen
C9/H7A 2.871 0.049 0.620 0.003998 0.005213 1.25
Motif II atom (O1) and anti-bonding orbital S1eC4 with an E(2) value of
H9A$$$N2 2.421 0.071 1.046 0.00731 0.009079 2.29 0.14 kcal mol1. In motif IV, there are three intermolecular BCPs
S2/N1 3.456 0.040 0.505 0.003177 0.004206 1.00 observed of which F1 atom makes two contacts with atoms H2A
H10A$$$H13A 2.380 0.034 0.488 0.003055 0.004059 0.96
and H3A in addition to H2A$$$H12A contact. The D. E(int) values for
Motif III
S2/S1 3.689 0.043 0.547 0.003366 0.004518 1.06
these interactions are in the range of 0.62e1.38 kcal mol1. The NBO
Motif IV result suggested that there is a charge transfer between the lone
H2A$$$F1 2.623 0.038 0.629 0.004387 0.005457 1.38 pair orbital 2 on the F1 atom and anti-bonding orbital C2eH2A with
Motif VI an E(2) value of 0.12 kcal mol1.
Br1/F1 3.068 0.052 0.877 0.005500 0.007298 1.73
According to the QTAIM calculation, motif V is stabilized by two
intermolecular Br1/H12A and H2A$$$C12 at their BCPs. The
strengths of these interactions are very similar (D.E(int): 0.56 and
C4/O1 and Br1/C1 contacts with the D. E(int) value in the range 0.57 kcal mol1). It is to be noted that the former interaction is of
0.90e51 kcal mol1. In order to understand the charge transfer the lone pair [LP(2)Br1]-anti-bonding C12eH12A orbital type of
from one monomer to the other monomer within the dimeric pair, interaction with an E(2) value of 0.19 kcal mol1. While in the latter
we performed NBO analysis. The result suggested that the charge interaction, a charge transfer takes place between bonding orbital
transfer occurs from the bonding orbital (C8eC9) to the anti- [s(C12eC13)] and anti-bonding orbital [s*(C2eH2A)] with second
bonding orbital (C7eH7A) with second-order perturbation energy order perturbation energy of 0.22 kcal mol1.
(E(2)) of 0.24 kcal mol1. The lone pair donor orbital 2 on the sulfur Motif VI is stabilized by an intermolecular Br/F contact at the
atom (S1) interacts with anti-bonding orbital N1eC5. The lone pair BCP with the electron density value of 0.052 eÅ3. It is of interest to
donor orbital 2 on the S2 makes contact with anti-bonding orbital note that this interaction is found to be the second most stabilizing
N1eC5. The former interaction scores E(2) value of 0.17 kcal mol1, interaction (D.E(int) ¼ 1.73 kcal mol1) in the title compound. The
while the latter contact provides 0.36 kcal mol1 towards stabili- NBO analysis indicated that the charge transfer is observed be-
zation. As shown in Fig. 5(a), these two interactions indicate the tween lone pair electron 1 on the F1 atom to the anti-bonding
presence of C/S contacts in motif I. It is of interest to note that Br1eC1 orbital with an E(2) value of 0.76 kcal mol1. Collectively,
other contacts present in this motif are weaker when compared to the hetero-halogen contact displays an important role towards the
the above mentioned contacts. stabilization of the title compound in the solid state.
In motif II, there are 3 intermolecular BCPs (H9A$$$N2, S2/N1
and H10A$$$H13A) observed with the electron density values in the
range of 0.034e0.071 eÅ3. The D. E(int) values for these in- 3.6. UVeVis spectra and frontier molecular orbitals
teractions are calculated to be 0.96e2.26 kcal mol1. The most
stabilizing contact is found to be H9A$$$N2 contact. From the NBO The UVeVisible spectrum for the title compound was recorded
analysis, we found that a charge transfer between lone pair orbital 1 in acetonitrile and the corresponding spectrum was simulated us-
on atom N2 and anti-bonding orbital C9eH9A with the E(2) value of ing the PBE1PBE/cc-pVTZ level of theory. As shown in Fig. 6(a), the
1.09 kcal mol1. Moreover, the intermolecular experimental and theoretical spectra are in good agreement. The
C10eH10A$$$H13AeC13 contact is of bonding and anti-bonding experimental spectrum shows an intense absorption at 302 nm.
type of interaction with E(2) value of 0.11 kcal mol1 (Fig. 5(b)). The corresponding absorption peak was calculated at 308 nm with

Fig. 5. Natural bond orbitals (NBO) showing the interactions between lone pair orbitals and anti-bonding orbitals (a) in motif I and (b) interaction between bonding and anti-
bonding orbitals in motif II.
 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240 237

Fig. 6. (a) Overlay diagram of observed and simulated UVeVis spectra and (b) Various HOMO and LUMO orbital spatial plot.

Table 4 form type II geometry [26]. It was also reported that the hetero-
Excitation energies (nm), oscillators strengths, various configurations along with halogen contacts predominately of type II geometry, owing to the
experimental absorption data for the title compound in acetonitrile solvent.
greater polarizability of the heavier halogen atoms. Desiraju and his
Excitation Energy f Main configuration Expt. co-worker further classified some of the contacts as quasi-type I
308.87 0.7304 HOMO - > LUMO (98%) 302 geometry which bridges the gap between type I and type II [53].
261.46 0.0265 H-1 - > LUMO (97%) 265 Our analysis consists of relatively more data for Br/F contact when
245.98 0.0232 H-2 - > LUMO (89%) 254 compared to the earlier report. It is important to note that 76
238.37 0.0573 H-4 - > LUMO (81%) e
contacts out of 170 prefer quasi-type I geometry (rq1eq2r<20 )
228.49 0.0442 HOMO - > Lþ2 (43%) 216
which is about ~45%. An analysis of Br/F contact distance vs. q1
angle suggested that q1 has some preferences. Most of the points
are concentrated between 120 and 180 region (Fig. 7(a)), while the
an oscillator strength of 0.730 in the TD-DFT calculation. The main
Br/F contact distance vs q2 angle are scattered. However, more
transition was due to the HOMO to LUMO transition with 98%
number of points is observed greater than 120 (Fig. 7(b)). The
contribution (Table 4). The selected frontier orbitals are shown in
distribution of q1 and q2 angles indicated that most of the points
Fig. 6(b). It is clearly seen from this figure that the HOMO and LUMO
appeared on the lower diagonal regions (Fig. 7(c)). This suggested
orbitals are mainly localized on the oxadiazole and thiophene
that the preferential polarization of the Br atom as d(þ). It is of
moieties, with only change in the spatial orientation of orbitals. A
interest to note the Br (q1) angles are more than the F (q2) angles in
hump observed at 265 nm and the corresponding peak was
125 instances and the Br/F contacts fall within the sum of the van
calculated to be at 261 nm with an oscillator strength of 0.265. This
der Waals radii of Br and F suggested that these contact could play
peak is mainly responsible for the transition from the HOMO-1 to
an important role in the crystal packing.
LUMO orbital with a contribution of 97%. It is also to be noted that
the HOMO-1 and HOMO-2 orbital is localized over the entire
molecule, while the LUMO and other unoccupied orbitals are 3.8. Molecular docking analysis
located mainly on the benzene moiety. This clearly indicates the
transition from the occupied to the unoccupied orbitals during To rationalize the potency of the title compound as an antima-
excitation. larial agent, the title compound was docked against Plasmodium
falciparum dihydrofolate reductase. The glide XP docking score for
the title compound along with the two control inhibitors is pre-
3.7. CSD analysis of Br/F interactions sented in Table 5. The results suggest that the binding affinity of the
title compound towards PfDHFR is nearly comparable with the
To understand the geometrical preferences of hetero-halogen chloroquine inhibitor, while the binding affinity of pyrimethamine
(Br/F) contact, we performed a CSD search (CSD version 5.37, is slightly better. In the chloroquine-DHFR complex, the residue ASP
November 2016) with the following criteria. (i) 3D coordinates 54 makes ionic interaction with the inhibitor whereas, Phe 58 is
determined (ii) R-factor  0.05 (iii) not disordered (iv) no errors (v) involved in a cationic$$$p interaction with the inhibitor. In
not polymeric (vi) no ions (vii) no powder structures and (viii) only pyrimethamine-DHFR complex, there are three hydrogen bonding
organics along with the contact distance is less than the sum of the interactions observed between the protein and ligand. The residue
van der Waals radii of interacting atoms. We found 127 hits which Asp 54 forms two hydrogen bonds with the ligand and the back-
resulted 169 Br/F contacts. The minimum, maximum and average bone Ile 14 makes hydrogen bond with one of the amino groups of
distance for this contact is observed to be 2.948, 3.319 and 3.201 Å, the ligand. In the case of title compound-DHFR complex, the in-
respectively. In the title compound, the Br/F distance is 3.068 Å teractions between protein and ligand are of van der Waals type of
and q1 (CeBr/F) and q2 (Br/FeC) angles are 168 and 167, interactions in nature (Fig. S2).
respectively. These angles indicated that the CeBr/FeC contact In order to gain more details around the ligand region, we
prefers to adopt type I trans geometry. It was reported that homo- performed QM/MM calculation using two different levels of the-
halogen (F/F) contact prefers to type I geometry, while the other ories as mentioned in the experimental section. The results indicate
homo-halogen (Br/Br, Cl/Cl, and I/I) contacts are preferred to that there is a good agreement with the binding energies between
238 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240

Fig. 7. (a) Distribution of Br/F distance vs. q1, (b) Distribution of Br/F distance vs. q2 and (c) Distribution of q1 vs. q2.

Table 5
The glide XP docking scores for the title compound and two known DHFR inhibitors. The relative binding energies are calculated using QM/MM method.

Compound Glide XP score (in kcal mol1) Binding energy [E(bind)] (in kcal mol1) Relative binding energy (in kcal mol1)

B3LYP/LACVP* M06-2X/cc-pVTZ B3LYP/LACVP* M06-2X/cc-pVTZ

Title compound (Present study) 5.4 18638.5 18637.1 0.0 0.0

Pyrimethamine 7.8 18593.4 18593.4 45.1 43.7
Chloroquine 5.0 18579.1 18581.5 59.4 55.6

B3LYP/LACVP* and M06-2X/cc-pVTZ levels of theory. It can be seen of green surfaces. This indicates that this fragment is important for
from Table 5, the title compound may form a stable complex with the stabilization of protein-ligand complex formation. The residues
PfDHFR than the control inhibitors. The relative binding energies of Thr 107 and Gly 44 make CeH/F type of interactions with the title
the control inhibitors are found to be 44e60 kcal mol1 higher than compound. These in-silico analyses collectively suggest that the
the title compound. title compound may be a promising anti-malarial lead by inhibiting
To understand the nature of non-covalent interactions between the DHFR enzyme.
PfDHFR and the title ligand, NCI surface around the ligand in the
active site of the PfDHFR protein was constructed. As shown in
4. Conclusions
Fig. 8, the broad surfaces around the bromothiophene ring indica-
tive of stabilizing van der Waals interactions. Specifically, residues
The title compound was synthesized, crystallized and the X-ray
Ile 14, Cys 15, Asp 54, Tyr 57 and Phe 58 are involved in the non-
diffraction analysis was performed. The crystal structural analysis
covalent interactions with the title compound. The residue Leu 46
revealed that the title compound is stabilized by various intermo-
makes at least four intermolecular contacts with the ligand. The
lecular interactions such as CeH $$$p, CeH /N, CeH /F, S/S,
fluorophenyl fragment of the ligand is also surrounded by a region
N/S and a short hetero halogen$$$halogen (Br/F) interactions.
 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240 239

Fig. 8. NCI surface around the title compound in the active site of PfDHFR protein. NCI surfaces show only intermolecular interactions and residues are shown within 4 Å from the
ligand. The gradient cut-off is s ¼ 0.30 au.

The strengths of these interactions were quantified using PIXEL, amino]-1,3,4-oxadiazoles and 2-[(5-aryl-1,3,4-oxadiazol-2-yl)imino]-5-
phenyl/methyl-4-thiazolidinones, Drug Res. 47 (1997) 1134e1138.
QTAIM and NBO analyses. The results suggested that weak in-
[5] B.S. Holla, R. Gonsalves, S. Shenoy, Synthesis and antibacterial studies of a new
teractions like a short Br/F contact and other intermolecular in- series of 1,2-bis(1,3,4-oxadiazole-2-yl)ethanes and 1,2-bis(4-amino-1,2,4-
teractions contacts (S/S, N/S) showed significant contribution triazol-3-yl)ethanes, Eur. J. Med. Chem. 35 (2000) 267e271.
towards the crystal packing established by various theoretical [6] S.L. Gaonkar, K.M.L. Rai, B. Prabhuswamy, Synthesis and antimicrobial studies
of a new series of 2-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}-5-substituted-
methods. A detailed CSD analysis was performed to understand the 1,3,4-oxadiazoles, Eur. J. Med. Chem. 41 (2006) 841e846.
geometrical preferences of Br/F contacts and suggested the pref- [7] X.J. Zou, L.H. Lai, G.Y. Jin, Z.X. Zhang, Synthesis, fungicidal activity, and 3D-
erential polarization of the heavier bromine atom as d(þ). Overall QSAR of pyridazinone-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazoles,
J. Agric. Food Chem. 50 (2002) 3757e3760.
trend indicated that this type of contact could play an important [8] S.S. Thakkar, P. Thakor, H. Doshi, A. Ray, 1,2,4-triazole and 1,3,4-oxadiazole
role in the crystal packing. The experimental and theoretical analogues: synthesis, MO studies, in silico molecular docking studies, anti-
UVeVis spectra were in close resemblance and suggested the malarial as DHFR inhibitor and antimicrobial activities, Bioorg. Med. Chem. 25
(2017) 4064e4075.
ligand-to-ligand charge transfer takes place within the molecule. [9] €
S.G. Küçükgüzel, E.E. Oruç, S. Rollas, F. Şahin, A. Ozbek, Synthesis, character-
The band gap energy indicated the kinetic stability of the molecule. ization and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles
A detailed in-silico analysis reveals that the title compound may be and some related compounds, Eur. J. Med. Chem. 37 (2002) 197e206.
[10] M.A. Ali, M. Shaharyar, Oxadiazole Mannich bases: synthesis and anti-
a promising anti-malarial candidate by inhibiting DHFR enzyme. mycobacterial activity, Bioorg. Med. Chem. Lett 17 (2007) 3314e3316.
[11] D. Zampieri, M.G. Mamolo, E. Laurini, M. Fermeglia, P. Paola, S. Pricl, E. Banfi,
Acknowledgements G. Scialino, L. Vio, Antimycobacterial activity of new 3,5-disubstituted 1,3,4-
oxadiazole-2(3H)-one derivatives. Molecular modeling investigations, Bio-
org. Med. Chem. 17 (2009) 4693e4707.
This work was funded by the Deanship of Scientific Research at [12] K. Dalip, S. Swapna, O.J. Emmanuel, S. Kavita, D. Kumar, S. Sundaree,
Princess Nourah Bint Abdulrahman University through the E.O. Johnson, K. Shah, An efficient synthesis and biological activity of novel
indolyl-1,3,4-oxadiazoles as potent anticancer agents, Bioorg. Med. Chem. Lett
Research Group Program (Grant No. RGP-1438-0010). ST thanks the
19 (2009) 4492e4494.
DST-SERB (SB/YS/LS-19/2014) and Prof. TRR grant for research [13] G.A. Pinna, G. Murineddu, C. Murruzzu, V. Zuco, F. Zunino, G. Cappelletti,
funding. ST and MJP would like to thank Laboratorio Nacional de R. Artali, G. Cignarella, L. Solano, S. Villa, Synthesis, modeling and antimitotic

mputo del Sureste (LNS-BUAP) for computational properties of tricyclic systems characterized by a 2-(5-phenyl-1H-pyrrol-3-
Superco
yl)-1,3,4-oxadiazole moiety, ChemMedChem 4 (2009) 998e1009.
resources. [14] G.D. Reddy, S. Park, H.M. Cho, T.J. Kim, M.E. Lee, Antiallergic activity profile
in vitro RBL-2H3 and in vivo passive cutaneous anaphylaxis mouse model of
new sila-substituted 1,3,4-oxadiazoles, J. Med. Chem. 55 (2012) 6438e6444.
Appendix A. Supplementary data
[15] A. Husain, M. Ajmal, Synthesis of novel 1,3,4-oxadiazole derivatives and their
biological properties, Acta Pharm. 59 (2009) 223e233.
Supplementary data related to this article can be found at [16] A. Savarino, A historical sketch of the discovery and development of HIV-1
https://doi.org/10.1016/j.molstruc.2018.07.102. integrase inhibitors, Expet Opin. Invest. Drugs 15 (2006) 1507e1522.
[17] N.D. James, J.W. Growcott, Zibotentan, Drugs Future 34 (2009) 624e633.
[18] G.W. Adelstein, C.H. Yen, E.Z. Dajani, R.G. Bianchi, 3,3-diphenyl-3-(2-alkyl-
References 1,3,4-oxadiazole-5-yl)propylcycloalkylamines, a novel series of antidiarrheal
agents, J. Med. Chem. 19 (1976) 1221e1225.
[1] K.D. Patel, S.M. Prajapati, S.N. Panchal, H.D. Patel, Review of synthesis of 1,3,4- [19] Y. Ducharme, M. Blouin, C. Brideau, A. Ch^ ateauneuf, Y. Gareau, E.L. Grimm,
oxadiazole derivatives, Synth. Commun. 44 (2014) 1859e1875. H. Juteau, S. Laliberte, B. MacKay, F. Masse, M. Ouellet, M. Salem, A. Styhler,
[2] M. Carbone, Y. Li, C. Irace, E. Mollo, F. Castelluccio, A. Di Pascale, G. Cimino, R.W. Friesen, The discovery of setileuton, a potent and selective 5-
R. Santamaria, Y.-W. Guo, M. Gavagnin, Structure and cytotoxicity of phidia- lipoxyhenase inhibitor, ACS Med. Chem. Lett. 1 (2010) 170e174.
nidines A and B: first finding of 1,2,4-oxadiazole system in a marine natural [20] X. Ouyang, E.L. Piatnitski, V. Pattaropong, X. Chen, H.-Y. He, A.S. Kiselyov,
product, Org. Lett. 13 (2011) 2516e2519. A. Velankar, J. Kawakami, M. Labelle, L. Smith II, J. Lohman, S.P. Lee,
[3] J.C. Buchanan, B.P. Petersen, S. Chamberland, Concise total synthesis of phi- A. Malikzay, J. Fleming, J. Gerlak, Y. Wang, R.L. Rosler, K. Zhou, S. Mitelman,
dianidine A and B, Tetrahedron Lett. 54 (2013) 6002e6004. M. Camara, D. Surguladze, J.F. Doody, M.C. Tuma, Oxadiazole derivatives as a
€ Ates, A. Kocabalkanli, G.O. Sanis, A.C. Ekini, A. Vidin, Synthesis and anti-
[4] O. novel class of antimitotic agents: synthesis, inhibition of tubulin polymeri-
bacterial activity of 5-aryl-2-[(a-chloro-a-phenylacetyl/a-bromopropionyl) zation, and activity in tumor cell lines, Bioorg. Med. Chem. Lett 16 (2006)
240 L.H. Al-Wahaibi et al. / Journal of Molecular Structure 1175 (2019) 230e240

1191e1196. [39] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
[21] M. Ogata, H. Atobe, H. Kushida, K. Yamamoto, In vitro sensitivity of Myco- J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson,
plasmas isolated from various animals and sewage to antibiotics and nitro- H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino,
furans, J. Antibiot. 24 (1971) 443e451. G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
[22] G. Barbarella, M. Zangoli, F. Di Maria, Synthesis and applications of thiophene J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
derivatives as organic materials, Adv. Heterocycl. Chem. 123 (2017) 105e167. J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers,
[23] D. Gramec, L.P. Masi c, M.S. Dolenc, Bioactivation potential of thiophene- K.N. Kudin, V.N. Staroverov, T. Keith, R. Kobayashi, J. Normand,
containing drugs, Chem. Res. Toxicol. 27 (2014) 1344e1358. K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi,
[24] D.K. Dalvie, A.S. Kalgutkar, S.C. Khojasteh-Bakht, R.S. Obach, J.P. O'Donnell, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo,
Biotransformation reactions of five-membered aromatic heterocyclic rings, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi,
Chem. Res. Toxicol. 15 (2002) 269e299. C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski,
[25] A.S. Eust
aquio, D. O'Hagan, B.S. Moore, Engineering fluorometabolite pro- G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas,
duction: fluorinase expression in Salinispora tropica yields fluorosalinospor- J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian 09, Revision D.01,
amide, J. Nat. Prod. 73 (2010) 378e382. Gaussian, Inc., Wallingford, CT, 2013.
[26] S.K. Nayaak, M. Kishore Reddy, T.N. Guru Row, D. Chopra, Role of hetero- [40] S. Grimme, J. Anthony, S. Ehrlich, H. Krieg, A consistent and accurate ab initio
halogen (F$$$X, X¼Cl,Br, and I) or homo-halogen (X$$$X, X¼F, Cl, Br, and I) parametrization of density functional dispersion correction (DFT-D) for the 94
interactions in substituted benzanilides, Cryst. Growth Des. 11 (2011) elements H-Pu, J. Chem. Phys. 132 (2010) 154104e154122.
1578e1596. [41] S.F. Boys, F. Bernardi, The calculation of small molecular interactions by the
[27] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M.C. Burla, G. Polidori, differences of separate total energies. Some procedures with reduced errors,
M. Camalli, SIR92-a program for automatic solution of crystal structures by Mol. Phys. 19 (1970) 553e566.
direct methods, J. Appl. Crystallogr. 27 (1994) 435. [42] A.K. Todd, AIMALL version 16.05.18, TK Gristmill Software, Overland Park KS,
[28] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Crystallogr. USA, 2017.
C71 (2015) 3e8. [43] W. Kohn, L.J. Sham, Self-consistent equations including exchange and corre-
[29] H.D. Flack, On enantiomorph-polarity estimation, Acta Crystallogr. A39 (1983) lation effects, Phys. Rev. 140 (1965) A1133eA1138.
876e881. [44] F.A. Bulat, A. Toro-Labbe
, T. Brinck, J.S. Murray, P. Politzer, Quantitative
[30] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, analysis of molecular surfaces: areas, volumes, electrostatic potentials and
M. Towler, J. van de Streek, Mercury: visualization and analysis of crystal average local ionization energies, J. Mol. Model. 16 (2010) 1679e1691.
structures, J. Appl. Crystallogr. 39 (2006) 453e457. [45] L.H. Al-Wahaibi, S. Sujay, G. Ganesh Muthu, A.A. El-Emam,
[31] S.K. Wolff, D.J. Grimwood, J.J. McKinnon, M.J. Turner, D. Jayatilaka, M.A. N.S. Venkataramanan, F.A.M. Al-Omary, H.A. Ghabbour, J. Percino,
Spackman, University of Western Australia, 2012. S. Thamotharan, Theoretical investigations of two adamantane derivatives: a
[32] P. Venkatesan, S. Thamotharan, R. Ganesh Kumar, A. Ilangovan, Invariant and combined X-ray, DFT, QTAIM analysis and molecular docking, J. Mol. Struct.
variable intermolecular interactions in functionalized malonic acid half- 1159 (2018) 233e245.
esters: X-ray, Hirshfeld surface and PIXEL energy analyses, CrystEngComm [46] R.A. Friesner, R.B. Murphy, M.P. Repasky, L.L. Frye, J.R. Greenwood,
17 (2015) 904e915. T.A. Halgren, P.C. Sanschagrin, D.T. Mainz, Extra Precision Glide: docking and
[33] P. Venkatesan, S. Thamotharan, A. Ilangovan, H. Liang, T. Sundius, Crystal scoring incorporating a model of hydrophobic enclosure for protein-ligand
structure, Hirshfeld surfaces and DFT computation of NLO active (2E)-2- complexes, J. Med. Chem. 49 (2006) 6177e6196.
(ethoxycarbonyl)-3-[(1-methoxy-1-oxo-3-phenylpropan-2-yl)amino]prop-2- [47] R. Sathya, S. Thamotharan, In silico based virtual screening and mixed mode
enoic acid, Spectrochim. Acta A 153 (2016) 625e636. QM/MM calculation identifies caffeine scaffold for designing potential in-
[34] P. Venkatesan, V. Rajakannan, N.S. Venkataramanan, A. Ilangovan, T. Sundius, hibitors for tyrosyl tRNA synthetase of Mycobacterium tuberculosis, Int. J.
S. Thamotharan, Structural investigation of (2E)-2-(ethoxycarbonyl)-3-[(4- Quant. Chem. 115 (2015) 187e195.
methoxyphenyl)amino]prop-2-enoic acid: X-ray crystal structure, spectros- [48] R.B. Murphy, D.M. Philipp, R.A. Friesner, A mixed quantum mechanics/mo-
copy and DFT, J. Mol. Struct. 1119 (2016) 259e268. lecular mechanics (QM/MM) method for large-scale modeling of chemistry in
[35] M. Udayakumar, K. Jagatheeswaran, S.S. Ganesan, N.S. Venkataramanan, protein environments, J. Comput. Chem. 21 (2000) 1442e1457.
S. Madan Kumar, K. Byrappa, Investigation of 9-(2-hydroxy-4,4-dimethyl-6- [49] J. Contreras-Garcia, E.R. Johnson, S. Keinan, R. Chaudret, J.P. Piquemal,
oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one: D.N. Beratan, W. Yang, NCIPLOT: a program for plotting non-covalent inter-
crystal structure, AIM and NBO analysis, J. Mol. Struct. 1133 (2017) 510e518. action regions, J. Chem. Theor. Comput. 7 (2011) 625e632.
[36] A. Gavezzotti, Efficient computer modeling of organic materials. The atom- [50] The PyMOL Molecular Graphics System, Version 1.8 Schro €dinger, LLC.
atom, Coulomb-London-Pauli (AA-CLP) model for intermolecular [51] R.F.W. Bader, A quantum theory of molecular structure and its applications,
electrostatic-polarization, dispersion and repulsion energies, New J. Chem. 35 Chem. Rev. 91 (1991) 893e928.
(2011) 1360e1368. [52] E. Espinosa, E. Molins, C. Lecomte, Hydrogen bond strengths revealed by to-
[37] A. Gavezzotti, Calculation of intermolecular interaction energies by direct pological analyses of experimentally observed electron densities, Chem. Phys.
numerical integration over electron Densities. 2. An improved polarization Lett. 285 (1998) 170e173.
model and the evaluation of dispersion and repulsion energies, J. Phys. Chem. [53] V.R. Pedireddi, D. Shekhar Reddy, B. Satish Goud, D.C. Craig, A. David Rae,
B 107 (2003) 2344e2353. G.R. Desiraju, The nature of halogen$$$halogen interactions and the crystal
[38] A. Gavezzotti, Calculation of intermolecular interaction energies by direct structure of 1,3,5,7-tetraiodoadamantane, J. Chem. Soc. Perkin Trans. 2 (1994)
numerical integration over electron Densities. I. electrostatic and polarization 2353e2360.
energies in molecular crystals, J. Phys. Chem. B 106 (2002) 4145e4154.