Insights into the nature of weak noncovalent interactions in 3-(4-fluorophenyl)-6-(2-fluorophenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a potential bioactive agent: X-ray, QTAIM and molecular docking analysis

Article abstract of DOI:10.1016/j.molstruc.2019.01.106

A thorough examination of weak interactions present in the crystal structure of the title compound was investigated. Intramolecular C–H?N and F?S interactions make the molecule as fused 6,5,5,5,6,6-membered ring system. Two of the closely related structur

Full text of DOI:10.1016/j.molstruc.2019.01.106

Accepted Manuscript
Insights into the nature of weak noncovalent interactions in 3-(4-fluorophenyl)-6-(2-
fluorophenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a potential bioactive agent: X-ray,
QTAIM and molecular docking analysis
Lamya H. Al-Wahaibi, Gopalan Akilandeswari, Ravisankar Anusha, Nora H. Al-
Shaalan, Omkulthom M. Alkmali, Ali A. El-Emam, Judith M. Percino, Subbiah
Thamotharan
PII:
S0022-2860(19)30124-3
DOI:
https://doi.org/10.1016/j.molstruc.2019.01.106
MOLSTR 26157
Reference:
To appear in: Journal of Molecular Structure
Received Date: 28 December 2018
Revised Date: 29 January 2019
Accepted Date: 31 January 2019
Please cite this article as: L.H. Al-Wahaibi, G. Akilandeswari, R. Anusha, N.H. Al-Shaalan, O.M. Alkmali,
A.A. El-Emam, J.M. Percino, S. Thamotharan, Insights into the nature of weak noncovalent interactions
in 3-(4-fluorophenyl)-6-(2-fluorophenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a potential bioactive
agent: X-ray, QTAIM and molecular docking analysis, Journal of Molecular Structure (2019), doi: https://
doi.org/10.1016/j.molstruc.2019.01.106.
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GRAPHICAL ABSTRACT

ACCEPTED MANUSCRIPT
Insights into the nature of weak noncovalent interactions in 3-(4-
fluorophenyl)-6-(2-fluorophenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, a
potential bioactive agent: X-ray, QTAIM and molecular docking analysis
Lamya H. Al-Wahaibia, Gopalan Akilandeswarib, Ravisankar Anushab, Nora H. Al-Shaalana,
Omkulthom M. Alkmalic, Ali A. El-Emamd, Judith. M. Percinoe, Subbiah Thamotharanb,*
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 Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint
Abdulrahman University, Riyadh 11671, Saudi Arabia
d Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura,
Mansoura 35516, Egypt
e Unidad de Polímeros y Electrónica Orgánica, Instituto de Ciencias, Benemérita Universidad
Autónoma de Puebla, Val3-Ecocampus Valsequillo, Independencia O2 Sur 50, San Pedro
Zacachimalpa, Pue. Mexico
________________
Corresponding author.
E-mail address: thamu@scbt.sastra.edu (S. Thamotharan).
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ABSTRACT
A thorough examination of weak interactions present in the crystal structure of the title
compound was investigated. Intramolecular C–H···N and F···S interactions make the
molecule as fused 6,5,5,5,6,6-membered ring system. Two of the closely related structures
show 1D-isostructurallity with the title compound. The crystal structure is stabilized by
different types of weak intermolecular C–H···N, C–H···F, C–H···π and S···π and π···π
interactions. The first two strongest dimers are stabilized by stacking interactions. The nature
of these interactions and their role was established through quantum theory of atoms-in-
molecules approach. The Hirshfeld surface analysis clearly reveals that the para-substituted
fluorine substantially change the contribution of intermolecular H···H and H···C contacts.
The molecular docking analysis suggests that the title compound shows anti-inflammatory
activity and selective against cyclooxygenase-1 (COX-1) enzyme and the 2-fluorophenyl and
triazole moieties of the title compound are involved in the π···π interactions with active site
aromatic residues.
Keywords: 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole; anti-inflammatory; PIXEL; QTAIM;
Molecular docking
1. Introduction
Non-covalent interactions between molecules play a vital role in supramolecular
chemistry, structural biology and materials science [1]. A thorough investigation of both
strong and weak non-covalent interactions is an essential aspect of crystal engineering as it
assists to tailor new materials with desired physicochemical properties [2-4]. The role of
conventional hydrogen bonds and π···π interactions is well recognized in crystal engineering
[5-7], structural chemistry and biology [8]. The importance of different types of weak
interactions in classical and non-classical nature in different organic materials was studied
using X-ray crystallography and a variety of theoretical approaches [9-12]. In order to
understand the importance of different weak interactions including halogen bonds in a
pharmaceutically active triazolothiadiazole derivative, we synthesized one of the
triazolothiadiazole derivatives bearing two fluorine atoms and its crystal structure has been
explored by single crystal X-ray diffraction.
The title compound possesses two azoles namely 1,2,4-triazole and 1,3,4-thiadiazole
and each of this azole has their own importance in different fields such as medicinal
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chemistry, agriculture and industrial applications. The fused products of these two azoles
possess versatile biological activities including anti-inflammatory [13,14], antimicrobial [13],
anticancer [15], analgesic [16], antioxidant [17] and antifungal [18] activities. Some of the
triazolothiadiazoles were also discovered as selective inhibitors of the c-Met kinase [19]. The
Cambridge Structural Database (CSD) search (version 5.39 updates August 2018) disclosed
that there are 64 hits containing 3,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazole derivatives
of which 8 hits (Fig. 1) found with phenyl moiety substituted at the 3 and 6 positions of the
fused triazolothiadiazole (CSD reference codes: HODNOE [20], ILETOK [21], KOFKOG
[22], RAPSUX [23], ROGGIE [24], XERZUQ [25], VEGVAE [26] and LEPQED [27]).
Fig. 1. Chemical structures of closely related analogs of the title compound.
In the present investigation, we used different theoretical approaches (PIXEL,
quantum theory of atoms-in-molecules (QTAIM), and molecular electrostatic potential and
Hirshfeld surface analysis) to study the weak intermolecular interactions existing in the title
compound. The PIXEL method was used to evaluate the intermolecular interaction energies
of different molecular pairs in the crystal structure of the title compound. Lattices energies
were also calculated using the same code for the title compound and its closely related
structures to understand the nature of crystal packing. The quantitative molecular electrostatic
potential surface was computed to identify the potential sites involved in the intermolecular
interactions in the crystal structure of the title compound. Further, Hirshfeld surface analysis
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was performed to quantify the contribution of different intermolecular contacts in the title
compound and its closely related structures and to delineate the role of fluorine substitutions
in the title compound. The topological properties of different weak interactions were
computed based on the Bader’s QTAIM approach [28]. In order to assess the potential
bioactivities of the title compound, we performed in-silico docking of the title compound
against different targets such as Ovis aries cyclooxygenase-1 (COX-1), Homo sapiens
cyclooxygenase-2 (COX-2) and lanosterol 14α-demthylase of Mycobacterium tuberculosis
(MtbCYP51) and Candida albicans (CaCYP51).
2. Experimental
2.1. Synthesis and crystallization
The title compound was synthesized starting with 4-fluorobenzohydrazide (1)
following the reaction sequences outlined in Scheme 1. A mixture of 4-amino-5-(4-
fluorophenyl)-4H-1,2,4-triazole-3-thiol 3 (2.1 g, 0.01 mol), 2-fluorobenzoyl chloride (1.40 g,
0.01 mol) and phosphorous oxychloride (10 mL) was heated under reflux for two hours. On
cooling, the reaction mixture was cautiously poured onto crushed ice (50 gm) and the
precipitated solid product was filtered, washed with saturated sodium hydrogen carbonate
solution and then with water, dried crystallized from ethanol to yield 2.42 g (77%) of the title
o
compound (A). M.p. 172-174 C (445-447 K) as colourless fine needle crystals. Suitable
XRD single crystals were obtained by slow evaporation of chloroform-ethanol solution (1:1)
at room temperature. 1H NMR (CDCl3, 500.13 MHz): δ 7.16-7.25 (m, 4H, Aromatic-H), 7.31-
7.33 (m, 2H, Aromatic-H), 7.54-7.56 (m, 2H, Aromatic-H). 13C NMR (CDCl3, 125.76 MHz):
δ 115.11, 115.92, 116.21, 120.73, 124.27, 127.54, 127.77, 133.45, 144.57, 158.43, 161.96
(Aromatic-C), 160.05 (C-3), 160.46 (C-8), 163.96 (C-6).
O
O
H
NH2
N
S-K+
CS2/KOH
EtOH
N
N
H
H
S
2
1
F
F
NH2NH2
N
N
F
O
N
N
N
S
Cl
F
F
SH
N
N
F
NH2
(A)
POCl3
3
Scheme 1. Synthesis of the title compound.
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2.2. Single crystal X-ray diffraction (SCXRD)
The X-ray intensity data were measured from single crystal of the title compound on a
Bruker APEK-II CCD diffractometer with monochromatic Mo K (λ = 0.71073 Å) radiation
α
at room temperature (293(2) K). Data reduction and the refinement of cell parameters were
performed using the program SAINT (Bruker AXS, 2014). The absorption correction was
applied using the multiscan method [29] implemented in the program SADABS (Bruker
AXS, 2014). The structure of the title compound was solved by the direct methods using the
program SHELXS-97 [30] and the structure was refined using the SHELXL-2017/4 program
[31]. The non-hydrogen atoms were refined anisotropically and the hydrogen atoms were
placed in idealized geometry using riding model with C-H=0.93 Å and Uiso(H)=1.2Ueq(C).
Highly disordered solvent (possibly water) was present in the channels parallel to the
crystallographic c axis. Since the disordered solvent molecules could not be identified, the
SQUEEZE routine of PLATON [32] was used to remove the effects of approximately 12
electron equivalents from 183 Å3 of potential solvent area volume. Crystal data, data
collection and structure refinement parameters are summarized in Table 1. The molecular
dimers were drawn using the program MERCURY [33].
2.3. Computational details
Crystal structure geometry of the title compound was used as a starting model for
geometry optimization and followed by vibrational frequency calculation. The optimized
structure was found to be minima with no imaginary frequency. Both calculations were
performed in the gas-phase with M06-2X/cc-pVTZ level of theory [34] using the Gaussian09
program [35]. Grimme’s empirical dispersion (D3) correction was included in all calculation
[36].
The Hirshfeld surface and the decomposed 2D fingerprint plots were generated for the
title compound and its closely related structures using CrystalExplorer package [37] in order
to analyze intermolecular interactions present in these structures. Further, we carried out
PIXEL calculation [38,39] to evaluate the strengths of various molecular pairs held by
different types of intermolecular interactions in the title compound and its closely related
structures. The lattice energy was also computed for these structures using PIXEL method
which partitioned into the Coulombic, polarization, dispersion and repulsion energy terms.
We successfully utilized the above two approaches for different systems and the details were
previously published [12, 40-45]. Using the PIXEL calculation, we identified energetically
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significant molecular pairs were identified. Furthermore, XPAC2.0 program [46,47] was used
to identify the common packing features present between the title compound and its closely
related structures. The quantitative molecular electrostatic potential map was constructed and
visualized on the three dimensional surface using the program WFA-SAS [48].
Further, the interaction energies (∆ECP) for these dimers were computed at their crystal
structure geometry with normalized bond lengths involving hydrogen atoms with M06-2X-
D3/cc-pVTZ level of theory. The ∆ECP energies were corrected for basis-set superposition
error (BSSE) using the counterpoise correction method proposed by Boys and Bernardi [49].
For the above molecular pairs, the topological properties were calculated using an approach of
quantum theory of atoms-in-molecules (QTAIM) from AIMALL package [50]. The
dissociation energy (DEint) for the interaction was estimated through an empirical formula
proposed by Espinosa-Molins-Lecomte [51].
2.4. Molecular docking analysis
The anti-inflammatory, antimicrobial and antifungal activities of the title compound
was investigated by in silico molecular docking against different targets such as cytochrome
P450 lanosterol-14α-demethylases (CYP51) of Mycobacterium tuberculosis (pdbid: 1EA1)
and Candida albicans (pdbid: 5V5Z) and two cyclooxygenases (Ovis aries COX-1, pdbid:
1EQG and Homo sapiens COX-2, pdbid: 5IKR). The preparation of protein and the ligand
molecules for the docking study was carried out as mentioned in our earlier report [12] using
the Schrödinger suite (Schrödinger Release 2016-3, LLC, New York, NY, 2016). The binding
energies of the docked pose of the compounds were calculated using the glide extra precision
(Glide XP) scoring scheme implemented in the Glide module [52]. To compare the binding
affinity of the title compound, we used different standard inhibitors: ibuprofen (COX-1),
mefenamic acid (COX-2) and Flucanazole (CYP51).
3. Results and discussion
3.1. Structural description
The title compound crystallizes in the tetragonal system with the space group of I41/a
and one molecule present in the asymmetric unit. The compound comprises four ring systems,
two six-membered (4-fluorophenyl and 2-fluorophenyl) and two fused five-membered rings
(thiadiazole and 1,2,4-triazole). In the solid state, the overall conformation of the molecule is
completely planar and rings are coplanar with each other as evident from the dihedral angles
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(2.5-7.3°) formed by the mean planes of these rings and the torsion angles T1 and T2 (Fig. 2).
It should be noted that the two intramolecular contacts (H15···N4 and F1···S1) provide
support to maintain the planarity and rigidity of the molecule in the crystalline state and make
the molecule as fused pseudo 6,5,5,5,6,6-membered ring system (Fig. 2).
Fig. 2. ORTEP diagram showing intramolecular C–H···N and F···S interactions in the title
compound along with atom-numbering scheme.
3.2. Conformational analysis and quantitative analysis of intramolecular interactions
In order to assess the role of above mentioned intramolecular contacts, we performed
rigid potential energy surface (PES) scan for the two torsion angles (T1 and T2) which
involve the rotation of terminal phenyl rings. The rigid PES scan was performed using
B3LYP/6-31+G(d) level of theory for these torsion angles separately from -180 to 180° with
the increment of 5°. The result suggests that the minimum energy conformer is found to be at
5° for T1 and 0° for T2 torsion angles (Fig. S1). These angles are close to the X-ray geometry
of title compound which favor the formation of intramolecular H15···N4 and F1···S1
contacts. Further, the molecule of title compound was fully optimized without any
geometrical constraints as mentioned in the experimental section. The optimized structure was
found to be very close to the X-ray structure. The root mean squared deviation (RMSD)
between X-ray and the optimized structures was calculated to be 0.12 Å. This result is also
suggesting the importance of intramolecular interactions in the stabilization of planar
molecular conformation of title compound.
To retrieve closely related structures of the title compound, we performed CSD search
using the chemical structure of the title compound with the exclusion of fluorine substituents
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as a template. This search yielded 8 hits and their chemical structures are depicted in Fig. 1.
To compare the conformation of title compound with its closely related known structures, two
important torsion angles (T1 and T2) which describe the conformation of these molecules are
used (Table S1) and the dihedral angles are formed between phenyl rings attached to the
central rings with respect to the mean plane of central triazolothiadiazole ring summarized
(Table S2).
Further, atoms of central two five-membered rings are used for structural
superimposition of the title compound with its closely related structures to see the effect of
substituents on phenyl rings (Fig. S2). These analyses collectively indicate that the 2-ethoxy
moiety in RAPSUX [53] affect the planarity of the molecule. The 2-ethoxy substituted phenyl
is oriented at an angle of 49° with respect to the mean plane of the central triazolothiadiazole
ring. This deviation is likely due to the absence of intramolecular contact between 2-
ethoxyphenyl and the N atom of thiadiazole ring. It should be noted that the effect of
substituents on phenyl ring attached to the thiadiazole ring on the conformation is marginal.
Further, we present a detailed analysis of topological properties of intramolecular
interactions at the BCP in the crystalline geometry of title compound and its closely related
structures based on the QTAIM approach. The topological properties for intramolecular
interactions (C–H···N and S involving contact) in these structures are summarized in Table 2
(a complete details are given in Table S3) and the molecular graphs showing the
intramolecular interactions are illustrated in Fig. S3. The analysis of the topological properties
for these intramolecular interactions suggests that the intramolecular C–H···N interaction as
found in the structure of title compound is invariant except in RAPSUX structure [53]. This
absence is due to the presence of ethoxy group at the ortho position of the phenyl ring
attached to the triazole ring. The dissociation energy (DEint) for these interactions ranging
from 2.08 (LEPQED [27] to 3.22 kcal mol-1 (HODNOE [20]). However, the ethoxy O makes
an intramolecular interaction (O1···N1) with the N atom of the thiadiazole moiety with DEint
of 1.92 kcal mol-1. It should be noted that these C–H···N interactions show the trend of
exponential decay (with R2 > 0.99) in the magnitude of electron density (ρ) and the Laplacian
2
of electron density ( ρ) with increasing length of the bond path (Fig. S4).
Moreover, the S atom is participating in an intramolecular contact in five structures.
The F/Cl···S contact is observed in three structures (A, ILETOK and LEPQED) and in
another two structures, H/C···S interactions were observed. The strongest S involving
interaction is found to be F···S in (A) with DEint of 4.25 kcal mol-1. A slight rotation of
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phenyl ring attached to thiadiazole ring in ROGGIE, RAPSUX, HODNOE and VEGVAE
structure avoids the formation of S involving intramolecular contact. It is also to be noted
that the |V(r) /G(r) ratio is calculated to be less than one for all the intramolecular contacts,
comparable to those reported for other hydrogen bonds [54].
3.3. Molecular dimers in the crystal structure
The crystal structure of the title compound A can be described as four units of dimer
(Fig. 3) and this dimer (motif III) is formed by intermolecular C–H···N interactions. The
adjacent dimers are interconnected by S···π contacts (motif IV). Further, the energetically
significant dimeric pairs were identified from the PIXEL energy calculation. The results
suggest that there are six dimers (I-VI) which are held together by different intermolecular
interactions (Table 3 and Fig. 4). The interactions energies (∆ECP) for these dimers were
further evaluated by DFT method as mentioned in the experimental section. It should be
mentioned that the interaction energies (Etot and ∆ECP) of dimers calculated by PIXEL and
DFT methods are comparable.
Fig. 3. Crystal structure of the title compound viewed down the c axis. The voids are
indicated as blue spheres. The symbol ‘+’ and small black spheres denote the 41 screw axis
and center of inversion, respectively.
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Fig. 4. Molecular dimers observed in the crystal structure of the title compound. The ring
centroid position is shown as small red sphere.
The molecular dimer I is formed by stacking of adjacent triazole rings related by
center of inversion with an Etot value of -9.2 kcal mol-1. The distance between the centroids of
the triazole ring is being 3.317(3) Å. The electrostatics and dispersive energy components are
contributing 34% and 66% towards the stabilization of this dimer. Further, to confirm the
existence and to quantify this stacking interaction, we performed QTAIM analysis. The
molecular graphs showing the presence of different intermolecular interactions in various
molecular pairs observed in the title compound are illustrated in Fig. S5 and the topological
properties for these intermolecular interactions are summarized in Table 4. In dimer I, two
symmetrical contacts (four BCPs in total) are presented between this dimer. One of the
contacts involved between N1 and C9, while the second contact is formed between N2 and
N3. The DEint for these contacts are nearly equal (0.95 and 0.92 kcal mol-1) in strength.
The second strongest molecular pair II is established by molecular stacking between
adjacent molecules (Etot = -8.4 kcal mol-1 with the contribution of 83% dispersive energy
towards the stabilization). There is a C5···C10 (π···π) contact observed between adjacent
molecules and the centroid-to-centroid distance (3.664(3) Å) between the triazole and 2-
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fluorophenyl rings supports for the formation in π···π interaction. QTAIM calculation reveals
that there are four (3, -1) bond critical points observed (N···C and C···C atom pairs) atoms
and confirms the existence of π···π stacking interactions between the molecular pair of II.
The DEint for these contacts ranging from 0.50 to 0.71 kcal mol-1.
The centrosymmetric dimer III is formed via intermolecular C–H···N interactions
(involving H11 and N2 atoms). These interactions generate a closed Rꢀꢀ(10) loop and the
interaction energy for this dimer calculated by the PIXEL method is being -7.1 kcal mol-1. For
the stabilization, the electrostatic energy (59%) is contributing more when compared to the
dispersion energy (41%) component. The topological analysis confirms the presence of these
closed loop structure with the DEint for each H···N contact is found to be 2.20 kcal mol-1.
The dimer IV is primarily stabilized by intermolecular S···π interaction and there are
non-bonded contacts observed between S1 atom and C atoms (C3 and C4) of the 2-
fluorophenyl ring. The intermolecular interaction energy (Etot) for this dimer is calculated to
be -4.9 kcal mol-1. The electrostatic (49%) and dispersion (51%) energies are contributing
nearly equal towards the stabilization of this molecular pair. The distance between S1 and the
centroid of the 2-fluorophenyl ring is 3.521(3) Å. This dimer was further subjected to QTAIM
analysis to delineate the nature of interactions present between molecules. The result exposes
the existence of S···π interactions with DEint for these contacts are 0.87 and 0.91 kcal mol-1. It
is important to note that there is an intermolecular C–H···N (BCP between H3 and N1 atoms)
interaction which displays a significant role in the stabilization of this dimer. The DEint for
this contact (1.24 kcal mol-1 is slightly stronger than the S···π interactions.
Intermolecular C–H···π (involving H5 and C13 atoms) interaction stabilizes the
molecular pair V with the Etot value of -4.3 kcal mol-1. The stabilization of this dimer is
essentially dispersive (73%) in nature. The topological analysis suggests that there are four
BCPs observed in the molecular pair which confirms the existence of C–H···π interaction in
addition to the weak intermolecular C–H···F interactions (Table 4 and Fig. S5). The C–H···π
interactions are slightly weaker than one of the C–H···F interactions as evident from the
dissociation energies for these interactions.
The dimer VI is held by intermolecular three-center C–H···F interactions which
generate a loop. The Etot value of this dimer is calculated to be -1.9 kcal mol-1 and this motif is
stabilized by predominantly dispersive in nature (73%). According to QTAIM analysis, the
presence of these interactions are confirmed through the (3, -1) bond critical points between H
and F atoms. The dissociation energy for these interactions were found to be 1.38 (H3···F1)
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and 1.28 (H2···F1) kcal mol-1. Overall, the results suggest that C–H···F interactions observed
in motif VI is the second strongest interactions in the crystal structure of the title molecule
(first strongest one is the C–H···N interaction observed in molecular pair III). It is worth
mentioning that the magnitude of electron density values for all the interactions observed in
different molecular pairs falls in the range [0.013 <
ρ
(e Å-3) < 0.236] proposed by Koch and
Popelier for H-bonds [55,56]. On the other hand, the magnitude of the Laplacian for C–H···N
and C–H···F interactions falls within the suggested limit [0.580 < 2ρ (e Å-5) < 3.355]. The
intermolecular C–H···N and C–H···F (involving ortho fluorine F1) interactions are displayed
important roles as compared to other weak interactions (they are in non-classical nature) in
the crystalline state as evident from the topological properties.
3.4. Hirshfeld surface (HS) analysis and 2D fingerprint plots (FP)
HS analysis was performed to gather decomposed 2D fingerprint plots for the title
compound and its closely related structures to quantify the contribution of various
intermolecular interactions in the respective crystal packing (Table S4). In the title compound,
there are three short contacts namely C5···C10 (motif II) and H11···N2 (motif III) and
S1···C3 (motif IV) are clearly visible on the HS and the H11···N2 contacts are appeared as
bright red spots among them as shown in Fig. 5(a).
In order to understand the role of second fluorine atom (para substituted F) in the
crystal packing, we compared the relative contributions of different intermolecular contacts in
the title compound and its closely related structure, ILETOK (4H, fluorine absent at this
position). From Fig. 5(b), one can clearly visualize the distinct fingerprint plots obtained for
these two structures. Most importantly, the contribution of intermolecular H···F contacts are
increased and there is a reduction of H···H (by 5.2%) and H···C/C···H (7.7%) in A, due to
the presence of para-substituted fluorine. Another distinct feature observed between these two
structures is the contribution of S···C/C···S contact which indicates the presence of S···π
interaction. In case of compound A, S···C/C···S contacts contribute 6.2% to the total HS area
and the corresponding contacts are contributing less than 2% in other closely related
structures. This is clearly indicating that the S···π interaction is unique in the title compound.
The intermolecular H···N/N···H, C···N/N···C and C···C contacts are comparable in these
two structures and H···S/S···H contacts are almost 2 times greater in the case of ILETOK. As
discussed in the previous section, the para-substituted fluorine (F2) stabilizes the motif V
along with two H···C contacts as observed from the topological analysis. Overall, this
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analysis indicates that para-substituted fluorine plays an important role in the crystal packing
in addition to ortho-substituted fluorine. Intermolecular C···C contacts are contributing 5.2%
to the total HS area and they are concentrated around de = di = 1.8 Å as green dots which
demonstrate the existence of π stacking interactions in the title compound (A). Further, to
confirm the presence of π stacking interactions, the HS was mapped with the shape index. In
this diagram, the pattern of convex blue and concave red triangles reveal the existence of
these interactions (Fig. S6).
Fig. 5. (a) Two different views of Hirshfeld surfaces of the title compound A and short
contacts are broken-circled and (b) the relative contributions of different intermolecular
contacts to the total Hirshfeld surface area in A and its closely related structure ILETOK
3.5. Common packing features and lattice energies
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Lattice energies were computed using the PIXEL method for the title compound A
and its 8 closely related structures (Table S5). It is noted that the lattice energies for these
molecules ranging from -32.2 (for title compound) to -47.1 kcal mol-1 (for HODNOE). The
higher lattice energy can be attributed to the presence of voids in the crystals of the title
compound. Moreover, the dispersion energy component is predominant (> 63%) towards the
stabilization and the remaining comes from the electrostatic energy component in all cases.
Further, the common packing features present between the title compound and its closely
related structures were analyzed. As shown in Fig. S7, the compound A (motif II) shares one-
dimensional isostructurality [46] only with ILETOK (dissimilarity index x =6.1 and stretch
parameter D = 0.23 Å) and XERZUQ (dissimilarity index x =10.7 and stretch parameter D =
0.34 Å).
3.6. Quantitative molecular electrostatic potential
The quantitative molecular electrostatic potentials (MESP) for the title compound at
its crystal structure geometry was analyzed to explore the electrostatic potential distribution
and to understand the nature of interactions that exist in the crystal packing. The 0.001 au
electron density isosurface of the title molecule of (A) is depicted in Fig. 6. The very strongly
positive electrostatic potential of the 2-fluorophenyl hydrogen atoms (Vs,max = 29.75 to 27.06
kcal mol-1) and the negative potential (Vs,min = -4.88 and -4.50 kcal mol-1) around F1 indicates
their propensities for hydrogen bonding. The positive electrostatic potential of the 4-
fluorophenyl hydrogen atoms is relatively weaker as compared to 2-fluorophenyl hydrogen
atoms and there is no σ-hole existing for the atom F1 as observed in a closely related structure
ILETEK. In contrast, there is a σ-hole along the C13–F2 bond with the Vs,max of -15.26 kcal
mol-1 and the Vs,min values of -16.86 and -16.79 kcal mol-1 which correspond to lone pairs of
F2 atom. The nitrogen atoms (N1 and N2) of the triazole ring have strong negative potentials
with Vs,min values of -41.92 and -40.18 kcal mol-1, respectively, and these two atoms are
involved in the intermolecular interactions as evident from PIXEL and QTAIM analysis. The
negative potential is observed for the lone pairs of S atom with Vs,min values of 0.30 and 0.99
kcal mol-1. It is of interest to note that there is a positive potential (σ-hole) with Vs,max value of
16.01 kcal mol-1 which is approximately perpendicular to the position of lone pairs. This is
clearly supports for the existence of motif IV in the title compound A.
14

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Fig. 6. Molecular electrostatic surface potentials of the title compound mapped over the
electron density isosurface at 0.001 au. The positive (Vs,max) and negative (Vs,min) potentials
are shown as small black and blue spheres, respectively.
3.7. Molecular docking analysis
The flexible ligand docking analysis revealed that the title compound may exhibit anti-
inflammatory, antimicrobial and antifungal activities as compared to control drugs. The
binding energies of the title compound (A) and control inhibitors for different targets are
summarized in Table 5. The binding pose of compound (A) and control drugs along with their
protein targets are depicted in Figs. 7 and S8-9. In both COX-1 and COX-2, the title
compound (A) makes two important π···π stacking interactions with residues Tyr 385 and Trp
387 through its 2F-phenyl ring. The residue Tyr 355 is also forming a stacking interaction
with the triazole ring of the compound (A) in the case of COX-1. It should be noted that
compound (A) is slightly more selective towards COX-1. Compound (A) binds with higher
affinity with both MtbCYP51 and CaCYP51 targets as compared to the control inhibitor
antifungal drug fluconazole. In MtbCYP51, again the 2F-phenyl ring of the title compound
involved in stacking interaction with Tyr 76 residue. The same residue is also participating in
stacking interaction with the triazole ring of the fluconazole inhibitor.
15

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16

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Fig. 7. Predicted binding mode of the title compound in different protein targets (a) COX-1 (b) COX-2 (c) MtbCYP51 and (d) CaCYP51.
17

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4. Conclusion
In the present study, pharmaceutically promising agent, 3-(4-fluorophenyl)-6-(2-
fluorophenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole was synthesized and its single X-ray
crystal diffraction analysis was performed. Two intramolecular (C–H···N and F···S) bonding
are important for maintaining the planarity of the molecule at some extent and the C–H···N
interaction was found to be invariant in a closely related structures. The crystal structure is
stabilized by different types (molecular stacking, S···π, C–H···N, C–H···π and C–H···F
interactions. Both intra and intermolecular interactions were quantified using QTAIM
approach. The results suggested that the intermolecular C–H···N and C–H···F (involving F
substituted at the ortho position) interactions play vital role in the stabilization of the crystal
structure of the title compound. Other weak non-covalent interactions (S···π and π···π and
N···π) also help to stabilize the crystal structure in a non-classical manner. Hirshfeld surface
analysis indicated that the para-substituted fluorine substantially alters the contribution of
intermolecular H···H and H···C contacts. The potential bioactivity of the title compound was
studied by molecular docking analysis and the result revealed that the title compound may
possess anti-inflammatory, antimicrobial, antifungal activities.
Acknowledgements
This work was funded by the Deanship of Scientific Research at Princess Nourah bint
Abdulrahman University through the Research Group Program (Grant No. RGP-1438-0010).
ST thanks the DST-SERB (SB/YS/LS-19/2014) and Prof. TRR grant for research funding. ST
and MJP would like to thank Laboratorio Nacional de Supercomputo del Sureste (LNS-
BUAP) for computational resources.
Competing interests
The authors declare no competing financial interest.
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Table 1. Crystal data and refinement parameters for the compound (A).
Crystal data
A
Chemical formula
Mr
C15 H8 F2 N4 S
314.31
Crystal system, space group
Temperature (K)
a, b, c (Å)
Tetragonal, I41/a
293(2)
29.6253(14)
29.6253(14)
6.2433 (4)
90, 90, 90
5479.5(5)
16
α, β, γ (°)
V (Å3)
Z
Radiation type
µ
Mo Kα
0.26
(mm-1)
Crystal size
0.24 × 0.12 × 0.08
Data collection
Diffractometer
Bruker APEX-II CCD
diffractometer
Muli-scan
Absorption correction
Tmin, Tmax
0.795, 0.931
No. of measured,
independent and observed [I
> 2σ (I)] reflections
Rint
48849, 3142, 1946
0.131
0.649
(sin θ/λ)max (Å−1)
Refinement
R[F2 > 2σ(F2)], wR(F2), S
No. of reflections
No. of parameters
H-atom treatment
0.048, 0.111, 1.08
2513
200
H-atom parameters
constrained
0.20, -0.19
1887657
∆
ρ
max, ∆
ρ
min (e Å-3)
CCDC No.

ACCEPTED MANUSCRIPT
Table 2
Topological parameters for intramolecular interactions in the title compound (A) and its closely related
structures [
: electron density (e/Å3), 2ρ: Laplacian of electron density (e/Å5); Vb: potential energy
density (a.u.), Gb: kinetic energy density (a.u.); Rij: bond path (Å) and DEint=
0.5×Vb in kcal mol-1].
ρ
–
2ρ
Interacting
atoms
Rij
Vb
Gb
DEint
|ꢀ |
ρ
ꢁ
ꢂꢁ
A
F1···S1
2.719
2.430
0.115
0.083
1.838
1.139
-0.013541 0.016303 0.83
-0.007327 0.009574 0.77
4.25
2.30
H15···N4
ILETOK
F1···S1
2.754
2.395
0.106
0.089
1.695
1.228
-0.012318 0.014949 0.82
-0.008024 0.010384 0.77
3.86
2.52
H5···N2
ROGGIE
H1···N4
HODNOE
H1···N4
KOFKOG
H12···S1
H1···N4
LEPQED
Cl1···S1
H5···N1
VEGVAE
H4···N4
XERZUG
C17···S1
H4···N2
2.300
2.295
0.106
0.108
1.483
1.507
-0.010053 0.012722 0.79
-0.010257 0.012946 0.79
3.15
3.22
2.559
2.402
0.114
0.088
1.536
1.209
-0.012361 0.014147 0.87
-0.007823 0.010181 0.77
3.88
2.45
3.002
2.494
0.128
0.076
1.531
1.038
-0.013332 0.014606 0.91
-0.006635 0.008701 0.76
4.18
2.08
2.308
0.105
1.451
-0.009945 0.012501 0.80
3.12
3.035
2.447
0.096
0.082
1.098
1.116
-0.009004 0.010196 0.88
-0.007182 0.009380 0.77
2.83
2.25

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Table 3. Interaction energy (in kcal mol-1) for various molecular pair along with centroid-centroid distance in (I). Cg1 and Cg3 are the
centroids of the 2-fluorophenyl and 4-fluorophenyl rings, respectively.
Motifs centroid-
centroid
Possible
Interactions
Geometry
(Å,°)a
distance
Symmetry code
ECoul
Epol Edisp
Erep Etot
∆ECP
(Å)
I
5.943
–x, –y, –z+1
–3.9 –1.9 –11.1
7.7 –9.2 –10.3
Molecular stacking
C9···N1
3.246(3)
3.317(3)
(Cg3···Cg3)
II
6.243
x, y, z–1
–1.5 –1.1 –13.0
7.2 –8.4 –10.3
Molecular stacking
C5···C10
3.353(4)
3.664(4)
2.39, 165
(Cg1···Cg3)
C11–H11···N2
III
IV
9.714
8.718
–x, –y, –z+2
–5.0 –2.9
–3.7 –1.2
–5.4
–5.1
6.2 –7.1 –6.4
5.1 –4.9 –6.0
–y+1/4,x+1/4, –z+1/4
S1···C3
S1···C4
C5–H5···C13
3.457(3)
3.486(3)
2.86, 130
V
9.364
–y–1/4,x+1/4, z–3/4
–y+1/4,x+1/4, –z–3/4
–1.2 –0.5
–0.5 –0.3
–4.7
–2.2
2.2 –4.3 –4.1
1.1 –1.9 –1.6
VI
12.385
C2–H2···F1
C3–H3···F1
2.63, 116
2.63, 116
aNeutron values are given for all D–H···A interactions.

ACCEPTED MANUSCRIPT
Table 4. Topological parameters for selected molecular pairs (I to VI) in the compound (A) [ρ: electron
density (e/Å3), 2ρ: Laplacian of electron density (e/Å5); Vb: potential energy density (a.u.), Gb: kinetic
energy density (a.u.); Rij: bond path (Å) and DEint= –
0.5×Vb in kcal mol-1].
2ρ
Interacting
atoms
Rij
Vb
Gb
DEint
|ꢀ |
ρ
ꢁ
ꢂꢁ
I
N1···C9
C9···N1
N2···N3
N3···N3
II
3.643
3.643
3.335
3.335
0.042
0.042
0.035
0.035
0.492
0.492
0.480
0.480
-0.003042 0.004074 0.75
-0.003042 0.004074 0.75
-0.002943 0.003960 0.74
-0.002943 0.003960 0.74
0.95
0.95
0.92
0.92
C3···N4
C5···C10
C6···N2
C11···N4
III
3.697
3.655
4.114
3.602
0.037
0.041
0.033
0.024
0.410
0.438
0.404
0.297
0.69
0.67
0.65
0.68
0.71
0.71
0.63
0.50
-0.002263 0.003261
-0.002267 0.003404
-0.002001 0.003094
-0.001581 0.002332
H11···N2
N2···H11
IV
2.415
2.415
0.069
0.069
1.028
1.028
-0.007008 0.008835 0.79
-0.007008 0.008835 0.79
2.20
2.20
H3···N1
S1···C3
S1···C4
V
2.917
3.684
3.542
0.045
0.040
0.034
0.644
0.502
0.481
-0.003954 0.005315 0.74
-0.002903 0.004054 0.72
-0.002769 0.003882 0.71
1.24
0.91
0.87
H15···F2
H5···C13
H4···C14
H14···F2
VI
2.811
2.944
3.026
2.942
0.023
0.026
0.029
0.017
0.385
0.397
0.377
0.325
-0.002534 0.003262 0.78
-0.002255 0.003188 0.71
-0.002180 0.003045 0.72
-0.001905 0.002640 0.72
0.80
0.71
0.68
0.60
H3···F1
H2···F1
2.701
2.727
0.038
0.036
0.636
0.593
-0.004387 0.005492 0.80
-0.004071 0.005110 0.80
1.38
1.28

ACCEPTED MANUSCRIPT
Table 5. The binding energies (in kcal mol-1) for the compound (A) and control inhibitors calculated by
Glide XP scoring scheme
Compound
Target
O.aries
COX-1
-8.953
H. sapiens M.tuberculosis C.albicans
COX-2
-7.906
-3.813
---
CYP51
-7.138
---
CYP51
-7.612
---
A
Mefanamic acid
Ibuprofen
Fluconazole
-8.525
---
---
---
---
-1.964
-2.727