Synthesis, crystallographic, computational and molecular docking studies of new acetophenone-benzoylhydrazones

Article abstract of DOI:10.1016/j.molstruc.2021.130275

Three aroylhydrazones, acetophenone-Benzoylhydrazone (I), p-hydroxy-acetophenone-benzoylhydrazone (II) and p-nitro- acetophenone-benzoylhydrazone (III) have been synthesized and further analyzed with the aid of IR, UV-Vis, and NMR spectroscopic and X-ray Crystallographic techniques. The optimized molecular structures were determined by Density Functional Theory (DFT) using the B3LYP function comprising the 6-311⁺⁺G (2d, 2p) basis set. The calculated and experimental results for the NMR spectroscopic technique were observed to be consistent. The two reported crystals are monoclinic in the same space group of P2_1/c. Hirshfeld surface analyses revealed H···H as the most important intermolecular interactions in compounds II and III. The molecular docking of the compounds against three enzymes - aldose reductase, aldehyde reductase, and β-glucosidase were also carried out where compound III displayed the best inhibition of the enzymes with a binding energy of -11.30, -9.58 and -11.10 Kcal mol^?1 against aldose reductase, aldehyde reductase, and β- glucosidase respectively.

Full text of DOI:10.1016/j.molstruc.2021.130275

Journal of Molecular Structure 1237 (2021) 130275
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, crystallographic, computational and molecular docking
studies of new acetophenone-benzoylhydrazones
a,∗
b
a
d
Temitope A. Ajayeoba , Joseph O. Woods , Ayowole O. Ayeni , Tomilola J. Ajayi ,
b
c
a
Raji A. Akeem , Eric C. Hosten , Olawale F. Akinyele
a
Department of Chemistry, Obafemi Awolowo University, Ile-Ife 220005, Nigeria
b
Department of Chemistry, University of Ibadan, Ibadan 200284, Nigeria
c
Department of Chemistry, Nelson Mandela University, Port Elizabeth 6031, South Africa
d
Department of Chemistry, Mangosuthu University of Technology, Durban 4000, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Three aroylhydrazones, acetophenone-Benzoylhydrazone (I), p-hydroxy-acetophenone-benzoylhydrazone
Received 5 November 2020
Revised 15 February 2021
Accepted 8 March 2021
Available online 23 March 2021
(
II) and p-nitro- acetophenone-benzoylhydrazone (III) have been synthesized and further analyzed with
the aid of IR, UV-Vis, and NMR spectroscopic and X-ray Crystallographic techniques. The optimized molec-
ular structures were determined by Density Functional Theory (DFT) using the B3LYP function comprising
++
the 6-311 G (2d, 2p) basis set. The calculated and experimental results for the NMR spectroscopic tech-
nique were observed to be consistent. The two reported crystals are monoclinic in the same space group
of P21/c. Hirshfeld surface analyses revealed H···H as the most important intermolecular interactions in
compounds II and III. The molecular docking of the compounds against three enzymes - aldose reduc-
tase, aldehyde reductase, and β-glucosidase were also carried out where compound III displayed the best
Keywords:
Hydrazones
Aldose reductase
DFT
Hirshfeld surface analysis
Molecular docking
−1
inhibition of the enzymes with a binding energy of -11.30, -9.58 and -11.10 Kcal mol against aldose re-
ductase, aldehyde reductase, and β- glucosidase respectively.
©
2021 Elsevier B.V. All rights reserved.
1
. Introduction
these enzymes also play a role during the development of disease
conditions such as cancer and sepsis [14–16]. Many experimental
studies with animals suggested that potent inhibitors of these en-
zymes could play an important role in preventing complications
like cataract and neuropathy that are associated with diabetes
[17–19].
Aroyl hydrazones are previously reported to show great bio-
logical activities, can impact biological processes mediated by en-
zymes and can serve as polydentate ligands in coordination chem-
istry in addition to catalytic properties and high thermal stabil-
ity [1–5]. For example, the use of oxidovanadium metal complexes
of hydroxylbenzoylhydrazone for the oxidation of alcohols to ke-
tones with up to 99% efficiency is documented in the literature
A good understanding of the nature of interaction with bind-
ing sites and possible mode of attachment via molecular docking
is desirable in understanding the mechanism of reactions of drugs
with the target sites. The use of Hirshfeld surface analysis involving
intermolecular interactions present within a crystal structure can
be effectively correlated with data from crystallographic studies as
seen in this study [20,21]. Literature search shows that a combi-
nation of experimental with computational methods on molecu-
lar structure, spectroscopic and docking studies of organic com-
pounds is now widely utilized [22–24]. Therefore, the determina-
tion of molecular structures, Hirshfeld surface analysis, spectro-
scopic studies and molecular docking of three synthesized aroyl
hydrazones with diabetic inducing enzymes is the focus of this
study.
[
6]. The importance of the flavone, hydrazide and hydrazone link-
age in suppressing the activity of α- and β- glucosidase which
are enzymes involved in carbohydrate metabolism has been well
highlighted in the literature, where most of the hydrazone com-
pounds studied inhibited the activity of the enzyme [7]. In addi-
tion, aroylhydrazones have high affinity for chelation toward bi-
ologically relevant metal ions, such as Mn(II), Fe(II) and Cu(II)
[
8–10].
Aldehyde reductase (ALR1) and Aldose reductase (ALR2) are
two enzymes that have been widely investigated in some compli-
cations reported alongside diabetes mellitus [11–13]. Furthermore,
∗
Corresponding author.
E-mail address: tajayeoba@oauife.edu.ng (T.A. Ajayeoba).
https://doi.org/10.1016/j.molstruc.2021.130275
0
022-2860/© 2021 Elsevier B.V. All rights reserved.

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Scheme 1. Synthetic route of the compounds.
2. Experimental section
2p) basis set was used as this was the most widely used stan-
dard in Gaussian to determine isotropic shielding constants of 1
H
2
.1. Reagents and instruments
and 13C for TMS (tetramethylsilane) which was used as a reference
molecule in the Gaussian setup” [31].
Acetophenone,
methyl-4-hydroxylbenzoate,
methyl-4-
nitrobenzoate, ethylbenzoate, hydrazine hydrate solution, were
procured from Sigma Aldrich and utilized with no additional
purification. 1H and 13C NMR spectra were acquired in d -DMSO
on a 300 MHz Bruker DMX avance spectrophotometer. Fourier
transform infrared (FT-IR) spectra for the synthesized compounds
2
.4. Molecular docking studies
6
Studies on molecular docking were performed to gain under-
standing of the binding orientation and interaction of compounds
I - III with the selected proteins. FRED from OpenEye software
−
1
within 4000 and 650 cm
were obtained on a PerkinElmer
[
32,33] was used to perform docking studies. After the genera-
Spectrum400 spectrophotometer. Electronic spectra in were de-
termined in a solution of ethanol on a Shimadzu UV-Vis 1800
Spectrophotometer.
tion of chemical structures, energy minimization and optimization
were carried out by (PM3) semi-empirical method associated with
ChemDraw 3D. The crystallographic structures of β-glucosidase,
aldehyde reductase and aldose reductase were retrieved from the
universal Protein Data Bank using PDB ID: 2O9R, 3FX4 and 1US0
2
.2. X-ray diffraction analysis
[
34,35]. Structures of the target proteins were then protonated
Block-shaped, single, white crystals of the hydrazones obtained
in 3D in the standard geometry using MOPAC 7.0 for the opti-
mization of energy. Co-crystals within each target protein were
identified as binding sites and further utilized as default parame-
ters in search of systematic conformations. First, co-crystals were
re-docked to optimize the docking protocol which was subse-
quently used for docking of all the three compounds (crystals).
Each compound had 10 poses generated for it to realize the fi-
nal binding positions. Final poses having the least binding form in
Chemguass4 were identified and visualized in the Discovery studio
[35].
in an ethanol medium were subjected to X-ray crystallographic
analysis. “Bruker KAPPA APEX II single crystal X-ray diffractome-
ter equipped with a 4-circle kappa goniometer and a CCD detec-
tor at 295(2) K was used in the collection of crystal data. The in-
strument consisted of a molybdenum fine focus sealed X-ray tube
as an X-ray source and an Oxford cryostream 700 system for
sample temperature control [25]. The structure was solved using
SHELXT-2014 [26] and refined by least square procedures using
SHELXL-2016 [27] with SHELXLE [28] as a graphical interface. Data
were recorded for absorption effects using the numerical method
implemented in SADABS. All non-hydrogen atoms were refined
anisotropically while all hydrogen atoms were refined isotropi-
cally. Details on the crystallographic data can be found as supple-
mentary materials in the Cambridge Crystallographic Data Centre
2
.5. Synthesis of hydrazones
An established method according to the literature [36,37]
was adopted and involved two steps depicted in Scheme 1.
00 mmol of hydrazine hydrate was stirred with equimo-
(
CCDC: 1876117, 1876118). The data can be requested at no cost via
4
www.ccdc.cam.ac.uk/data_request/cif.
lar quantities of methylbenzoate, 4-nitromethylbenzoate and 4-
hydroxylmethylbenzoate respectively in 150 mL of ethanol on a
water bath and then refluxed for 12 hours. The resultant yellowish
solution was concentrated using rotary evaporator to give a white
crystalline precipitate of the respective hydrazides. The precipitates
formed, were filtered with the aid of a suction pump, washed with
40 % ethanol and allowed to dry over CaCl2 in the desiccator.
The hydrazones were synthesized by stirring equimolar quan-
tities of the hydrazide respectively with acetophenone in 100 mL
ethanol and further refluxed for 6 hours. The solvent was allowed
to evaporate slowly until white needle-like crystalline precipitates
were obtained. These were filtered and washed with 40 % ethanol.
The precipitate was air-dried for 20 minutes and then placed in a
desiccator over CaCl2.
2
.3. Theoretical calculations
Gaussian 09, revision B01 was utilized to carry out all elec-
tronic structure calculations. Structural optimization was done via
a “mixed basis set at unrestricted UB3LYP/GENECP level of theory”.
+
+
The B3LYP level and 6-311 G (2d, 2p) basis set were utilized with
the atoms in the compounds. “In the process of the DFT calcula-
tions, energy values of frontier orbital were determined using the
most stable conformation of the reported compounds. NMR shield-
ing constants were predicted using the Gauge-Including Atomic Or-
bitals - DFT method (GIAO–DFT) in the gaseous and deuterated
++
dimethyl sulfoxide (DMSO) medium” [29,30]. “The 6-311 G (2d,
2

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Fig. 1. The experimental IR spectrum of compound I.
Table 1
Experimental data (ppm) for the 1H NMR chemical
Table 2
UV-Vis electronic data (nm) for com-
shifts for Compounds I – III.
pounds I - III.
I
II
III
Compounds
Experimental
π → π∗
n → π∗
CH3
Ar-H
N-H
O-H
2.39
1.98
2.4
7.43 – 7.89
6.87 – 7.84
10.54
7.45 – 8.36
I
225
220
250
290
290
310
10.80
-
11.10
-
II
III
10.10
3
. Results and discussion
ν(N-N) vibration showed a similar trend to what was observed
in the other bands. The infrared spectra data revealed the induc-
tive effects of the substituents on the system. [41]. In addition, OH
3
.1. NMR spectral data
stretching frequency was at 3406 cm 1 in compound II while NO2
−
The 1H NMR experimental data for compounds I – III are pre-
group resonated as two bands observed at 1348 and 1512 cm in
−1
sented in Table 1 while the experimental 1H NMR spectra and
1H/13C theoretical data for all the hydrazones are given in Tables
compound III.
1
a – 1c and Fig. 1 respectively (Supplementary Information). The
3.3. UV-Vis analysis
spectra and calculated data revealed the formation of the com-
pounds, as well as the role played by the para- substituents by
The experimental data are presented in Table 2 for the three
compounds. Two electronic transitions were prominent in the re-
ported UV-Vis spectra of the hydrazones. The band that occurred
at 225 nm in I is ascribed to the π → π∗ and this band under-
went hypsochromic shift to higher energy in II to 220 nm and
bathochromic shift to lower energy in III to 250 nm [42].
The second prominent band at 290 nm in I and II is due to
n → π∗ transition and shifted significantly to 310 nm in III. This
could be attributed to the nitro- substituent on the benzene ring
as it had been reported to lead to an increase in the wavelength of
absorption in similar compounds [43].
way of inductive effects. The methyl (CH ) signal resonated at 2.39
3
ppm in compound I, at 1.98 ppm in II, and 2.40 ppm in III. The
aromatic protons resonated in the range 7.43 -7.89 ppm in I, at
7.87-7.84 ppm in II and 7.45-8.36 ppm in III. The diagnostic N-H
signal for hydrazones appeared at 10.80 ppm for the compound I
while it shifted upfield to 10.58 ppm in II and further downfield
in III to 11.10 ppm as similarly observed in the literature [38,39].
These shifts are the effects of the electron-donating cum electron-
withdrawing properties impacted by the hydroxyl and the nitro
groups on the hydrazones. The signal that appeared at 10.10 ppm
in compound II was due to the hydroxyl substituent [40].
3
.4. X-ray diffraction data analysis
3
.2. Vibrational analysis
The ORTEP diagrams of compounds II and III are presented
Fig. 1 presents the experimental FT-IR spectrum of I while those
in Fig. 2 with the crystallographic data of the reported com-
pounds summarized in Table 3 while the packing diagrams are in
Fig. 4 (Supplementary Information). Also, the summary of hydro-
gen bonding interactions is presented in Table 4. The bond pa-
rameters of the synthesized compounds showed some similarity
with each other, and within normal ranges of similar compounds
reported in the literature [44,45]. In the presented compounds,
of II and III are in Figs. 2a and 2b (Supplementary Information).
The following diagnostic bands “ν(N-H), ν(C=O), ν(C=N) and ν(N-
N)” have been identified in the infrared spectra of the hydrazones
−1
[
33]. The prominently broad band observed at 3200 cm
in I is
attributed to ν(N-H) and remained in the same position in II but
−1
shifted to higher wavenumber at 3265 cm in compound III.
−
1
˚
The ν(C=O) band appeared at 1639 cm
in I and there was
the azomethine (C=N) bond distances are 1.289(18) A for II and
˚
a bathochromic shift to lower energy of this bands in II to 1620
1.291(17) A for III, indicating that they are typical double bonds.
cm 1. The azomethine ν(C=N) bond resonated at 1577 cm
−
−1
and
The bond distances between atoms C(1) and N(1) [1.3576(18) A for
˚
−1
−1
˚
shifted to 1537 cm and 1600 cm in II and III respectively. The
II and 1.352(17) A for III] lie between the values for single and
3

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Fig. 2. Molecular Structures of II (above) and III (below)
Table 3
Crystallographic data for compounds II and III.
II
III
Formula
C15H14N2O2
254.28
C15H13N3O3
283.28
Formula Weight
Crystal System
Monoclinic
P 21/n
Monoclinic
P 21/c
Space group
a/A˚
b/A˚
c/A˚
10.9389(8)
7.3005(4)
16.2909(12)
90
5.0414(2)
32.7645(10)
8.2176(3)
90
α/º
β/º
γ /º
V/A˚
109.001(3)
90
93.129(2)
90
3
1230.10(15)
4
1355.35(8)
4
Z
Dcalc/g/cm3
1.373
1.388
λ(MoKa)( A˚ )
F000
0.71073
0.71073
592
536
Crystal Size [mm]
Temperature (K)
0.10 x 0.53 x 0.65
200
0.07 x 0.23 x 0.77
200
Theta Min-Max [Deg]
Reflections collected/unique
Final R indices [I > 2s(I)]
Max/min., ꢀρ
2.0, 28.4
14130/3084
R1 = 0.0420, wR2 = 0.1200
0.31/-0.23
2.5, 28.3
25740/3377
R1 = 0.0502,wR2 = 0.1377
0.28/-0.23
Table 4
Distances ( A˚ ) and angles (º) involving hydrogen bonds in compounds II and III.
D-H···A
d(D-H)( A˚ )
d(H···A)( A˚ )
d(D···A)( A˚ )
Angle(D-H···A)(º)
II
O(1)-˗H(1)···O(2)
N(1)—H(1A)···O(1)
C(3)—H(3B) ···O(1)
III
0.8500(2)
0.8300(2)
0.9800
1.8200(2)
2.5510(16)
2.5200
2.6481(14)
3.1514(16)
3.4407(18)
167.00(2)
130.00(13)
157.00
N(2)—H(2)···O(3)
C(3)—H(3A)···N(3)
C(13)—H(13)···O(1)
C(26)—H(26)···O(3)
0.8600(2)
0.9800
2.1800(2)
2.4700
3.0261(14)
3.4181(18)
3.3920(4)
3.4353(19)
166.70(15)
162.00
0.9500
2.5900
143.00
0.9500
2.5600
153.00
D= Donor, H= Hydrogen, A= Acceptor
4

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Fig. 3. Optimized geometry, LUMO and HOMO of compounds I - III.
Table 5
low electrophilicity index due to mesomeric effect involving the
hydroxyl group.
The global reactivity descriptors (eV) computed of compounds I -
III.
Parameters (eV)
I
II
III
3
.6. Hirshfeld surface analysis
EHOMO
-0.30604
-0.19557
-0.15034
0.30604
0.19557
0.05524
0.25081
18.1028
- 0.25081
0.5694
-0.30388
-0.19071
-0.11317
0.30388
0.19071
0.05659
0.24730
17.6709
-0.24730
0.5403
-0.30659
-0.20065
-0.10594
0.30659
0.20065
0.05147
0.25362
19.4288
-0.25362
0.6249
ELUMO
Fig. 4 presents the diagrams of “inter-contacts by conventional
Energy Bandgap
Ionization potential
Electron affinity
Chemical hardness
Electronegativity
Chemical softness
Chemical potential
Electrophilicity index
mapping of dnorm on molecular HSs”. Short contact areas are de-
picted in red colour on the Hirshfeld surfaces, while the long dis-
tances are indicated blue areas. The most important intermolec-
ular interactions in the form of hydrogen bonds are denoted by
red spots and are attributed to the O acceptor atom and H donor.
“
The large red regions in the dnorm surface are also indicative of
the probable polymeric nature of the studied compound. The ex-
tensions of the molecule represented the donor and acceptor in-
teraction of O-H……O atoms” [29,52,53]. The red spots indicated ar-
eas in which the Oxygen links to the neighbouring complex units
through O-H bonds involving the hydroxyl group. The O…H con-
tacts accounted for about 9.4 % of the total interactions that are en-
countered within the studied system. Pictures of the HS “mapped
over shape index (SI)” as well as “curvedness for the studied com-
plex” of the two compounds are presented in Fig. 5 (Supplemen-
tary Information). The value of intermolecular distance of interac-
double bonds; this observation is attributed to conjugation effects
in the reported compounds [46].
The C–H···O and C–H···N interactions were also observed in ad-
dition to the classical inter- and intramolecular N–H···O and N–
H···N hydrogen bonds. The oxygen atom also serves as an accep-
tor for an intra-molecular N–H···O hydrogen bond supported by
the amino group of the aminoaroyl moiety as observed in the lit-
erature [47]. The stability of crystals of the reported compounds
were enhanced by the presence of intermolecular hydrogen bonds
and pi···pi stacking. Both compounds have a monoclinic crys-
tal system and the geometric parameters of the molecules agree
well with those of similar hydrazones reported in the literature
˚
tion between the molecule and its extension is 2.164 and 1.687A
˚
for II and 2.038 and 2.038 A in III as shown in Fig. 5.
Figs. 6 and 7 contained the 2D plots of the various atom-atom
interactions as well as the percentage contributions of the interac-
tions. A significant role is played by the H….H hydrogen bonding
interactions within the molecular packing of the studied complex.
For II, H….H hydrogen bonding interactions accounts for 41.4 % of
the whole intermolecular interactions in the studied system and
[
48,49].
3
.5. Theoretical data of the optimized geometry
3
0.0 %, in III. Other interactions include C…H (17 %), N …H (3 %),
C…C (3 %) and H…O (8 %) contacts in II, while there were C…
15 %), N…H (3 %), C…C (3 %) and H…O (13 %) of these contacts
The determination of properties like HOMO (Highest Occupied
H
Molecular Orbital)) and LUMO (Lowest Unoccupied Molecular Or-
bital) provided information on the electronic properties of the
synthesized compounds [50,51]. Some of the parameters of in-
terest include, “energy band gap” |EHOMO - ELUMO| “ionization po-
tential”, “electron affinity”, “chemical hardness”, “chemical soft-
ness”, “electronegativity”, “chemical potential”, “electrophilicity in-
dex” and “maximum charge transfer index”. These were evaluated
and summarized in Table 5 for the newly synthesized compounds.
The optimized geometry and data for compound I are given in
Fig. 3 and Table 4a (Supplementary information) respectively.
All the chemical parameters from ionization potential to elec-
trophilicity index were impacted by the inductive effect of the sub-
stituent on the aromatic ring and followed a similar trend. For ex-
ample, the presence of the OH group in compound II is seen in its
(
in III. “All these interaction distances are significantly longer than
the van der Waal radii sum of the two elements sharing the in-
teraction” [29,54]. In addition, HS analysis reflects the presence of
short H-bonds interactions like C-H…O and C-H...N which are also
identified from the crystallographic data.
3.7. Molecular docking results
The binding energies are presented in Table 6 while the binding
modes and interaction of all the reported compounds within the
active sites of β-glucosidase are shown in Table 7. Within the active
site of the enzyme, compounds II and III were found to have high
5

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Fig. 4. The Hirshfeld surface of compounds II and III mapped with dnorm.
Fig. 5. The intermolecular interaction distance between the donor and acceptor molecules in II is 2.164 and 1.687 A˚ and in III is 2.038 and 2.038 A˚
Fig. 6. (a) The summary of intermolecular interactions and their percentages in the crystal structure of II. (b)The full and decomposed fingerprint plots of H…H, O…H, H…C,
H…O and C H contacts in compound II.
...
Fig. 7. The summary of intermolecular interactions and their percentages in the crystal structure of III. (b)The full and decomposed fingerprint plots of H…H, O…H, H…C,
H…O and C H contacts in compound III.
...
6

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Table 6
ChemGuass4 score of Compounds I - III against target Beta Glucosidase, Aldehyde Re-
ductase and Aldose Reductase Enzymes
Beta Glucosidase
(PDB ID: 2O9R)
Aldehyde Reductase
(PDB ID: 3FX4)
Aldose Reductase
(PDB ID: 1US0)
Compounds
I
-9.790227
-11.016876
-11.099652
-8.240333
-8.509027
-9.575003
-10.811021
-10.879704
-11.302615
II
III
Table 7
Binding Interactions of Compounds I - III with amino acid residues of Respective Target Enzymes
−1
−1
−1
−1
binding energy values of -11.09 Kcalmol
and -11.02 Kcalmol
to the values for III (-10.8159 Kcal mol and 10.8859 Kcal mol )
respectively with the enzyme amino acid residues. Compound I
respectively. It is noteworthy to observe that all the compounds
interacted closely with the same amino acid residues (LEU300,
CYS303, TRP20, VAL47 and THR113) of the enzyme.
was found to have a binding energy value (-9.79 Kcal mol 1) which
is lower than those of II and III but fall within the range of val-
ues which could be considered moderate for an active inhibitor.
The illustration for the binding interaction of the crystals with the
active pocket of β-glucosidase enzyme also revealed that amino
acid residues such as TRP326, GLU409 and TRP410 are the inter-
acting groups with the hydrazones crystals in the enzyme active
pocket. The high binding energy value recorded for II and III could
be accounted for by the increased interaction with the protein due
to the presence of hydroxyl and nitro groups which have been
linked to an increased binding energy in drug candidates [55,56].
Compound III was found to display the highest free binding en-
−
4. Conclusion
The syntheses as well as the characterization of three ben-
zoylhydrazones using spectroscopic tools are presented here. The
chemical parameters of the hydrazones were further explored us-
++
ing DFT method at B3LYP/ 6-311 G (2d, 2p) level. Intermolecular
interactions like H….H, C...H, O…H bonding were identified within
the crystalline state of the compounds by Hirshfeld Surface Analy-
sis. Molecular docking investigations of the hydrazones against β-
glucosidase, ALR1 and ALR2 showed the binding energy and modes
of interactions of the compounds inside the enzymes active pock-
ets. The hydrazones generally exhibited high free binding energy
towards all the enzymes with the interaction modes of the III in-
side the active site of ALR2 enzyme being the highest, suggesting
that it could be further explored in diabetes and its associated con-
ditions.
−1
ergy value of -9.58 Kcal mol
against ALR1. The binding affin-
ity of I and II were found to be moderate with values of -8.24
−
Kcal mol 1 and -8.51 Kcal mol
−1
respectively. The major amino
acid residues of the enzyme interacting with the compounds were
TRP22, TYR50, ARG312 and ASP45.
The results of molecular docking of ALR2 enzyme against the
compounds showed that III has the highest value (-11.30 Kcal
−
mol 1). The binding affinity of compounds I and II was very close
7

T.A. Ajayeoba, J.O. Woods, A.O. Ayeni et al.
Journal of Molecular Structure 1237 (2021) 130275
Declaration of Competing Interest
[27] G.M. Sheldrick, Acta Crystallogr C71 (2015) 3e8.
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