Digdem Tatlidil1, Muhammad Asam Raza2, Necmi Dege3, Aysen Alaman Agar1, Umme Farwa2, Shafiq Ur Rehman4. 1. Faculty of Arts and Sciences, Department of Chemistry, Ondokuz Mayıs University, Samsun 55020, Turkey. 2. Department of Chemistry, Hafiz Hayat Campus, University of Gujrat, Gujrat 54000, Pakistan. 3. Faculty of Arts and Sciences, Department of Physics, Ondokuz Mayıs University, Samsun 55200, Turkey. 4. Department of Chemistry, University of Central Punjab, Lahore 54590, Pakistan.
Abstract
Imines are multipurpose pharmacophores, simply accessible compounds, and have a broad range of usage in several areas of chemistry especially in medicine. Two novel compound imines, (E)-4-methyl-2-((o-tolylimino)methyl)phenol (1) and (E)-2-(((4-methoxybenzyl)imino)methyl)-4-methylphenol (2), were synthesized with effective product via reported protocol in the literature. Single crystal X-ray diffraction (SCXRD) was employed for structural exposition, disclosing that both compounds are orthorhombic. To optimize the newly designed imines, a B3LYP functional with a basis set 6-31G(d,p) was mainly considered. DFT results were utilized to check correlation between the data recovered from SCXRD outcomes and also to measure the energy difference. Hirshfeld surface study was done to demonstrate the intermolecular contacts along the percentage of interaction in the overall crystalline compound. Molecular operating environment program was tested against AChE and BChE enzymes to perform a modeling study of the compounds. The docking score and binding affinity of the compounds revealed that 2 showed comparatively more inhibition than 1. In silico ADMET studies exposed the physiochemical nature of these novel compounds, and it also unveiled that both compounds behaved as drug-like candidates.
Imines are multipurpose pharmacophores, simply accessible compounds, and have a broad range of usage in several areas of chemistry especially in medicine. Two novel compound imines, (E)-4-methyl-2-((o-tolylimino)methyl)phenol (1) and (E)-2-(((4-methoxybenzyl)imino)methyl)-4-methylphenol (2), were synthesized with effective product via reported protocol in the literature. Single crystal X-ray diffraction (SCXRD) was employed for structural exposition, disclosing that both compounds are orthorhombic. To optimize the newly designed imines, a B3LYP functional with a basis set 6-31G(d,p) was mainly considered. DFT results were utilized to check correlation between the data recovered from SCXRD outcomes and also to measure the energy difference. Hirshfeld surface study was done to demonstrate the intermolecular contacts along the percentage of interaction in the overall crystalline compound. Molecular operating environment program was tested against AChE and BChE enzymes to perform a modeling study of the compounds. The docking score and binding affinity of the compounds revealed that 2 showed comparatively more inhibition than 1. In silico ADMET studies exposed the physiochemical nature of these novel compounds, and it also unveiled that both compounds behaved as drug-like candidates.
Imines are now well recognized by the name of Schiff bases. Amines
are reacted by a condensation process with derivatives of aldehydes
and ketones to give imines. Dyes and coordination polymers are synthesized
using Schiff bases on a large scale.[1] Imines
based ligands are considered the most reliable ligands owing to the
lesser efforts required for their synthesis and notable versatility.
Transition metals formed various types of stable complexes with these
ligands and consequently played an extensive part in the advancement
of coordination chemistry.[2] The condensation
process of diamines with salicylaldehyde yields imine based ligands
that have [N2O2] donor sets and are available
for formation of stable coordination compounds.[3] The biological activity of salicylaldehydes and their derivatives
was studied.[4,5]The process of biosynthesis
of an ergosterol is inhibited by using
a derivative of benzylamine that was also prescribed to cure not only
tinea pedis and tinea corporis but also tinea cruris.[6] Transition metals form a very stable complex assembly with
salicylaldehyde that is used as an antimalarial.[7] The cell toxicity of imines was determined by a LDH cell
toxicity test, and antiproliferative activity was determined by means
of MTT cell proliferation.[8]Schiff
bases are known as an imperative class of carbon-based compounds
with extensive biological applications.[9] Synthesis of novel therapeutic imines is now under an important
consideration of pharmaceutical researchers for treatment of several
illnesses. A number of studies have discussed the biotic actions of
imines, together with their herbicidal, anticancer, and antimycotic
activities.[10]Molecules with an active
site of receptors can be studied by molecular
modeling which also supports the analysis of the structure–activity
relationship (SAR) of compounds.[11] Modeling
studies also exhibit the binding energies, contact approach, and locations
of interactions.[12] The interactions of
molecules fitted with receptor protein are helpful in examining the
nonhydrophilic interaction, hydrogen bonding, and binding energy.[13]Density Functional Theory (DFT) was accomplished
to minimize the
energy of those solids molecules having large numbers of electrons.
In the past, DFT was used just for calculations of bond structure
and properties of solids molecules; however, now DFT calculations
are carried out for quantum chemical analysis.[14] The best methodology to devise DFT is given by Kohn and
Sham in which they explained a practical approach for measuring the
energy properties. The Thomas Fermi approximation which considers
the energy and density relationship and its effects supports much
of the DFT studies.[15] DFT is also helpful
in order to determine the strength of the bond, electron affinities,
and ionization energies.[16] Molecular assembly
directs the various electrochemical parameters as well as the contact
of drug molecular binding sites. Hence, the foundation of in silico study is mainly the assessment of the lowest most
energy value of a molecule. DFT is used for computation of relative
conformational energies.[17,18]A neurodegenerative
syndrome often known as Alzheimer’s
disease (AD) is common among old age people and develops as continuous
memory loss and cognitive failure. The lower level of acetylcholine
(Ach) concentration in the brain is the foremost cause of AD. A number
of reported methods have been observed for improvement of cholinergic
neurotransmission, including the rise of acetylcholine synthesis,
presynaptic acetylcholine release, and lessening the synaptic acetylcholine’s
degradation with cholinesterase inhibitors. The inhibitors of acetylocholinoesterase
(AChE) and butyrylcholinoesterase (BChE) are well thought as significant
targets for therapeutic plans of AD.[19] In
a current study new salicylaldehyde derived imines have been synthesized
with imperative biological activity. The structure of their compounds
has been elucidated by means of SCXRD and their computational studies
have been performed by density functional theory, molecular modeling,
adsorption, distribution, metabolism, excretion, and toxicity (ADMET).
Materials and Methods
In this work the chemicals used
were ethanol, amine, aromatic aldehyde,
and others reagents/solvents. They were of analytical grade and purchased
from Merck (Germany).
Synthesis of (E)-4-methyl-2-((o-tolylimino)methyl)phenol imine
(1) and (E)-2-(((4-methoxybenzyl)imino)methyl)-4-methylphenol
imines
(2)
Imines were designed by the stated method
with some modifications.[20] (E)-4-methyl-2-((o-tolylimino)methyl)phenol 1 and (E)-2-(((4-methoxybenzyl)imino)methyl)-4-methylphenol 2 were synthesized in ethanol (20 mL) by refluxing o-toluidine (0.02 mmol), (4-methoxyphenyl)methanamine (0.02
mmol), respectively, with 2-hydroxy-5-methylbenzaldehyde (0.02 mmol)
in ethanol (20 mL). Crystal materials were attained after the mixture
was stirred up to 5 h under reflux, washed with ethanol, and dried
at room temperature. The synthetic route for 1 and 2 is given in Scheme .
Scheme 1
Synthetic Scheme of 1 and 2
Single
Crystal Structure Analysis
The image plate diffractometer
STOE IPDS II was run up to 296 K to
obtain the SCXRD. The structural assemblies of compounds were elucidated
by SHELXT as a direct method[21] and processed
completely via full-matrix least-squares process along with the WinGX
program[22] associated also with the SHELXL
module.[23] The chief parameters of anisotropic
displacement were added to refine the non-hydrogen atoms. The crystallographic
tools were PLATON,[24] ORTEP-3,[22] and MERCURY,[25] utilized
for the structural demonstration along the evaluation of consequences.
Density Functional Theory
A density
functional theory (DFT) study was positively led by means of Gaussian
09 using B3LYP as a functional method along the 6-31G(d,p) basis set
to minimize the energy of compounds.[26−28] The B3LYP method mainly
comprises Becke’s three-parameter (B3) exchange functional
in conjunction with the Lee Yang and Parr (LYP) associated functional.[29] Gauss View 5.0 software was run to calculate
the energy gap measurement of the synthesized compounds and other
outcomes of the DFT studies.[30] To optimize
compounds, the input records were obtained from the crystal assembly
data of the corresponding compound in order to get good coherence
using the empirical data.[31]
Hirshfeld Surfaces Analysis
Hirshfeld
surface analysis (HS) was executed to explore and determine the involvement
of the various interactions in a crystalline environment.[32] Crystal Explorer 17.5 software was used to calculate
two-dimensional (2D) fingerprint plots for analysis of surface contact
on a Hirshfeld surface.[33] The dnorm is known as normalized contact distance that depends
upon de and di that are measured from a standard equation.[34]
Molecular Modeling Studies
Compounds 1 and 2 were docked by Molecular Operating Environment
(2016.08) software.[2] In molecular modeling
two PDB files 1EVE and 1P0I,
the first one for AChE (acetylocholinoesterase) and the second for
BChE (butyrylcholinoesterase) enzymes, were chosen. The 2D molecule-receptor
interactions were exhibited by means of MOE. The docking outcomes,
contacts of ligand, and surface analyses were viewed by means of the
Discovery Studio program.
In Silico Adsorption, Distribution,
Metabolism, Excretion, and Toxicity
The evaluation profile
of the ADMET is significant for newly discovered drugs and assessment
of their pharmacodynamic activities. ADMET deals with promising parameters
as physiochemical properties, pharmacokinetics, synthetic accessibility,
drug likeness, and lipophilicity of newly synthesized compounds. At
present, a number of sources are available as online and offline to
check the drug-like potential of synthesized compounds.[35] In the current study, in silico analysis was done using the admetSAR online available prediction
tool (http://lmmd.ecust.edu.cn:8000/).
Results
and Discussion
SCXRD Assessment of 1 and 2
Compounds were synthesized by
the reported protocol
with good yield and recrystallized just on the slow rate of solvent
evaporation at room temperature. The reaction completion was analyzed
via thin layer chromatography (TLC). The structure elucidation of 1 and 2 was done by single crystal X-ray diffraction
analysis. X-ray diffraction assessment of 1 was accomplished
and the outcomes are arranged in Table . The geometry of the crystallized compound is orthorhombic,
with formula unit Z = 4, C15H15NO, and also having space group P212121. The structure of the compound is illustrated
in Figure that also
displays the intramolecular (O1–H1···N1) H-bonding.
However, intra-atomic distances in the molecular structure C15H15NO are 1.291(3) Å and 1.429(3) Å between
C8–N1 and N1–C7 groups, respectively. In a unit cell,
the crystal assembly of the compound is exhibited in Figure . In the case of 2 X-ray analysis data are also given in Table . Data have revealed that the compound crystallized
in orthorhombic form, with formula unit Z = 4, C16H17NO2 and also has P212121 space group. The structure
of the compound, shown in Figure , also possesses intramolecular (O1–H1···N1)
H-bonding, although the intra-atomic distances in the structure of
C16H17NO2 are 1.469(3) Å and
1.270(3) Å between N1–C9 and N1–C8, respectively.
The crystal assembly of 2 in a unit cell is exhibited
in Figure .
Table 1
Single Crystal X-ray Diffraction Data
of Synthesized Compounds
crystal data
1
2
CCDC
2090884
2090885
empirical formula
C15H15NO
C16H17NO2
formula weight
225.28
255.30
temp/K
296(2)
293(2)
crystal system
orthorhombic
orthorhombic
space group
P212121
P212121
a/Å
7.6501(6)
5.7310(2)
b/Å
12.0632(10)
12.9388(8)
c/Å
13.6914(16)
18.8260(10)
α/deg
90
90
β/deg
90
90
γ/deg
90
90
vol/Å3
1263.5(2)
1395.99(12)
Z
4
4
ρcalcg/cm3
1.184
1.215
μ/mm–1
0.074
0.080
F(000)
480.0
544.0
crystal size/mm3
0.72 × 0.323 ×
0.09
0.72 ×
0.323 ×
0.09
radiation
Mo Kα (λ = 0.71073)
MoKα (λ = 0.71073)
2Θ
range for data
collection/°
4.5 to 51.97
3.82
to 56.134
index ranges
–8
≤ h ≤ 9, –14 ≤ k ≤ 14, –16 ≤ l ≤ 16
–7 ≤ h ≤ 6, –17 ≤ k ≤ 17, –24 ≤ l ≤ 24
reflections collected
8899
24167
independent reflections
2485 [Rint = 0.0525, Rsigma = 0.0412]
3369 [Rint = 0.0655, Rsigma = 0.0313]
data/restraints/parameters
2485/0/158
3369/0/176
goodness-of-fit on F2
0.968
0.947
final R indexes [I ≥ 2σ(I)]
R1 = 0.0395, wR2 = 0.0779
R1 = 0.0369, wR2 = 0.0867
final R indexes [all data]
R1 = 0.0635, wR2 = 0.0849
R1 = 0.0579, wR2 = 0.0959
largest diff. peak/hole/e Å–3
0.10/–0.10
0.08/–0.12
Flack parameter
1(2)
–0.8(17)
Figure 1
A single crystal structure
of 1.
Figure 2
A close crystal assembly
of 1.
Figure 3
A single crystal structure
of 2.
Figure 4
A close crystal assembly
of 2.
A single crystal structure
of 1.A close crystal assembly
of 1.A single crystal structure
of 2.A close crystal assembly
of 2.
HOMO–LUMO
Analysis
Gaussian
09 software was used to optimize the newly prepared imine based compounds
using the B3LYP functional and with basis set of 6-31G (d,p). The
energy minimized structures of 1 and 2 were
illustrated in Figure . To compare DFT and XRD outcomes, optimized values of bonds (length
and angle) were attained. It has depicted from evaluation of experimental
and theoretical results that there is a strong coherence found as
shown in Tables –5. Moreover,
agreement in DFT and XRD estimations were also expressed on the basis
of correlation coefficient (R2). In 1, R2 values measured both for
bond length and bond angle are 0.9581 and 0.6454, respectively, also
shown in Figures and 7. In 2, R2 values are 0.9861 (bond length) and 0.9424 (bond angle) as presented
in Figures and 9. These consequences determined that the electrochemical
parameters were approximately the same; therefore, the correlation
coefficient is near to 1.0. An inconsequential variance in 1 was due to the different design phase of both studies. The HOMO,
HOMO–1, LUMO, and LUMO+1 energy orbitals and their energy gaps
between the different orbitals were also determined by DFT. The calculated
energy gap in HOMO and LUMO of 1 was 0.14361, although
for HOMO–1 and LUMO+1 it was 0.2296 as given in Figure . The energy gap for the HOMO
and LUMO of 2 was 0.1592 and in the same way for HOMO–1
and LUMO+1 was 0.21745 (Figure ). The energy gap in 1 and 2 is relatively satisfactory to stabilize the compounds.[36]
Figure 5
DFT energy minimized structures of the synthesized 1 and 2.
Table 2
Comparison of Bond Lengths for 1
length/Å
length/Å
atom
atom
XRD
DFT
atom
atom
XRD
DFT
O1
C14
1.369(3)
1.36269
C7
C2
1.406(3)
1.41684
N1
C7
1.429(3)
1.41726
C7
C6
1.390(3)
1.40752
N1
C8
1.291(3)
1.30560
C14
C13
1.389(3)
1.40376
C9
C10
1.401(3)
1.41379
C2
C3
1.391(4)
1.40183
C9
C14
1.405(3)
1.42294
C2
C1
1.515(4)
1.51024
C9
C8
1.456(3)
1.44639
C13
C12
1.384(4)
1.39024
C10
C11
1.393(3)
1.39265
C6
C5
1.386(4)
1.39629
C11
C12
1.400(4)
1.41536
C3
C4
1.373(4)
1.39968
C11
C15
1.516(3)
1.51293
C5
C4
1.376(4)
1.39857
Table 5
Comparison of Bond Angles for 2
angle/deg
angle/deg
atom
atom
atom
XRD
DFT
atom
atom
atom
XRD
DFT
C13
O2
C16
117.40(17)
118.77
C10
C15
C14
122.14(19)
121.38
C8
N1
C9
119.75(19)
120.34
C3
C4
C5
121.7(2)
121.80
C6
C7
C2
118.67(17)
119.01
C15
C14
C13
119.2(2)
119.33
C6
C7
C8
120.39(16)
120.59
O2
C13
C14
124.2(2)
124.39
C2
C7
C8
120.94(18)
120.39
O2
C13
C12
116.67(19)
115.52
C6
C5
C4
117.12(19)
117.66
C12
C13
C14
119.1(2)
120.08
C6
C5
C1
121.39(19)
121.63
C15
C10
C11
117.6(2)
118.31
C4
C5
C1
121.5(2)
120.70
C15
C10
C9
120.9(2)
120.93
C5
C6
C7
122.47(18)
122.01
C11
C10
C9
121.4(2)
120.72
O1
C2
C7
121.33(18)
121.46
C4
C3
C2
120.77(19)
120.12
O1
C2
C3
119.45(17)
119.16
C11
C12
C13
120.7(2)
119.78
C3
C2
C7
119.23(19)
119.36
C12
C11
C10
121.3(2)
121.09
N1
C8
C7
121.94(18)
122.005
N1
C9
C10
109.66(17)
111.58
Figure 6
Correlation determination for bond lengths of 1.
Figure 7
Correlation determination for bond angles of 1.
Figure 8
Correlation determination for bond lengths of 2.
Figure 9
Correlation determination for bond angles of 2.
Figure 10
Energy Gap Measurement (HOMO–LUMO
and HOMO–1–LUMO+1)
of 1.
Figure 11
Energy Gap Measurement
(HOMO - LUMO and HOMO–1 - LUMO+1)
of 2.
DFT energy minimized structures of the synthesized 1 and 2.Correlation determination for bond lengths of 1.Correlation determination for bond angles of 1.Correlation determination for bond lengths of 2.Correlation determination for bond angles of 2.Energy Gap Measurement (HOMO–LUMO
and HOMO–1–LUMO+1)
of 1.Energy Gap Measurement
(HOMO - LUMO and HOMO–1 - LUMO+1)
of 2.
Hirshfeld
Surface Analysis
In crystalline
molecules, Hirshfeld surface (HS) analysis is done to check the intermolecular
contacts and also explain the surface features of the molecules. Crystal
Explorer is run by loading up CIF files as input files for Hirshfeld
analysis. The HS is diagrammed by means of distinctive colors (blue,
white, and red), and is primarily governed by radii distances.[37] Molecular surfaces are transparent to show the
imagining in a similar alignment, wherever this was determined. The dnorm surface is valuable representing adjacent
interactions and its values start from the negative side to the positive
end. The more negative values denote a closer interaction as compared
to standard rvdW (van der Waals radii)
and vice versa for positive values, although, a reference surface
resolution was considered to exhibit a HS along the 3D dnorm with the set range (−0.25 to 1.3 Å).
The red spots represent nearer contacts (dnorm value: negative), white spots seemed due to an alike variation around
the zero value, and blue colors displayed extended contacts (dnorm value, positive). The HS illustration of 1 and 2 is given in Figure in dnorm fashions.
Figure 12
Hirshfeld
surfaces mapped for dnorm.
Hirshfeld
surfaces mapped for dnorm.To study the contacts between atoms, 2D fingerprint plots
of 1 and 2 are plotted in Figures and 14. It was revealed
from all interactions that H···H contacts are mostly
considered in the prepared compounds. H···H interactions
were seen as 56.2% and 54.4% of all interactions in 1 and 2, respectively. After hydrogen interactions, C···H/C···H
contacts were nearly 32.3% in 1 and 30.1% in 2. The H···O/H··· O contacts were about
5.6% for 1, whereas they were 13.0% for 2. In 1 other interactions are 1.8% for N···H/N···H
and 1.1% for C···C/C···C. Compound 2 also has 1.7% for N···H/N···H
and 0.4% for C···N/C···N. These interactions
played a major role in stabilizing the crystal assembly of both compounds.
Figure 13
2D fingerprint
plots of interactions along their corresponding
percentages for 1.
Figure 14
2D fingerprint
plots of interactions along their corresponding
percentages for 2.
2D fingerprint
plots of interactions along their corresponding
percentages for 1.2D fingerprint
plots of interactions along their corresponding
percentages for 2.To check
the enzyme inhibition potential of synthesized imines, molecular modeling
was accomplished. The binding affinity and docking score values exposed
that 2 executed effective inhibition as compared to 1. For inhibition of AChE and BChE, the docking score values
for 1 were −14.5496 and −16.5711 and also
binding affinity values −13.0807 and −15.0943, respectively.
Compound 2 exhibited contacts on AChE with docking score
−19.2255 and binding affinity −14.2516, although the
BChE −19.2986 docking score and −15.9512 binding affinity
values are also listed in Table . The true docked posture of 1 and 2 with AChE and BChE are shown in Figures , 16, 17, and 18. Compound 1 exhibited
interaction (Figure ) with the binding position of AChE as π–π interactions
with Tyr334, Phe330, and Trp279.
Table 6
Docking Outcomes
of Synthesized 1 and 2
AChE
BChE
enzymes compounds
docking score
binding affinity (kcal/mol)
docking score
binding affinity (kcal/mol)
1
–14.5496
–13.0807
–16.5711
–15.0943
2
–19.2255
–14.2516
–19.2986
–15.9512
Figure 15
Docking view of 1 with AChE.
Figure 16
Docking view of 2 with AChE.
Figure 17
Docking
view of 1 with BChE.
Figure 18
Docking
view of 2 with BChE.
Docking view of 1 with AChE.Docking view of 2 with AChE.Docking
view of 1 with BChE.Docking
view of 2 with BChE.π–Alkyl contacts with His440, Tyr334, Phe330, and
Tyr121 and conventional interaction by Asp72 were also seen with 1. Similarly, Trp279, Tyr121, Tyr334, Asp72, Phe330, and His440
are amino acid positioned on the binding furrow, 2 showed
various interactions (Figure ) with these residues. π–π stacked interaction
with Tyr 121, Tyr334, and Phe330 through π–alkyl interactions
were shown by Trp279, Phe330, and His 440. The newly synthesized compounds
also showed intermediate types of interaction with the 1POI receptor
site. Compound 1 displayed π–π connections
with Trp82 and Phe329. Compound 1 also had π–alkyl
contacts with Leu286 and Phe329 and conventional contact with Gly116.
(Figure ). The contacts
of BChE (Figure ) were also presented with Trp82 and Leu286 by means of π–alkyl
and π–π interactions with Leu286 but conventional
contacts with Gly116.
In Silico ADMET Evaluation
Currently, various parameters associated
to drug properties of
formulated compounds have been determined by in silico ADMET studies using the Swiss online available AdmetSAR tool. Most
of the parameters discussed are lipophilicity, water-solubility, drug
likeness, pharmacokinetics, and medicinal chemistry. These distinctive
characteristics explain that either the formulated compounds exhibit
drug-likeness or not. According to the Lipinski rule, the values of
log Po/w (iLOGP) for
both synthesized 1 and 2 were 2.41 and 2.83,
respectively. Similarly, the solubility log S (ESOL)
values were −3.90 and −3.60, respectively for 1 and 2. These prepared compounds also showed
Lipinski zero violation. The synthetic accessibility of compounds
was in good range and 2 gave a higher value of 2.59 for
it. The gastrointestinal absorption rate is also high in both compounds.
Compounds 1 and 2 showed inhibition of cytochrome
as CYP2C19 and CYP1A2, while 2 also inhibited CYP2D6
and CYP3A4. The physicochemical parameters of the compounds are presented
in Tables –12.
Table 7
Physicochemical Parameters
of the
Synthesized Compoundsa
code
formula
MW
NHA
NAHA
F Csp3
NRB
NHBA
NHBD
MR
TPSA (Å2)
1
C15H15NO
225.29
17
12
0.13
2
2
1
72.09
32.59
2
C16H17NO2
255.31
19
12
0.19
4
3
1
77.87
41.82
Notation: number of heavy atoms
(NHA), number of aromatic heavy atoms (NAHA), F (fraction), number
of rotatable bonds (NRB), number of H-bond acceptors (NHBA), number
of H-bond donors (NHBD), molar refractivity (MR), topological polar
surface area (TPSA).
Table 12
Medicinal Chemistry of Synthesized
Compounds
code
PAINS
Brenk
lead likeness
synthetic
accessibility
1
0 alert
1 alert
no
2.46
2
0
alert
1 alert
yes
2.59
Notation: number of heavy atoms
(NHA), number of aromatic heavy atoms (NAHA), F (fraction), number
of rotatable bonds (NRB), number of H-bond acceptors (NHBA), number
of H-bond donors (NHBD), molar refractivity (MR), topological polar
surface area (TPSA).
Conclusions
To treat
the existing and new diseases, a number of research efforts were
carried out to synthesize novel therapeutical agents. Nitrogen-based
compounds have attracted the attention of pharmaceutical chemists
toward the designing of innovative chemical agents against several
diseases. In the present study, two active imines were synthesized
starting from different amines using a very easy route and also inexpensive
resources. Structural confirmation of both compounds was carried out
by single-crystal X-ray diffraction analysis (SCXRD). DFT results
showed that a close agreement exists between values of practical and
computational studies. To study several contacts of the crystalline
compounds, Hirshfeld surface analysis (HS) was also done, illustrating
that the H···H bond contacts were the foremost contributors
in interactions of imines. However, to check the in silico inhibitory action of both compounds, a molecular modeling study
was executed against enzymes. 2D and 3D molecule–enzyme contacts
and their docking positions also proposed that compounds are moderate
inhibitors against esterase enzymes. ADMET studies of compounds elucidated
the pharmacokinetic parameters of compounds. Both compounds gave good
values against all parameters although 2 exhibits higher
synthetic accessibility than 1. The computational and
practical investigations recommended that these imines might be utilized
in the therapeutic field based on their in vivo and
supplementary studies.
Scheme 1
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16
Figure 17
Figure 18