Structure and POM analyses of 2-{(2Z)-2-[(2R)-2-ethoxy-4-oxo-2H-chromen-3(4H)-ylidene]hydrazinyl}benzonitrile with promising parasitological activity

Article abstract of DOI:10.1007/s11164-015-2143-x

Functionalised chromanone (4) is prepared by the condensation of aryldiazonium salt (2) and enaminones (1) in ethanol at room temperature. The structure of (4) was determined by spectral (IR, ¹H and ¹³C NMR), elemental and X-ray diff

Full text of DOI:10.1007/s11164-015-2143-x

Res Chem Intermed
DOI 10.1007/s11164-015-2143-x
Structure and POM analyses of 2-{(2Z)-2-[(2R)-2-
ethoxy-4-oxo-2H-chromen-3(4H)-ylidene]hydrazinyl}
benzonitrile with promising parasitological activity
Khadijah Al-Zaydi1 Saad M. Alshehri2
•
•
Taibi Ben Hadda3
Received: 9 January 2015 / Accepted: 18 June 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Functionalised chromanone (4) is prepared by the condensation of
aryldiazonium salt (2) and enaminones (1) in ethanol at room temperature. The
1
structure of (4) was determined by spectral (IR, H and 13C NMR), elemental and
X-ray diffraction analysis. Compound 4 (C18H15N3O3) crystallizes in the mono-
˚
clinic space group P21/c with a = 7.9182(5), b = 21.729(2), c = 9.6217(7) A,
3
˚
b = 97.293(6)°, V = 1642.0(2) A , Z = 4. The molecule of compound (4) is bent
at the C-16 atom with a C15–O2–C16–C8 torsion angle of 46.18(3)°. Intramolecular
phenolic N–HÁÁÁO hydrogen bonds are also formed. Intermolecular hydrogen
bonding and p–p stacking hold the molecules together. The average distance
˚
between stacked benzene ring planes is 4.488(12) A. The preliminary POM anal-
yses of 4 confirm the coexistence of two combined antibacterial and antiparasite
pharmacophore sites. Therefore, compound 4 is promising and it should be screened
without hesitation against virulent and pathogenic biotargets.
Keywords Chromen-3-one-derived candidate drug Á Antimicrobial Á Enaminone Á
2-Arylhydrazononitriles Á X-ray crystal structure determination
&
Taibi Ben Hadda
taibi.ben.hadda@gmail.com
Khadijah Al-Zaydi
kalzaydi@kau.edu.sa; alzaydi_kh@yahoo.com
1
2
3
Department of Chemistry, Sciences Faculty for Girls, King Abdulaziz University,
P.O. Box 50918, Jeddah 21533, Kingdom of Saudi Arabia
Department of Chemistry, King Saud University, P.O. Box 2455, Riyadh 11451,
Kingdom of Saudi Arabia
Materials Chemistry Laboratory, Faculty of Sciences, Mohammed First University,
60000 Oujda, Morocco
123

K. Al-Zaydi et al.
Introduction
Chromene-one-derived functionalized moieties are a potential class of compounds
which have been found to possess a wide range of medicinal properties, including
antibacterial/antifungal [1], anti-neoplastic/anti-ulcer [2–4], antiviral and enzymatic
inhibition [5]. The quantitative relationship between the chemical structure and
biological activity has received considerable attention in recent years because it
allows one to predict theoretical bioactivity without an inordinate amount of
experimental time and demanding efforts. Computational methods for predicting
compounds with specific pharmacodynamics, pharmacokinetic, or toxicological
properties are useful for facilitating drug discovery and drug safety evaluation. In
modern computational chemistry, pharmacophores are used to define the essential
features of compounds such as hydrophobic compounds, aromatic compounds,
hydrogen bond acceptors, hydrogen bond donors, cations or anions. As a result,
there is an increasing interest in exploring novel methodologies for the synthesis and
biological screening of more heterocyclic compounds [6–13].
Motivated by the idea above and in continuation of our previous work on similar
systems [14–16], in the present study, the title compound 2-{(2Z)-2-[(2R)-2-ethoxy-
4-oxo-2H-chromen-3(4H)-ylidene]hydrazinyl}-benzonitrile (4), was synthesized
from the reaction of aryldiazonium salt (2) with enaminone (1) according to
reported methods, and its pharmaceutical properties were calculated using Petra,
Osiris and Molinspiration (POM) analyses.
Experimental
Materials and methods
All materials and solvents used were reagent grade and used as received. The
melting points of all the compounds were measured on a Gallenkamp electrothermal
melting point apparatus. The infrared (IR) absorption spectra were measured on a
1
Nicolet Magna 520 FT-IR (Fourier transform-infrared) spectrophotometer. H and
13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DPX
400 MHz spectrometer in deuterated dimethylsulfoxide (DMSO-d6) using tetram-
ethylsilane (TMS) as an internal reference; chemical shifts were expressed as d
values. Mass spectra were performed on a Shimadzu GCMS-QP 1000EX mass
spectrometer at 70 eV. Microwave irradiation was carried out using a commercial
microwave oven (SGO 390 W). Elemental analyses were carried out at the
Microanalytical Center at Cairo University.
Crystallographic analysis
The crystals were mounted on a glass fiber. All measurements were performed on an
Enraf-Nonius FR590 and the data were collected at a temperature of 20 1 °C
using the scanning technique to a maximum of 27.12°. The structure was solved by
direct method using the SIR-92 software package and refined by full-matrix least
123

Structure and POM analyses of 2-{(2Z)-2-[(2R)-2-ethoxy-4…
squares. Non-hydrogen bond atoms were refined anisotropically. Hydrogen atoms
were located geometrically and were refined isotropically.
Preparation of 3-[(2-cyanophenyl)hydrazono]-2-ethoxy-chroman-one (4)
A cold solution of aryldiazonium salt (0.1 mol) (2) was prepared by adding a
solution of sodium nitrite (1.5 g in 10 mL of H2O) to a cold solution of aryl amine
(0.1 mol) in concentrated hydrochloric acid (HCl, 5 mL) with stirring. The resulting
solution of the aryldiazonium salt was then added to a cold solution of enaminones
(1) in ethanol (EtOH, 50 mL) containing sodium acetate (0.1 mol). The mixture was
stirred at room temperature for 1 h and the solid product (4) so formed was collected
by filtration and crystallized from ethanol.
Dark orange crystals from ethanol. Yield 90 %. M.p. 154–156 °C. IR (KBr,
m cm-1): 3200 (NH), 3081 (C–H aromatic), 2944 (C–H aliphatic), 2221 (C:N),
1651 (C=O) and 1605 (C=N). 1H-NMR (400 MHz, DMSO-d6, d ppm): 1.10 (t, 3H,
CH3CH2), 3.82 (q, 2H, CH2CH3), 5.98 (s, 1H, CH), 7.20–8.75 (m, 8H, Ar–H) and
14.10 (s, 1H, NH). 13C-NMR (100 MHz, DMSO-d6, d ppm): 15.40 (CH3CH2O),
64.41 (CH3CH2O), 98.23 (CH), 116.18 (CN), 100.42, 119.37, 122.20, 123.54,
124.47, 127.52, 131.68, 133.68, 135.43, 137.919, 145.05 (aromatic carbons), 156.77
(C=N–N), and 178.62 (C=O). MS (EI, 70 eV): m/z (%) = 321 (26.9) [M?].
Elemental analyses of C18H15N3O3 (321.33): calcd. C 67.28, H 4.71, N 13.08;
found: C 67.12, H 4.80, N 13.15 %.
H
O
O
H
O
O
l
C
N
N
NMe2
3A
Ar
NMe2
N
N
Ar
2
1
O
O
N
NMe2
O
O
EtOH/NaOAc
-NHMe2
N
NHAr
NHAr
O
4
3B
O
O
O
N
C
N
N
Ar =
H
Ar
Scheme 1 Preparation and real structure of the bioactive candidate (4)
123

K. Al-Zaydi et al.
Results and discussion
Chemistry
2-{(2Z)-2-[(2R)-2-ethoxy-4-oxo-2H-chromen-3(4H)-ylidene]hydrazinyl}benzonitrile
was formed by an equimolar reaction of aryldiazonium salt (2) and enaminones (1)
according to Scheme 1. The prepared compound was stable to air and moisture and
soluble in EtOH and DMSO and it sharply melted at 154 °C. The spectral and
analytical data agreed well with the proposed structure [17–20].
X-ray structure determination of compound (4)
A single crystal of chromene derivative 4 was obtained by recrystallization with
ethanol. A dark orange crystal of C18H15N3O3 having approximate dimensions of
0.21 9 0.27 9 0.15 mm was mounted on a glass fibre. All measurements were made
in the x-scan technique on a Enraf-Nonius FR590 with graphite monochromatized
MoKa radiation. The structure was solved by direct methods using the program SIR-
92 [21]. The non-hydrogen atoms were refined anisotropically by the full-matrix least-
squares technique using the program SHELXL-97 [22]. All H atoms were located
Table 1 Crystal data and
Crystal data
structure refinement for 4
Empirical formula
Formula weight
Temperature
C18H15N3O3
321.336
298 K
˚
0.71073 A
Wavelength
Crystal system, space group Monoclinic, P21/c
Unit cell dimensions
˚
a = 7.9182(5) A
a = 90.00°
˚
b = 21.729(2) A
b = 97.293(6)°
c = 90.00°
V = 1642.0(2) A
˚
c = 9.6217(7) A
3
˚
Volume
Z
4
Calculated density
Data collection
Limiting indices
Refinement
1.300 Mg m-3
-7 B h B 7, 0 B k B 20, 0 B l B 9
Refinement on F2
Refinement method
R(all) = 0.0980
R(gt) = 0.0596
wR(ref) = 0.1897
Parameters
Only coordinates of H atoms
Full-matrix least-squares refinement
D/rmax = 0.000
3
˚
Dqmax = 0.339e A
3
˚
Dqmin = -0.294e A
208
wR(gt) = 0.1651
Reflections
Extinction correction: none
1486
123

Structure and POM analyses of 2-{(2Z)-2-[(2R)-2-ethoxy-4…
˚
geometrically and treated using a riding model, with O–H = 0.84 A, N–H = 0.88 A,
˚
˚
C–H = 0.95–0.98 A and Uiso(H) = 1.2Ueq(Caromatic, Namine) and Uiso(H) = 1.5Ueq
(Cmethyl, Ohydroxyl).
Details of the crystal and experimental data are listed in Table 1. Selected bond
distances and bond angles are given in Tables 2, 3 and 4. The molecular structure of
the title compound (4) is shown in Fig. 1. Packing and hydrogen bonding
interactions are illustrated in Fig. 2.
As shown in Fig. 2, the two terminal benzene rings bearing a cyano group are
parallel and centro-inversion symetric relative to each other. The pyranone ring
O1C9/C8C16/O2C15/C10C9 with the benzene rings C10–C15–O2–C16 and C15–
O2–C16–C8 is oriented at dihedral angles of 27° and 46°, respectively. So, in the
molecule of compound (4), the molecule is bent at the C-16 atom with a C15–O2–
C16–C8 torsion angle of 46.18(3). Pairs of molecules, related by inversion centres,
form intermolecular N–HÁÁÁOC2H5 hydrogen bonds to produce a dimer. And
intramolecular phenolic N–HÁÁÁO hydrogen bonds are also formed. Intermolecular
hydrogen bonding and p–p stacking hold the molecules together. The average
˚
distance between stacked benzene ring planes is 4.488(12) A.
˚
Table 2 Bond lengths (A) and
angles (°) for (4)
O1–C9
1.235(7)
1.380(7)
1.415(7)
1.365
C3–C4
1.354(9)
1.453(9)
1.37(1)
O2–C15
C2–C1
O2–C16
C4–C5
O3–C16
C5–C6
1.384(9)
1.390(8)
1.437(7)
1.468(7)
1.394(8)
1.355(9)
1.384(9)
1.377(9)
119.4(5)
126.8(4)
119.2(4)
118.6(4)
122.7(4)
119.5(4)
119.2(4)
118.7(5)
121.6(6)
121.6(6)
119.9(6)
120.2(5)
121.8(5)
O3–C17
1.4846
C6–C7
N1–C1
1.151(9)
1.329(6)
1.392(6)
1.311(6)
1.382(8)
1.389(8)
122.1(5)
117.4(4)
113.3(4)
115.4(4)
122.1(5)
119.6(5)
116.3(4)
121.2(5)
120.0(6)
120.4(6)
119.2(5)
116.9(5)
111.2
C8–C9
N2–N3
C9–C10
N2–C7
C10–C11
C11–C12
C12–C13
C13–C14
C16–O3–C17
N3–C8–C9
C8–N3–N2
N3–N2–C7
N2–C7–C6
N2–C7–C2
C7–C2–N1
C2–C3–C4
C3–C4–C5
C3–C4–C5
C4–C5–C6
C5–C6–C7
C7–C2–C3
N3–C8
C2–C3
C2–C7
O1–C9–C8
C9–C8–C16
C8–C16–O2
C16–O2–C15
O2–C15–C10
C15–C10–C9
C10–C9–C8
C10–C11–C12
C11–C12–C13
C12–C13–C14
C13–C14–C15
C14–C15–O2
O2–C16–O3
123

K. Al-Zaydi et al.
Table 3 Torsion angles (°) for
(4)
O1–C9–C8–N3
N2–N3–C8–C9
N3–N2–C7–C6
N2–C7–C2–C1
O1–C9–C10–C11
C8–C9–C10–C15
C9–C10–C15–O2
2.6(8)
0.7(7)
O2–C16–C8–C9
-38.9(6)
-1.5(8)
0.1(9)
C11–C10–C15–C14
C10–C11–C12–C13
C11–C12–C13–C14
C12–C13–C14–C15
O2–C16–O3–C17
C2–C7–C6–C5
-3.0(7)
2.0(7)
-0.6(9)
0.1(9)
8.3(8)
9.2(7)
-60.5(7)
0.1(8)
-1.8(8)
C10–C15–O2–C16 -27.0(7)
C2–C3–C4–C2
-0.8(9)
0.4(9)
C15–O2–C16–C8
46.2(6)
C7– C3–C4–C5
˚
Table 4 Hydrogen-bond parameters (A, °) for (4)
˚
D–H (A)
˚
˚
D–HÁÁÁA
HÁÁÁA (A)
DÁÁÁA (A)
D–HÁÁÁA (°)
N2–H2ÁÁÁO1
C3–H8AÁÁÁO3B
C17–H17AÁÁÁC12C
0.96
1.941
2.666
2.894
2.6367(5)
3.406(5)
3.761(4)
127
134
151
0.961
0.960
Fig. 1 View of the title compound (4) with the atom numbering scheme. Displacement ellipsoids for
non-H atoms are drawn at the 50-% probability level
Supplementary information
Crystallographic data for the structural analysis has been deposited with the
Cambridge Crystallographic Data Centre, CCDC No. 727169 for compound (4).
Copies of this information can be obtained free of charge from: The Director,
123

Structure and POM analyses of 2-{(2Z)-2-[(2R)-2-ethoxy-4…
Fig. 2 View of the packing and the intermolecular N–H–O hydrogen bonds (blue lines) to produce a
dimer of the title compound (4) down the a axis. H atoms not involved in H-bonding were kept for more
details. (Color figure online)
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: ?44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
Does compound (4) make a difference in drug design?
The analysis of theoretical toxicity risks for compound 4 using the Osiris program
showed it is less toxic than standard clinical drugs and can be used as a therapeutic
agent. From the data evaluated, the structure is supposed to be non-mutagenic when
run through the mutagenicity assessment of a coordinated system and, as far as
irritating and reproductive effects are concerned, the compound 4 is at low risk
comparable with standard drugs used. The hydrophilicity of 4 has been expressed in
terms of the cLogP value. It has been established that the absorption or permeation
is greatly affected by the hydrophilicity (value of cLogP). Accordingly, when
cLogP is higher than 5, the absorption or permeation decreases. On this basis, most
of tested compounds have cLogP values within the acceptable criteria and are active
at different IC50 values because another crucial parameter should be taken in
consideration. This does not concern the geometrical conformation of pharma-
cophore because it is resolved and fixed for compound 4 via O1–H intramolecular
interaction (Fig. 3). This intra-template effect is in favor of constituting an
important O1–N1 antiparazite pharmacophore site, as is hypothesized by POM
theory [23–32].
We have calculated an overall drug-score (DS) for compound 4 and can now
compare the score with that of standard drugs (Table 5). The DS combines drug-
likeness, cLogP, log S, molecular weight, and toxicity risks, in one handy value that
may be used to judge the compound’s overall potential to qualify for a drug. The
reported compound 4 showed an excellent DS as compared with standard drugs
used in commerce [23–32].
123

K. Al-Zaydi et al.
CH3
O
H
O
N
O
δ-
N
H
δ+
N
δ-
δ-
δ-
δ-
: Antiparasite Pharmacohore site
: Antibacterial Pharmacohore site
δ+
Fig. 3 Identification of combined antibacterial/antiparasite pharmacophore sites of 4
Table 5 POM analyses of compound (4)
Osiris calculations
Molinspiration calculations
MUT
TUM
IRRIT
RE
???
???
???
???
-4.31
-6.22
0.32
cLogP
4.298
VOL
GPCRL
ICM
KI
284
TPSA
84
321
6
-0.29
-0.55
-0.68
-0.73
-0.44
-0.25
Mol. weight
O, N number
NONH
NV
Sol
1
NRL
PI
DL
0
DS
NR
4
EI
Higly toxic (—), slightly toxic (?), non-toxic (???)
MUT mutagenic, TUM tumorigenic, IRRIT irritant, RE reproductive effective, Sol solubility, DL drug
likeness, DS drug-score, TPSA total molecular polar surface area, NONH number of OH–N or O–NH
interaction, NV number of violation of five Lipinsky rules, NR number of rotation, VOL volume. GPCRL
GPCR ligand, ICM ion channel modulator, KI kinase inhibitor, NRL nuclear receptor ligand, PI protease
inhibitor, EI enzyme inhibitor
Conclusions
2-{(2Z)-2-[(2R)-2-ethoxy-4-oxo-2H-chromen-3(4H)-ylidene]hydrazinyl}benzonitrile
(4) was prepared by the method reported earlier. This compound formed highly
stable pharmacophore sites. We calculated the overall DS of the compound, which
combines drug-likeness, cLogP, log S, molecular weight, and toxicity risks in one
handy value that may be used to judge the compound’s overall qualifications as a
drug. The reported compound 4 showed an excellent DS as compared with standard
drugs used in commerce. Based on its structural properties, it can be used as a
potential antibacterial/antiparasite agent in the future. Because 4 has two coordi-
native pockets, another important profile of 4 is its ability to be used as an attractive
ligand in coordination chemistry.
123

Structure and POM analyses of 2-{(2Z)-2-[(2R)-2-ethoxy-4…
Acknowledgments We gratefully acknowledge the Department of Chemistry, Sciences Faculty for
Girls at the King Abdulaziz University in Jeddah, Kingdom of Saudi Arabia for their support of this work.
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