Syntheses of novel 2-oxo-1,2-dihydroquinoline derivatives: Molecular and crystal structures, spectroscopic characterizations, Hirshfeld surface analyses, molecular docking studies and density functional theory calculations

Article abstract of DOI:10.1016/j.molstruc.2020.128461

Sixteen new quinoline derivatives (3–18) have been synthesized through cyclocondensation, nucleophilic substitution and alkylation reactions. All the obtained compounds have been characterized using ¹H-, ¹³C and ¹⁹F NMR spectroscopic measurements. The molecular and crystal structures of four of these compounds (10, 11, 15 and 18) have also been further examined by single crystal X-ray crystallography. The predicted spectral data were also obtained and compared to the experimental results using density functional theory (DFT). in order to understand the non-bonding intermolecular interactions in solid phase crystal packing. The closest contacts between active atoms of the four studied molecules were identified through both 2D and 3D Hirshfeld surface analyses. The different structures of the four compounds are optimized and their both energies highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO), as well as their clouds are evaluated. The obtained experimental results are correlated to the calculated ones and showed great compatibility. Finally, molecular docking studies are performed to investigate the binding patterns of the title compounds with the Protein Data Bank (PDB: 1M17) inhibitor targets and showed good insights on the possible interactions using the Auto-Dock Vina program.

Full text of DOI:10.1016/j.molstruc.2020.128461

Journal Pre-proof
Syntheses of novel 2-oxo-1,2-dihydroquinoline derivatives: Molecular and crystal
structures, spectroscopic characterizations, Hirshfeld surface analyses, molecular
docking studies and density functional theory calculations
Yassir Filali Baba, Halil Gökce, Youssef Kandri Rodi, Sonia Hayani, Fouad Ouazzani
Chahdi, Abdellatif Boukir, Jerry P. Jasinski, Manpreet Kaur, Tuncer Hökelek, Nada
Kheira Sebbar, El Mokhtar Essassi
PII:
S0022-2860(20)30786-9
DOI:
https://doi.org/10.1016/j.molstruc.2020.128461
MOLSTR 128461
Reference:
To appear in: Journal of Molecular Structure
Received Date: 5 January 2020
Revised Date: 12 May 2020
Accepted Date: 14 May 2020
Please cite this article as: Y.F. Baba, H. Gökce, Y.K. Rodi, S. Hayani, F.O. Chahdi, A. Boukir,
J.P. Jasinski, M. Kaur, T. Hökelek, N.K. Sebbar, E.M. Essassi, Syntheses of novel 2-oxo-1,2-
dihydroquinoline derivatives: Molecular and crystal structures, spectroscopic characterizations, Hirshfeld
surface analyses, molecular docking studies and density functional theory calculations, Journal of
Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.128461.
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Syntheses of novel 2-oxo-1,2-dihydroquinoline derivatives: molecular and
crystal structures, spectroscopic characterizations, Hirshfeld surface
analyses, molecular docking studies and Density Functional Theory
calculations.
Yassir Filali Babaa, Halil Gökceb, Youssef Kandri Rodia, Sonia Hayania, Fouad Ouazzani Chahdia,
Abdellatif Boukirc, Jerry P. Jasinskid, Manpreet Kaurd, Tuncer Hökeleke, Nada Kheira Sebbarf,g*
El Mokhtar Essassif
,
aLaboratory of Applied Organic Chemistry, Faculty of Science and Techniques, Sidi Mohamed Ben Abdellah University,
B.P. 2202, Routed 'Imouzzer, Fez 30050, Morocco;
bGiresun University, Vocational High School of Health Services, Department of Medical Services and Techniques,
28100 Giresun, Turkey;
cLaboratory of Biotechnology Microbien and Molecules Bioactives LB2MB, Faculty of Science and Techniques, Sidi
Mohamed Ben Abdellah University, B.P. 2202, Route 'Imouzzer, Fez 30050, Morocco;
dDepartment of Chemistry, Keene State College, 229 Main Street, Keene, NH 03435-2001, USA;
eDepartment of Physics, Hacettepe University, 06800 Beytepe, Ankara, Turkey;
fLaboratoire de Chimie Appliquée et Environnement, Equipe de Chimie Bioorganique Appliquée, Faculté des sciences,
Université Ibn Zohr, Agadir, Morocco;
gLaboratoire de Chimie Organique Hétérocyclique, Centre de Recherche des Sciences des Médicaments, Pôle de
Compétences Pharmacochimie, Mohammed V University in Rabat, Faculté des Sciences, Av. Ibn Battouta, BP 1014
Rabat, Morocco.
Abstract
Sixteen new quinoline derivatives (3–18) have been synthesized through cyclocondensation,
nucleophilic substitution and alkylation reactions. All the obtained compounds have been
1
13
19
characterized using H-, C- and F-NMR spectroscopic measurements. The molecular and
crystal structures of four of these compounds (10, 11, 15 and 18) have also been further
examined by single crystal X-ray crystallography. The predicted spectral data were also
obtained and compared to the experimental results using density functional theory (DFT). in
order to understand the non-bonding intermolecular interactions in solid phase crystal
packing. The closest contacts between active atoms of the four studied molecules were
identified through both 2D and 3D Hirshfeld surface analyses. The different structures of the
four compounds are optimized and their both energies highest occupied molecular orbitals
(HOMO) and lowest unoccupied molecular orbitals (LUMO), as well as their clouds are
evaluated. The obtained experimental results are correlated to the calculated ones and showed
great compatibility. Finally, molecular docking studies are performed to investigate the
binding patterns of the title compounds with the Protein Data Bank (PDB: 1M17) inhibitor
targets and showed good insights on the possible interactions using the Auto-Dock Vina
program.
Keywords: Quinolines, NMR Characterization, X-ray Crystallography, Molecular
docking, Hirshfeld surface analysis, DFT calculations.
______________
Corresponding authors:
Dr. Nada Kheira Sebbar
Tel:+212615011615;E-mail:snounousebbar@gmail.com

1.Introduction
Heterocyclic compounds have paved the way for interesting achievements in the fight against
many life-threatening diseases [1]. These compounds offer a high degree of structural
Therefore, it is diversity conferring a broad spectrum to the therapeutic field. Therefore, is not
surprising that the development of new synthesis methodologies of new biologically active
heterocyclic compounds constitutes a very important goal for synthetic organic chemists [2].
Quinolines and their derivatives have contributed substantially to the regression of microbial
diseases. The development of quinolone-based antibiotics began in 1962 with the discovery of
nalidixic acid, which was used to treat urinary tract infections [3]. Quinoline derivatives are a
classical division of organic chemistry and many of these molecules have shown remarkable
biological properties, including exceptional activities, such as, antimalarial [4], antibacterial
[5-6], antifungal [7], anticancer [8-9] and anti-inflammatory [10-11] effects. Some of these
compounds are endowed with other various activities, such as antituberculosis [12], analgesic
[13], cardiovascular [14], antibiotic [15], antihypertensive [16], tyrosine kinase (PDGF-RTK)
inhibition [17] and anti-HIV [18-19]. Additionally, the quinoline ring plays an important role
in the development of new antitumoral agents, as their derivatives have shown excellent
results through different mechanisms of action. They are growth inhibitors by cell cycle
arrest, apoptosis agents, angiogenesis inhibitors, disruption of cell migration, and modulation
of nuclear receptor responsiveness [20-21]. Furthermore, the quinine I (Scheme 1) was the
first and most widely used as antimalarial agent due especially to the presence of the
quinoline scaffold, followed by closely related derivatives, chloroquine II (Scheme 1) and
mefloquine III (Scheme 1) [22]. Several promising anti-inflammatory and antitumor
therapeutic agents are also built on quinoline structure. Alternatively, quinoline derivatives
provide a framework for industrial use, including organic light-emitting diodes (OLEDs) and
photovoltaic cells, as well as solvents for terpenes and resins [23]. In addition, quinoline-
based dyes such as ethyl red iodide IV (Scheme 1) and pinacyanol V (Scheme 1) have been
used as a pigment for photographic plates since the nineteenth century according to their
heterocyclic aromatic chromophore and basic characteristics [24].
Due to its presence and importance as pharmacophore in a wide range of natural and
synthesized products, the development of new quinoline-based structures requires a great
effort of synthesis methodology and architectural design. This is a quintessential aspect of our
research. The objective of this work is to prepare and characterize new 2-oxo-1,2-
dihydroquinoline carboxamide derivatives (3-18) in multi-step methodology. The starting

material containing quinoline moiety, is achieved by a cyclocondensation reaction involving
isatin and malonic acid in refluxing acetic acid in the presence of sodium acetate. The
compound 1 obtained reacts with an excess of thionyl chloride, leading to quinoline-4-
carboxylic acid chloride 2 which in turn reacts with various substituted anilines, 2,4-
difluoroaniline; 3-chloro-4-fluoroaniline and 3-trifluoromethyl-aniline, to afford the new
quinolines 3-6. Furthermore, the alkylation reactions of the four latter compounds with three
different alkyl halides, such as, ethyl iodide, propargyl bromide and ethyl bromoacetate, are
carried out in phase transfer catalysis conditions allowing the formation of the new
dialkylated compounds 7-18, whose structures have been elucidated by spectral data (Nuclear
1
19
Magnetic Resonance H ,13C and F). The structures of compounds 10, 11, 15 and 18 were
confirmed by single crystal X-ray diffraction. The structures assigned were also confirmed by
predicting the corresponding spectroscopic data and Z-matrix coordinates using DFT
theoretical calculations at the B3LYP/6-311G (d,p) level of theory and molecular docking
studies from the Protein Data Bank (PDB: 1M17) on an inhibitor were carried out using Auto-
Dock Vina program. Compounds 10, 11, 15 and 18 were further studied by Hirshfeld surface
analyses, molecular docking studies, and DFT calculations.
Scheme 1.Chemical structures of quinine (I), chloroquine (II), mefloquine (III), ethyl red iodide (IV) and
pinacyanol (V).
2. Material and methods
2.1. Spectral data measurements
The spectroscopic characterizations of the synthesized compounds (3-18) were achieved by
recording their NMR spectra: 1H NMR (300 MHz),13C NMR (75 MHz),19F NMR (282 MHz),
respectively, which were measured on a Bruker Advance DPX 300 instrument, using CDCl3
and DMSO-d6 as solvents. The chemical shifts (δ) were expressed in ppm and the coupling

constants (J) in Hertz (Hz) and their multiplicities were expressed as: m = multiplet, q =
quartet, t = triplet, dd = double doublet, d = doublet, and s = singlet, down field from TMS
[tetramethylsilane, Si(CH3)4], which has been assigned to a chemical shift of zero, and used as
an internal reference. Thin layer chromatography (TLC) and column chromatography were
carried out on silica plates (Merck 60 F254) and silica gel (Merck 60, 230-400 mesh),
respectively. Melting points of compounds (3-18) were measured in open capillaries and were
uncorrected.
2.2. Preparation of compounds (7-18) by alkylation reaction under PTC conditions
Derivative 1 reacts with an excess of thionyl chloride (SOCl2), forming intermediate 2
which is used later for an acylation reaction by a variety of aniline derivatives (aniline, 2,4-
difluoroaniline, 3-chloro-4-fluoroaniline or 3-trifluoromethyl-aniline). The reaction leads to
new quinoline derivatives (3-6) with excellent yields. Prominently, the alkylation of 2-oxo-N-
phenyl-1,2-dihydroquinoline-4-carboxamide derivatives (3-6) with ethyl iodide, propargyl
bromide and ethyl bromoacetate prompts the formation of the dialkylated compounds (7-18)
with good yields (Scheme 2).
C
C
B
A
B
A
C
O
OH
O
NH
B
A
O
Cl
O
N
R1
O
SOCl2
NH2
R1 Br
N
O
N
O
N
O
N
reflux, 2h
K2CO3, BTBA
DMF
CHCl3
H
H
H
R1
3:A=B=C=H
4:A=F;B=H; C=F
5:A=H; B=Cl; C=F
6:A=C=H; B=CF3
1
7: A=B=C=H;R1= -CH2CH3
2
8: A=F;B=H; C=F;R1= -CH2CH3
9: A=H; B=Cl; C=F;R1= -CH2CH3
10: A=C=H; B=CF3;R1= -CH2CH3
11: A=B=C=H;R1= -CH2-C≡CH
12: A=F;B=H; C=F;R1= -CH2-C≡CH
13: A=H; B=Cl; C=F;R1= -CH2-C≡CH
14: A=C=H; B=CF3;R1= -CH2-C≡CH
15: A=B=C=H;R1= -CH2COOEt
16: A=F;B=H; C=F;R1= -CH2COOEt
17: A=H; B=Cl; C=F;R1= -CH2COOEt
18: A=C=H; B=CF3;R1=-CH2COOEt
A: H or F
B: H or Cl or CF3
C: H or F
R1= -CH2CH3; -CH2-C≡CH; -CH2COOEt
Scheme 2. Syntheses of 2-oxo-1,2-dihydroquinoline carboxamide derivatives (3-6) and their N-alkylated
derivatives (7-18).
2.3. Synthesis of compound 1: 2-oxo-1,2-dihydroquinoline-4- carboxylic acid:
To a solution of 10 mmol of isatin and 10 mmol of malonic acid in 30 ml of acetic acid was
added 1 mmol of sodium acetate. The mixture was refluxed for 24 h. After cooling, 100 ml of
ice-water were added. The precipitate obtained was washed several times with ethanol [25].
Yield (%) = 90; mp = 553 K; 1H NMR (300 MHz, CDCl3): 6.86 (s, 1H, CH); 7.2-8.16 (m, 4H,
13
CHarom); 12.17 (s, 1H, NH); 13.9 (s, 1H, OH). C NMR (75 MHz, CDCl3): 167.2 (COOH),

163.0 (C=O), 141.7-139.8 (Cq-Cq), 131.3 (CHarom), 126.5 (CHarom), 123.8 (CH), 122.6 (Cq),
116.2 (CHarom).
* General procedure: syntheses of the compounds (3-6)
ꢀ Step 1 : acyl chloride preparation
To 10 mmol of the product 1, 10-15 ml of thionyl chloride (SOCl2) was added, the mixture
was then refluxed for 2 h. The excess of thionyl chloride was evaporated under reduced
pressure, and then the intermediate acyl chloride 2 was obtained, and used immediately for
the next step without any purification.
ꢀ Step 2 : action of aniline derivatives
To the acyl chloride 2 in 10 ml of chloroform, were added at 0°C 1.5 eq of an aniline
derivative (aniline, 2,4-difluoroaniline, 3-chloro-4-fluoroaniline or 3-trifluoromethyl-aniline).
The reaction mixture was left at room temperature for 2 h. Then, the residue obtained was
recrystallized from the mixture of solvents (DMSO / H2O), leading to the formation of the
new carboxamide compounds (3-6).
2-oxo-N-phenyl-1,2-dihydroquinoline-4-carboxamide: 3
1
Yield (%) = 92; mp > 623 K; H NMR (300 MHz, DMSO-d6): 6.93 (s, 1H, CHarom), 7.15 (t,
3
3
1H, JH-H = 7.2 Hz, CHarom), 7.22 (t, 1H, JH-H = 7.2 Hz, CHarom), 7.38 (m, 3H, CHarom), 7.56
(td, 1H, 3JH-H = 7.2 Hz, 4JH-H = 1.1 Hz, CHarom), 7.73 (t, 1H, 3JH-H = 7.7 Hz, CHarom), 10.74 (s,
1H, NH), 12.02 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 164.77 (C=O), 161.82
(C=O),146.48 (Cq),139.68-138.93 (Cq-Cq), 131.49 (CHarom), 129.31 (2 CHarom), 126.17
(CHarom), 124.76 (CHarom), 122.79 (CHarom), 120.48 (2 CHarom), 120.33 (CHarom),116.47 (Cq),
116.24 (CHarom).
N- (2,4-difluorophenyl) -2-oxo-1,2-dihydroquinoline-4-carboxamide: 4
Yield (%) = 98 %; mp > 623 K; 1H NMR (300 MHz, DMSO-d6): 6.72 (s, 1H, CHarom), 7.13-
7.26 (m, 2H, CHarom), 7.36-7.44 (m, 2H, CHarom), 7.54-7.6 (m, 1H, CHarom), 7.74-7.82 (m, 1H,
CHarom), 10.57 (s, 1H, NH), 12.02 (s, 1H, NH).13C NMR (75 MHz, DMSO-d6): 165.22
(C=O), 161.61 (C=O), 160.23 (dd, Cq, 1JC-F = 243.75 Hz, 3JC-F = 11.25 Hz), 156 (dd, Cq, 1JC-F
= 248.25 Hz, 3JC-F = 12.75 Hz), 145.88 (Cq), 139.75 (Cq), 131.47 (CHarom), 128.3 (dd, CHarom
,
2
4J = 9.9 Hz, 4J = 2.85 Hz), 126.13 (CHarom), 122.69 (CHarom), 121.85 (dd, CHarom, J= 12.67
2
Hz, 4J= 4.5 Hz), 120.8 (CHarom), 116,45 (Cq), 116.22 (CHarom), 111.8 (dd, CHarom, J= 22.5
Hz, 4J= 3.75 Hz ), 104.97 (dd, CHarom, 2J= 24 Hz, 2J= 24 Hz).19F NMR (282 MHz, DMSO-d6):
δ = -112.69 (d, 1F, 3JC-F = 6,2 Hz), δ = -116.70 ppm (d, 1F, 3JC-F = 6,2 Hz).

N- (3-chloro-4-fluorophenyl) -2-oxo-1,2-dihydroquinoline-4-carboxamide: 5
Yield (%) = 93 %; mp > 623 K; 1H NMR (300 MHz, DMSO-d6): 6.75 (s, 1H, CHarom), 7.24 (t,
3
3
3H, JH-H = 7.2 Hz, CHarom), 7.37-7.67 (m, 4H, CHarom), 7.74 (d, 1H, JH-H = 7.8 Hz, CHarom),
3
4
8.08 (dd, 1H, JH-H = 6.9 Hz, JH-H = 2.4 Hz, CHarom), 10.93 (s, 1H, NH); 12.04 (s, 1H,
1
NH).13C NMR (75 MHz, DMSO-d6): 164.89 (C=O), 161.63 (C=O),154.15 (d, Cq, JC-F
=
242.25 Hz), 145.88-139.77 (Cq-Cq), 136.22 (d, Cq, 4JC-F = 3.75 Hz), 131.53 (CHarom), 126.22
3
(CHarom), 122.75 (CHarom), 122.03 (CHarom), 120.95 (d, CHarom, JC-F = 6.75 Hz), 120.84 (d,
3
2
2
CHarom, JC-F = 7.5 Hz), 119.7 (d, Cq, JC-F = 18 Hz), 117.55 (d, CHarom, JC-F = 21.75 Hz),
116.27 (Cq), 116.23 (CHarom). 19F NMR (282 MHz, DMSO-d6): δ = -121.47 ppm.
2-oxo-N- (3 - (trifluoromethyl) phenyl) -1,2-dihydroquinoline-4-carboxamide: 6
1
Yield (%) = 91 %; mp > 623 K; H NMR (300 MHz, DMSO-d6): 6.79 (s, 1H, CHarom), 7.22
3
4
3
(td, 1H, JH-H = 6.9 Hz, JH-H = 0.9 Hz, CHarom,), 7.39 (d, 1H, JH-H = 8.1 Hz, CHarom), 7.50-
7.74 (m, 2H, CHarom), 7.76 (dd, 1H, 3JH-H = 8.1 Hz, 4JH-H = 0.6 Hz, CHarom), 7.96 (d, 1H, 3JH-H
= 8.1 Hz, CHarom), 8.27 (s, 1H, CHarom), 11.08 (s, 1H, NH), 12.08 (s, 1H, NH).13C NMR (75
MHz, DMSO-d6): 165.19 (C=O), 161.66 (C=O), 145.87 (Cq), 139.80-139.76 (Cq-Cq), 131.53
3
(CHarom), 130.59 (CHarom), 129.97 (q, Cq, JC-F = 31.5 Hz), 126.34 (Cq), 126.22 (CHarom),
124.03 (CHarom), 122.76 (CHarom), 122.03 (CHarom), 121.03 (q, CHarom, 3JC-F = 4.5 Hz), 120.85
3
(CHarom), 116.53 (q, CHarom, JC-F = 4.5 Hz), 116.27 (Cq), 116.24 (CHarom). 19F NMR (282
MHz, DMSO-d6): δ = -61.32 ppm (3F, CF3).
*General procedure: syntheses of the compounds (7-18)
Strategies for functionalization of the two amide functions
10 mmols of each of the compounds derived from 2-oxo-1,2-dihydroquinoline-4-carboxamide
(3, 4, 5 and 6) in 10 ml of DMF were mixed with 2.2 eq of (ethyl iodide, propargyl bromide
or ethyl bromoacetate), 5 eq of K2CO3 and 0.1 eq of tetra n-butylammonium bromide
(TBAB). The reaction mixture was stirred at room temperature in DMF for 6 h. After removal
of the salts by filtration, the DMF was evaporated under reduced pressure, and the resulting
residues were dissolved in dichloromethane. The organic phase was dried over Na2SO4 and
then concentrated under vacuum. The pure compound was separated on column liquid
chromatography, using a mixture of hexane / ethyl acetate (3/1) as eluent, allowing to the
preparation of the new and various N-alkylated carboxamide compounds (7-18).
N-ethyl, N-phenyl- (1-ethyl-2-oxo-1,2-dihydroquinoline-4)-carboxamide: 7
Yield (%) = 76 %; mp > 414,15 K; 1H NMR (300 MHz, CDCl3) : 1.25 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.31 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.05 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.23 (q, 2H, 3JH-H
7.2 Hz, CH2), 6.37 (s, 1H, CHarom); 7.04-7,07 (m, 2H, CHarom); 7.15-7.19 (m, 3H, CHarom),
=

7.26-7.33(m, 2H, CHarom), 7.56 (m, 1H, CHarom), 7.8(m, 1H, CHarom).13C NMR (75 MHz,
CDCl3): 166.44 (C=O), 160.67 (C=O), 145.22 (Cq), 141.15-139.05 (Cq-Cq), 130.92 (CHarom),
129.45 (2CHarom), 127.99 (CHarom), 127.63 (2CHarom), 127.01 (CHarom), 122.21 (CHarom),
119.93 (CHarom), 118.44 (Cq), 114.40 (CHarom), 44.46 (CH2), 37.19 (CH2), 13.06 (CH3), 12.57
(CH3).
N-ethyl, N-(2,4-difluorophenyl)- (1-ethyl-2-oxo-1,2-dihydroquinoline-4)-carboxamide: 8
Yield (%) = 65 %; mp > 416,15 K; 1H NMR (300 MHz, CDCl3) : 1.26 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.33 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.09 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.24 (q, 2H, 3JH-H
=
7.2 Hz, CH2), 6.47 (s, 1H, CHarom), 6.68-6.80 (m, 2H, CHarom), 7.05 (m, 1H, CHarom), 7.23-
7.74 (m, 5H, CHarom).13C NMR (75 MHz, CDCl3): 166.92 (C=O), 162.24 (dd, Cq, 1JC-F = 231
1
Hz, 3JC-F = 12 Hz), 160.53 (C=O), 158.30 (dd, Cq, JC-F = 251.25 Hz, 3JC-F = 12 Hz), 144.67
4
(Cq), 139.15 (Cq), 131.15 (CHarom), 130.9 (dd, CHarom, J = 9.75 Hz, 4J = 2.85 Hz), 126.84
4
(CHarom), 125.24 (dd, Cq, J = 11.77 Hz, 4J = 4.5 Hz), 122.19 (CHarom), 119.09 (m, CHarom),
118.00 (CHarom), 117,79 (Cq), 114,40 (CHarom), 111.98 (dd, CHarom, 2J= 22.5 Hz, 4J= 4.5 Hz),
2
19
105.35 (dd, CHarom, J= 25.5 Hz), 43.91 (CH2), 37.32 (CH2), 12.70 (CH3), 12.56 (CH3). F
NMR (282 MHz, CDCl3): δ = -112.69 (d, 1F, 3JC-F = 6,2 Hz), δ = -116.70 ppm (d, 1F, 3JC-F
=
6,2 Hz).
N-ethyl,
carboxamide: 9
Yield (%) = 80 %; mp > 419,15 K; 1H NMR (300 MHz, CDCl3) : 1.28 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.30 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.02 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.26 (q, 2H, 3JH-H
N-(3-chloro-4-fluorophenyl)-
(1-ethyl-2-oxo-1,2-dihydroquinoline-4)
=
7.2 Hz, CH2), 6.38 (s, 1H, CHarom), 6.94 (dd, 2H, 3JH-H = 6.3 Hz, 4JH-H = 1.2 Hz, CHarom), 7.16
(m, 1H, CHarom), 7.26-7.37 (m, 2H, CHarom), 7.56-7.72 (m, 2H, CHarom).13C NMR (75 MHz,
CDCl3): 166.29 (C=O), 160.50 (C=O), 159.02 (Cq), 157.35 (d, Cq, 1JC-F = 250.5 Hz), 144.77-
139.13 (Cq-Cq), 137.85 (Cq), 131.25 (CHarom), 129.72 (CHarom), 127.7 (d, CHarom, 3JC-F = 7.5
2
Hz), 126.63 (CHarom), 122.35 (CHarom), 121.8 (d, Cq, JC-F = 18.9 Hz), 119.89 (CHarom),
3
2
118.06 (Cq), 117.20 (d, CHarom, JC-F = 7.5 Hz), 117.55 (d, CHarom, JC-F = 22.12 Hz), 114.61
(CHarom), 44.62 (CH2), 37.34 (CH2), 13.00 (CH3), 12.57 (CH3). 19F NMR (282 MHz, CDCl3) :
δ = -114.64 ppm.
N-ethyl,
carboxamide: 10
Yield (%) = 63 %; mp > 422,15 K; 1H NMR (300 MHz, CDCl3) : 1.25 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.33 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.09 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.24 (q, 2H, 3JH-H
7.2 Hz, CH2), 6.35 (s, 1H, CHarom), 7.26-7.43 (m, 5H, CHarom,), 7.56-7,77 (m, 3H, CHarom).13C
N-(3-trifluoromethylphenyl)-
(1-ethyl-2-oxo-1,2-dihydroquinoline-4)-
=

NMR (75 MHz, CDCl3): 166.43 (C=O), 163.05 (C=O), 145.87 (Cq), 139.80-139.22 (Cq-Cq),
3
131.28 (CHarom), 130.79 (CHarom), 130.14 (CHarom), 129.45 (q, Cq, JC-F = 31.5 Hz), 126.82
3
3
(Cq), 126.65 (CHarom), 124.70 (q, CHarom, JC-F = 3.75 Hz), 124.17 (q, CHarom, JC-F = 3.75
Hz), 122.40 (CHarom), 119.21 (CHarom), 116.27 (Cq), 114.57 (CHarom), 44.50 (CH2), 37.23
(CH2), 13.04 (CH3), 12.49 CH3).19F NMR (282 MHz, CDCl3) : δ = -61.32 ppm (3F, CF3).
N- (prop-2-yn-1-yl), N-phenyl- (1-prop-2-yn-1-yl -2-oxo-1,2-dihydroquinoline-4)-
carboxamide: 11
Yield (%) = 75 %; mp > 424,15 K; 1H NMR (300 MHz, CDCl3) : 2.21 (t, 1H, 4JH-H = 2.4 Hz,
≡CH), 2.36 (t, 1H, 4JH-H = 2.4 Hz, ≡CH), 4.74 (d, 2H, 4JH-H = 2.4 Hz, CH2), 4.97 (d, 2H, 4JH-H
= 2.4 Hz, CH2), 6.42 (s, 1H, CHarom), 7.18-7.22 (m, 5H, CHarom), 7.33 (td, 1H, 3JH-H = 8.1 Hz,
4JH-H = 0.9 Hz, CHarom), 7.46 (d, 1H, 3JH-H = 8.4 Hz, CHarom), 7.6 (td, 1H, 3JH-H = 7.2 Hz, 4JH-H
= 1.5 Hz, CHarom), 7.81 (dd, 1H, 3JH-H = 8.4 Hz, 4JH-H = 1.2 Hz, CHarom).
13C NMR (75 MHz, CDCl3): 166.26 (C=O), 160.06 (C=O), 145.09 (Cq), 140.62-138.75 (Cq-
Cq), 131.28 (CHarom), 129.57 (2 CHarom), 128.61 (CHarom), 127.45 (2 CHarom), 126.91
(CHarom), 122.95 (CHarom), 119.80 (CHarom), 118.25 (Cq), 115.04 (CHarom), 78.24 (C≡), 77.51
(C≡), 72.89 (≡CH), 72.60 (≡CH), 38.88 (CH2), 31.63 (CH2).
N-
(prop-2-yn-1-yl),
N-(2,4-difluorophenyl)-
(1-prop-2-yn-1-yl
-2-oxo-1,2-
dihydroquinoline-4)-carboxamide: 12
Yield (%) = 73 % ; mp > 416,15 K; 1H NMR (300 MHz, CDCl3): 2.22 (t, 3H, 4JH-H = 2.4 Hz,
≡CH), 2.32 (t, 3H, 4JH-H = 2.4 Hz, ≡CH), 4.28 (d, 2H, 4JH-H = 2.4 Hz, CH2), 5.00 (d, 2H, 4JH-H
= 2.4 Hz, CH2), 6.52 (s, 1H, CHarom), 6.68-7.76 (m, 8H, 8CHarom).13C NMR (75 MHz,
1
CDCl3): 164.91 (C=O), 159.94 (C=O), 160.23 (dd, Cq, JC-F = 243.75 Hz, 3JC-F = 11.25 Hz),
156 (dd, Cq, 1JC-F = 248.25 Hz, 3JC-F = 12.75 Hz), 144.53 (Cq), 138.78 (Cq), 131.49 (CHarom),
4
128.3 (dd, CHarom, J = 9.9 Hz, 4J = 2.85 Hz), 126.13 (CHarom), 122.69 (CHarom), 121.85 (dd,
2
4
CHarom, J= 12.67 Hz, J= 4.5 Hz), 119.58 (CHarom), 117.68 (Cq), 115.23 (CHarom), 115.07
2
4
2
(CHarom), 112.1 (dd, CHarom, J= 21.9 Hz, J= 3.75 Hz), 105.41 (dd, CHarom, J= 23.7 Hz),
77.44 (C≡), 76.50 (C≡), 73.54 (≡CH), 72.70 (≡CH), 37.93 (CH2), 31.71 (CH2). 19F NMR (282
MHz, CDCl3) : δ = -112.69 (d, 1F, 3J= 6,2 Hz), δ = -116.70 ppm (d, 1F, 3JC-F = 6,2 Hz).
N- (prop-2-yn-1-yl), N-(3-chloro-4-fluorophenyl)- (1-prop-2-yn-1-yl -2-oxo-1,2-
dihydroquinoline-4)-carboxamide:13
Yield (%) = 80 % ; mp > 432,15 K; 1H NMR (300 MHz, CDCl3) : 2.21 (t, 3H, 4JH-H = 2.4 Hz,
≡CH); 2.39 (t, 3H, 4JH-H = 2.4 Hz, ≡CH); 4.77 (d, 2H, 4JH-H = 2.4 Hz, CH2); 4.97 (d, 2H, 4JH-H
= 2.4 Hz, CH2); 6.42 (s, 1H, CHarom); 7.32-7.78 (m, 8H, CHarom,). 13C NMR (75 MHz, CDCl3):

1
166.09 (C=O), 159.91 (C=O), 154.15 (d, Cq, JC-F = 259.5 Hz), 144.64-138.80 (Cq-Cq),
3
137.01 (Cq), 131.62 (CHarom), 129.82 (CHarom), 127.81 (d, CHarom, JC-F = 7.75 Hz), 126.53
2
(CHarom), 123.10 (CHarom), 119.76 (CHarom), 117.87 (Cq), 117.3 (d, CHarom, JC-F = 51 Hz),
115.29 (CHarom), 77.,69 (C≡), 77.36 (C≡), 73.62 (≡CH), 72.78 (≡CH), 38.86 (CH2), 31.75
(CH2). 19F NMR (282 MHz, CDCl3) : δ = -114.62 ppm.
N- (prop-2-yn-1-yl), N-(3-(trifluoromethyl)phenyl)- (1-prop-2-yn-1-yl -2-oxo-1,2-
dihydroquinoline-4)-carboxamide:14
Yield (%) = 71 %; mp > 404,15 K; 1H NMR (300 MHz, CDCl3): 2.21 (t, 3H, 4JH-H = 2.4 Hz,
≡CH), 2.39 (t, 3H, 4JH-H = 2.4 Hz, ≡CH), 4.77 (d, 2H, 4JH-H = 2.4 Hz, CH2), 4.97 (d, 2H, 4JH-H
= 2.4 Hz, CH2); 6.42 (s, 1H, CHarom); 7.32-7.78 (m, 8H, CHarom,).13C NMR (75 MHz, CDCl3):
166.09 (C=O), 159.85 (C=O), 144.71 (Cq), 141.13-138.69 (Cq-Cq), 131.61 (CHarom), 130.76
3
(CHarom), 130.22 (CHarom), 126.53 (CHarom), 125.30 (q, CHarom, JC-F = 4.1 Hz), 124.22 (q,
3
CHarom, JC-F = 4 Hz), 123.10 (CHarom), 119.78 (CHarom), 117.89 (Cq), 115.23 (CHarom), 77.71
(C≡), 77.36 (C≡), 73.56 (≡CH), 72.68 (≡CH), 38.67 (CH2), 31.56 (CH2).19F NMR (282 MHz,
CDCl3) : δ = -61.32 ppm (3F, CF3).
N- (2-ethoxy-2-oxoethyl), N-phenyl- (1-2-ethoxy-2-oxoethyl -2-oxo-1,2-dihydroquinoline-
4)-carboxamide : 15 [26]
Yield (%) = 71 % ; mp > 398,15 K; 1H NMR (300 MHz, CDCl3): 1.18 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.36 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.16 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.32 (q, 2H, 3JH-H
=
7.2 Hz, CH2), 4.65 (s, 2H, OCH2), 4.97 (s, 2H, OCH2), 6.49 (s, 1H, CH), 7.03-8.08 (m, 9H,
CHarom). 13C NMR (75 MHz, CDCl3): 168.55 (C=O), 167.72 (C=O), 167.20 (C=O), 160.71
(C=O), 145.45 (Cq), 141.67-139.29 (Cq-Cq), 131.39 (CHarom), 129.58 (2CHarom), 128.42
(CHarom), 127.63 (CHarom), 127.31 (2CHarom), 123.01 (CHarom), 119.47 (CHarom), 118.19 (Cq),
113.81 (CHarom), 61.77 (CH2), 61.73 (CH2). 51.53 (CH2), 43.79 (CH2), 14.21 (CH3), 14.05
(CH3).
N- (2-ethoxy-2-oxoethyl), N-(2,4-difluorophenyl)- (1-2-ethoxy-2-oxoethyl -2-oxo-1,2-
dihydroquinoline-4)-carboxamide: 16
Yield (%) = 75 %; mp > 419,15 K; 1H NMR (300 MHz, CDCl3) : 1.18 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.35 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.18 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.32 (q, 2H, 3JH-H
=
7.2 Hz, CH2), 4.93 (s, 2H, OCH2), 5.13 (s, 2H, OCH2), 6.51 (s, 1H, CHarom), 6.79-6.89 (m,
2H, CHarom), 7.13 (m, 1H, CHarom), 7.34-7.82 (m, 5H, CHarom). 13C NMR (75 MHz, CDCl3):
1
167.35 (C=O), 166.79 (C=O), 165.12 (C=O), 160.93 (C=O), 160.02 (dd, Cq, JC-F = 243.75
Hz, 3JC-F = 12 Hz), 155.89 (dd, Cq, 1JC-F = 248.25 Hz, 3JC-F = 12.75 Hz), 145.81 (Cq), 140.05

(Cq), 131.79 (CHarom), 128.3 (dd, CHarom, 4J = 9.9 Hz, 4J = 2.85 Hz), 125.83 (CHarom), 123.06
(CHarom), 122.01 (dd, CHarom, 2J= 12.75 Hz, 4J= 4.5 Hz), 120.76 (CHarom), 116,65 (Cq), 116,42
2
4
2
(CHarom), 112.12 (dd, CHarom, J= 23.25 Hz, J= 4.5 Hz ), 104.97 (dd, CHarom, J= 24 Hz, 2J=
19
24 Hz), 61.68 (CH2), 61.61 (CH2), 51.50 (CH2), 43.84 (CH2), 14.20 (CH3), 14.01 (CH3). F
NMR (282 MHz, CDCl3): δ = -112.65 (d, 1F, 3JC-F = 6,2 Hz), δ = -116.79 ppm (d, 1F, 3JC-F
=
6,2 Hz).
N- (2-ethoxy-2-oxoethyl), N-(3-chloro-4-fluorophenyl)- (1-2-ethoxy-2-oxoethyl -2-oxo-
1,2-dihydroquinoline-4)-carboxamide: 17
1
3
Yield (%) = 80 %; mp > 473 K; H NMR (300 MHz, CDCl3): 1.19 (t, 3H, JH-H = 7.2 Hz,
CH3), 1.36 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.18 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.33 (q, 2H, 3JH-H
=
7.2 Hz, CH2), 4.59 (s, 2H, OCH2), 5.00 (s, 2H, OCH2), 6.51 (s, 1H, CHarom), 6.90-8.01 (m,
7H, CHarom). 13C NMR (75 MHz, CDCl3): 168.36 (C=O), 167.62 (C=O), 167.06 (C=O),
160.55 (C=O), 157.61 (d, Cq, 1JC-F = 250.73 Hz), 145.00-139.35 (Cq-Cq), 138.16 (d, Cq, 4JC-F
3
= 3.75 Hz), 131.72 (CHarom), 129.82 (CHarom), 127.71 (d, CHarom, JC-F = 7.5 Hz), 127.30
(CHarom), 123.15 (CHarom), 121.92 (CHarom), 121.92 (d, Cq, 3JC-F = 18.75 Hz), 119.43 (CHarom),
2
117.80 (CHarom), 117.35 (d, CHarom, JC-F = 21.75 Hz), 114.02 (CHarom), 61.89 (CH2), 61.11
(CH2), 52.03 (CH2), 44.14 (CH2), 14.22 (CH3), 14.02 (CH3). 19F NMR (282 MHz, CDCl3): δ
= -121.74 ppm.
N- (2-ethoxy-2-oxoethyl), (3-(trifluoromethyl)phenyl)- (1-2-ethoxy-2-oxoethyl -2-oxo-1,2-
dihydroquinoline-4)-carboxamide: 18
Yield (%) = 79 % ; mp > 433,15 K; 1H NMR (300 MHz, CDCl3): 1.14 (t, 3H, 3JH-H = 7.2 Hz,
CH3), 1.32 (t, 3H, 3JH-H = 7.2 Hz, CH3), 4.13 (q, 2H, 3JH-H = 7.2 Hz, CH2), 4.31 (q, 2H, 3JH-H
=
7.2 Hz, CH2), 4.61 (s, 2H, OCH2), 4.93 (s, 2H, OCH2), 6.46 (s, 1H, CH), 7.00-7.51 (m, 7H,
CHarom), 8.00-8.03 (m, 1H, CHarom). 13C NMR (75 MHz, CDCl3): 168.34 (C=O), 167.57
(C=O), 167.08 (C=O), 160.51 (C=O), 145.87 (Cq), 145.06-139.28 (Cq-Cq), 131.69 (CHarom),
3
130.85 (CHarom), 130.29 (CHarom), 129.21 (2 CHarom), 127.29 (CHarom), 125.15 (q, Cq, JC-F
=
3
3.75 Hz), 124.21 (q, Cq, JC-F = 3.75 Hz), 123.12 (CHarom), 119.50 (CHarom), 117.80 (Cq),
113.95 (CHarom), 62.01 (CH2), 61.75 (CH2), 51.35 (CH2), 43.81 (CH2), 14.16 (CH3), 14.00
(CH3).19F NMR (282 MHz, CDCl3): δ = -61.72 ppm (3F, CF3).

2.3. Single crystal X-ray diffraction
2.3.1. Crystal structures of the 2-oxo-1,2-dihydroquinoline derivatives (10, 11,
15 and 18)
The crystallographic analyses of the 2-oxo-1,2-dihydroquinoline derivatives (10, 11, 15
and 18), obtained by cyclocondensation, substituted anilines and alkylation reactions, confirm
the structures of the compounds (Fig.1 and Table 1). It is interesting to note that compound 11
ꢀ
crystallizes in the triclinic system (P 1), compounds 15 and 18 crystallize in the monoclinic
system (I 2/a) and compound 10 crystallizes in the orthorhombic system (Pbca). The
crystallographic data have been assigned to CCDC deposition numbers (see Table 1)
2.4. Computational details
Density Functional Theory (DFT) methods are very important owing to cost of
computations and reliable results for complex molecules in quantum chemistry. In this
method, frequently Becke-3-Lee-Yang-Parr (B3LYP) functionals are used [27]. For the
molecular orbital computations, the 6-311G(d,p) basis set was selected and the Gaussian 09W
software package [28] was used. Firstly, molecular optimizations of compounds 10, 11, 15
and 18 were carried out using the atomic coordinates in the CIF files, obtained from the
crystallographic studies, and other geometry optimized computations were made based on
their optimized structures. In order to visualize the intermolecular interactions in the crystals
of compounds 10, 11, 15 and 18 Hirshfeld surface (HS) analyses were carried out by using
CrystalExplorer17.5 [29]. Also, in this study, Highest Occupied Molecular Orbital (HOMO)
and Lowest Unoccupied Molecular Orbital (LUMO) analyses for compounds 10, 11, 15 and
18 were mostly formed from π and π * molecular orbitals of the aromatic groups,
1
respectively. The H- and 13C-NMR chemical shifts of compounds 10, 11, 15 and 18 were
calculated with the Gauge-Including Atomic Orbital (GIAO) approach by using the
B3LYP/6-311G(d,p) basis set and compared with the experimental NMR spectra in a DMSO-
d6 solvent. Finally, molecular docking studies between compounds 10, 11, 15 and 18 and
inter-molecular interactions between the macromolecules (PDB ID: 1M17) were carried out
employing the AutoDock Vina free software program [43].
2.5. Molecular geometric properties
The geometry optimized molecular structures along with the numbering (scheme 2) for
compounds 10, 11, 15 and 12 are shown in Fig. 2. The geometry optimized bond lengths and
angles of the title molecules were calculated using the B3LYP functional along with the 6-
311G(d,p) basis set. Some important and selected theoretical and experimental geometric
parameters are listed in Table 2. From Table 2, we can see that there are some mismatches

between the experimental and geometry optimized molecular structures. It is noted that the
optimized structures are calculated in the gas phase, while the experimental structures are
obtained from the data collected in the solid phase. In the oxo-dihydroquinoline group, the
O1=C1 bond length was calculated as 1.22430 Å (for compound 10), 1.22289Å (O1A=C1A)
(for compound 11), 1.22337Å (for compound 15) and 1.22326Å (for compound 18) with the
B3LYP/6-311G(d,p) functional/basis set. These bonds were determined experimentally as
1.234(3) Å (for compound 10), 1.231(2) Å (O1A=C1A) (for compound 11), 1.226(3) Å (for
compound 15) and 1.230(3) Å (for compound 18). The corresponding bond (O1=C9
according to the reported numbering scheme) has been calculated as 1.231 Å , 1.230 Å and
1.228 Å with B3LYP/6-311++G(d,p) for ethyl 1-ethyl-2-oxo-1,2-dihydroquinoline-4-
carboxylate and ethyl-6-chloro-1-ethyl-2-oxo-1,2-dihydroquinoline-4-carboxylate [30],
respectively. On the other hand, the N1—C1 and N1—C9 bond lengths were calculated as
1.40521 Å and 1.39253 Å (for compound 10), 1.39376 Å and 1.39376 Å (for compound 11),
1.40882 Å and 1.39342 Å (for compound 15) and 1.40895 Å and 1.39311 Å (for compound
18), respectively, with the B3LYP/6-311G(d,p) functional/basis set. The experimentally
determined corresponding bond lengths were 1.383(3) Å and 1.393(3) Å (for compound 10),
1.389(3) Å and 1.397(3) Å (for compound 11), 1.382(2) Å and 1.390(3) Å (for compound 15)
and 1.380(2) Å and 1.392(3) Å (for compound 18), respectively. In the literature [30], these
bond lengths are very compatible with our results. We may also pay attention to some
important bond angles in the oxo-dihydroquinoline group. The bond angles C1—N1—C9,
O1—C1—N1 and O1—C1—C2 were calculated as 122.7(2)°, 120.9(2)° and 122.9(2)°,
respectively, (for compound 10), 123.16(18)°, 121.2(2)° and 122.9(2)°, respectively, (for
compound 11), 123.48(16)°, 121.34(19) and 123.13(18)°, respectively, (for compound 15)
and 123.59(16)°, 121.35(18)° and 123.16(18)°, respectively (for compound 18). These values
are smaller than 120° because of the presence of the oxo-dihydroquinoline ring as explained
in the literature [30]. For example, in the heterocyclic 4-hydroxy-2-oxo-1,2-dihydroquinoline-
7-carboxylic acid molecule [31], the bond angles C1—C2—C3 and C2—C3—C4 were
reported as 119.66° and 119.4°, respectively. The C1—N1—C9, O1—C1—N1 and O1—
C1—C2 bond angles were calculated as 123.04954°, 121.40406° and 122.94433°,
respectively (for compound 10), 123.44171°, 121.44592° and 123.24597°, respectively (for
compound 11), 123.39328°, 121.17736 and 123.39068°, respectively (for compound 15) and
123.46631°, 121.22491° and 123.39693°, respectively (for compound 18), with the B3LYP/6-
311G(d,p) functional/basis. These bond lengths and angles are generally compatible with the
corresponding values in similar structures [30-31].

2.6. HOMO-LUMO Analysis
The Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular
Orbital (LUMO) parameters are very important to understand aspects of the quantum
chemistry mechanism and the chemical reaction pathways. Usually, HOMO is known as a
donor, while LUMO is known as an acceptor [32-33]. While HOMO energy is related to the
ionization potential, LUMO energy is related to the electron activation. Other important
parameters are the energy gap values of the compounds. The energy differences between
HOMO and LUMO are called the energy band gaps (ꢀE=ELUMO-EHOMO), and for the
stabilities of the structures they are very crucial, where the higher-gap energy is more stable
than the lower-gap energy. Additionally, the HOMO–LUMO gaps for compounds 10, 11, 15
and 18 were calculated as 4.2273 eV, 4.3394 eV, 4.3675 eV and 4.2972 eV, respectively.
From these results, we can conclude that the sum of the electronic and zero-point energies of
compound 10 is relatively low (the most stable structure according to the energy results) and
its gap is small. Furthermore, by using HOMO and LUMO energy values we can calculate the
other important parameters such as the Ionization potential=I = -EHOMO; the electron affinity
=A = -ELUMO; the chemical hardness= η = (I-A)/2; the electrophilicity index, ω = ꢁ2/2η and
softness, ζ = 1/2η. These parameters have been calculated and given in Table 3. The HOMO’s
and LUMO’s (HOMO-LUMO cloud distributions) (Fig. 3) were obtained and simulated from
the optimized molecular geometries using the .chk files in the gas phase at the B3LYP/6-
311G(d,p) functional/levels.
2.7. NMR Analyses
Theoretical studies on geometric structures, NMR chemical shifts and HOMO-LUMO
analyses for compounds 10, 11, 15 and 18 were performed by the B3LYP functional [27-34]
method by using the 6-311G(d,p) basis set. Gaussian 09W software [28] was used to compute
the aforementioned electronic structure properties, while GaussView5 software [35] was used
to monitorize these computed features. The initial structures for all computations were carried
out using the atomic coordinates from the CIF files, obtained from the crystallographic
studies.
The optimized geometrical parameters for compounds 10, 11, 15 and 18 were obtained in
the gas phase. For the theoretical NMR chemical shift analyses, all molecular structures were
1
optimized within chloroform with the IEF-PCM model [36]. Then, 13C- and H-NMR
chemical shifts for compounds 10, 11, 15 and 18 were found with the GIAO method [37] by
using the same computational procedures and the same solvation model parameters. The

ꢇꢈꢉ
NMR isotropic chemical shift values were calculated via the equation ꢁꢂꢅꢃꢄ. = ꢆ
− ꢆꢂꢅꢃꢄ.
ꢂꢃꢄ.
ꢇꢈꢉ
[where ꢁꢂꢅꢃꢄ. is the isotropic chemical shift of any atom within the compound, ꢆ
is the
ꢂꢃꢄ.
isotropic absolute shielding value of carbon (average of four) and hydrogen (average of
twelve) atoms within TMS and ꢆꢂꢅꢃꢄ. is the isotropic absolute shielding value of any atom
within the compound]. The isotropic absolute shielding values computed at the B3LYP/6-
311G(d,p) functional/levels within chloroform of TMS (tetramethyl silane) were found as
1
32.00 ppm for protons and 184.9 ppm for carbons. The experimental and computed H- and
13C-NMR chemical shifts are given in Tables 4 and 5. Generally, the observed and calculated
1H- and 13C-NMR chemical shifts are in a very good agreement with the corresponding
literature values [31, 38]. There are fourteen 13C- and fifteen 1H-NMR chemical shifts for the
title molecules that we can locate precisely as may be seen in Tables 4 and 5.
2.8. Hirshfeld surface analyses
Hirshfeld surface analysis may be used to research all of the possible inter-molecular
interactions via contact atoms (donor and acceptor groups) within the crystal packing of any
crystalline compound. The normalized contact distance function (dnorm) may be used to
analyze the close contact interaction distances (the inter-molecular interaction distances
between donor and acceptor groups in effective sites of molecular groups within an
interaction) on its related 3D dnorm Hirshfeld surfaces. The 3D dnorm surfaces and their related
2D fingerprint graphics were depicted via the Crystal Explorer program software used to
investigate the Hirshfeld surfaces of compounds 10, 11, 15 and 18 (Hirshfeld, 1977; Wolff,
Grimwood, McKinnon, Turner, Jayatilaka & Spackman, 2012; Spackman & Jayatilaka, 2009;
M.A. Spackmann, McKinnon & Jayatilaka, 2008) [39-42].
ꢊꢂ − ꢎꢏꢐꢑ ꢊꢒ − ꢎꢏꢐꢑ
ꢒ
ꢂ
ꢊꢋꢄꢌꢍ
=
+
ꢎꢏꢐꢑ
ꢎꢏꢐꢑ
ꢒ
ꢂ
where di is the length from a point on the surface to the nearest inside nucleus, and de is the
length from a point on the surface to the nearest external nucleus. They are represented by the
red (for short distances), blue (for medium distances) and green (for long distances) regions
on their mapped surfaces. Likewise, dnorm is the normalized contact distance depending upon
di and de distances and the van der Waals radius (ꢎꢏꢐꢑ). Its 3D related surface is mapped by
the red, white and blue colors. The red (negative value) and blue (positive value) regions
indicate inter-molecular distances for contacts shorter and longer than the sum of ꢎꢓꢐꢑ
respectively. Moreover, the white regions (zero value) represents the inter-molecular
distances for contacts close/equal to the sum of ꢎꢓꢐꢑ
,
.

The depicted 3D dnorm surfaces and their reduced related 2D fingerprint histograms are
given in Figs. 4 and 5, respectively. The presence of the red points on the 3D dnorm surfaces of
compounds 10, 11, 15 and 18 indicates the existence of inter-molecular interactions. The
interactions with major contributions within the crystal packings of all four compounds are
due to the van der Waals interactions of the H…H species with the percentage values of 43.9%
(for compound 10), 39.1% (for compound 11), 53.9% (for compound 15) and 39.1% (for
compound 18). For compounds 10, 11, 15 and 18, the O…H/H…O interactions were obtained
with the percentage values of 14.6%, 17.5%, 28.5% (the second major contribution for
compound 15) and 21.96% (the second major contribution for compound 18), respectively,
while the C…H/H…C and C…C species indicating the existence of the C-H…π and π…π
interactions within the crystal packings were computed with the percentage values of 6.2%,
35.7% (the second major contribution for compound 11), 11.8% and 11.3% and 6.6%, 5.9%,
2.8% and 2.7%, respectively. The second and third major contributions in compounds 10 and
18 are resulted from F…H/H…F interactions with the percentage values of 22.5% and 17.7%,
respectively. Finally, the F…F and F…O/O…F interaction species within compounds 10 and 18
were found with the percentage values of 3.3% and 3.6%, respectively.
2.9. Molecular Docking Studies
A molecular docking study was performed to determine the existence of the inter-molecular
interactions between the target protein (PDB ID: 1M17) and the ligand compounds (10, 11, 15
and 18). The molecular docking analyses were carried out by using the AutoDock Vina
program [43]. The high-resolution crystal structure of macromolecule 1M17 was taken from
the RCSB Protein Data Bank website [44]. The macromolecule 1M17 is formed by
interactions among a protein group (Epidermal Growth Factor Receptor (EGFR)), a ligand
compound ([6,7-bis(2-methoxy-ethoxy)quinazoline-4-yl]-(3-ethynylphenyl)amine) and water
molecules. For docking protocol, the target protein EGFR was obtained by deleting the ligand
compound and water molecules mentioned within the macromolecule 1M17, while the initial
molecular geometries of the ligand compounds (10, 11, 15 and 18) were obtained by the
single crystal X-ray diffraction studies. The PDB files of the target protein (EGFR) and the
ligand compounds were created by using DS Visualizer (Discover Studio Visualizer) program
software (Dassault Systems BIOVIA) [45]. Moreover, the visualizations of the inter-
molecular interactions between the ligand compounds and the target protein were depicted by
using DS Visualizer program software. As in Ref. 44, the molecular docking analysis in this
study was done to put forth the activity and inter-molecular interaction profile of the
compounds within this study against EGFR.

The ligand compounds (10, 11, 15 and 18) were docked into space containing the active site
region of target protein 1M17. The active sites of this target protein. are residues LEU694,
ALA719, LEU764, THR766, GLN767, LEU768, MET769, PRO770, PHE771, GLY772,
LEU820, THR830 and ASP831. The dimensions of the research space volume were decided
as (40 Å × 42 Å × 44 Å) of the grid size (spacing = 0.375 Å). The position of this research
space volume was set as 23.0, 0.5 and 53.6 for the x, y and z coordinates of the center.
According to the results of the molecular docking analysis, the obtained binding affinities and
RMSD values for ten different poses of the ligand compounds docked onto macromolecule
1M17 are listed in Table 6. In order to be able to talk about an acceptable molecular docking
analysis, the calculated RMSD values are expected to be less than 2 Å [46]. The best binding
affinity values for all four ligand compounds docked onto macromolecule 1M17 were
computed as -8.40 kcal/mol (for compound 10), -8.80 kcal/mol (for compound 11), -7.80
kcal/mol (for compound 15) and -8.60 kcal/mol (for compound 18). According to these
binding affinity results, compound 11 may be an effective docking material for epidermal
growth factor receptor tyrosine kinase. The 2-D and 3-D visuals of the inter-molecular
interactions for the best binding poses of the ligand compounds docked into macromolecule
1M17 can be seen in Fig. 6. Moreover, Table 7 shows the inter-molecular hydrogen bond
interactions and their distances between the compounds 10, 11, 15 and 18 with
macromolecule 1M17. The hydrogen bond formation was taken to connect between the
ketone =O atom in 4-carboxamide of the ligand compound 10 and the OH group in the
residue THR830 of the target protein with a value of 3.18 Å of the interaction distance.
Similarly, a π…π stacking interaction was formed between the delocalized π-electrons of the
2-oxo-1,2-dihydroquinoline ring of compound 10 with the delocalized π-electrons of the
phenyl ring in residue PHE699 of the macromolecule. The conventional hydrogen bond
interaction for ligand compound 11 was formed between an =O atom in the 2-oxo-1,2-
dihydroquinoline ring and the OH group in the residue THR830 is at a distance of 2.90 Å,
while the π…π stacking interaction was taken over by the delocalized π-electrons of the
phenyl rings in the ligand and residue of PHE699. Four conventional hydrogen bond
interactions were obtained between ligand compound 15 and the macromolecule. Three
interactions were formed between the oxygen atoms in 2-ethoxy-2-oxoethyl of the ligand
compound and the polar groups in the residues of THR766, THR830 and CYS751 with
distances of 2.98 Å, 2.97 Å and 3.37 Å, respectively, while one hydrogen bond interaction
was found between an =O atom in the 2-oxo-1,2-dihydroquinoline ring and cationic -NH3

group of residue LYS721. Finally, the hydrogen bond interactions between the oxygen atoms
of 2-ethoxy-2-oxoethyl in ligand compound 18 and the OH groups of the residues THR830
and THR766 in the macromolecule 1M17 were recorded at 2.79 Å and 3.00 Å, respectively.
The other interaction species [halogen (fluorine), π-anion, π-sigma, π-sulfur, alkyl and π-
alkyl] for all four compounds are shown in Fig. 6 along with their interaction distances.
3. Conclusion
These studies reflect that 2-oxo-1,2-dihydroquinoline is a nucleus likely to be used in a drug
discovery area and medicines. Moreover, in this work, we report the syntheses of novel 2-
oxo-1,2-dihydroquinoline derivatives: 7-18. The structures of four compounds 10, 11, 15 and
18 have been identified by using single crystal X-ray crystallography and spectroscopic
techniques. The theoretical approach used in this work allows a relatively good reproduction
1
13
19
of X-ray geometrical parameters, spectral data, and H-, C- and F-NMR chemical shifts.
Hirshfeld surfaces were employed to confirm the existence of intermolecular interactions in
compounds 10, 11, 15 and 18. The experimental spectroscopic data were well reproduced by
using quantum chemical DFT theoretical calculations and in silico-based molecular docking
studies.
Acknowledgements
Author would like JTM thanks Tulane University for support of the Tulane Crystallography
Laboratory.
Abbreviations
DMSO-dimethylsulfoxyde
HOMO-highest occupied molecular orbital
LUMO-lowest unoccupied molecular orbital
NMR- Nuclear magnetic resonance
PDB-Protein Data Bank
DFT- Density Functional Theory
DCM- Dichloromethane
References
1. Alcaide, B.; Almendros, P.; Aragoncillo, C.; Highly reactive 4-membered ring nitrogen-
containing heterocycles: Synthesis and properties. Curr. Opin. Drug Discov. Dev, 2010, 13,
685–597.
2. Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C.; Collective synthesis of
natural products by means of organocascade catalysis. Nature, 2011, 475(7355), 183–188.

3. Lesher, G. Y.; Froelich, E. J.; Gruett, M. D.; Bailey, J. H.; Brundage, R. P.; 1,8-
Naphthyridine Derivatives. A New Class of Chemotherapeutic Agents. Journal of Medicinal
and Pharmaceutical Chemistry, 1962, 5(5), 1063–1065.
4. Trivedi, A.; Dodiya, D.; Surani, J.; Jarsania, S.; Mathukiya, H.; Ravat, N.; V.; Shah Facile
one-pot synthesis and antimycobacterial evaluation of pyrazolo[3,4d]pyrimidines. Archiv
Pharmazie. 2008, 341, 435-439.
5. Dlugosz, A.; & Dus, D.; Synthesis and anticancer properties of pyrimido[4,5-b]quinolines.
Farmaco. 1996, 51 (5), 364-374.
6. Šamšulová, V.; Poláková, M.; Horák, R.; Šedivá, M.; Hradil P.; Synthetic approach to
novel glycosyltriazole-3-hydroxyquinolone conjugates and their antimicrobial properties. J.
Mol. Struct. 2019, 1177, 16-25.
7. El-Sayed, O.A.; Al-Bassam, B.A.; Hussein, M.E.; Synthesis of some novel quinoline-3-
carboxylic acids and pyrimidoquinoline derivatives as potential antimicrobial agents. Archiv
Pharmazie. 2002, 335, 403-410.
8. El-Sayed, O.A.; El-Bieh, F.M.; El-Aqeel, S.I.; Al-Bassam, B.A.; Hussein; M.E.; Novel 4-
aminopyrimido[4,5-b]quinoline derivatives as potential antimicrobial agents. Bollettino
Chimico Farmaceutico. 2002, 141, 461-465.
9. Gayathri, K.; Radhika, R.; Shankar, R.; Malathi, M.; Savithiri, K.; Sparkes, H.A.; Howard,
J.A.K.; Mohan. P.S.; Comparative theoretical and experimental study on novel tri- quinoline
system and its anticancer studies, J. Mol. Struct. 2017, 1134, 770-780.
10. El-Sayed, O.A.; Al-Turki, T.M.; Al-Daffiri, H.M.; Al-Bassam, B.A.; Hussein, M.E.;
Tetrazolo[1,5-a] quinoline derivatives as anti-inflammatory and antimicrobial agents.
Bollettino Chimico Farmaceutico. 2004, 143, 227-238.
11. Gavrilov, M.Y.; Mardanova, L.G.; Kolla, V.E.; Konshin. M.E.; Synthesis,
antiinflammatory and analgesic activities of 2-arylamino-5,6,7,8-tetrahydroquinoline-3-
carboxamides. Pharmaceut. Chem. J. 1988, 22, 554-556.
12. Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P.;
Structure-activity relationships for a series of quinoline-based compounds active against
replicating and nonreplicating Mycobacterium tuberculosis. J. Med. Chem. 2009, 52, 2109-
2118.
13. Mai, A.; Rotili, D.; Tarantino, D.; Nebbioso, A.; Castellano, S.; Sbardella. G.;
Identification of 4-hydroxyquinolines inhibitors of p300/CBP histone acetyltransferases.
Bioorg. Med. Chem. Lett. 2009, 19, 1132-1135.
14. Rano, T.A.; Mc Master, E.S.; Pelton, P.D.; Yang, M.; Demarest, K.T.; Kuo. G.H.; Design
and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a
1,2,3,4-tetrahydroquinoline platform. Bioorg. Med. Chem. Lett. 2009, 19, 2456-2460.
15. Mahamoud, A.; Chevalier, J.; Davin-Regli, A.; Barbe, J.; Quinoline derivatives as
promising inhibitors of antibiotic efflux pump in multidrug resistant Enterobacter aerogenes
isolates. Curr. Drug. Target. 2006, 7, 843-847.
16. Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J.T.;
Synthesis, anticonvulsant and antihypertensive activities of 8-substituted quinoline
derivatives. Biol. Pharm. Bull. 2004, 27, 1683-1687.

17. Maguire, M.P.; Sheets, K.R.; Mc Vety, K.; Spada, A.P.; Zilberstein. A.; A new series of
PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives. J. Med. Chem.
1994, 37, 2129-2137.
18. Wilson, W.D.; Zhao, M.; Patterson, S.E.; Wydra, R.L.; Janda, L.; Strekowski, L.;
Schinazi. R.F.; Design of RNA interactive anti-HIV agents: unfused aromatic intercalators.
Med. Chem. Res. 1992, 2, 102-110.
19. Chakraborty, B.; Dutta, D.; Mukherjee, S.; Das, S.; Maiti. N.C.; Synthesis and biological
evaluation of a novel betulinic acid derivative as an inducer of apoptosis in human colon
carcinoma cells (HT-29). Eur J. Med. Chem. 2015, 102, 93-105.
20. Li, L.N.; Zhang, H.D.; Yuan, S.J.; Yang, D.X.; Wang, L.; Sun. Z.X.; Differential
sensitivity of colorectal cancer cell lines to artesunate is associated with expression of β-
catenin and E-cadherin. Eur. J. Pharmacol, 2008, 588, 1-8.
21. Kouznetsov, V.V.; Rojas Ruíza, F.A.; Vargas Méndeza, L.Y.; Gupta. M. P.; Simple C-2-
Substituted Quinolines and their Anticancer Activity. Lett. Drug. Des. Discov, 2012, 9, 680-
686.
22. Achan, J.; Talisuna, A.O.; Erhart, A.; Yeka, A.; Tibenderana, J.K.; Baliraine, F.N.;
Rosenthal, P.J.; D’Alessandro. U.; Quinine, an old anti-malarial drug in a modern world: Role
in the treatment of malaria. Malar J., 2011, 10, 1-12.
23. Joomyung, V. J.; Petersson, E. J.; Chenoweth M. D.; Rational Design and Facile
Synthesis of a Highly Tunable Quinoline-Based Fluorescent Small-Molecule Scaffold for
Live Cell Imaging. J. Am. Chem. Soc, 2018,140(30), 9486-9493.
24. Chanda, T.; Verma, R.K.; Singh, M.S.; InCl3-driven regioselective synthesis of
functionalized/annulated quinolines: Scope and limitations. Chem. Asian J., 2012, 7, 778–
787.
25. Filali Baba, Y.; Kandri Rodi, Y. ; Misbahi, K.; Chahdi Ouazzani, F.; Kerbal, A.; Essassi,
E. M.; Synthesis and reactivity of new heterocyclic systems derived from quinoline, J. Mar.
Chim. Heterocycl. 2014, 13, 72-80.
26. Filali Baba, Y.; Hokelek, T.; Kaur, M.; Jasinski, J.; Sebbar, N. K.; Kandri Rodia. Y.;
Crystal structure, Hirshfeld surface analysis and DFT studies of ethyl 2-{4-[(2-ethoxy-2-
oxoethyl)(phenyl)carbamoyl]-2-oxo-1,2-dihydroquinolin-1yl}acetate. Acta Cryst . 2019, E75,
1753–1758.
27. Becke. A.D.; Density functional thermochemistry III. The role of exact exchange. J.
Chem. Phys. 1993, 98, 5648-5652.
28. Frisch, M.J.; Trucks, G.; Schlegel, H.B.; Scuseria, G.; Robb, M.; Cheeseman, J.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.; Gaussian 09, revision A. 1, Gaussian
Inc. Wallingford CT, 2009, 27, 34.
29. Turner M.;, Mc Kinnon, J.; Wolff, S.; Grimwood, D.; Spackman, P.; Jayatilaka, D.;
Spackman,
M.;
CrystalExplorer17,
University
of
Western
Australia,.
http://hirshfeldsurface.net. 2017.
30. Filali Baba, Y.; Sert, Y.; Kandri Rodi, Y.; Hayani, S.; Mague, J.T.; Prim, D.; Marrot, J.;
Ouazzani Chahdi, F.; Sebbar, N. K.; Essassi. E. M.;Synthesis, crystal structure, spectroscopic
characterization, Hirshfeld surface analysis, molecular docking studies and DFT calculations,
and antioxidant activity of 2-oxo-1,2-dihydroquinoline-4-carboxylate derivatives. Journal of
Molecular Structure. 2019, 1188, 255-268.

31. Ulahannan, R.T.; Panicker, C.Y.; Varghese, H.T.; Van Alsenoy, C.; Musiol, R.; Jampilek,
J.; Anto, P.; Spectroscopic (FT-IR, FT-Raman) investigations and quantum chemical
calculations of 4-hydroxy-2-oxo-1, 2-dihydroquinoline-7-carboxylic acid. Spectrochim. Acta
A. 2014, 121, 404-414.
32. Fukui K.; Role of frontier orbitals in chemical reactions. Science. 1982, 218, 747-754.
33. Parr, R.G.; Pearson. R.G.; Absolute hardness: companion parameter to absolute
electronegativity, J. Am. Chem. Soc. 1983, 105, 7512-7516.
34. Lee, C.; Yang, W.; Parr. R.G.; Development of the Colle-Salvetti correlation-energy
formula into a functional of the electron density, Phys. Rev. B, 1988, 37(2), 785-789.
35. Dennington, R.; Keith, T.; Millam J.; GaussView, Version 5, Shawnee Mission KS,
Semichem Inc. 2009.
36. Cancès, E.; Mennucci, B.; Tomasi, J.; A New Integral Equation Formalism for the
Polarizable Continuum Model: Theoretical Background and Applications to Isotropic and
Anisotropic Dielectrics, J. Chem. Phys. 1997, 107(8), 3032-3041.
37. London F.; Théorie Quantique des Courants Interatomiques dans les Combinaisons
Aromatiques, J. Phys. Radium. 1937, 8(10), 397-409.
38. Al-Otaibi, J.S.; Al-Wabli. R.I.;Vibrational spectroscopic investigation (FT-IR and FT-
Raman) using ab initio (HF) and DFT (B3LYP) calculations of 3-ethoxymethyl-1, 4-
dihydroquinolin-4-one. Spectrochim. Acta A. 2015, 137, 7-15.
39. Hirshfeld, F.L.; Bonded-Atom Fragments for Describing Molecular Charge Densities,
Theor. Chim. Acta. 1977, 44(2), 129-138.
40. Wolff, S.K.; Grimwood, D.J.; McKinnon, J.J.; Turner, M.J.; Jayatilaka, D.; Spackman.
M.A.; CrystalExplorer, Version 3.1, 2012.
41. Spackman, M.A.; Jayatilaka, D.; Hirshfeld Surface Analysis, Cryst. Eng. Comm. 2009, 11,
19-32.
42. Spackmann, M.A.; McKinnon, J.J.; Jayatilaka, D; Electrostatic Potentials Mapped on
Hirshfeld Surfaces Provide Direct Insight into Intermolecular Interactions in Crystals, Cryst.
Eng. Comm. 2008, 10, 377-388.
43. Trott, O.; Olson. A.J.; J. Comput. Chem. 2010, 31(2), 455-461.
44. Stamos, J.; Sliwkowski, M.X.; Eigenbrot, C.; Structure of the Epidermal Growth Factor
Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor, J.
Biol. Chem. 2002, 277(48), 46265-46272.
45. Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San
Diego, Dassault Systèmes, 2016.
46. Kramer, B.; Rarey, M.; Lengauer, T.; Evaluation of the FLEXX Incremental Construction
Algorithm for Protein–Ligand Docking. Proteins: Struct. Funct. Genet. 1999, 37(2), 228-241.

Figure Captions
Fig. 1 ORTEP drawings of compounds 10, 11, 15 and 18 showing atom numbering schemes
and displacement ellipsoids drawn at the 50% probability level.
Fig. 2 Geometry optimized theoretical structures for compounds 10, 11, 15 and 18 using the
B3LYP functional at the 6-311G(d,p) level of theory.
Fig. 3 HOMO-LUMO molecular orbital cloud distributions for compounds 10, 11, 15 and 18
calculated at the B3LYP/6-311G(d,p) level of theory. HOMO-LUMO energy levels and gap
calculations are displayed in eV’s.
Fig. 4 Complimentary views of the three-dimensional surfaces for compounds 10, 11, 15 and
18 plotted over dnorm in the range -0.35 to 1.34 a.u.
Fig. 5 A view of the two-dimensional fingerprint plots for compounds 10, 11, 15 and 18
showing (a) all interactions and separated into (b) H…H and/or, (c) O…H/H…O and/or, (d)
H…C/C…H and/or, (e) C…H/H…C and/or, (f) C---C and/or, (g) F…H/H…F and/or, (h)
F…O/O…F interactions. The di and de values are closest internal and external distances (in
Å) from given points on the Hirshfeld surface contacts.
Fig. 6 A view of the 2-D and 3-D visuals of the intermolecular interactions for the best
binding poises of ligand compounds 10, 11, 15 and 18 docking with the residues of
macromolecule 1M17. Intermolecular hydrogen bond interactions and their distances
between compounds 10, 11, 15 and 18 with macromolecule 1M17 are given in Table 7.

Table 1. Experimental details for compounds 10, 11, 15 and 18.
Compound 10
C21H19F3N2O2
1954732
Compound 11
2(C22H16N2O2)
19547664
Compound 15
C24H24N2O6
1959642
Compound 18
C25H23F3N2O6
1954744
Chemical formula
CCDC Deposition
Number
hexane / DCM (3/1)
Recrystallization
solvent
Mr
388.38
orthorhombic, P
bca
680.73
triclinic, P̊
436.45
monoclinic, I 2/a
504.45
monoclinic, I 2/a
ŭ
Crystal system, space
group
293
293
293
16.9368 (5),
15.4130 (4),
18.4562 (6)
109.254 (4)
293
Temperature (K)
a, b, c (Å)
17.1196 (5), 8.0328 10.7160 (7),
(3), 27.6991 (6)
16.8605 (4), 16.2855
(4), 18.5440 (5)
11.3615 (7),
16.5479 (8)
81.273 (5), 85.833
(5), 64.001 (7)
1789.8 (2)
110.389 (3)
α, β, γ (°)
V (Å3)
Z
3809.1 (2)
8
4548.4 (3)
8
4772.8 (2)
8
2
Cu Kα
0.91
Cu Kα
0.66
Cu Kα
0.76
Cu Kα
0.99
Radiation type
µ (mm-1)
Data collection
Rigalu Oxford
Diffraction, Gemini
Xcalibur, Eos,
Gemini
Rigalu Oxford
Diffraction,
Rigalu Oxford
Diffraction, Gemini
Diffractometre
Gemini
26345, 3682, 2879 12436, 6721, 4730
8768, 4330, 3266
9504, 4549, 3642
No. Of measured,
independent and
observed [I > 2σ(I)]
reflections
Rint
0.037
0.615
0.028
0.615
0.018
0.613
0.017
0.613
(sinθ/λ)max (Å−1)
Refinement
0.053, 0.160, 1.02
R[F2 > 2σ(F2)],
wR(F2), S
0.068, 0.230, 1.06
0.051, 0.161, 1.05
0.053, 0.170, 1.03
3682
265
0.54, −0.40
6721
469
0.19, −0.17
4330
291
0.32, −0.18
4549
344
0.30, −0.32
No. Of reflections
No. Of parametres
ꢀρmax, ꢀρmin (e Å−3)
Table 2. Selected geometry optimized parameters for compounds 10, 11, 15 and 18.
Bond angles (°) Bond lenghts (Å)
Optimized bond angles
X-Ray
DFT/B3LYP
6-311 G(d,p)
Optimized
bond lenghts
X-Ray
DFT/B3LYP
6-311 G(d,p)
Compound 10
C1—N1—C9
C1—N1—C20
C9—N1—C20
C10—N2—C11
C10—N2—C18
C11—N2—C18
O1—C1—N1
O1—C1—C2
122.7(2)
116.9(2)
120.3(2)
124.3(2)
117.6(2)
117.8(2)
120.9(2)
122.9(2)
116.2(2)
119.1(8)
113.6(3)
123.04954
115.59882
121.32950
124.06661
116.52548
118.73550
121.40406
122.94433
115.64671
112.11618
113.61563
F1—C17
F2—C17
F3—C17
O1—C1
O2—C10
N1—C1
N1—C9
N1—C20
N2—C10
N2—C11
N2—C18
1.398(8)
1.305(7)
1.307(6)
1.234(3)
1.224(3)
1.383(3)
1.393(3)
1.473(4)
1.354(3)
1.433(3)
1.480(3)
1.34989
1.35395
1.35062
1.22430
1.22040
1.40521
1.39253
1.47364
1.38096
1.48162
1.42692
N1—C1—C2
F3—C17—C13
N2—C18—C19
Compound 11

C1A—N1A—C9A
C1A—N1A—C17A
C9A—N1A—C17A
C10A—N2A—C11A
C10A—N2A—C20A
C11A—N2A—C20A
O1A—C1A—N1A
O1A—C1A—C2A
N1A—C1A—C2A
O2A—C10A—N2A
O2A—C10A—C3A
N2A—C10A—C3A
123.16(18)
116.57(19)
120.3(2)
123.96(17)
117.2(2)
118.82(19)
121.2(2)
122.9(2)
115.88(17)
122.8(2)
119.40(19)
117.62(17)
123.44171
115.74820
120.77735
124.28665
117.06747
117.63524
121.44592
123.24597
115.30811
122.61845
119.86221
117.46279
O1A—C1A
O2A—C10A
N1A—C1A
N1A—C9A
N1A—C17A
N2A—C10A
N2A—C11A
N2A—C20A
C1A—C2A
C2A—C3A
C3A—C4A
C3A—C10A
1.231(2)
1.223(3)
1.389(3)
1.397(3)
1.470(3)
1.350(3)
1.432(3)
1.475(3)
1.441(3)
1.340(3)
1.440(3)
1.502(3)
1.22289
1.21936
1.40833
1.39376
1.47149
1.37826
1.43654
1.47545
1.45453
1.35132
1.44736
1.51222
Compound 15
116.51546
116.21487
123.39328
115.79115
120.80438
116.06128
124.14860
118.32629
121.17736
123.39068
115.42804
Compound 18
120.91140
116.65320
123.46631
115.83665
120.69077
124.71138
121.22491
123.39693
115.37814
119.67303
121.47893
118.84534
121.40431
C16—O4—C17
C11—O6—C12
C1—N1—C9
C1—N1—C10
C9—N1—C10
C14—N2—C15
C14—N2—C19
C19—N2—C15
O1—C1—N1
O1—C1—C2
N1—C1—C2
116.08(19)
116.8(2)
O1—C1
O2—C14
O3—C16
O4—C16
O4—C17
O5—C11
O6—C11
O6—C12
N1—C1
1.226(3)
1.223(2)
1.198(2)
1.325(2)
1.464(3)
1.190(3)
1.317(3)
1.459(4)
1.382(2)
1.390(3)
1.453(2)
1.22337
1.21932
1.20435
1.34175
1.45222
1.20114
1.34712
1.45120
1.40882
1.39342
1.45186
123.48(16)
116.80(17)
119.69(16)
116.79(16)
124.24(15)
117.60(15)
121.34(19)
123.13(18)
115.52(17)
N1—C9
N1—C10
C18—O3—C19
C22—O6—C23
C1—N1—C9
C1—N1—C17
C9—N1—C17
C10—N2—C11
O1—C1—N1
O1—C1—C2
N1—C1—C2
N1—C9—C4
N1—C9—C8
C8—C9—C4
O4—C10—N2
121.3(3)
F1—C25
F2—C25
F3—C25
O1—C1
O2—C18
O3—C18
O3—C19
O4—C10
O5—C22
O6—C22
O6—C23
N1—C1
1.331(4)
1.306(4)
1.363(4)
1.230(3)
1.196(4)
1.324(3)
1.428(5)
1.218(3)
1.195(2)
1.327(2)
1.462(3)
1.380(2)
1.392(3)
1.35031
1.35553
1.34952
1.22326
1.20192
1.34725
1.45364
1.21714
1.20686
1.33664
1.45467
1.40895
1.39311
116.02(18)
123.59(16)
116.90(17)
119.47(16)
124.32(15)
121.35(18)
123.16(18)
115.49(17)
119.80(16)
121.84(18)
118.35(19)
122.07(18)
N1—C9
Table 3. The global reactivity descriptors calculated in the gas phase for compounds 10, 11, 15 and 18.
Parameters (eV)
ELUMO (eV)
EHOMO (eV)
Energy band gap |EHOMO - ELUMO
Ionization potential (I = -EHOMO
Compound 10 Compound 11 Compound 15 Compound 18
-1.9521
-6.1794
4.2273
6.1794
1.9521
2.1137
0.2366
4.0658
-4.0658
3.9104
1.9236
-1.9353
-6.2747
4.3394
6.2747
1.9353
2.1697
0.2304
4.1050
-4.1050
3.8833
1.8920
-1.7200
-6.0875
4.3675
6.0875
1.7200
2.1838
0.2290
3.9038
-3.9038
3.4892
1.7876
-1.9176
-6.2148
4.2972
6.2148
1.9176
2.1486
0.2327
4.0662
-4.0662
3.8476
1.8925
|
)
Electron affinity (A = -ELUMO
)
Chemical hardness (η = (I-A)/2)
Chemical softness (ζ = 1/2η)
Electronegativity (χ = (I+A)/2)
Chemical potential (ꢁ = -(I+A)/2)
Electrophilicity index (ω = 2/2η)
Maximum charge transfer index (ꢀNmax. = -ꢁ/η)

Table 4.The experimental and computed 13C-NMR isotropic chemical shifts (with
respect to TMS, all values in ppm) for compounds 10, 11, 15 and 18.
Compound 10
Compound 11
Compound 15
δcal. δexp. (Atoms δcal. δexp. (Atoms
)
Compound 18
δexp. (Atoms
166.43 (C1)
126.65(C2)
139.22(C3)
116.27(C4)
130.79(C5)
124.70(C6)
131.28(C7)
114.57(C8)
139.80(C9)
163.05(C10)
145.87(C11)
124.17(C12)
126.82(C13)
119.21(C14)
122.40(C15)
130.14(C16)
44.50(C18)
13.04(C19)
37.23(C20)
12.49(C21)
129.45(C17)
-
δcal.
δexp. (Atoms
δcal.
)
)
)
165.3
127.2
153.4
125.9
134.4
127.5
138.0
119.6
148.3
175.1
155.1
130.0
137.9
130.6
136.9
134.4
53.0
16.5
41.5
13.8
134.9
-
166.26(C1A)
126.91(C2A)
138.91(C3A)
118.25(C4A)
128.61(C5A)
122,95(C6A)
131.27(C7A)
115.04(C8A)
140.62(C9A)
160.06 (C10A)
145,09 (C11A)
127.45(C12A)
127,45(C13A)
119.80(C14A)
129.57(C15A)
129.57(C16A)
31,63(C17A)
77.51(C18A)
72.60(C19A)
38.88(C20A)
78.24(C21A)
72.89(C22A)
-
164.5
160.71(C1)
127.63(C2)
141.67(C3)
118.19(C4)
123.01(C5)
119.47(C6)
131.39(C7)
113.81(C8)
139.29(C9)
167.20(C14)
43.79(C10)
167.72(C11)
61.73(C12)
14.05(C13)
51.53 (C15)
61.77 (C17)
14.21(C18)
145.45(C19)
129.58(C20)
129.58(C21)
128.42(C22)
127.31(C23)
127.31(C24)
168.55(C26)
-
165.3
124.4
155.0
125.9
135.9
127.8
137.8
119.2
147.9
175.6
46.5
176.9
68.1
15.9
56.1
68.3
160.51 (C1)
127.29(C2)
139.28(C3)
117.80(C4)
123.12(C5)
119.50(C6)
131.69(C7)
113.95(C8)
145.06(C9)
167.08(C10)
145.87(C11)
130.85(C12)
125.15(C13)
130.29(C14)
129.21(C15)
129.21(C16)
43.81(C17)
167.57(C18)
61.75(C19)
14.16(C20)
51.35(C21)
168.34(C22)
62.01(C23)
14.00(C24)
124.21(C25)
165.2
124.2
154.8
125.3
135.8
128.2
138.2
119.1
148.0
175.6
151.3
134.7
138.8
134.1
136.9
140.9
46.7
125.9
154.1
126.0
134.7
128.2
138.0
120.5
147.7
174.2
150.0
135.8
135.5
135.2
136.5
134.0
33.8
82.6
75.0
42.7
83.1
75.4
-
16.0
151.5
136.9
135.6
135.5
136.2
135.2
178.1
-
176.6
67.1
16.4
55.8
178.5
68.6
-
-
-
-
-
-
-
-
-
-
15.9
135.0

Table 5. The experimental and computed 1H-NMR isotropic chemical shifts (with respect to TMS, all values in ppm)
for compounds 10, 11, 15 and 18.
Compound 10
δexp.( Atoms)
Compound 11
δexp. ( Atoms)
6.42(H2A)
7.81(H5A)
7.18-7.22(H6A)
7.6(H7A)
7.18-7.22(H8A)
7.33(H12A)
7.46(H13A)
Compound 15
δexp. ( Atoms)
Compound 18
δexp. ( Atoms)
δcal.
6.06
8.25
7.52
7.87
7.50
7.09
7.63
7.79
7.93
3.12
4.72
2.04
1.55
1.25
4.79
3.59
1.28
1.09
1.03
-
δcal.
6.15
8.23
7.57
7.89
7.58
7.64
7.73
7.53
7.29
7.16
3.95
5.95
1.77
3.96
5.60
1.88
-
δcal.
6.23
8.38
7.55
7.78
7.03
7.61
7.65
7.51
7.29
7.62
4.05
5.85
4.18
4.12
1.48
1.47
1.25
3.90
5.25
4.23
4.35
1.28
1.42
1.51
δcal.
6.27
8.39
7.56
7.77
7.01
7.81
7.76
7.76
8.10
4.07
5.72
4.92
3.93
1.37
1.00
1.27
3.81
5.22
4.30
4.40
1.53
1.30
1.45
-
6.35 (H2A)
7.56-7,7 (H5A)
7.26-7.4 (H6A)
7.26-7.4(H7A)
7.26-7.4(H8A)
7.26-7.4(H12A)
7.26-7.4(H13A)
7.56-7,7(H14A)
7.56-7,7(H16A)
4.24(H20A)
4.24(H20B)
1.33(H21A)
1.33(H21B)
1.33(H21C)
4.09(H18A)
4.09(H18B)
1.25(H19A)
1.25(H19B)
1.25(H19C)
-
6.49(H2A)
7.03-8.08 (H5A)
7.03-8.08(H6A)
7.03-8.08(H7A)
7.03-8.08(H8A)
7.03-8.08(H20A)
7.03-8.08(H21A)
7.03-8.08(H22A)
7.03-8.08 (H23A)
7.03-8.08(H24A)
4.16(H10A)
6.46(H2A)
8.00-8.03(H5A)
7.00-7.51(H6A)
7.00-7.51(H7A)
7.00-7.51(H8A)
7.00-7.51(H16A)
7.00-7.51 (H14A)
7.00-7.51 (H13A)
7.00-7.51 (H12A)
4.93(H17A)
7.18-7.22(H14A)
7.18-7.22(H15A)
7.18-7.22(H16A)
4.74(H17A)
4.74(H17B)
2.21(H19A)
4.97(H20A)
4.97(H20B)
2.36(H22A)
4.93 (H17B)
4.13 (H19A)
4.13(H19B)
1.14 (H20A)
1.14 (H20B)
1.14 (H20C)
4.61 (H21A)
4.61(H21A)
4.31 (H23A)
4.31(H23B)
1.32 (H24A)
1.32 (H24B)
1.32(H24C)
4.16(H10B)
4.97(H12A)
4.97(H12B)
1.18 (H13A)
1.18 (H13B)
1.18 (H13C)
4.32(H15A)
4.32(H15B)
4.65(H17A)
4.65(H17B)
1.36 (H18A)
1.36 (H18B)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.36 (H18C)
-
Table 6. AutoDock Vina results of the binding affinities and RMSD values for ten different poses for
compounds 10, 11, 15 and 18.
for compound 10
for compound 11
Mode
Affinity
(kcal/mol)
-8.40
RMSD
l.b.
Affinity
(kcal/mol)
-8.80
RMSD u.b.
RMSD l.b.
RMSD u.b.
0.000
3.998
3.890
4.122
3.913
2.084
2.833
2.870
3.136
2.443
0.000
7.627
6.274
7.517
7.120
3.808
5.578
5.444
4.795
4.220
0.000
0.793
1.880
2.356
1.274
2.528
2.194
2.616
2.093
0.000
2.440
2.488
5.240
6.725
6.726
6.004
3.636
2.925
6.608
1
2
3
4
5
6
7
8
9
-8.30
-8.30
-8.20
-8.20
-8.10
-8.00
-7.90
-7.90
-8.60
-8.40
-8.20
-8.10
-7.80
-7.50
-7.50
-7.50
-7.90
-7.40
2.092
10
for compound 15
0.000
for compound 18
0.000
-7.80
-7.50
-7.50
-7.50
-7.50
-7.20
-7.20
-7.10
0.000
2.566
3.443
4.413
4.722
3.442
3.588
1.962
-8.60
-8.40
-8.40
-8.40
-8.40
-8.10
-8.00
-8.00
0.000
6.314
6.458
6.971
6.756
7.344
5.807
2.439
1
2
3
4
5
6
7
8
1.915
1.684
2.430
2.830
2.050
1.727
1.382
2.768
4.532
4.569
2.124
4.165
3.935
1.935

-7.00
-6.70
1.860
2.413
6.160
4.415
-7.90
-7.90
3.783
3.294
7.927
7.072
9
10
Table 7. The inter-molecular hydrogen bond interactions and their distances between compounds 10, 11,
15 and 18 with the macromolecule 1M17.
for the compound 10
Residue group
Ligand group
Distance (Å) Interaction
Conventional hydrogen
bond
Carbon hydrogen bond
OH group in THR830
=O atom in carboxamide
F atom in trifluoromethyl
3.18
3.34
CH2 group in GLY772
for the compound 11
Residue group
Ligand group
Distance (Å) Interaction
Conventional hydrogen
bond
OH group in THR830
=O atom in in oxoquinolin
2.90
for the compound 15
Residue group
Ligand group
Distance (Å) Interaction
Conventional hydrogen
bond
Conventional hydrogen
bond
Conventional hydrogen
bond
NH2 group in LYS721
OH group in THR766
OH group in THR830
Sg group in CYS751
=O atom in oxoquinolin
3.14
2.98
2.97
3.37
O atom in ethyl acetate
=O atom in ethyl acetate
=O atom in ethyl acetate
Conventional hydrogen
bond
for the compound 18
Residue group
Ligand group
Distance (Å) Interaction
Conventional hydrogen
bond
Conventional hydrogen
bond
OH group in THR766
OH group in THR830
O atom in ethyl acetate
3.00
2.79
=O atom in ethyl acetate