One-pot strategy for thiazole tethered 7-ethoxy quinoline hybrids: Synthesis and potential antimicrobial agents as dihydrofolate reductase (DHFR) inhibitors with molecular docking study

Article abstract of DOI:10.1016/j.molstruc.2021.130748

Over the world and especially the developing countries, one of the major threats to human health is antibiotic resistance due to antibiotics abuse. This challenge can be solved by discovering new targets and inhibitors. The current study involved synthesi

Full text of DOI:10.1016/j.molstruc.2021.130748

Journal of Molecular Structure 1242 (2021) 130748
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
One-pot strategy for thiazole tethered 7-ethoxy quinoline hybrids:
Synthesis and potential antimicrobial agents as dihydrofolate
reductase (DHFR) inhibitors with molecular docking study
Yousry A. Ammara,∗, Sondos M.A. Abd El-Hafezb,∗, Sadia A. Hesseinb, Abeer M. Alib,
Ahmed A. Askarc, Ahmed Ragaba,∗
a Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, 11884, Cairo, Egypt
b Department of Chemistry, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
c Department of Botany and Microbiology, Faculty of Science (Boys), Al-Azhar University, Nasr City, 11884, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Over the world and especially the developing countries, one of the major threats to human health is
antibiotic resistance due to antibiotics abuse. This challenge can be solved by discovering new targets
and inhibitors. The current study involved synthesis quinoline based thiazole analogues for quinoline an-
tibiotic class using classic organic synthesis. The designed derivatives were tested against eight standard
microbial pathogens. Among them, seven derivatives showed good antimicrobial activity with MIC and
MBC values ranged between (0.97–62.5) μg/mL, and (1.94–118.7) μg/mL, respectively. Additionally, the
active derivatives displayed good activity against three MDR bacterial stains. Compounds 11b, and 5a ex-
hibited to be the most active derivatives against S. aureus and E. coli with MIC (1.95–7.81) μg/mL and
MBC (3.31–15.62) μg/mL followed by other derivatives compared with Ciprofloxacin and Vancomycin. Be-
sides, compounds 6, 11c, and 15 appeared the most active derivatives against MDR P. aeruginosa with MIC
and MBC values lower than 10 μg/mL. These derivatives considered effective for treating bacterial infec-
tion by inhibiting DHFR enzyme that showed IC50 values (10.02–25.11) μM in comparison to Trimetho-
prim (18.95 μM). Molecular docking study against DHFR enzyme (1DLS) was carried out, and the active
derivatives bind to some the nearly the same amino acid residues as MTX that support our hypothesis.
Furthermore, the MEP surfaces were generated using DFT calculation to determine the regions might be
responsible for forming different types of interaction and confirm the binding mode in docking study.
Received 11 March 2021
Revised 1 May 2021
Accepted 20 May 2021
Available online 29 May 2021
Keywords:
7-ethoxy quinoline
Antimicrobial activity
MBC
MDRB
DHFR
Molecular docking
molecular electrostatic potential by DFT
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
midis (MRSE), methicillin-resistant S. aureus (MRSA), vancomycin-
resistant S. aureus (VRSA), extended-spectrum b-lactamase (ESBL)-
Bacterial infections caused by Gram-positive, Gram-negative
and mycobacterial pathogens, are responsible for most hospital-
acquired infections and lead to extensive mortality and burden on
global healthcare systems [1–3]. The emergency and a wide spread
of drug-resistant organisms such as methicillin-resistant S. epider-
producing E. coli and drug-resistant TB (DR.-TB) has already in-
creased up to the alarming level in the recent decades and is asso-
ciated with considerable mortality [4,5]. The antibiotics have con-
tributed enormously to treating bacterial infection because they
significantly decrease the mortality rate [6]. However, with the
overuse of antibiotics, bacterial resistance appeared gradually. In
1961, the first case of methicillin-resistant Staphylococcus aureus
(MRSA) was reported, for which only a few antimicrobial agents
were effective [7]. In 1988, vancomycin-resistant Enterococci (VRE)
was also identified, increasing this problem’s significance [8,9]. If
there is no action taken place, then there is an estimate of drug-
resistant infections that will kill 10 million people a year by 2050
[10]. Another reason for developing new antibiotics is decreasing
their own toxicity and side effects [11]. Thus, it is imperative to de-
velop novel antimicrobial agents active against drug-sensitive and
Abbreviations: DHFR, Dihydrofolate reductase; MIC, Minimal inhibitory concen-
trations; MBC, Minimal bactericidal concentration; MFC, Minimal fungicidal concen-
tration; MDR, Multidrug resistance; CLSI, Clinical Laboratory Standards Institutes;
NADP+
, Nicotinamide adenine dinucleotide phosphate; RMSD, Root-mean-square
deviation; MEX, Methotrexate; MEP, Molecular Electrostatic Potential; DFT, Density
functional theory; 1H NMR, Proton nuclear magnetic resonance; 13 C NMR, Carbon-
13 nuclear magnetic resonance; MS, Mass spectra; IR, Infrared spectra; IZ, inhibition
zone and measured by millimeter (mm); SAR, Structure activity relationship.
∗
Corresponding authors.
E-mail
addresses:
yossry@azhar.edu.eg.com
(Y.A.
Ammar),
ahmed_ragab@azhar.edu.eg, ahmed_ragab7@ymail.com (A. Ragab).
https://doi.org/10.1016/j.molstruc.2021.130748
0022-2860/© 2021 Elsevier B.V. All rights reserved.

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Fig. 1. Rational design illustrated the structure of available marketing quinoline, thiazole antibiotics and designed compounds.
drug-resistant bacterial infections. Thus, drug-resistant pathogens
have already posed one of the most serious threats to public
health; therefore, discovering new and more effective antimicro-
bial drugs is very important, and many studies have made efforts
to design new agents [12].
dihydrofolate to tetrahydrofolate in the folate cycle and inhibition
of this enzyme may lead to bacterial death by abnormal synthesis
of tetrahydrofolate, and therefore the thymine synthetase will be
interrupted. It is a promising target for the treatment of bacterial
infections [46–48]. According to the data as mentioned earlier and
in continuation to our efforts concerning the synthesis of bioac-
tive heterocyclic compounds [49–57], the rationale of this work
depends on developing new therapeutically active units via the
synthesis of some new quinolines and its coupling with thiazole
derivatives containing ethoxy group for increase the lipophilicity
and represent more than one pharmacophoric moiety in a single
structure hoping to obtain new quinoline hybrids with potent an-
timicrobial agents. These derivatives were screened for eight stan-
dard pathogens including two fungal and six bacterial strains, both
minimal inhibitory and bactericidal or fungicidal concentration was
evaluated for the most active derivatives. Further, the active deriva-
tives were tested against three multidrug resistance pathogens be-
side determine the DHFR enzyme to study the synthesized deriva-
tive mode of action. Finally, the molecular docking study was per-
formed to verify the action target and binding mode. Besides, the
molecular electrostatic potential was achieved to support the dock-
ing study.
The synthetic antibacterial agents that include Cinoxacin,
Ciprofloxacin, Nalidixic acid, Norfloxacin, and Ofloxacin belong to
the quinolone class compounds, sharing quinoline as the basic ring
skeleton (Fig. 1). The quinolone class of antibacterial has been
spectacularly successful and continues to dominate the field of
antibacterial therapeutics with great influence [13,14]. Therefore,
the development of quinolone-based compounds, as antibacterial
agents, will add to antibiotics’ repertoire to combat drug resis-
tance [15]. Furthermore, halogen-substituted quinoline compounds
have been of particular interest, because the halogen atom plays
a key role in the exhibition of biological activities as anticancer,
anti-inflammatory, antioxidant, antimicrobial and soon [16–20]. It
is not coincidental that the first effective antibiotics used to treat
microbes is the penicillin’s, (Fig. 1) that contains a thiazole ring
[21].
Thiazole ring is a member of five heterocyclic compounds with
a strong and electron-rich fragment (SCN). It was reported that
thiazole moiety founds a vital part of natural compounds as thi-
amine (vitamin B), bacitracin, thiamine pyrophosphate (TPP), and
antibiotics as penicillin and micrococcin [22]. Furthermore, thiazole
nucleus exhibited a wide range of pharmacological activities, as
anti-inflammatory [23,24], antipyretic and analgesic activities [25],
anticancer [26,27], antiviral [28], anticonvulsant [29,30], antioxi-
dant [31], antidiabetic [32], and antibacterial [33,34], as well as has
ability to inhibit various enzymes as dolichol phosphate mannose
synthase inhibitor [35], IMP dehydrogenase [36], dihydrofolate re-
ductase [37] aldose reductase [38], and deoxyxylulose 5-phosphate
reductoisomerase [39]. Previously, it was reported that thiazole
could inhibit bacterial growth by inhibiting the biosynthesis of
some certain bacterial lipids as sulphathiazole [40–42], as well as
a large class of antibiotic known as penicillin antibiotics that of-
ten affective against many bacterial infections caused by staphy-
lococci and streptococci as Benzylpenicillin, Amoxicillin, and Phe-
noxymethylpenicillin [43–45]. Dihydrofolate reductase is a pivotal
enzyme involved in the cell growth and proliferation by reducing
2. Materials and methods
2.1. Experimental
2.1.1. Chemistry
All melting points are recorded on digital Gallen Kamp MFB-
595 instrument and may be uncorrected. The IR spectra (KBr)
(cm−1) were measured on a JASCO spectrophotometer. 1H NMR
spectra were recorded on Bruker spectrometers (at 400 MHz) and
are reported relative to deuterated solvent signals in deuterated
dimethyl sulfoxide (DMSO–d6). 13C NMR spectra were recorded
on Bruker Spectrometers (at 101 MHz) in deuterated dimethyl-
sulfoxide (DMSO–d6). The purity of the synthesized compounds
was monitored by TLC. Elemental analyses were carried out by the
Micro analytical Research Center, Faculty of Science, Cairo Univer-
sity. Analytical results for C, H and N were within –/+ 0.4 of the
calculated values.
2

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
2.1.1.1. 2-Chloro-7-ethoxyquinoline-3-carbaldehyde (1) was prepared
according to the reported methods [58,59]. Yield: 76% as yellow
crystals from ethyl acetate; Mp.:155–157 °C; IR: ν/cm−1: 3074,
3008 (CH-Ar), 2981, 2879 (CH-Alip.), 1689 (C = O), 1620 (C = N);
1H NMR (400 MHz, DMSO–d6) δ/ppm 1.39 (t, J = 6.8 Hz, 3H, -
OCH2CH3), 4.25 (q, J = 6.8 Hz, 2H, -OCH2CH3), 7.34 (d, J = 8.8 Hz,
1H, Ar-H), 7.37 (s, 1H, Ar-H), 8.14 (d, J = 8.8 Hz, 1H, Ar-H), 8.83
(s, 1H, -CH-Q4), 10.29 (s, 1H, -CHO); Anal. Calcd for C12H10ClNO2
(235.67): C, 61.16; H, 4.28; N, 5.94; Found: C, 61.23; H, 4.16; N,
6.04%.
124.92, 127.48, 128.05, 131.50, 133.11, 135.92, 143.07, 149.02 (C=N),
151.64 (C=C-N), 161.94 (C-OEt), 163.98 (C=O), 169.12 (S-C=N); MS
(EI, 70 eV): m/z (%) 454 (M+) (22.4%), 380 (61.6%), 353 (42.9%),
334 (40.1%), 285 (51.4%), 261 (46.8%), 215 (78.8%), 136 (67.5%),
148 (55.1%), 76 (100%), 57 (43.3%); Anal. Calcd. for C21H18 N4O4S2
(454.52): C, 55.49; H, 3.99; N, 12.33; Found: C, 55.75; H, 4.07; N,
12.16%.
2.1.1.6. 5-((7-Ethoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)−3-
(alkyl)−2-thioxothiazolidin-4-ones (5a, b). A mixture of compound
1 (0.01 mol) and 3-methyl or 3-phenyl-2-thioxothiazolidin-4-one
(0.01 mol) was added to acetic acid (20 mL) containing sod.
acetate (0.2 g). The reaction mixture was heated under reflux for
5 h, left to cool and poured onto ice-cold water containing few
drops of 1 N HCl. The precipitate that formed was collected by
filtration, washed with water and recrystallized from ethanol.
2.1.1.2. 7-Ethoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
(2).
2–chloro-7-ethoxyquinoline-3-carbaldehyde (1) (0.01 mol), was
dissolved in 20 mL acetic acid (70%) and heated under reflux for
3 h. The obtained product was filtrated after cooling and washed
with ethanol serval times then air dried and recrystallized from
ethanol.
Yield: 68% as brown from ethanol; Mp.: 260–262 °C; IR:
ν/cm−1 3143 (NH), 3070 (CH-Ar), 2970, 2930, 2846 (CH-Alip.),
1681 (C = O), 1627 (C = N); 1H NMR (400 MHz, DMSO–d6)
1.38 (t, J = 7.0 Hz, 3H, -OCH2CH3), 4.12 (q, J = 6.9 Hz, 2H, -
OCH2CH3), 6.81 (s, 1H, Ar-H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H, Ar-
H), 7.83 (d, J = 8.8 Hz, 1H, Ar-H), 8.43 (s, 1H, -CH-Q4), 10.18
(s, 1H, -CHO), 12.05 (s, 1H, NH, exchangeable by D2O); 13C NMR
(101 MHz, DMSO–d6) δ/ppm 14.85 (-OCH2CH3), 64.35 (-OCH2CH3),
98.56, 112.92, 113.21, 122.91, 133.19, 142.72, 144.07 (Ar-Cs), 162.32
2.1.1.7. 5-((7-Ethoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)−3-
methyl-2-thioxothiazolidin-4-one (5a). Yield: 76% as orange powder
from ethanol; Mp.: 262–264 °C; IR: ν/cm−1: 3469 (NH), 3058 (CH-
Ar), 2964, 2903, 2856 (CH-Alip.), 1705, 1650 (C=O), 1618 (C=N);
1H NMR (400 MHz, DMSO-d6) δ/ppm 1.42 (s, 3H, -OCH2CH3); 3.44
(s, 3H, -N-CH3), 4.40 (q, 2H, -OCH2CH3), 6.91 (d, J = 7.6 Hz, 1H,
Ar-H), 7.45 (d, J = 9.2 Hz, 1H, Ar-H), 7.74 (s, 1H, Ar-H), 8.26 (s, 1H,
-CH-methine), 8.54 (s, 1H, -CH-Q4), 12.11 (s, 1H, NH exchangeable
by D2O); MS (EI, 70 eV): m/z (%) = 346 (M+) (33.6%), 239 (47.9%),
238 (34.9%), 157 (64.8%), 147 (100%),108 (58%), 104 (33%), 86
(28.2%); Anal. Calcd. for C16 H14 N2O3S2 (346.42): C, 55.48; H, 4.07;
N, 8.09; Found): C, 55.62; H, 4.31; N, 8.01%.
–
(C OEt), 163.62 (C = O), 189.78 (CHO); Anal. Calcd. for C12H11 NO3
(217.07): C, 66.35; H, 5.10; N, 6.45; Found: C, 66.42; H, 5.19; N,
6.28%.
2.1.1.3. Synthesis of Schiff’ bases (3, 4).
A mixture of 1 or 2
(0.01 mol), 2-aminothiazole or 4-amino-N-(thiazol-2-yl)benzene
sulfonamide (0.01 mol) in ethanol/acetic acid (5/20 mL) was
heated under reflux for 3 h. The solid so formed was filtered off
and recrystallized from the suitable solvent.
2.1.1.8. 5-((7-Ethoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)−3-
phenyl-2-thioxothiazolidin-4-one (5b). Yield: 82% as red powder
from ethanol; Mp.: dec. 236 °C; IR: ν/cm−1: 3152 (NH), 3070, 3036
(CH-Ar), 2981, 2939, 2879 (CH-Alip.), 1718, 1660 (C=O); 1H NMR
(400 MHz, DMSO-d6) δ/ppm 1.41 (t, 3H, -OCH2CH3); 4.24 (q, 2H,
-OCH2CH3) 6.80–6.83 (d, J = 8.0 Hz, 2H, Ar-H), 7.39–7.40 (t, 2H,
Ar-H), 7.57 (d, J = 8.3 Hz, 2H, Ar-H), 7.72 (s, 1H, Ar-H), 7.96 (s, 1H,
CH- methine), 8.28–8.24 (t, 1H, Ar-H), 8.52 (s, 1H, -CH-Q4), 12.13
(s, 1H, NH exchangeable by D2O), 13C NMR (101 MHz, DMSO–d6)
δ/ppm 14.87 (CH3), 64.61 (-OCH2CH3), 107.63, 114.25, 121.55,
122.25, 123.42, 126.62, 127.19, 129.86, 131.13, 135.95, 138.59,
145.40, 149.34, 150.55, 161.38, 162.70, 167.13 (C=O), 167.92 (C-OH),
194.18 (C=S); Anal. Calcd. for C21H16 N2O3S2 (408.49): C, 61.75; H,
3.95; N, 6.86; Found: C, 61.48; H, 4.07; N, 6.74%.
2.1.1.4. 7-Ethoxy-3-((thiazol-2-ylimino)methyl)quinolin-2(1H)-one (3).
Yield: 75% as orange crystals from ethanol; Mp.: 198–200 °C; IR:
(v/cm–1) 3360 (NH), 3093 (CH-Ar), 2970, 2939, 2843 (CH-alip.),
1658 (C = O),1631 (C = N); 1H NMR (400 MHz, DMSO–d6) δ/ppm
1.36 (t, 3H, -OCH2CH3); 4.10–4.13 (q, 2H, -OCH2CH3), 6.85 (d, 1H,
CH-thiazole), 6.88 (d, 1H, CH-thiazole), 7.17 (s, 1H, Ar-H), 7.64 (d,
J = 8.8 Hz, 1H, Ar-H), 7.82 (d, J = 8.8 Hz, 1H, Ar-H), 7.93 (s, 1H,
CH=methine), 8.42 (s, 1H, -CH-Q4), 12.03 (s, 1H, NH exchangeable
by D2O); 13C NMR (101 MHz, DMSO–d6) δ/ppm 14.85 (OCH2CH3),
64.35 (-OCH2CH3), 98.61, 112.91, 113.20, 122.88, 124.49, 133.15,
–
140.80, 142.73, 144.08, 161.50 (C = N), 162.29 (C OEt), 163.60
(C = O), 170.03 (S- C = N); MS (EI, 70 eV): m/z (%) = 299
(M+) (42.4%), 276 (54.7%), 268 (83%), 255 (72.6%), 193 (74.4%), 173
(65%), 134 (56%), 75 (100%), 57 (69%), 54 (59.4%); Anal. Calcd. for
C15H13N3O2S (299.35): C, 60.19; H, 4.38; N, 14.04; Found 60.38; H,
4.24; N, 14.21%.
2.1.1.9. 2-Amino-5-((7-ethoxy-2-oxo-1,2-dihydroquinolin-3-
yl)methylene)thiazol-4(5H)-one (6). A solution of quinoline deriva-
tive 1 (0.01 mol) and 2-aminothiazol-4-one (0.01 mol) in glacial
acetic acid (15 mL) containing sod. acetate 0.5 gm was refluxed
for 7 h, and then allowed to cool. The precipitate that formed
was collected by filtration, washed with ethanol and recrystallized
from a mixture of DMF//EtOH (1:1).
2.1.1.5. 4-(((7-Ethoxy-2-oxo-1,2-dihydroquinolin-3-
yl)methylene)amino)-N-(thiazol-2-yl)benzene-sulfonamide (4). Yield:
71% as dark red powder from acetic acid; Mp.: 198–200 °C; IR:
ν/cm−1: 3360 (NH), 3093 (CH-Ar), 2978, 2935, 2885 (CH-alip.),
1665 (C=O), 1612 (C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm
1.41 (t, J = 6.9 Hz, 3H, OCH2CH3), 4.23 (q, J = 6.7 Hz, 2H, -
OCH2CH3), 6.77 (d, 1H, CH-thiazole), 6.83 (d, 1H, CH-thiazole),
7.21 (d, J = 6.4 Hz, 1H, Ar-H), 7.26 (d, 1H, Ar-H), 7.54 (d, J = 8.4 Hz,
1H, Ar-H), 7.73 (s, 1H, CH= methine), 7.81 (d, J = 8.8 Hz, 2H, Ar-H),
7.83–7.93 (m, 1H, Ar-H), 8.16 (d, J = 8.8 Hz, 1H, Ar-H), 8.78 (s,
1H, -CH-Q4), 10.57, 12.67(2 s, 2H, 2NH exchangeable by D2O);
13C NMR (101 MHz, DMSO–d6) δ/ppm 14.91 (OCH2CH3), 64.35
(-OCH2CH3), 106.57, 108.55, 113.18, 115.68, 118.90, 119.88, 122.82,
Yield: 63% as Orange crystals; Mp.: > 300 °C; IR: v/cm–1
3356, 3159 (NH, NH2), 3059 (CH-Aro.), 2978, 2935, 2881 (CH-
Alip.), 1725, 1661 (C=O), 1624 (C=N); 1H NMR(400 MHz, DMSO-
d6) δ/ppm 1.35 (t, 3H, CH3-CH2O), 4.11 (q, 2H, CH3CH2O), 6.81
(s, 2H, NH2 exchangeable by D2O), 7.70–7.69 (d, J = 8.80 Hz, 2H,
Ar–H), 7.96 (s, 1H, Ar-H), 9.09 (s, 1H, C=CH methine), 9.35 (s,
1H, -CH-Q4), 11.94 (s, 1H, NH exchangeable by D2O); 13C NMR
(101 MHz, DMSO-d6) δ/ppm 14.92 (CH3-CH2O), 64.13 (CH3CH2O),
98.68, 112.52, 113.76, 123.16, 124.24, 130.88, 139.60, 141.08, 148.17
(C=C), 154.76 (C-NH2), 158.10 (C-OEt), 161.59, 161.90 (2C=O); Anal.
Calc. C15H13N3O3S (315.35): C, 57.13; H, 4.16; N, 13.33; Found: C,
57.33; H, 4.03; N, 13.52.
3

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
2.1.1.10. 2-((Arylamino)−5-((2-chloro-7-ethoxyquinolin-3-
2.1.1.14. Synthesis of N-substituted hydrazino-1-carbothioamide (9a-
b). To a solution of 2-chloro-quinoline derivative 1 (0.01 mol)
in ethanol (20 mL) containing acetic acid (1 mL), an appropri-
ate thiosemicarbazide derivatives, namely thiosemicarbazide, N-
phenyl-thiosemicarbazide (0.01 mol) was added. The reaction mix-
ture was refluxed for 2 h. allowed to cool and the solid so formed
was crystallized from the proper solvent.
yl)methylene)thiazol-4(5H)-one (7a,b).
A mixture of the formyl
derivative 1 (0.01 mol), 2-aryliminothiazolidin-4-one (0.01 mol),
and sod. acetate (0.5 g) in acetic acid (20 mL) was heated at
8
h with stirring. After the reaction mixture was allowed to
cool, the precipitate formed was collected by filtration, dried and
recrystallized from ethanol.
2-((2-Chloro-7-ethoxyquinolin-3-yl)methylene)hydrazine-1-
carbothioamide (9a)
2.1.1.11. 2-((4-Chlorophenyl)amino)−5-((7-ethoxy-2-oxo-1,2-
Yield: 70% as yellowish brown crystals from ethanol; Mp.: 200–
202 °C; IR ν/cm−1: 3434, 3375, 3252 (NH, NH2), 3046 (CH-Ar),
2975, 2935, 2875 (CH-Alip.), 1619 (C=N); 1H NMR (400 MHz,
DMSO-d6) δ/ppm 1.38 (t, J = 6.6 Hz, 3H, -OCH2CH3); 4.16 (q,
J = 6.9 Hz, 2H, -OCH2CH3), 7.15 (s, 1H, Ar-H), 7.20 (s, 2H, NH2
exchangeable by D2O), 7.79 (d, J = 8.8 Hz, 1H, Ar-H), 8.21 (s,
1H, Ar-H), 8.43 (s, 1H, -CH-Q4), 9.08 (s, 1H, -CH= methine), 11.71
(s, 1H, NH exchangeable by D2O); 13C NMR (101 MHz, DMSO-d6)
δ/ppm 14.84 (-OCH2CH3); 64.28 (-OCH2CH3),107.26, 121.12, 122.46,
123.86, 130.05, 136.03, 137.68, 149.17, 149.42, 161.53, 178.65 (C=S);
MS (EI, 70 eV): m/z (%) 310 (M+2) (15.5%), 308 (M+) (68.9%), 255
(47.6%), 230 (71.8%), 221 (56.7%),218 (100%).140 (53.9%),137 (51.7%);
Anal. Calcd. for C13H13ClN4OS (308.78): C, 50.57; H, 4.24; N, 18.14;
Found: 50.39; H, 4.17; N, 18. 29%.
dihydroquinolin-3-yl)methylene)thiazol-4(5H)-one (7a). Yield: 68%
as yellowish brown powder; Mp.: 298–300 °C; IR: ν/cm−1: 3463,
3204 (NH), 3049 (CH-Ar), 2984, 2943, 2845 (CH-Alip.), 1678, 1648
(C=O), 1627 (C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm 1.34 (t,
3H, -OCH2CH3); 4.07 (q, 2H, -OCH2CH3), 6.77 (d, J = 8.0 Hz, 2H,
Ar-H), 7.12 (s, 1H, Ar-H), 7.44 (d, J = 6.8 Hz, 2H, Ar-H), 7.67 (d,
J = 8.4 Hz, 1H, Ar-H), 7.75 (d, 1H, Ar-H), 7.87 (s, 1H, -CH= me-
thine), 8.00 (s, 1H,-CH-Q4), 11.87, 12.28 (2 s, 2H, 2NH exchangeable
by D2O); 13C NMR (101 MHz, DMSO-d6) δ/ppm 14.91 (-OCH2CH3);
64.13 (-OCH2CH3), 98.66, 112.48, 113.72, 122.43, 123.67, 125.08,
126.63, 129.50, 129.85, 130.97, 131.30, 137.95, 140.49, 141.30, 151.23
(C=N), 153.84 (C-OEt), 161.35, 162.12 (2C=O); MS (EI, 70 eV): m/z
(%) 427 (M+2) (22.2%), 425 (M+) (40.4%), 414 (43.1%), 393(74.7%),
389 (50.9%), 369 (44.8%), 362 (92%), 260 (66%), 248 (60.6%),
148 (94.8%), 87(100%),64(50.9%); Anal. Calcd. for C20H16 ClN3O3S
(425.89): C, 59.22; H, 3.79; N, 9.87; Found: C, 59.49; H, 3.89; N,
9.71%.
2.1.1.15. 2-((2-Chloro-7-ethoxyquinolin-3-yl)methylene)-N-
phenylhydrazine-1-carbothioamide (9b). Yield: 65% as yellow
crystals from ethanol; Mp.: 208–210 °C; IR: ν/cm-1: 3268, 3124
(NH), 3035 (CH-Ar), 2978, 2954, 2893 (CH-alip.), 1620 (C=N);
1H NMR (400 MHz, DMSO-d6) δ/ppm 1.41 (t, J = 6.9 Hz, 3H,
-OCH2CH3); 4.24 (q, J = 6.9 Hz, 2H, -OCH2CH3), 7.26 (t, J = 7.4 Hz,
1H, Ar-H), 7.32 (dd, J = 9.0, 2.3 Hz, 1H, Ar-H), 7.34 (s, 1H, Ar-H),
7.42 (t, J = 7.8 Hz, 2H, Ar-H), 7.58 (d, J = 7.6 Hz, 2H, Ar-H),
7.91 (d, J = 8.8 Hz, 1H, Ar-H), 8.60 (s, 1H, -CH-Q4), 9.27 (s, 1H,
-CH= methine), 10.25, 12.15 (2 s, 2H, 2NH exchangeable by D2O);
13C NMR (101 MHz, DMSO-d6) δ/ppm 14.89 (-OCH2CH3);. 64.40
(-OCH2CH3), 107.46, 121.38, 122.50, 123.80, 126.18, 126.76, 128.69,
130.24, 136.42, 138.46, 139.40, 149.41, 149.63, 161.75, 176.71
(C=S); Anal. calc. C17 H17 ClN4OS (384.88). C, 59.29; H, 4.45; N,
14.56; Found: C, 59.01, H, 4.22; N, 14.44%.
2.1.1.12. 2-((4-Bromophenyl)amino)−5-((7-ethoxy-2-oxo-1,2-
dihydroquinolin-3-yl)methylene)thiazol-4(5H)-one (7b). Yield: 67%
as brown powder; Mp.: dec. 270 °C; IR: ν/cm−1: 3443, 3283 (NH),
3049 (CH-Ar), 2979, 2939, 2841 (CH-Alip.), 1659, 1648 (C=O); 1H
NMR (400 MHz, DMSO-d6) δ/ppm 1.37 (t, 3H, -OCH2CH3); 4.09 (q,
2H, -OCH2CH3), 6.85 (d, 2H, Ar-H), 7.02 (s 1H, Ar-H), 7.61 (d, 2H,
Ar-H), 7.74 (d, J = 6.4 Hz, 2H, Ar-H), 7.91 (s, 1H, -CH= methine),
8.05 (s, 1H, -CH-Q4), 11.93, 12.37 (2 s, 2H, 2NH exchangeable by
D2O); 13C NMR (101 MHz, DMSO-d6) δ/ppm 14.91 (-OCH2CH3),
64.12 (-OCH2CH3), 98.61, 112.47, 113.70, 117.29, 120.21, 121.10,
122.25, 122.74, 124.06, 125.07, 126.55, 130.93, 131.29, 132.40,
132.74, 140.47, 141.27, 150.07 (C=N), 154.54 (C-OEt), 161.33, 162.10
(2C=O); Anal. Calcd. for C23H16 BrN3O3S (470.34): C, 53.63; H,
3.43; N, 8.93; Found: C, 53.45; H, 3.58; N, 9.06%.
2.1.1.16. Methyl-2-(2-(2-((2-chloro-7-ethoxyquinolin-3-
yl)methylene)hydrainyl)−4-oxothiazol-5(4H)-ylidene)acetate
(10).
A mixture of thiosemicarbazone derivative 9a (0.01 mol), dimethyl
acetylene dicarboxylate (0.01 mol) in methanol (20 mL) was
heated under reflux for 2 h., then, the solid product was collected
by filtration and recrystallized from dioxane
2.1.1.13. 2-(5-((7-Ethoxy-2-oxo-1,2-dihydroquinolin-3-
yl)methylene)−4-oxo-4,5-dihydrothiazol-2-yl)acetonitrile
(8). To
a
suspension of quinoline derivative 1 (0.001 mol) and 2-(4-
Yield: 85% as light yellow powder; Mp.: 258–260 °C; IR: v/cm–1
3421 (NH), 3060 (CH-Aro.), 2980, 2950 (CH-Alip.), 1728, 1700
(2C=O); 1H NMR (400 MHz, DMSO-d6) δ/ppm =1.40 (s, 3H, -
OCH2CH3); 3.77 (s, 3H, OCH3), 4.25 (q, J = 7.4 Hz, 2H, -OCH2CH3),
6.67 (s, 1H, CH- vinilic), 7.35 (d, J = 8.0 Hz, 2H, Ar-H), 8.15 (s,
1H, Ar-H), 8.74 (s, 1H, -CH-Q4), 8.82 (s, 1H, -CH= methine), 11.97
(s, 1H, NH exchangeable by D2O); 13C NMR (101 MHz, DMSO-d6)
δ/ppm 14.87 (-OCH2CH3), 55.64 (OCH3), 65.36 (-OCH2CH3), 106.76,
113.71, 117.57, 120.06, 125.27, 126.98, 132.18, 133.40, 135.23, 144.12,
156.25, 158.29, 161.34, 165.49 (C=O), 168.49; MS (EI, 70 eV): m/z
(%) = 420 (M+2) (24.8%), 418 (M+) (25.5%), 391 (44.1%), 373 (47.2%),
369 (100%), 351 (79.4%), 317 (48%), 282 (44.6%), 247 (59.8%), 239
(65.8%), 169 (51.5%), 66 (72.4%); Anal.Calc. C18 H15ClN4O4S (418.85):
C, 51.62; H, 3.61; N, 13.38. Found: C, 51.6; H, 3.58; N, 13.18.
oxo-4,5-dihydrothiazol-2-yl)acetonitrile (0.01 mol) in acetic acid
(20 mL), sod. acetate (0.5 g) was added. The solution was refluxed
for 6 h. The precipitate that formed was filtered and washed with
ether. The product was dried and recrystallized from a mixture of
methanol/DMF.
Yield: 77% as brown powder; Mp.: dec. 220 °C; IR: ν/cm-
1: 3160 (NH), 3069 (CH-Ar), 2961, 2938 (CH-Alip.), 2207 (CN),
1706, 1652 (C=O), 1621 (C=N); 1H NMR (400 MHz, DMSO-d6)
δ/ppm 1.35 (s, 3H, -OCH2CH3), 4.06 (q, 4H, CH2 -OCH2CH3), 7.85
(s, 1H, Ar-H), 8.17 (d, 2H, Ar-H), 8.73 (s, 1H, -CH= methine),
9.16 (s, 1H, -CH-Q4), 11.70 (s, 1H, NH exchangeable by D2O);
13C NMR (101 MHz, DMSO-d6) δ/ppm 14.94 (-OCH2CH3), 19.01
(CH2), 56.50 (OCH2CH3), 105.11, 115.54 (CN), 121.33, 127.53, 130.44,
136.88, 138.33, 141.26, 144.50 (Ar-Cs), 156.08 (C=C), 160.35 (C-
OEt), 161.96, 164.26 (2C=O), 168.55 (S-C=N); MS (EI, 70 eV): m/z
(%) = 339 (M+) (6.1%), 338 (11.6%), 161 (43.7%), 131 (43.7%), 119
(58%), 105 (100%), 94 (52.4%), 77 (93.6%), 56 (33.2%); Anal. Calcd.
for C17 H13N3O3S (339.37): C, 60.17; H, 3.86; N, 12.38; Found: C,
60.32; H, 3.76; N, 12.18%.
2.1.1.17. 2-(2-((2-Chloro-7-ethoxyquinolin-3-
yl)methylene)hydrazinyl)−4-arylthiazoles (11a-c). To
a
solution
of the thiosemicarbazone derivative 9a (0.01 mol) in ethanol/acetic
acid (15/5 mL), phenacyl bromide derivatives (0.01 mol) and
4

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
triethylamine (0.5 mL) were added. The reaction mixture was re-
fluxed for 5 h. The solid product that formed was filtered, washed
with ethanol, dried, and recrystallized from a proper solvent.
7.74–7.84 (m, 1H, Ar-H), 7.91–8.03 (m, 1H, Ar-H), 8.18–8.31 (m, 1H,
Ar-H), 8.47 (s, 1H, -CH-Q4), 8.66 (s, 1H, CH= methine), 11.92 (s, 1H,
NH exchangeable by D2O), 13C NMR (101 MHz, DMSO-d6) δ/ppm
14.93 (-OCH2CH3); 64.07 (-OCH2CH3), 98.75, 112.42, 113.72, 121.24,
122.34, 131.24, 136.38, 137.17, 140.78, 141.88, 144.51, 158.52, 161.86;
Anal. Calc.C15H14 ClN5OS (347.82). C, 51.80, H, 4.06; N, 20.14; Found:
C, 51.63; H, 4.00; N, 20.11.
2.1.1.18. 2-(2-((2-Chloro-7-ethoxyquinolin-3-
yl)methylene)hydrazinyl)−4-phenylthiazole (11a). Yield: 91% as
brown powder from ethanol; Mp.: 218–220 °C; IR: v/cm–1 = 3178
(NH), 3056 (CH-Aro.), 2980, 2935 (CH-Alip.), 1648, 1625 (C=N); 1H
NMR (400 MHz, DMSO-d6) δ/ppm δ 1.34–1.37 (m, 3H, -OCH2CH3);
4.09 (q, J = 7.2 Hz, 2H, -OCH2CH3), 7.26 (s, 1H, CH-thiazol), 7.40
(d, J = 6.8 Hz, 2H, Ar-H), 7.48 (t, J = 7.4 Hz, 1H, Ar-H), 7.76 (s, 1H,
Ar-H), 7.88 (d, J = 7.6 Hz, 1H, Ar-H), 8.09 (t, 1H, Ar-H), 8.19 (t, 1H,
Ar-H), 8.26 (d, J = 8.4 Hz, 1H, Ar-H), 8.79 (s, 1H, -CH-Q4), 9.00 (s,
1H, -CH=methine), 11.85 (s, 1H, NH exchangeable by D2O); MS (EI,
70 eV): m/z (%) = 411 (M+2) (32%), 409 (M+) (12.9%), 407 (23.7%),
404 (36.7%), 340 (54.4%), 266 (30.4%), 109 (43%), 66 (68.5%), 52
(100%), 50 (32.5%); Anal. Calc. C21H17 ClN4OS (408.9): C, 61.68; H,
4.19; N, 13.70; .Found: C, 61.61; H, 4.07; N, 13.58.
2.1.1.22. 2-(2-((2-Chloro-7-ethoxyquinolin-3-
yl)methylene)hydrazinyl)thiazol-4(5H)-one (13). To
a solution of
the thiosemicarbazone derivative 9a (0.01 mol) in ethanol/acetic
acid (15/5 mL), ethyl chloroacetate (0.01 mol), and Sod. acetate
(0.5 g) were added, the mixture was heated under reflux for 4 h.,
then cooled and treated with ice-cold water, the obtained product
filtered and recrystallized from dioxane.
Yield 68% as yellow powder; Mp.: 246–248 °C; IR:
v/cm–1
=
3421 (NH), 3041 (CH-Aro.), 2974, 2930 (CH-Alip.),
1715 (C=O), 1619 (C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm
1.42 (t, 3H, -OCH2CH3); 3.96 (s, 2H, -CH2), 4.24 (q, J = 6.0 Hz,
2H, -OCH2CH3), 7.33 (d, J = 9.2 Hz, 1H, Ar-H), 7.35 (s, 1H, Ar-H),
8.10 (d, J = 8.4 Hz, 1H, Ar-H), 8.67 (s, 1H, -CH-Q4), 8.78 (s, 1H,
CH= methine), 12.11 (s, 1H, NH exchangeable by D2O); 13C NMR
(101 MHz, DMSO-d6) δ/ppm 14.87 (-OCH2CH3), 33.66 (-CH2), 64.43
(-OCH2CH3), 107.44, 121.32, 122.30, 123.62, 130.82, 136.63, 149.42,
150.03, 152.11, 157.17 (C-C=N), 162.06 (C-OEt), 174.10 (C=O); Anal.
Calc. C15H13ClN4O2S (348.81): C, 51.65; H, 3.76; N, 16.06. Found:
C, 51.28; H, 3.71; N, 16.0.
2.1.1.19. 4-(2-(2-((2-Chloro-7-ethoxyquinolin-
3yl)methylene)hydrazinyl)thiazol-4-yl)phenol (11b). Yield 72% as
yellow powder from ethanol; Mp.: 200–202 °C; IR: v/cm–1 3429
(OH), 3159 (NH), 3078 (CH-Ar), 2974, 2931, 2889 (CH-alip.), 1620
(C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm 1.43 (t, J = 7.0 Hz,
3H, -OCH2CH3); 4.24 (q, J = 7.0 Hz, 2H, -OCH2CH3), 6.80 (d,
J = 8.7 Hz, 2H, Ar-H), 7.12 (s, 1H, CH-thiazol), 7.31 (d, J = 8.4 Hz,
1H, Ar-H),7.33 (d, J = 8.8 Hz, 1H, Ar-H), 7.69 (d, J = 8.4 Hz, 2H,
Ar-H), 8.09 (d, J = 9.0 Hz, 1H, Ar-H), 8.41 (s, 1H, -CH= methine),
8.70 (s, 1H, -CH-Q4), 9.58 (s, 1H, NH exchangeable by D2O),
12.48 (s, 1H, OH exchangeable by D2O); 13C NMR (101 MHz,
DMSO-d6) δ/ppm 19.04 (-OCH2CH3); 64.33 (-OCH2CH3), 101.53,
107.33, 115.80, 121.22, 122.56, 124.18, 126.31, 127.42, 130.45,
134.61, 136.64, 148.78, 149.23, 157.59, 161.47 (C=N), 167.94 (C-
OH); MS (EI, 70 eV) m/z (%) 426 (M+2) (24.3%), 424 (M+) (28.7%),
419 (40%), 410 (76%), 393 (86.1%), 386 (62.8%), 220 (45.9%), 194
(77.8%), 128 (50.1%), 119 (68.8%), 80 (100%), 46 (50.3%); Anal.
Calc. C18 H17 ClN4O2S(424.90): C, 59.36; H, 4.03; N, 13.19. Found: C,
59.19; H, 4.01; N, 13.12.
2.1.1.23. 5-Acetyl-2-(2-((2-chloro-7-ethoxyquinolin-3-
yl)methylene)hydrazinyl)thiazol-4-(5H)-one
(14).
A
solution
of the thiosemicarbazone derivative 9a (0.01 mol) and 3-
chloropentandione (0.01 mol) in ethanol/acetic acid (15/5 mL)
was treated with sod. acetate (0.5 g). The reaction mixture was
heated under reflux for 4 h., then cooled and treated with ice-cold
water, the obtained product was filtered and crystallized from
ethanol.
Yield 68% as yellow crystal; Mp.: 216–218 °C; IR: v/cm–1 3146
(NH), 3033 (CH-Aro.), 2977, 2935, 2824 (CH-Alip.), 1711 (CO), 1620
(C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm 1.26 (s, 3H, CH3-
acetyl); 1.39 (t, 3H, -OCH2CH3), 4.19 (q, 3H, -OCH2CH3 + CH-
thiazole), 7.28 (s, 2H, Ar-H), 8.10 (s, 1H, Ar-H), 8.42 (s, 1H, -
CH-Q4), 8.70 (s, 1H, CH-methin), 12.64 (s, 1H, NH exchange-
able by D2O); 13C NMR (101 MHz, DMSO-d6) δ/ppm 14.87 (-
OCH2CH3); 60.67, 24.74 (CH3), 64.34 (-OCH2CH3), 107.32, 118.16,
121.17, 122.49, 123.58, 130.64, 132.72, 135.16, 148.87, 149.51, 161.69
2.1.1.20. 2-(2-((2-Chloro-7-ethoxyquinolin-
3yl)methylene)hydrazinyl)−4-(4-chlorophenyl)thiazole
(11c). Yield
68% as dark yellow powder from dioxane; Mp.: 201–203 °C;
IR: ν/cm−1: 3278 (NH), 3078 (CH-Ar), 2978, 2939, 2843 (CH-
alip.), 1624 (C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm 1.37 (t,
J = 6.9 Hz, 3H, -OCH2CH3); 4.10 (q, J = 6.8 Hz, 2H, -OCH2CH3),
6.85 (d, J = 8.4 Hz, 1H, Ar-H), 7.01 (s, 1H, CH-thiazol), 7.26 (d,
J = 8.8 Hz, 1H, Ar-H), 7.30 (d, J = 8.8 Hz, 1H, Ar-H), 7.55 (d,
J = 8.4 Hz, 1H, Ar-H), 7.67 (d, J = 8.8 Hz, 1H, Ar-H), 7.81 (d,
J = 8.0 Hz, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 8.25 (s, 1H, -CH= me-
thine), 8.69 (s, 1H, -CH-Q4), 11.60 (s, 1H, NH exchangeable by
D2O); MS (EI, 70 eV): m/z (%) = 445 (M+2) (14.9%), 443 (M+)
(5.6%), 372 (49%), 271 (21.1%), 77 (100%), 71 (30.3%), 50 (79.4%), 48
(31.1%); Anal. Calc. C21H16 Cl2N4OS (443.35): C, 56.89; H, 3.64; N,
12.64. Found: C, 56.76; H, 3.57; N, 12.82;
(C-OEt), 162.30, 169.28 (C=O); MS (EI, 70 eV): m/z (%) = 392 (M+2
)
(34.6%), 390 (M+) (30.9%), 368 (51.6%), 367 (84.4%), 363 (42.2%),
327 (70.9%), 307 (50.6%), 211 (46%), 149 (79.8%), 119 (100%), 102
(50.2%), 68 (46.4%); Anal.Calc. C17 H15ClN4O3S (390.84): C, 52.24; H,
3.87; N, 14.34. Found: C, 52.32; H, 3.56; N, 14.14%
2.1.1.24. 2-(2-(-(2-chloro-7-ethoxyquinolin-3-
yl)methylene)hydrazinyl)−4-methyl-5-(-p-tolyldiazenyl)
thiazole
(15). A mixture of the thiosemicarbazone derivative 9a (0.01 mol),
hydrazonoyl chloride (0.01 mol) and triethylamine (3 drops) in
methanol (15 mL) was heated under reflux for 6 h., cooling the
precipitated solid was filtered out and recrystallized from ethanol.
Yield 61% as reddish-brown powder; Mp.: 180–182 °C; IR:
v/cm–1 3418 (NH), 3056 (CH-Aro.), 2961, 2924 (CH-Alip.), 1619
2.1.1.21. 2-(2((2-Chloro-7-ethoxyquinolin-3-yl)methylene)hydrazinyl)
thiazol-4-amine (12). A mixture of the thiosemicarbazone deriva-
tive 9a (0.01 mol), chloroacetonitrile, (0.01 mol), sodium acetate
(0.01 mol) in ethanol/acetic acid (15/5 mL) was refluxed for 6 h.,
the reaction mixture was allowed to cool and the solid that
formed was filtered off dried and crystallized from dioxane.
Yield 61% as deep red powder; Mp.: 252–254 °C; IR
v/cm–1 = 3384, 3256, 3161 (NH2, NH), 3088(CH-Aro.), 2980, 2937,
2888 (CH-Alip.), 1648, 1625 (C=N); 1H NMR (400 MHz, DMSO-d6)
δ/ppm 1.35 (t, 3H, -OCH2CH3); 4.07 (q, J = 5.6 Hz, 2H, -OCH2CH3),
6.75 (s, 2H, NH2 exchangeable by D2O), 7.42 −7.66 (m, 1H, Ar-H),
(C=N); 1H NMR (400 MHz, DMSO-d6) δ/ppm 1.41 (t, 3H,
-
OCH2CH3); 2.28 (s, 3H, CH3), 2.59 (s, 3H, CH3), 4.20 (q, J = 6.0 Hz,
3H, -OCH2CH3), 7.17 (s, 1H, Ar-H), 7.31 (s, 2H, Ar-H), 7.87 (d,
J = 9.6 Hz, 1H, Ar-H), 8.02 (s, 1H, Ar-H), 8.21 (s, 1H, Ar-H), 8.48
(s, 1H, Ar-H), 8.77 (s, 1H, -CH-Q4), 9.19 (s, 1H, CH= methine), 11.74
(s, 1H, NH exchangeable by D2O), 13C NMR (101 MHz, DMSO-d6)
δ/ppm 14.86 (-OCH2CH3); 19.02, 17.02 (CH3), 64.34 (-OCH2CH3),
5

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Scheme 1. Illustrate synthesis of formyl quinoline and formation of new Schiff’s base with some sulfa derivatives.
111.30, 114.76, 114.82, 121.30, 122.04, 122.57, 123.99, 130.15, 130.65,
136.19, 137.65, 141.58, 149.24, 149.52, 155.52, 161.63, 178.69; MS
(EI, 70 eV): m/z (%) 466 (M+2) (35.5%), 464 (M+) (64.8%), 456
(98.2%), 421 (70.1%), 332 (50.8%), 325 (85.3%), 317 (50.4%), 299
(71.9%), 243 (50.6%), 220 (100%), 156 (80.1%), 123 (70.2%); Anal.
Calc. C21H21ClN6OS (464.97): C, 59.41; H, 4.55; N, 18.07. Found: C,
59.36; H, 4.52; N, 18.02.
It was interesting to investigate the reactivity of the formyl
derivative
the active methylene moiety. Thus, condensation of 2-chloro-
3-formyl quinoline derivative with 3-methyl or phenyl-2-
1 with a different type of thiazolidinones through
1
thioxothiazolidin-4-one in the presence of sodium acetate caused
hydrolysis for the chlorine atom and gave the corresponding aryli-
dene derivatives 5a, b. The IR spectrum of 5b displayed absorption
bands at 3152, 1718, 1660 cm−1 assignable to NH and CO groups.
Its 1H NMR spectrum displayed three new singlet signals at δ 7.96,
8.52 and 12.13 ppm corresponding to CH-methine, quinoline-H4
(CH-Q4) and NH groups, respectively, in addition to the ethoxy and
aromatic protons. The 13C NMR spectrum was characterized by the
presence of ethoxy carbons at δ 14.87 and 64.61 ppm and signals
at δ 107.63–162.70 ppm assignable to aromatic carbons addition to
signals at δ 167.13, 167.92 and 194.18 ppm corresponding to two
C=O and C=S carbon atoms.
2.1.2. Biological activity
The antimicrobial activity involving the inhibition zone mea-
surement as well as minimal inhibitory concentration and min-
imal bactericidal/fungicidal concentration for standard and mul-
tidrug resistance bacterial and enzymatic assay was performed ac-
cording to reported methods and supplementary material [60–64].
2.2. Computational study
Furthermore, 2-amino-5-((7-ethoxy-2-oxo-1,2-dihydroquinolin-
3-yl)methylene)thiazol-4(5H)-one (6) was obtained upon reaction
of the 3-formyl quinoline derivative 1 with 2-aminothiazol-4(5H)-
one in the presence of fused sodium acetate. The IR spectra of the
isolated product showed the presence of NH2 and C=O groups at
3356, 3159, 1725 and 1661 cm−1. The 1H NMR spectrum showed
four singlet signals at δ 6.81, 9.09, 9.35 and 11.94 ppm due to
NH2, CH=methine, CH-Q4 and NH protons, respectively. Similarly,
the interaction of 2-chloro-3-formylquinoline derivative 1 with 2-
(chloro or bromo phenylamino)thiazolidine-4-one affected conden-
sation with the hydrolysis of the chlorine to produce the corre-
sponding arylidene derivatives 7a,b. The assignment of the struc-
ture of compounds 7a,b were assigned on analytical and spectro-
scopic data. Thus, the IR spectrum of 7a as example displayed ab-
sorption bands at 3204, 1678 and 1648 cm−1 assignable to NH and
C=O groups. The 1H NMR spectrum showed singlet signals at δ
7.87, 8.00 ppm for CH=methine, CH-Q4 and two singlet signals at δ
11.87 and 12.28 ppm exchangeable with D2O for 2NH in addition to
the ethoxy and aromatic protons. Its 13C NMR exhibited the ethoxy
carbons at δ 14.91 and 64.13 ppm with the aromatic and car-
bonyl carbons. Interestingly, the reaction of the formyl derivative 1
with 2-(4-oxo-4,5-dihydrothiazol-2-yl)acetonitrile in the presence
of sodium acetate gave the corresponding arylidene thiazolidi-
none derivative 8. The product has proceeded through the formyl
group’s condensation with the methylene attached to the carbonyl
group (endo) rather than the exomethylene group (Scheme 2). Its
IR spectrum displayed a new absorption band at 2207 and 1706
assignable to CN and CO groups. The 1H NMR spectrum displayed
new singlet signals at δ 4.06 and 8.73 ppm corresponding to the
CH2 and CH=methine protons.
Molecular docking study for the most active derivatives inside
the active site of DHFR enzyme assay was performed according to
the reported method [65] using the Molecular Operating Environ-
ment docking tool 10.2008 (MOE). At the same time, the molecular
electrostatic potential was obtained through Gaussian 09 software
after optimized the synthetized derivatives with DFT calculation
using the B3LYP hybrid functional and standard 6–31G(d) basis set
according to the reported method [66].
3. Results and discussion
3.1. Chemistry
The synthetic approach adopted to obtain the target com-
pounds is depicted in Schemes 1–3. The starting material 7-
ethoxy-2-chloro-3-formylquinoline (1) was prepared according to
literature procedure [58,59] by Vilsmeier Haack reaction of 3-
ethoxyacetanilide. The chlorine atom in quinoline derivative 1 was
subjected to hydrolysis upon its boiling with diluted acetic acid to
yield a formulated product 7-ethoxy-2-oxo-1,2-dihydroquinoline-3-
carbaldehyde (2). Condensation of the chloro derivative 1 or the
keto derivative 2 with amino thiazole or sulfathiazole produced
one product in each cases which formulated as the Schiff’s base
derivatives 3 and 4. The IR spectrum of compound 4 showed ab-
sorption bands’ appearance at 3360, 1665 and 1612 cm−1 corre-
sponding to NH, CO and C=N groups, respectively. The 1H NMR
spectrum exhibited two signals at δ 1.41 and 4.23 ppm as triplet
and quartet for the ethoxy group, two doublets at δ 6.77 and
6.83 ppm for thiazole protons. Also, three singlet signals at δ 8.78,
10.57, 12.67 ppm assignable for quinoline-H4, and two NH groups,
in addition to eight protons related to the aromatic protons and
CH=N group between δ 7.21 to 8.16 ppm.
Chalcogensemicarbazones (CSCs) are expressions that refer to
condensation between semicarbazide or thiosemicarbazide with
carbonyl compounds that manifest a broad spectrum of biological
activities [67–71]. Thus, 2-chloro-7-ethoxy-3-formylquinoline
1
6

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Scheme 2. Showed formation of quinoline-arylidine hybridized with thiazolid-4-one derivatives.
was condensed with thiosemicarbazide derivatives to afford the
corresponding quinoline thiosemicarbazone derivatives (9a-b). The
structure of compound 9a was based on analytical and spectral
data. There are bands in the IR spectra in 3434, 3375 and 3252
cm−1 regions for NH2, NH groups. 1H NMR spectrum of revealed
signals at δ 7.20 and 11.71 ppm corresponding to NH2 and NH, ex-
changeable with D2O group in addition to other signals due to the
rest of the molecule. 13C NMR spectrum of its compound showed
signals for the ethoxy group at δ 14.84, 64.28 and thiocarbonyl
signal (C=S) at δ 178.65 ppm. We have extended our synthetic pro-
gram to utilize structures 9a as the key starting material to furnish
quinoline derivatives containing thiazole moiety. Thus, treatment
of compound 9a with dimethyl acetylene dicarboxylate in boiling
methanol produced a single product that formulated as methyl 2-
(2-(2-(-(2-chloro-7-ethoxyquinolin-3-yl)methylene)hydrazinyl)−4-
oxothiazol-5-(4H)-ylidene)acetate(10) Evidence for the assigned
structure being provided by analytical and spectroscopic data.
The IR spectrum of compound 10 showed the appearance of
absorption bands 3421, 1728, 1700 cm−1 corresponding to the
amide and carbonyl groups. The 1H NMR spectrum exhibited two
additional singlet signals at δ 3.77 and 6.67 ppm assignable to
the protons of methoxy and CH=methine groups and a singlet
signal at δ 11.97 ppm for proton in the NH group of hydrazinyl
derivative. Its 13C NMR showed methoxy carbon at δ 55.64 ppm
and two signals at δ 165.49, 168.49 for two carbonyl groups
(Scheme 3).
Furthermore, thiosemicarbazone derivative 9a were subjected
to cycloalkylation on the hope of obtaining many biologically activ-
ity thiazole derivatives. Thus, when thiosemicarbazone derivative
9a was left to react with phenacyl bromides, the corresponding
thiazolidine derivatives 11a-c were obtained. Spectral data were
in favor of these proposed thiazole structures. The IR spectrum of
4-(4-hydroxy phenyl)−2-hydrazinyl thiazole derivative 11b showed
absorption bands at 3429, 3159 and 1620 cm−1 due to OH, NH
and C=N functional groups, respectively. While, 1H NMR spec-
trum exhibited five singlet signals at δ 7.12, 8.41, 8.70, 9.58 and
12.48 ppm due to thiazole-H5, CH=methine CH-Q4, NH and OH
protons, respectively. The 13C NMR showed signals for C=N and
C-OH at δ 161.47 and 167.94 ppm, respectively. 2-(2-((2-chloro-
7-ethoxyquinolin-3-yl)methylene)hydrazinyl)thiazol-4-amine (12)
was obtained through the reaction of thiosemicarbazone derivative
9a with chloroacetonitrile. Thus, the IR spectrum of 4-amino-2-
hydrazinyl thiazol-4-one derivative 12 revealed bands for NH2,
NH, C=N group appeared at 3384, 3256, 3161 and 1625 cm−1
.
The 1H NMR showed singlet signal integrated for two protons
at δ 6.75 attributed to amino protons (NH2), the aromatic and
methine protons appeared at δ 7.32–8.47 ppm, while CH-quinoline
appeared at δ 8.47 ppm. Its 13C NMR exhibited the ethoxy carbons
at δ 14.93 and 64.07 ppm, and the aromatic carbons in the region
δ 98.75 to 161.86 ppm. Also, 2-(2-((2-chloro-7-ethoxyquinolin-
3-yl)methylene)hydrazinyl)thiazol-4(5H)-one (13) was obtained
upon treatment of the thiosemicarbazone derivative 9a with ethyl
chloroacetate in acetic acid containing sod. acetate, the reaction
7

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Scheme 3. Showed cyclization of thiosemicarbazone with the halogenated reagent to formed thiazole derivatives 10–15.
proceeded through alkylation and ethanol elimination (Scheme 3).
Correct analytical and spectroscopic data established the struc-
ture of the product 13. Its IR spectrum revealed characteristic
absorption bands at 3421 and 1715 cm−1 assigned for NH and
C=O groups. While its 1H NMR spectrum (DMSO-d6) showed new
strong singlet signal at δ 3.96 ppm for methylene group, and three
singlet signals at δ 8.67, 8.78, and 12.11 ppm for quinoline, me-
thine proton and NH group. On the other hand, 13C NMR exhibited
CH2 carbon and carbonyl carbon at δ 33.66 and δ 174.10 ppm.
3.2. Biological activity
3.2.1. Antimicrobial screening with SAR study
The newly synthesized quinoline-thiazole hybrid molecules 2–
15 were evaluated for their in vitro antimicrobial activity against
six bacterial strains and two fungal pathogens. The results of an-
timicrobial activity are summarized in Table S1 and represented
by the diameter of their inhibition zone (IZ) according to reported
methods [60,62,64]. Our study aimed to investigate whether func-
tional group modification at the C3 position introduces the thiazole
moiety in parent 3-formyl quinoline derivative.
Finally,
5-Acetyl-2-(2-((2-chloro-7-ethoxyquinolin-3-
yl)methylene)hydrazinyl)thiazol-4-(5H)-one (14) and 2-(2-(-(2-
chloro-7-ethoxyquinolin-3-yl)methylene)hydrazinyl)−4-methyl-
5-(-p-tolyldiazenyl)thiazole (15) were achieved via reaction of
thiosemicarbazone derivative 9a with ethyl 2-chloropropanoate
and 2-oxo-N-tolylpropanehydrazonyl chloride, respectively. The IR
spectrum of acetyl thiazolidinone derivative 14 showed absorption
bands at 3146 and 1711 cm−1 due to NH and C=O functional
groups. Also, 1H NMR spectrum of 5-acetyl-thiazolidine-4-one
derivative 14 exhibited a singlet signal at δ 1.26 ppm for a methyl
group, while the ethoxy protons appeared as triplet and quartet
at δ 1.39 and 4.19 ppm, and a singlet signal at δ 12.64 ppm due
to NH proton. Furthermore, the 13C NMR spectra showed signals
at δ 24.74, 162.30 and 169.28 ppm for methyl and two carbonyl
carbons, respectively. This reaction proceeded through alkylation
followed by cyclization via elimination one mole of ethanol.
In general, all the synthesized quinoline derivatives showed
good to excellent antibacterial activity, where quinoline derivatives
1, 3, 4, 12, 13, 8, and 11a showed low antibacterial activity. Fur-
thermore, 7-ethoxy quinoline derivatives 2, 5b, 7a, 7b, and 9 ex-
hibited moderate activity. While, seven quinoline-thiazole deriva-
tives 5a, 6, 10, 11b, 11c, 14, and 15 revealed the highest antibacte-
rial activity nearly or slightly increase to Tetracycline as the abroad
positive control and the designed derivatives exhibited potency to
gram-positive than gram-negative bacteria. On the other hand, for
antifungal activity nine compounds 5a, 5b, 6, 7a, 10, 11b, 11c, 14,
and 15 that observed good antifungal activity, while other deriva-
tives displayed moderate to resistance activity compared with Am-
photericin B, as well as the tested derivatives demonstrated activity
against C. albicans than F. oxysporum strain.
8

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Table 1
In vitro the MIC and MBC/MFC expressed by (mg/mL) of the thiazole-quinoline hybrid derivatives against pathogenic bacteria and fungi.
Test
Most active thiazolo-quinoline derivatives
Positive control
Pathogen name
Gram-positive
name
5a
6
10
11b
11c
14
15
Tetr.
Amp.
B. subtilis
S. aureus
E. faecalis
E. Coli
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MFC
MIC
MFC
1.95
3.9
3.9
7.81
1.95
3.9
3.9
15.62
24.99
62.5
4.5
31.25
40.62
62.5
87.5
62.5
93.75
15.62
18.74
62.5
87.5
31.25
43.75
–
–
6.63
14.05
15.62
31.25
9.25
6.63
9.2
–
7.81
15.62
0.97
1.94
7.81
15.62
27.77
55.54
3.9
5.57
5.57
5.57
3.9
7.81
7.81
15.62
3.9
–
10.58
1.95
15.62
15.62
31.25
7.81
118.7
7.81
–
–
3.7
18.5
6.63
0.97
1.94
5.57
10.58
7.81
12.49
7.81
15.62
15.62
29.77
15.62
9.25
7.41
7.81
14.05
15.62
31.25
5.57
10.58
27.77
41.65
62.5
87.5
–
Gram-negative
7.81
62.5
–
14.05
31.25
59.37
5.57
87.5
15.62
27.77
55.54
18.51
36.5
18.5
–
P. aeruginosa
S. typhi
31.25
53.12
15.62
28.11
31.25
41.65
55.54
87.5
55.5
–
88.8
–
31.25
56.25
31.25
54.12
55.5
–
6.63
7.81
12.49
15.62
26.55
10.58
9.25
–
Fungi
C. albicans
F. oxysporum
9.25
15.62
34.62
31.25
65.62
17.57
18.51
29.61
16.57
31.25
59.25
–
–
86.8
–
3.2.2. Structure activity relationship (SAR) study
fluence of position four in thiazole derivatives 11a-c, we replaced
the aryl group by amino and carbonyl groups as derivative 12
and 13, respectively. However, this modification causes dramati-
cally decrease efficiency against all the tested strains. Neverthe-
less, the introduction of acetyl on the 5-position of thiazolidine-
4-one of compound 13 afforded 5-acetyl thiazolidine-4-one deriva-
tive 14, which exhibited high inhibitory potency and broad spec-
trum against bacterial strains with IZ values (19 0. 12 - 26 0.
Based on the antimicrobial results in Table S1, some inter-
esting activity relationships were detected. Firstly, hydrolysis of
chloro quinoline derivative 1 to afforded 2-oxo-quinoline deriva-
tive 2 increase activity from (12
0. 32 – 15
0. 74) mm to
(9 0. 62 – 21 0. 17) mm, but the introduction of thiazole
or sulphathiazole results in decrease activity than expected. Sec-
ondly, introducing the N-alkyl rhodanine to quinoline derivatives
as 5a,b cause enhancement in antimicrobial activity, and the pres-
ence of methyl increase activity than phenyl groups. N-methyl rho-
danine 5a displayed excellent antibacterial activity with inhibition
5) mm, and antifungal activity between (18
0.56 - 20
0.15)
mm. Further, it was observed that 5-azotolyl-thiazolidine quino-
line hybrid 14 revealed similar antimicrobial potency with IZ val-
zone (IZ) from (22 0.14) mm to (33
0.2) mm compared to N-
ues (19
0. 25- 25
0. 78) mm, (19
0. 78- 21
0. 45) mm
phenyl derivative 5b (18 0. 34 - 22
0. 24) mm and Tetracy-
towards bacterial and fungal strains, respectively.
cline (21
0.45 to 25
0.62) mm. Moreover, quinoline deriva-
0.79
0.33) mm compared to N-phenyl-rhodanine derivative 5b
0. 5- 22 0. 14) mm and Amphotericin B (18 0.32-
tive 5a exhibited antifungal potency ranged between (20
3.2.3. Minimal inhibitory concentrations (MIC) and minimal
- 24
(13
bactericidal/fungicidal concentration (MBC/MFC)
Our work extended to evaluate minimal inhibitory concen-
trations (MIC) and minimal bactericidal/fungicidal concentration
(MBC/MFC), for the most promising derivatives depending on inhi-
bition zone values. As illustrated in Table 1, the most active deriva-
tives 5a, 6, 10, 11b, 11c, 14, and 15 in a combination of quino-
line and substituted-thiazole were evaluated for their in-vitro an-
timicrobial activity by two folds serial dilution technique according
to Clinical Laboratory Standards Institutes (CLSI) guidelines as de-
scribed in reported methods [63,72,73]. The MICs, MBCs, and MFCs
values were compared with broad-spectrum Tetracyclines and Am-
photericin B under the same assay conditions.
22 0.2) mm. Also, 2-aminothiazole derivative 6 showed excellent
inhibitory activity against all tested strains with IZ values (21 0.
54- 31
0.17) mm. Replacement one proton of 2-amino thiazole
derivative 6 by aryl group as (4-chlorophenyl or 4-bromophenyl)
in 7a,b derivatives revealed moderate antimicrobial potency, which
suggested that the amino group was essential for antimicrobial ac-
tivity due to the lone pair of electron on amino group are more
localized on nitrogen instead of aromatic amines as in 7a and 7b
derivatives.
Substitution the amino group in compound 6 with acetonitrile
group in thiazolidine-4-one derivative 8 at position two in thiazole
moiety resulted in the loss of activity, as well as displayed resis-
tance to S. aureus, S. typhi and F. oxysporum pathogens. Further-
more, thiosemicarbazone derivatives 9a, and 9b exhibited good ac-
tivity against gram-positive strains with no activity for gram neg-
ative strains. Besides, both derivatives 9a and 9b demonstrated
Firstly, it is interesting to observe that these most active
derivatives exhibited an inhibition effect better than the positive
controls. For gram-positive strains, the seven thiazolo-quinoline
derivatives showed potency with MICs values (1.95–15.62) μg/mL
and MBCs values (3.9–31.25) μg/mL compared with Tetracycline
that exerted bacterial inhibitory (31.25–62.5) μg/mL and bacterici-
dal values (40.62–93.75) μg/mL. Among the tested derivatives 5-
acetyl thiazolidinyl quinoline derivative 14 displayed the lowest
activity member against S. aureus with MIC value (62.5 μg/mL)
and MBC value (118.7 μg/mL). In contrast, 2-hydrazinylthiazole
derivative 11b showed excellent potency with MIC and MBC val-
ues 5.57 μg/mL. Quinolines containing N-methyl rhodanine 5a and
4-(hydroxyphenyl)thiazol-4-one 11b demonstrated the same an-
tibacterial potential against B. subtilis with sixteen and ten folds
higher than Tetracycline for MIC and MBC values, respectively. The
tested quinoline derivatives revealed a significant potency against
E. faecalis strain with MIC values (0.97–15.62) μg/mL and MBC val-
ues (1.94–31.25) μg/mL and rhodanine derivatives showed the best
derivative 5a and order of activity can be represented as 5a< 6 <
sensitivity to C. albicans strain with IZ values (19
0.16 and
18 0.27) mm. Additionally, thiazole-4-one derivative 10 involved
methyl acrylate moiety in position five in the thiazole ring showed
equivalent activity as Tetracycline and lower activity than Ampho-
tericin B. To our delight, 4-aryl-2-hydrazonyl thiazole derivatives
11a-c possessed a significant antimicrobial activity except the un-
substituted phenyl group bearing compound 11a decrease the an-
timicrobial activity. For instance, the hydroxy group’s presence in
position four in the aryl group in compound 11b afforded a broad
spectrum and higher antimicrobial activity than chlorine atom in
derivative 11c. This activity may be related to hydroxy groups that
exert electron-donating to phenyl ring than chlorine atom that dis-
played electron-withdrawing effect. Subsequently, to study the in-
9

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Table 2
In vitro antibacterial activity of the most potent compounds against multidrug resistant bacteria (MDRB).
Tested pathogens
S. aureus ATCC 33591
E. coli ATCC BAA-196
P. aeruginosa ATCC BAA-2111
Code
IZ
MIC
MBC
IZ
MIC
MBC
IZ
MIC
MBC
5a
25
26
15
24
22
20
19
26
23
0.23
0.19
0.41
0. 35
0.12
0.65
0.12
0.5
3.9
7.41
11.1
15.98
3.31
15.62
18.5
31.25
1.48
6.63
24 0.11
6.25
7.81
9.25
3.9
11.87
14.83
18.5
25
22
0. 99
0.5
6.25
4.44
7.81
7.81
5.2
11.87
6.66
15.62
15.98
9.88
18.5
7.8
6
5.55
8.88
1.95
7.81
9.25
15.62
0.78
3.9
21
21
26
22
0. 3
0.44
0.15
0. 2
10
21 0.33
21 0. 66
24 0. 88
11b
11c
14
7.41
6.25
8.88
15.62
1.57
1.38
11.87
15.98
31.25
3.14
20 0. 66
20
0.44
9.25
3.9
15
17
28
0.46
0.98
27 0. 54
Van.
Cip.
25
20
0.47
0.85
1.95
2.5
3.31
4.5
0.65
22 0.2
2.76
11b < 15 < 14 < 10 < 11c. On the other hand, the active quino-
line derivative had potential antimicrobial activity against gram-
negative bacterial strains. These derivatives possessed inhibitory
potential ranged between (0.97–55.5) μg/mL and MBC values be-
tween (1.94–88.8) μg/mL, except methyl acrylate thiazole deriva-
tive 10 that showed resistance to E. Coli with MIC (62.5 μg/mL) and
(87.5 μg/mL) values higher than the positive control. Remarkably,
thiazolo-quinoline derivative 11b showing the best inhibition and
bactericidal ability against E. Coli and P. aeruginosa with MIC val-
ues (0.97, and 5.57) μg/mL and MBC values (1.94 and 10.58) μg/mL,
which are superior to Tetracycline. The rhodanine quinoline deriva-
tive 5a was found to be a more active antibacterial agent against S.
typhi with MIC and MBC values 3.9, 6.63 μg/mL, respectively. Also,
both quinoline derivatives 6, and 15 exhibited the same activity
against S. typhi with five MIC and four MBC folds higher than posi-
tive control and order of activity can be represented as 5a < 6 and
15 < 11b < 10 < 11c < 14.
three strains were selected for this purpose known as S. aureus
(ATCC 33591), E. coli (ATCC BAA-196), and P. aeruginosa (ATCC BAA-
2111). Vancomycin and Ciprofloxacin were selected as commercial
positive control antibiotic.
By analyzing the data obtained in Table 2, the most active
thiazolo-quinoline derivatives displayed a variable degree of inhi-
bition against MDR bacterial species. Generally, the tested deriva-
tives exhibited MIC values between (1.95–9.25) μg/mL, and MBC
values (3.31–18.50) μg/mL with MIC and MBC values less than 10,
20 μg/mL, respectively. Notably, a poor activity was observed for
5-azotolyl thiazole derivative 15 against S. aureus and E. coli, but
this derivative exhibited the most promising derivative against P.
aeruginosa with MIC value 3.9 μg/mL, and MBC value 7.8 μg/mL
in comparison to Ciprofloxacin and Vancomycin (MIC; 2.5, and
1.95 μg/mL), (MBC; 4.5, and 3.31 μg/mL), respectively, and that
may be related to the presence of azo-tolyl group. Also, the or-
der of activity against P. aeruginosa represented as 15 < 6 < 11c <
5a < 11b < 14. The quinoline derivatives 5a, 6, 10, 11b, 11c, and
14 demonstrated bacteriostatic activity with MIC values ranged be-
tween (1.95–9.25) μg/mL against the tested strains compared with
Vancomycin (0.78–1.95) μg/mL and Ciprofloxacin (1.38–3.9) μg/mL.
In the same way, these derivatives showed bactericidal potency
with MBC values (3.31–18.5) μg/mL for S. aureus and E. coli, and
the most resistance derivatives that had N-methyl rhodanine 5a
and 4-aryl-2-hydrazinyl thiazole (11b, 11c) hybrid with quinoline
derivative.
Furthermore, due to it was reported that most of the fungi
observed resistance to antimicrobial drugs [74], our work aimed
to investigate this modification in quinoline structure against two
fungal strains. The antifungal activity of quinoline hybrid com-
pounds was evaluated against C. albicans and F. oxysporum. Among
the tested derivatives, four thiazolo-quinoline compounds have
better antifungal activity than the Amphotericin B. For C. albicans
the order of synthesized compound to sensitivity described as 5a
< 11b < 11c < 6 < 15 < 10 < 14, while the sensitivity order
against F. oxysporum arranged as 5a < 11b < 6 < 11c < 14 <
10 < 15 with slightly difference between both strains. Both N-
methyl rhodanine and 4-(4-hydroxyphenyl)−2-hydrazinyl-thiazole
hybrid with 7-ethoxy quinoline derivatives 5a and 11b had better
antifungal activity with MIC values (7.81, and 15.62) μg/mL, (9.25,
and 18.51) μg/mL and MFC values (12.49, and 26.55) μg/mL, and
(17.57, and 29.61) μg/mL, respectively. Further, 2-aminothiazol-4-
one and 4-(4-chlorophenyl)−2-hydrazinylthiazole combined with
quinoline moiety to obtain derivatives 6, and 11c exhibited in-
hibitory and fungicidal activity lower than compounds 5a and 11c,
but still higher than Amphotericin B. In addition, poor antifungal
activity was observed for 10, 14, and 15 against two fungi species.
This decrease may be due to specific substituents in position five
in thiazole bioactive core as methyl acrylate, acetyl group, and azo-
tolyl groups.
Finally, with respect to the structure-activity relationship, the
results showed that hybridization of quinoline moiety to thiazole
derivatives enhance resistance to bacterial strains, especially, when
a hybrid with 2-thioxothiazol-4-one and substituted-2-hydrazinyl
thiazole derivative and all these derivatives exhibited MBC/MIC ra-
tio ranged between (1–2), i.e., these derivatives had bactericidal
potency.
3.2.5. In-vitro dihydrofolate reductase (DHFR) inhibitory assay
Previously, it was reported that the modification of quinoline
derivative with a group with hydrophilicity and polar surface area
could increase antibacterial activity by improving tissue penetra-
tion, yet maintaining strong repression [75,76]. The most active
thiazole-quinoline derivatives were investigated against DHFR en-
zyme as a potential antibacterial target using the Trimethoprim as
a positive control. The tested derivatives showed inhibitory activity
Finally, modification of the 3-formyl quinoline derivative with
different substituent thiazole as a bioactive core enhance antibac-
terial rather than antifungal activity. Besides, all tested derivatives
exhibited a bactericidal and fungicidal mode according to CLSI
standard when applied MBC/MIC and MFC/MIC ratio that obtained
values between (1–2).
IC50 values ranged between 10.02
compared with Trimethoprim 18.25
Table 3.
1.05 μM to 27.45
0.73 μM
0.65 μM as described in
It was found 4-(4–hydroxy)−2-hydrazinyl thiazolo-quinoline
derivative 11b revealed the better inhibitory activity with IC50
value (10.02
the aryl group from hydroxy to chlorine atom as in compound 11c
causes a decrease in inhibitory activity to 19.37 1.33 μM, but
still near to standard. Additionally, the IC50 values for N-methyl
1.05 μM). In contrast, replacing the substituent in
3.2.4. Drug resistance study
The drug resistance activity of most active derivatives 5a, 6, 10,
11b, 11c, 14, and 15, against three pathogens was evaluated. The
10

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Table 3
The structure of the most active derivatives 5a, 6, 10, 11b, 11c, 14,
and 15 were constructed using Chembiodraw 2014 and exported
to MOE according to the reported method [78]. The validation pro-
cess was performed by redocking the co-crystallized ligand to re-
produce the experimental binding pattern and indicating that the
docking process is suitable by demonstrating lower Root-mean-
Determination of DHFR inhibitory activity of
thiazolo-quinoline derivatives expressed by (μM).
Compounds
DHFR IC50 (Mean
SEM, μM)
5a
16.33
18.04
22.60
10.02
19.37
27.45
25.11
18.25
0.73
1.55
0.81
1.05
1.33
0.73
0.98
0.65
6
10
˚
square deviation (RMSD) =1.12 A. Methotrexate is a co-crystallized
11b
ligand and observed binding energy S =−24.44 Kcal/mol, with
11c
eight hydrogen bonds and the length of these bonds less than
14
˚
4.5 A, between the residue and groups of the ligand.
15
Trimethoprim
The thiazolo-quinoline derivatives revealed that binding en-
ergy ranged between (−16.21 to −23.96) Kcal/mol, as represented
in Table 4. The most active DHFR inhibitor 4-(4–hydroxy)−2-
hydrazinyl thiazolo-quinoline derivative 11b showed the highest
binding energy S = −23.96 Kcal/mol. This derivative generated
three hydrogen bonds between the residues Ser59, Arg28, and
Glu30 with NH of hydrazinyl, oxygen of ethoxy group, and hydroxy
rhodanino-quinoline 5a and 2-aminothiazolo-quinoline derivative
are still less than the standard (16.33 0.73) μM, and
(18.04 1.55) μM, respectively.
6
Finally, the previous results illustrate that the tested thiazolo-
quinoline derivatives’ antibacterial activity depends on the
structure-activity relationship. It can be concluded that the pres-
ence of thiocarbonyl 5a, amino 6, and aryl containing electron-
donating group 11b in thiazole core can enhance antibacterial ac-
tivity. These activities were confirmed by inhibition of DHFR en-
zyme that important for the synthesis of NADP+ which required
for the biosynthesis of purine nucleotides, thymidine (precursor for
DNA replication) and therefore lead to the disruption of DNA syn-
thesis and the death.
˚
group of with bond lengths of 2.78, 2.68 and 2.35 A, respectively.
Besides, the ethoxy group of quinoline and thiazole core forming
hydrophobic interaction as well as one arene-arene interaction be-
tween the residue Phe34 and phenyl ring of phenol (Fig. 2a,b).
Notably, the carbonyl of quinoline at position two and oxy-
gen of ethoxy group forms two hydrogen bond acceptors with
the residues Ser64 and Ser59, respectively, with binding energy
S = −20.92 for N-methyl rhodanine derivative 5a (Fig. 3a,b). Mean-
while, the modeling is shown in (Fig. 4a,b) that compound 6
can form two hydrogen bonds through the amino in thiazole and
carbonyl of quinoline with Asn64, and Asp21. Furthermore, thi-
azole derivatives 10, 11c, 14, and 15 showed only one hydro-
gen bond the active site’s residues. In comparison, compound 11c
formed one arene-cation between Lys 68 and the phenyl of a 4-
chlorophenyl group that attached in position four of the thiazole
ring. Also, compound 15 displayed one arene-arene between pyri-
dine ring of quinoline derivative and Phe 31 (All figure in sup-
3.3. Computational study of the binding mode
To understand the most active thiazolo-quinoline derivatives’
binding mode, molecular docking study was performed inside the
active site of DHFR (PDB: 1DLS), which was obtained from the pro-
tein data bank. According to the reported method, the active site
of protein was generated according to the default protocol [65,77].
Table 4
Molecular modeling study of the most promising derivatives 5a, 6, 10, 11b, 11c, 14, and 15 DHFR (PDB: IDLS).
Cpd. No.
5a
S Kcal/mol
Amino acids residues Ligand atoms
Distance ˚A
Strength%
Hydrophobic interaction
−20.92
Asn64
Ser59
C=O of quinoline
2.87
3.10
40
21
Leu67, Asp21, Gln35,
Arg28, Phe31, Pro61,
lle60, Tyr22
Oxygen of ethoxy
6
−19.18
−17.69
Asn64
Asp21
C=O of quinoline
2.90
2.63
22
61
Arg28, Pro26, Tyr22,
Phe34, Val115, Ser54,
Pro61, Phe31, lle60
Asn64, Gln35, Ser59,
Tyr22, lle60, Asp21,
Gly20, Pro61, Lys68,
Phe31, Phe34, Leu67
Tyr22, Asn64, Phe31,
Pro61, Ala9
NH2 group
10
Arg28
C=O of thiazole
2.59
50
11b
11c
14
−23.96
−18.87
−17.57
−16.21
−24.44
Ser59
Arg28
Glu30
Ser59
Lys68
NH of hydrazinyl
Oxygen of ethoxy
OH of phenol
2.78
2.68
2.35
3.04
-
91
95
85
27
-
Oxygen of ethoxy
Aryl group
Phe31, lle60, Tyr22,
Pro61, Leu67, Arg70,
Asn64, Leu67
Arg28
C=O of acetyl
2.43
55
Tyr22, Thr56, lle16,
Ser59, Phe34, lle60,
Phe31, Pro61
15
Arg28
Phe31
N of quinoline
2.79
–
55
–
Asn64, Pro61, Thr58,
Tyr22, lle60, Ser59,
lle18, Phe34
Pyridine of quinoline
MEX.
Arg70
Arg70
Asn64
Arg28
Asn64
Val115
Lle7
C=O of carboxylate
2.96
36
Pro61, lle60,
oxygen of carboxylate 2.35
oxygen of carboxylate 2.92
60
Ser59, Tyr22,
32
Val8, Ala9,
C=O of carboxylate
C=O of amide
2.91
2.49
2.75
3.16
2.83&2.7
–
17
Leu67, Tyr121,
Gln35
20
NH2 of pyrimidine
NH2 of pyrimidine
NH2 of pyrimidine
pyrazine ring
35
13
Gln30
Phe34
39&63
–
MEX.= Methotrexate, (-) arene-cation interaction, (- -) arene-arene interaction.
11

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Fig. 2. (a). 2D for compound 11b docked into DHFR binding site, (b). 3D for compound 11b docked into DHFR binding site.
12

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Fig. 3. (a). 2D for compound 5a docked into DHFR binding site, (b). 3D for compound 5a docked into DHFR binding site.
13

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Fig. 4. (a). 2D for compound 6 docked into DHFR binding site, (b). 3D for compound 6 docked into DHFR binding site.
plementary material). These docking results supported the enzy-
matic assay and showed that thiazole ring in many causes could
form lower binding energy besides the quinoline ring. This combi-
nation can improve antibacterial activity through inhibition DHFR
enzyme.
ing Gaussian 09 software. We can determine both the electron-
deficiency regions (blue) and electron-rich regions (red) from MEP
maps. These regions might be responsible for forming different in-
teraction types as (hydrogen bonds, arene-arene, and arene-cation)
between these sites in molecules and active sites in a biological
target. As represented in Fig. 5, the positive charge (blue) may be
located on the nitrogen of thiazole, quinoline rings, and hydrazinyl
groups. In contrast, the negative charge (red) was displayed on
ethoxy’s oxygen, besides the carbonyl of the 2-oxo-quinoline and
thiazolidinone derivative. The presence of positive and negative
area in designed molecules explained why these positions could
form hydrogen bonds with the residues of active sites in DHFR en-
zyme, which agreement with docking study.
3.4. Molecular electrostatic potential (MEP) maps
The electronic distribution around the molecular surface can
be represented as MEP. The most active derivatives’ molecular
structure was built and optimized with Density functional the-
ory (DFT) calculation using the B3LYP hybrid functional and stan-
dard 6–31G(d) basis set according to the reported method [66] us-
14

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
Fig. 5. MEP surfaces of the most active thiazolo-quinoline derivatives.
4. Conclusion
ues nearly to the commercial antibacterial agents as Ciprofloxacin
and Vancomycin, while in the case of P. aeruginosa the more sensi-
tive derivatives are 15, 6, 11c, 11b that demonstrated values nearly
to the positive control. The potency of the synthesized derivative
against bacteria was proved by inhibiting the DHFR enzyme that
interrupted thymidylate and DNA biosynthesis with IC50 values
ranged between (10.02–25.11) μM with three compounds 11c, 6,
and 5a lower than Trimethoprim (18.95 μM), and four derivatives
observed inhibitory slightly higher than control. Docking study il-
lustrated that DHFR inhibition, probably, may explain the mecha-
nism of antibacterial activity. Molecular surface mapping explained
the distribution of electron around the designed compounds and
confirmed the binding mode and therefore, these compounds are
good options for developing new antibacterial agents.
Overall, this study’s main aim involves designing and synthe-
sizing new quinoline-based thiazole as a new target for antimi-
crobial activity against standard and MDR bacteria then compu-
tational study involving molecular docking and molecular electro-
static potential were studied to confirm the binding mode. The
synthesized derivatives were considered analogues for quinoline
and penicillin classes of antibiotics due to quinoline and thia-
zole pharmacophores’ presence. All the designed derivatives were
screened for antimicrobial activity, and the results displayed seven
derivatives 5a, 6, 10, 11b, 11c, 14, and 15 showed a good antimicro-
bial and antifungal activity against the tested strains with higher
and broad-spectrum MIC and MBC/ MFC values compared with
Tetracycline and Amphotericin B. Furthermore, the active deriva-
tives revealed better antibacterial activity than antifungal activ-
ity and therefore, our work was extended to study the activity of
these derivatives on MDR bacteria as S. aureus, E. coli, and P. aerug-
inosa. The synthetic thiazolo-quinoline derivatives showed strong
inhibition zones, and most of them showed MIC and MBC values
lower than 10 μg/mL, and 20 μg/mL. Additionally, some derivatives
as 5a, 6, 11b, and 11c, against S. aureus, and E. coli reveled val-
Author statements
Yousry A. Ammar; Conceptualization, Methodology, Resources
Writing
- original draft, Writing - review & editing, Supervi-
sion. Sondos M. A. Abd El-Hafez; Conceptualization, Methodol-
ogy, Performed the experiments, Methodology, Investigation, Re-
sources, Writing - original draft. Sadia A. Hessein: Conceptualiza-
15

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
˙
˙
tion, Methodology, Resources, Writing - Original Draft, Supervision.
Abeer M. Ali; Conceptualization, Methodology, Resources, Writing -
Original Draft, Supervision. Ahmed A. Askar; Performed the exper-
iments for biological parts only. Ahmed Ragab; Conceptualization,
Methodology, Software, Formal analysis, Validation, Methodology,
Investigation, Data Curation, Writing - Original Draft, Writing Re-
view & Editing, Visualization.
[22] S. Eryılmaz, E. Türk Çelikog˘lu, Ö. Idil, E. Inkaya, Z. Kozak, E. Mısır, M. Gül,
Derivatives of pyridine and thiazole hybrid: synthesis, DFT, biological evalu-
ation via antimicrobial and DNA cleavage activity, Bioorg. Chem. 95 (2020),
doi:10.1016/j.bioorg.2019.103476.
[23] S.B. Bari, S.D. Firake, Exploring anti-inflammatory Potential of thiazolidi-
none derivatives of benzenesulfonamide via synthesis, molecular dock-
ing and biological evaluation, Anti-Inflamm. Anti-Allergy Agents Med.
Chem. (Formerly Curr. Med. Chem. Anti-Allergy Agents). 15 (2016) 44–
53.
[24] R.K. Satsangi, S.M. Zaidi, V.S. Misra, 1-(4-substituted-thiazol-2-yl)hydantoins as
anti-inflammatory and CNS-active agents, Pharmazie 38 (1983) 341–342 http:
//europepmc.org/abstract/MED/6611633.
Declaration of Competing Interest
[25] W. Klose, U. Niedballa, K. Schwarz, I. Böttcher, Nichtsteroidale Entzündung-
shemmer, 17. Mitt.1) 4.5-Bis(4-methoxyphenyl)-2-arylthio-azole mit antiphlo-
gistischer Wirkung, Arch. Pharm. (Weinheim). 316 (1983) 941–951, doi:10.
1002/ardp.19833161108.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
[26] T.I. de Santana, M. de O. Barbosa, P.A.T. de M. Gomes, A.C.N. da Cruz, T.G. da
Silva, A.C.L. Leite, Synthesis, anticancer activity and mechanism of action of
new thiazole derivatives, Eur. J. Med. Chem. 144 (2018) 874–886, doi:10.1016/
j.ejmech.2017.12.040.
Supplementary materials
[27] E. Brantley, V. Patel, S.F. Stinson, V. Trapani, C.D. Hose, H.P. Ciolino,
G.C. Yeh, J.S. Gutkind, E.A. Sausville, A.I. Loaiza-Pérez, The antitumor
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130748.
drug
candidate
2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole
in-
duces NF-κB activity in drug-sensitive MCF-7 cells, Anticancer. Drugs.
16 (2005) https://journals.lww.com/anti-cancerdrugs/Fulltext/2005/02000/
The_antitumor_drug_candidate.4.aspx.
Reference
[28] C. Nitsche, V.N. Schreier, M.A.M. Behnam, A. Kumar, R. Bartenschlager,
C.D. Klein, Thiazolidinone–Peptide Hybrids as Dengue Virus Protease Inhibitors
with Antiviral Activity in Cell Culture, J. Med. Chem. 56 (2013) 8389–8403,
doi:10.1021/jm400828u.
[1] R. Wang, X. Yin, Y. Zhang, W. Yan, Design, synthesis and antimicrobial evalua-
tion of propylene-tethered ciprofloxacin-isatin hybrids, Eur. J. Med. Chem. 156
(2018) 580–586, doi:10.1016/j.ejmech.2018.07.025.
[2] G.-.F. Zhang, S. Zhang, B. Pan, X. Liu, L.-.S. Feng, 4-Quinolone derivatives and
their activities against Gram positive pathogens, Eur. J. Med. Chem. 143 (2018)
710–723, doi:10.1016/j.ejmech.2017.11.082.
[29] M. Mishchenko, S. Shtrygol, D. Kaminskyy, R. Lesyk, Thiazole-Bearing 4-
Thiazolidinones as New Anticonvulsant Agents, Sci. Pharm. 88 (2020), doi:10.
3390/scipharm88010016.
[30] N. Ergenç, G. Capan, Synthesis and anticonvulsant activity of new 4- thi-
azolidone and 4-thiazoline derivatives, Farmaco 49 (1994) 133–135 http://
europepmc.org/abstract/MED/8003182.
[3] Y.-.Q. Hu, S. Zhang, Z. Xu, Z.-.S. Lv, M.-.L. Liu, L.-.S. Feng, 4-Quinolone hy-
brids and their antibacterial activities, Eur. J. Med. Chem. 141 (2017) 335–345,
doi:10.1016/j.ejmech.2017.09.050.
[4] M. BARBER, Methicillin-resistant staphylococci, J. Clin. Pathol. 14 (1961) 385–
393, doi:10.1136/jcp.14.4.385.
[31] M. Djukic, M. Fesatidou, I. Xenikakis, A. Geronikaki, V.T. Angelova, V. Savic,
M. Pasic, B. Krilovic, D. Djukic, B. Gobeljic, M. Pavlica, A. Djuric, I. Stanojevic,
D. Vojvodic, L. Saso, In vitro antioxidant activity of thiazolidinone derivatives
of 1,3-thiazole and 1,3,4-thiadiazole, Chem. Biol. Interact. 286 (2018) 119–131,
doi:10.1016/j.cbi.2018.03.013.
[5] P. Goldsworthy, A. McFarlane, Howard Florey, Alexander Fleming and the fairy
tale of penicillin, Med. J. Aust. 176 (2002) 178–180 http://www.mja.com.au/
public/issues/176_04_180202/gol10735.html.
[6] J.J. Aguilera-Correa, J. Esteban, M. Vallet-Regí, Inorganic and Polymeric
Nanoparticles for Human Viral and Bacterial Infections Prevention and Treat-
ment, Nanomater 11 (2021), doi:10.3390/nano11010137.
[32] S. Yasmin, F. Capone, A. Laghezza, F.D. Piaz, F. Loiodice, V. Vijayan, V. De-
vadasan, S.K. Mondal, Ö. Atlı, M. Baysal, A.K. Pattnaik, V. Jayaprakash, A. Lavec-
chia, Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARγ Ag-
onists and their Antidiabetic Effects on Type 2 Diabetes, Sci. Rep. 7 (2017)
14453, doi:10.1038/s41598- 017-14776-0.
[7] A.Y. Hwang, J.G. Gums, The emergence and evolution of antimicrobial resis-
tance: impact on a global scale, Bioorg. Med. Chem. 24 (2016) 6440–6445.
[8] X.-.M. Zhang, H. Guo, Z.-.S. Li, F.-.H. Song, W.-.M. Wang, H.-.Q. Dai, L.-.X. Zhang,
J.-.G. Wang, Synthesis and evaluation of isatin-β-thiosemicarbazones as novel
agents against antibiotic-resistant Gram-positive bacterial species, Eur. J. Med.
Chem. 101 (2015) 419–430, doi:10.1016/j.ejmech.2015.06.047.
[33] A. Kamal, S.F. Adil, J.R. Tamboli, B. Siddardha, U.S.N. Murthy, Synthesis of
coumarin linked naphthalimide conjugates as potential anticancer and antimi-
crobial agents, Lett. Drug Des. Discov. 6 (2009) 201–209.
[34] S. Mamidala, S.R. Peddi, R.K. Aravilli, P.C. Jilloju, V. Manga, R.R. Vedula, Mi-
crowave irradiated one pot, three component synthesis of a new series of hy-
brid coumarin based thiazoles: antibacterial evaluation and molecular docking
studies, J. Mol. Struct. 1225 (2021) 129114, doi:10.1016/j.molstruc.2020.129114.
[35] T.K. Smith, B.L. Young, H. Denton, D.L. Hughes, G.K. Wagner, First small molec-
ular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a val-
idated drug target in African sleeping sickness, Bioorg. Med. Chem. Lett. 19
(2009) 1749–1752, doi:10.1016/j.bmcl.2009.01.083.
[9] A.C. Uttley, Vancomycin-resistant enterococci, Lancet 2 (1988) 57–58.
[10] R. on A. Resistance, Antimicrobial resistance: tackling a crisis for the health
and wealth of nations, Rev. Antimicrobial Resist. (2014).
[11] M. Krátký, J. Vinšová, J. Stolarˇíková, Antimicrobial activity of rhodanine-3-
acetic acid derivatives, Bioorg. Med. Chem. 25 (2017) 1839–1845, doi:10.1016/
j.bmc.2017.01.045.
[12] C.L. Ventola, The antibiotic resistance crisis: part 1: causes and threats, P T 40
(2015) 277–283 https://pubmed.ncbi.nlm.nih.gov/25859123.
[36] P. Franchetti, L. Cappellacci, M. Pasqualini, R. Petrelli, V. Jayaprakasan, H.N. Ja-
yaram, D.B. Boyd, M.D. Jain, M. Grifantini, Synthesis, conformational analysis,
and biological activity of new analogues of thiazole-4-carboxamide adenine
dinucleotide (TAD) as IMP dehydrogenase inhibitors, Bioorg. Med. Chem. 13
(2005) 2045–2053, doi:10.1016/j.bmc.2005.01.007.
[13] S. Ali, A. Wisal, M.N. Tahir, A.Ali Abdullah, S. Hameed, M.N. Ahmed, One-pot
synthesis, crystal structure and antimicrobial activity of 6-benzyl-11-(p-tolyl)-
6H-indolo[2,3-b]quinoline, J. Mol. Struct. 1210 (2020) 128035, doi:10.1016/j.
molstruc.2020.128035.
[14] G.S. Bisacchi, Origins of the Quinolone Class of Antibacterials: an Expanded
“Discovery Story, J. Med. Chem. 58 (2015) 4874–4882, doi:10.1021/jm501881c.
[15] J.-.M. Rolain, C. Abat, M.-.T. Jimeno, P.-.E. Fournier, D. Raoult, Do we need new
antibiotics? Clin. Microbiol. Infect. 22 (2016) 408–415, doi:10.1016/j.cmi.2016.
03.012.
[37] W.D. Alrohily, M.E. Habib, S.M. El-Messery, A. Alqurshi, H. El-Subbagh,
E.-S.E. Habib, Antibacterial, antibiofilm and molecular modeling study of some
antitumor thiazole based chalcones as a new class of DHFR inhibitors, Microb.
Pathog. 136 (2019) 103674.
[38] S. El-sayed, K. Metwally, A.A. El-Shanawani, L.M. Abdel-Aziz, A.A. El-Rashedy,
M.E.S. Soliman, L. Quattrini, V. Coviello, C. la Motta, Quinazolinone-based
rhodanine-3-acetic acids as potent aldose reductase inhibitors: synthesis, func-
tional evaluation and molecular modeling study, Bioorg. Med. Chem. Lett. 27
(2017) 4760–4764, doi:10.1016/j.bmcl.2017.08.050.
[16] K. Douadi, S. Chafaa, T. Douadi, M. Al-Noaimi, I. Kaabi, Azoimine quinoline
derivatives: synthesis, classical and electrochemical evaluation of antioxidant,
anti-inflammatory, antimicrobial activities and the DNA /BSA binding, J. Mol.
Struct. 1217 (2020) 128305, doi:10.1016/j.molstruc.2020.128305.
[17] R. Suresh, S. Muthusubramanian, R. Senthilkumaran, G. Manickam, SnCl2-
Catalyzed Selective Atom Economic Imino Diels–Alder Reaction: synthesis of 2-
(1H-Pyrrolo[2,3-b]pyridin-3-yl)quinolines, J. Org. Chem. 77 (2012) 1468–1476,
doi:10.1021/jo202256z.
[39] C. Zinglé, D. Tritsch, C. Grosdemange-Billiard, M. Rohmer, Catechol–rhodanine
derivatives: specific and promiscuous inhibitors of Escherichia coli deoxyxylu-
lose phosphate reductoisomerase (DXR), Bioorg. Med. Chem. 22 (2014) 3713–
3719, doi:10.1016/j.bmc.2014.05.004.
[40] N.C. Desai, N. Bhatt, H. Somani, A. Trivedi, Synthesis, antimicrobial and cyto-
toxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles, Eur. J. Med.
Chem. 67 (2013) 54–59, doi:10.1016/j.ejmech.2013.06.029.
[18] T.K. Köprülü, S. Ökten, S¸ . Tekin, O. Çakmak, Biological evaluation of some
quinoline derivatives with different functional groups as anticancer agents, J.
Biochem. Mol. Toxicol. 33 (2019) e22260, doi:10.1002/jbt.22260.
[19] X. Zhang, T. Yao, M.A. Campo, R.C. Larock, Synthesis of substituted quinolines
by the electrophilic cyclization of n-(2-alkynyl)anilines, Tetrahedron 66 (2010)
1177–1187, doi:10.1016/j.tet.2009.12.012.
[41] A.I. Khalaf, R.D. Waigh, A.J. Drummond, B. Pringle, I. McGroarty, G.G. Skellern,
C.J. Suckling, Distamycin Analogues with Enhanced Lipophilicity:
Synthesis
and Antimicrobial Activity, J. Med. Chem. 47 (2004) 2133–2156, doi:10.1021/
jm031089x.
[42] J.J. Harnett, V. Roubert, C. Dolo, C. Charnet, B. Spinnewyn, S. Cornet, A. Rolland,
J.-.G. Marin, D. Bigg, P.-.E. Chabrier, Phenolic thiazoles as novel orally-active
neuroprotective agents, Bioorg. Med. Chem. Lett. 14 (2004) 157–160, doi:10.
1016/j.bmcl.2003.09.077.
[20] K.D. Katariya, S.R. Shah, D. Reddy, Anticancer, antimicrobial activities of quino-
line based hydrazone analogues: synthesis, characterization and molecular
docking, Bioorg. Chem. 94 (2020) 103406, doi:10.1016/j.bioorg.2019.103406.
[21] I. Althagafi, N. El-Metwaly, T.A. Farghaly, New Series of Thiazole Derivatives:
synthesis, Structural Elucidation, Antimicrobial Activity, Molecular Modeling
and MOE Docking, Mol. 24 (2019), doi:10.3390/molecules24091741.
16

Y.A. Ammar, S.M.A.A. El-Hafez, S.A. Hessein et al.
Journal of Molecular Structure 1242 (2021) 130748
[43] J. Dien Bard, J.A. Hindler, H.S. Gold, B. Limbago, Rationale for Eliminat-
ing Staphylococcus Breakpoints for β-Lactam Agents Other Than Penicillin,
Oxacillin or Cefoxitin, and Ceftaroline, Clin. Infect. Dis. 58 (2014) 1287–1296,
doi:10.1093/cid/ciu043.
novel di-substituted sulfonylquinoxaline derivatives, Bioorg. Chem. 104 (2020)
104164, doi:10.1016/j.bioorg.2020.104164.
[62] M.A.M.S. El-Sharief, S.Y. Abbas, M.A. Zahran, Y.A. Mohamed, A. Ragab, Y.A. Am-
mar, New 1, 3-diaryl-5-thioxo-imidazolidin-2, 4-dione derivatives: synthesis,
reactions and evaluation of antibacterial and antifungal activities, Zeitschrift
Fur Naturforsch. - Sect. B J. Chem. Sci. (2016) 71, doi:10.1515/znb-2016-0054.
[63] M.A. Salem, A. Ragab, A.A. Askar, A. El-khalafawy, A.H. Makhlouf, One-pot syn-
thesis and molecular docking of some new spiropyranindol-2-one derivatives
as immunomodulatory agents and in vitro antimicrobial potential with DNA
gyrase inhibitor, Eur. J. Med. Chem. 188 (2020) 111977, doi:10.1016/j.ejmech.
2019.111977.
[44] F.D. Lowy, Antimicrobial resistance: the example of Staphylococcus aureus, J.
Clin. Invest. 111 (2003) 1265–1273, doi:10.1172/JCI18535.
[45] A.J. Wright, The Penicillins, Mayo Clin. Proc. 74 (1999) 290–307, doi:10.4065/
74.3.290.
[46] C.M. Czekster, A. Vandemeulebroucke, J.S. Blanchard, Kinetic and Chemical
Mechanism of the Dihydrofolate Reductase from Mycobacterium tuberculosis,
Biochemistry 50 (2011) 367–375, doi:10.1021/bi1016843.
[47] A. Raju, S. Kulkarni, M.K. Ray, M.G.R. Rajan, M.S. Degani, E84G mutation in
dihydrofolate reductase from drug resistant strains of Mycobacterium tubercu-
losis (Mumbai, India) leads to increased interaction with Trimethoprim, Int. J.
Mycobacteriology. 4 (2015) 97–103, doi:10.1016/j.ijmyco.2015.02.001.
[48] I.H. Gilbert, Inhibitors of dihydrofolate reductase in leishmania and try-
[64] M.A. Salem, A. Ragab, A. El-Khalafawy, A.H. Makhlouf, A.A. Askar, Y.A. Am-
mar, Design, synthesis, in vitro antimicrobial evaluation and molecular docking
studies of indol-2-one tagged with morpholinosulfonyl moiety as DNA gyrase
inhibitors, Bioorg. Chem. 96 (2020) 103619, doi:10.1016/j.bioorg.2020.103619.
[65] A.S. Hassan, A.A. Askar, A.M. Naglah, A.A. Almehizia, A. Ragab, Discovery
of New Schiff Bases Tethered Pyrazole Moiety: design, Synthesis, Biological
Evaluation, and Molecular Docking Study as Dual Targeting DHFR/DNA Gy-
rase Inhibitors with Immunomodulatory Activity, Mol. 25 (2020), doi:10.3390/
molecules25112593.
panosomes, Biochim. Biophys. Acta
doi:10.1016/S0925-4439(02)00088-1.
- Mol. Basis Dis. 1587 (2002) 249–257,
[49] H.F. Rizk, M.A. El–Borai, A. Ragab, S.A. Ibrahim, Design, synthesis, biolog-
ical evaluation and molecular docking study based on novel fused pyra-
zolothiazole scaffold, J IRAN CHEM SOC 17 (2020) 2493–2505, doi:10.1007/
s13738-020-01944-9.
[66] L.-.L. Wang, N. Battini, R.R.Y. Bheemanaboina, M.F. Ansari, J.-.P. Chen, Y.-.P. Xie,
G.-.X. Cai, S.-.L. Zhang, C.-.H. Zhou,
A new exploration towards aminothia-
[50] A.M.S. El-sharief, Y.A. Ammar, A. Belal, M.A.M.S. El-sharief, Y.A. Mohamed,
A.B.M. Mehany, G.A.M. Elhag, A. Ragab, Design, synthesis, molecular docking
and biological activity evaluation of some novel indole derivatives as potent
anticancer active agents and apoptosis inducers, Bioorg. Chem. 85 (2019) 399–
412, doi:10.1016/j.bioorg.2019.01.016.
zolquinolone oximes as potentially multi-targeting antibacterial agents: design,
synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV,
Eur. J. Med. Chem. 179 (2019) 166–181, doi:10.1016/j.ejmech.2019.06.046.
[67] E.A. Fayed, Y.A. Ammar, A. Ragab, N.A. Gohar, A.B.M. Mehany, A.M. Far-
rag, In vitro cytotoxic activity of thiazole-indenoquinoxaline hybrids as apop-
totic agents, design, synthesis, physicochemical and pharmacokinetic studies,
Bioorg. Chem. 100 (2020) 103951, doi:10.1016/j.bioorg.2020.103951.
[68] Y.A. Ammar, S. AM, M. El-Sharief, M.M. Ghorab, Y.A. Mohamed, A. Ragab,
S.Y. Abbas, New imidazolidineiminothione, imidazolidin-2-one and imidazo-
quinoxaline derivatives: synthesis and evaluation of antibacterial and antifun-
gal activities, Curr. Org. Synth. 13 (2016) 466–475.
[69] Y. Yu, D.S. Kalinowski, Z. Kovacevic, A.R. Siafakas, P.J. Jansson, C. Stefani,
D.B. Lovejoy, P.C. Sharpe, P.V. Bernhardt, D.R. Richardson, Thiosemicarbazones
from the Old to New: iron Chelators That Are More Than Just Ribonu-
cleotide Reductase Inhibitors, J. Med. Chem. 52 (2009) 5271–5294, doi:10.
1021/jm900552r.
[51] Y.A. Ammar, S.Y. Abbas, M.A.M.S. El-Sharief, M.A.E.-R. Salem, A.R. Mohamed,
Synthesis and characterization of new imidazolidineiminothione and bis-
imidazolidineiminothione derivatives as potential antimicrobial agents, Eur. J.
Chem. 8 (2017) 76–81, doi:10.5155/eurjchem.8.1.76-81.1542.
[52] Y.A. Ammar, A.M. El-Sharief, Y.A. Mohamed, A.B. Mehany, A. Ragab, Synthe-
sis, spectral characterization and pharmacological evaluation of novel thiazole-
oxoindole hybrid compounds as potential anticancer agents, Al-azhar Bull. Sci.
29 (2018) 25–37 Al-Azhar Bull. Sci. 29 (2018) 25–37, doi:10.21608/absb.2018.
33767.
[53] Y.A. Ammar, A.M. Sh El-Sharief, A. Belal, S.Y. Abbas, Y.A. Mohamed,
A.B.M. Mehany, A. Ragab, Design, synthesis, antiproliferative activity, molec-
ular docking and cell cycle analysis of some novel (morpholinosulfonyl) isatins
with potential EGFR inhibitory activity, Eur. J. Med. Chem. (2018) 156, doi:10.
1016/j.ejmech.2018.06.061.
[70] H. Beraldo, D. Gambino, The wide pharmacological versatility of semicar-
bazones, thiosemicarba-zones and their metal complexes, Mini Rev. Med.
Chem. 4 (2004) 31–39, doi:10.2174/1389557043487484.
[54] M.M.S. Wassel, A. Ragab, G.A.M. Elhag Ali, A.B.M. Mehany, Y.A. Ammar, Novel
adamantane-pyrazole and hydrazone hybridized: design, synthesis, cytotoxic
evaluation, SAR study and molecular docking simulation as carbonic anhy-
drase inhibitors, J. Mol. Struct. 1223 (2021) 128966, doi:10.1016/j.molstruc.
2020.128966.
[71] O.R. Klisuric´, S.J. Armakovic´, S. Armakovic´, S. Markovic´, T.R. Todorovic´, G. Por-
talone, K. Novovic´, J. Lozo, N.R. Filipovic´, Structural, biological and in-silico
study of quinoline-based chalcogensemicarbazones, J. Mol. Struct. 1203 (2020)
127482, doi:10.1016/j.molstruc.2019.127482.
[72] Y.A. Ammar, A.A. Farag, A.M. Ali, A. Ragab, A.A. Askar, D.M. Elsisi, A. Belal, De-
sign, synthesis, antimicrobial activity and molecular docking studies of some
novel di-substituted sulfonylquinoxaline derivatives, Bioorg. Chem. 104 (2020)
104164, doi:10.1016/j.bioorg.2020.104164.
[73] P.A. Wayne, M07: Methods for Dilution Antimicrobial Susceptibility Tests For
Bacteria That Grow Aerobically, 11th Edition, Clin. Lab. Stand. Inst., 2018.
[74] A.A.M. Mohammed, G.A.R.Y. Suaifan, M.B. Shehadeh, P.N. Okechukwu, Design,
synthesis and antimicrobial evaluation of novel glycosylated-fluoroquinolones
derivatives, Eur. J. Med. Chem. 202 (2020) 112513, doi:10.1016/j.ejmech.2020.
112513.
[55] M.M.S. Wassel, W.M. Gamal Eldin, A. Ragab, G.A.M. Elhag Ali, Y.A. Ammar, An-
tiviral Activity Of Adamantane-Pyrazole Derivatives Against Foot And Mouth
Disease Virus Infection In Vivo And In Vitro With Molecular Docking Study, J.
Appl. Vet. Sci. 5 (2020) 37–46, doi:10.21608/javs.2020.118001.
[56] M.M.S. Wassel, Y.A. Ammar, G.A.M. Elhag Ali, A. Belal, A.B.M. Mehany, A. Ragab,
Development of adamantane scaffold containing 1,3,4-thiadiazole derivatives:
design, synthesis, anti-proliferative activity and molecular docking study tar-
geting EGFR, Bioorg. Chem. (2021) 104794, doi:10.1016/j.bioorg.2021.104794.
[57] S.I. Eissa, A.M. Farrag, S.Y. Abbas, M.F. El Shehry, A. Ragab, E.A. Fayed, Y.A. Am-
mar, Novel Structural hybrids of quinolone and thiazole moieties: synthesis
and evaluation of antibacterial and antifungal activities with molecular mod-
eling studies, Bioorg. Chem. (2021) 104803, doi:10.1016/j.bioorg.2021.104803.
[58] I. Sato, T. Nakao, R. Sugie, T. Kawasaki, K. Soai, Enantioselective synthesis of
substituted 3-quinolyl alkanols and their application to asymmetric autocatal-
ysis, Synthesis (Stuttg) 2004 (2004) 1419–1428.
[59] M.R. Herbert, D.L. Siegel, L. Staszewski, C. Cayanan, U. Banerjee, S. Dhamija,
J. Anderson, A. Fan, L. Wang, P. Rix, A.K. Shiau, T.S. Rao, S.A. Noble, R.A. Hey-
man, E. Bischoff, M. Guha, A. Kabakibi, A.B. Pinkerton, Synthesis and SAR of
2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5,
Bioorg. Med. Chem. Lett. 20 (2010) 5718–5721, doi:10.1016/j.bmcl.2010.08.014.
[60] Y.A. Ammar, A.A. Farag, A.M. Ali, S.A. Hessein, A.A. Askar, E.A. Fayed, D.M. El-
sisi, A. Ragab, Antimicrobial evaluation of thiadiazino and thiazolo quinoxa-
line hybrids as potential DNA gyrase inhibitors; design, synthesis, characteriza-
tion and morphological studies, Bioorg. Chem. 99 (2020) 103841, doi:10.1016/
j.bioorg.2020.103841.
[75] G.A.R.Y. Suaifan, A.A.M. Mohammed, Fluoroquinolones structural and medic-
inal developments (2013–2018): where are we now? Bioorg. Med. Chem. 27
(2019) 3005–3060, doi:10.1016/j.bmc.2019.05.038.
[76] R. Bartzatt, S.L.G. Cirillo, J.D. Cirillo, Antibacterial Derivatives of Ciprofloxacin
to Inhibit Growth of Necrotizing Fasciitis Associated Penicillin Resistant Es-
cherichia coli, J. Pharm. 2013 (2013) 1–7, doi:10.1155/2013/517638.
[77] A. Ragab, S.A. Fouad, O.A.A. Ali, E.M. Ahmed, A.M. Ali, A.A. Askar, Y.A. Am-
mar, Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: de-
sign, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bac-
teria as Dual DNA Gyrase and DHFR Inhibitors, Antibiotics 10 (2021) 162,
doi:10.3390/antibiotics10020162.
[78] Ibrahim S. A., Rizk H. F., Aboul-Magd D. S., Ragab A., Design, synthesis of new
magenta dyestuffs based on thiazole azomethine disperse reactive dyes with
antibacterial potential on both dyes and gamma-irradiated dyed fabric, Dyes
and Pigments (2021) In press, doi:10.1016/j.dyepig.2021.109504.
[61] Y.A. Ammar, A.A. Farag, A.M. Ali, A. Ragab, A.A. Askar, D.M. Elsisi, A. Belal, De-
sign, synthesis, antimicrobial activity and molecular docking studies of some
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