Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies

Article abstract of DOI:10.1016/j.bmc.2019.07.035

In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized twenty-five analogs (1–25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase enzyme under positive control acarbose (IC₅₀ = 38.45 ± 0.

Full text of DOI:10.1016/j.bmc.2019.07.035

Accepted Manuscript
Synthesis of quinoline derivatives as diabetic II inhibitors and molecular dock-
ing studies
Muhammad Taha, Sadia Sultan, Syahrul Imran, Fazal Rahim, Khalid Zaman,
Abdul Wadood, Ashfaq Ur Rehman, Nizam Uddin, Khalid Mohammed Khan
PII:
S0968-0896(19)30763-1
https://doi.org/10.1016/j.bmc.2019.07.035
BMC 15019
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 May 2019
17 July 2019
19 July 2019
Please cite this article as: Taha, M., Sultan, S., Imran, S., Rahim, F., Zaman, K., Wadood, A., Ur Rehman, A., Uddin,
N., Mohammed Khan, K., Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies,
Bioorganic & Medicinal Chemistry (2019), doi: https://doi.org/10.1016/j.bmc.2019.07.035
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Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies
Muhammad Tahaa, Sadia Sultanb,c, Syahrul Imranc, Fazal Rahimd, Khalid Zamand, Abdul
Wadoode, Ashfaq Ur Rehmane, Nizam Uddinf, Khalid Mohammed Khang
aDepartment of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman
Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
bFaculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, 42300 Bandar
Puncak Alam, Selangor D. E., Malaysia
cAtta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA Cawangan
Selangor Kampus Puncak Alam, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia.
dDepartment of Chemistry, Hazara University, Mansehra-21300, Pakistan
eDepartment of Biochemistry, Abdul Wali Khan University Mardan, Mardan-23200, Pakistan.
fDepartment of Chemistry, University of Karachi, Karachi 75270, Pakistan.
gH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
Karachi, Karachi-75270, Pakistan
Abstract
In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized
twenty-five analogs (1-25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase
enzyme under positive control acarbose (IC50 = 38.45 ± 0.80 µM). From the activity profile it
was foundthat analogs 1, 2, 3, 4, 11, 12 and 20with IC50values 12.40 ± 0.40, 9.40 ± 0.30, 14.10 ±
0.40, 6.20 ± 0.30, 14.40 ± 0.40, 7.40 ± 0.20 and 13.20 ± 0.40 µMrespectively showed most
potent inhibition among the series even than standard drug acarbose(IC50 = 38.45 ± 0.80 µM).
Here in the present study analog 4 (IC50 = 6.20 ± 0.30 µM)was found with many folds better α-
glucosidase inhibitory activity than the reference drug. Eight analogs like 5, 7, 8, 16, 17, 22, 24
and 25 among the whole series displayed less than 50 % inhibition. The substituents effects on
phenyl ring thereby superficially established through SAR study. Binding interactions of analogs
and the active site of ligands proteins were confirmed through molecular docking study.
Spectroscopic techniques like 1H-NMR, 13C-NMR and ESIMS were used for characterization.
Keywords: quinoline derivatives; Synthesis; diabetic II;α-glucosidase; Molecular docking
1.0. Introduction
Diabetes mellitus is the most common and serious ailment of the 21st century. The survey
report of international diabetes federation shows that there are almost 415 million peoples are
 Correspondence and reprints
E-mail: E-mail: taha_hej@yahoo.com and mtaha@iau.edu.saTel: 00966502057370
1

suffering from thisobstacle. It is characterized by a metabolic disorder, where the body cannot
produceenough insulin resulting in blood glucose level disturbance. High levels of glucose in
blood endorse some severedifficulties to human organs like eyes, nerves, kidneyand heart [1]. In
this regard, the basic strategy to control glucose level in blood is delaying the absorption of
glucose through inhibiting α-glucose enzyme [2].α-glucosidase is an enzyme that hydrolyzed
polysaccharides and disaccharides [3].Dietary carbohydrates are the main reason of the
progression of diabetes mellitus and can be controlled by inhibiting of α-glucosidase
activityresulting in decline postprandial hyperglycemia [4, 5].
Quinoline and their analogs prove its promising potentials as therapeutic agents like anti-
bacterial, anti-fungal [6], anti-cancer [7], anti-convulsant [8], anti-leishmanial [9], anti-malarial
[10] anti-Zaka virus [11], anti-plasmodium [12], anti-proliferative [13], proton pump inhibiters
[14], anti-ulcer [15], anti-trypanosomal [16], anti-inflammatory [17], anti-diabetes [18] anti-
tubercular [19], anti-hypertensive [20] and anti-oxidant agent [21].
In search of lead candidate, our research group has been reported various N-containing
heterocyclic moieties as a potent inhibitor against urease, thymidine phosphorylase, beta-
glucuronidase and α-amylase [25-27]. Our group has already reported quinoline derivatives as α-
glucosidase inhibitor [28]. With the hope to further explore the potential ofquinoline as an α-
glucosidase inhibitor, here in this study we have synthesized twenty-fiveanalogs (1-25) of
quinoline-based Schiff base as a potent class of in vitroα-glucosidase (E. coli) inhibitor.
2.0. Results and Discussion
2.1. Chemistry
Methyl quinoline-6-carboxylate and hydrazine hydrate were reacted in methanol as
solvent and refluxed the reaction mixture for six hrs.To obtained quinoline-6-carbohydarzide.
The intermediate quinoline-6-carbohydarzide was then reacted with various aromatic aldehydes
in ethanol and the reaction mixture was acidified with few drops of glacial acetic acid and
refluxed for 3hrs. to obtained pure product of quinoline-based Schiff base (1-25). (Scheme-1).
All compounds were confirmed as singal isomer by proton nmr unlike the mixtures of isomer
reported [29].
2

O
O
O
NH2
N
O
N
H
N2H4. H2O
RCHO
EtOH
N
H
R
N
MeOH
Rfx, 6 hrs
N
N
Few drops of AcOH
1-25
(
)
Rfx, 3 hrs
Scheme- 1: Synthesis of quinoline-based Schiff base derivatives (1-25)
Table-1:Quinoline based Schiff base derivatives and its α-glucosidase inhibitory activity (1-25)
S.NO
R
IC50 ( µM ± SEMa) S.NO
R
IC50( µM ± SEMa)
OH
1
12.40 ± 0.40
14
28.90 ± 0.60
HO
F
OH
OH
N
N
2
3
9.40 ± 0.30
15
16
38.40 ± 1.00
OH
14.10 ± 0.40
NAb
OH
4
5
6.20 ± 0.30
17
18
NAb
OH
N
OH
NAb
23.50 ± 0.60
3

O
OH
O
NO2
6
7
37.60 ± 0.80
19
20
48.50 ± 1.30
13.20 ± 0.40
OH
OH
NAb
NO2
S
8
9
NAb
21
22
23
35.70 ± 0.80
NO2
OH
18.40 ± 0.50
21.60 ± 0.60
NAb
O
OH
O
10
28.60 ± 0.70
O
11
14.40 ± 0.40
24
NAb
OH
O
O
4

F
12
13
7.40 ± 0.20
25
NAb
O
48.20 ± 1.10
Acarbosec
(Std)
38.45 ± 0.80µM
F
SEMais the standard error mean,NAbnotactive, Acarbosec standard drug for α-glucoscidase
inhibitory activity
2.2. In vitroα-glucosidase activity
The basic goal of our research work is to recognized a lead molecule have a great affinity
toward enzyme inhibitions. With this hope, we have synthesized twenty-five analogs of
quinoline-based Schiff base (1-25) and evaluated for their in vitroα-glucosidase inhibitory
activity under positive control of reference drug acarbose (IC50= 38.45 ± 0.80 µM).The
inhibitory potential of our synthesized analogs with IC50 values ranging between (IC50=6.20 ±
0.30 to -48.20 ± 1.10µM). Analogs 1, 2, 3, 4, 11, 12,and 20 with IC50 value12.40 ± 0.40, 9.40 ±
0.30, 14.10 ± 0.40, 6.20 ± 0.30, 14.40 ± 0.40, 7.40 ± 0.20 and 13.20 ± 0.40 µM respectively
displayed outstanding inhibitory activity many fold better than the standard drug acarbose (IC50=
38.45 ± 0.80 µM). Furthermore analogs 6,9, 10, 14, 18, 21 and 23 with IC50 value37.60 ± 0.80,
18.40 ± 0.50, 21.60 ± 0.60, 28.90 ± 0.60, 23.50 ± 0.60, 35.70 ± 0.80 and 28.60 ± 0.70µM
respectively were found with good inhibitory activity. Analogs13, 15 and 19 (IC50=48.20 ± 1.10,
38.40 ± 1.00 and 48.50 ± 1.30 µM respectively were found in moderate inhibitory potentials,
while analogs 5, 7, 8, 16, 17, 22, 24 and 25were found with potentials less than 50% inhibitions.
SAR study was thereby established to know the effects of substituents on the phenyl ring of
aldehyde toward enzyme inhibitions.
It was observed that analogs with two OH group on phenyl ring displayed
auspiciousinhibitory activity.With this respect analog 4, a 3,4-dihydroxyanalog (IC50 = 6.20 ±
0.30 µM)displayed superior α-glucosidase inhibitory activity among the series. Relocation of
OH-groups from 3 and 4-position and their respective existence to each on phenyl ring decline
5

the inhibitory activity, therefore analog 1,2 and 3 (IC50 = 12.40 ± 0.40, 9.40 ± 0.30and 14.10 ±
0.40 µM) were found with less inhibitory potential than analog 4 (Figure 1).
O
O
N
N
N
H
N
H
OH
OH
OH
N
N
HO
IC50 = 12.40 ± 0.40 µM
1
IC50 = 9.40 ± 0.30 µM
2
O
O
N
N
N
N
H
OH
H
N
N
OH
OH
OH
IC50 = 14.10 ± 0.40 µM
IC50 = 6.20 ± 0.30 µM
3
4
Figure-1:SAR comparison of most potent analogs
If we compared the inhibitory activity of analogs 9, 10 and 11, all contain methoxy and
hydroxyl-group on phenyl ring, but analog 11 (IC50= 14.40 ± 0.40 µM) having OH-group at 3-
position and OMe-group at 4-position was found with much better inhibitory potential than
analog 9 and 10 (IC50= 18.40 ± 0.50 µM and IC50= 21.60 ± 0.60 µM respectively). It was found
out that relocation of one or both groups from 3 and 4-positionon phenyl ring decreases their
inhibitory potentials(Figure 2).
6

O
O
N
N
N
H
N
H
OH
OH
N
N
O
O
IC50 = 18.40 ± 0.50 µM
IC50 = 21.60 ± 0.60µM
9
10
O
N
N
H
N
OH
IC50 = 14.40 ± 0.40 µM
O
11
Figure-2:SAR comparison of potent analogs
In compounds 12-14 the polarity of C-F bond which is useful in enzyme inhibition, but
the attachment position of fluorine atom on phenyl ring play a significant role to inhibit the
enzyme activity. Therefore analog 12 (IC50= 7.40 ± 0.20 µM) have fluorine atom at 2-position on
phenyl ring exhibited more significantα-glucosidase inhibitory activity than analogs13 (IC50=
48.20 ± 1.10 µM) and 14(IC50= 28.90 ± 0.60 µM) that have fluorine atom at 3 and 4-position on
phenyl ring respectively. The more significantα-glucosidase inhibitory activity shown by analog
12 may be due to the position of fluorine atom attached on the phenyl ring.
It was observed through SAR study that isomers of a compound have not equally
inhibited the activity because each isomer has a different affinity toward the active site of ligands
proteins. In heterocyclic compounds the position of heteroatom changed from one isomer to
other isomers directly affects the inhibitory activity. Due to this reason analog 15 (IC50= 38.40 ±
1.00 µM) have nitrogen atom at 2-position on pyridine ring and was found with α-glucosidase
inhibitory potential higher than analog 16 and 17 where the position of nitrogen atom in pyridine
ring changed from 2 to 3 and 4-position on pyridine ring exhibited α-glucosidase inhibitory
activity with less than 50% inhibition.
7

2.3. Docking study
The BD approach was performed to explore the possible binding mode of the synthesized
inhibitors in the binding site other than the substrate binding site due to the non-competitive type
of inhibition of the synthesized derivatives against the α-glucosidase enzyme. Consequently, it
was observed that the top-ranked conformations of all the compounds were well accommodated
in arbitrary cryptic sites, for example; some compounds accommodated in the site-1 and other
wherein site-2 of α-glucosidase enzyme and were involved in various type of interactions with
the active site residues of α-glucosidase enzyme. i.e., Lys126, Phe157, Asn241, and Arg137, etc.
The detail of docking scores and interactions for all the compounds are listed in Table 2. The
docking conformation of the most active compound (compound 1-4) showed four interactions
with the active site residues. The oxygen atom of the hydroxyl moiety of the phenyl ring of the
compound established hydrogen bond with active site residue Lys126and Glu171 (Figure 3B).
Whereas the nitrogen and double bonded oxygen atom of quinoline rings of the compound form
the second hydrogen bond with active site residue Arg137. This strong bonding network might
be one of the reasons for this compound to show the highest activity in the series. If we compare
the structure of compound 4 to 2 and 3, the only difference is the position of hydroxyl moieties at
the phenyl ring. The position of hydroxyl moiety plays a role in the activity of these compounds,
and the docking results showed that the most favorable positions are the -para and -ortho
positions for the hydroxyl moiety. For example, when the hydroxyl moieties are present in -
paraand -orthopositions of the phenyl ring showed more interactions with the active site residues
as compared to the compounds (compound 2) when hydroxyl moieties present at other positions
(Figure 3C). Like the position, the number of hydroxyl moieties also plays a role in the
biological activities of these compounds. For example, when two hydroxyl groups present in the
compounds showed good activities (Table-1) as well as good interactions as compared to the
compounds having a single hydroxyl group (Table-2). The docking conformation of a compound
having methoxy moiety (compound 11) instead of hydroxyl moiety (compound 4) showed fewer
interactions with active site residues as well as less activity (Figure 3D). In case of a compound
having electronegative fluorine-substituted phenyl ring (compound 12) also showed good
biological activity but unexpectedly, this compound showed a smaller number of interactions
with active site residues of the enzyme (Figure 3E). The good activity of this compound might
be due to the strong bonds established by this compound as compared to others (Table 2).
8

Overall the docking results showed that compounds having two OH groups were observed with
more activity and good interactions with compounds having single OH substituted phenyl ring.
As the number of a hydroxyl group, the position of hydroxyl moiety is also crucial for activity.
The electronegative fluorine moiety is favorable for activity whereas the methoxy group is
detrimental for activity. Furthermore, a good correlation was observed between biological
activities and docking scores of these compounds (Table-1 and 2).
Figure-3:The Blind Docked conformations of most active compounds.(A) The surface
representation of the enzyme including two cryptic sites (site-1 & site-2) due to the non-
competitive behavior of the synthesized derivatives. (B)the 3D binding mode of compound
4,(C)for compound 2, (D) for compound 11 and (E) for compound 12 against the α-glucosidase
enzyme.
9

Table 2:Docking scores and report of predicted interactions of docked conformations.
Comp. No. D.scores
(S)
Interaction Report
Ligand
Receptor
Interaction Distance E(kcal/mol)
1
O
N
33
1
O
ASP 349 H-donor
ND2 ASN 241 H-acceptor
N ARG 312 pi-H
3.28
3.25
4.35
-1.3
-0.8
-0.7
-11.8252
6-ring
6-ring
O 33
O 33
O 33
ASP 132
pi-H
4.44
3.1
-1.0
-0.8
-0.9
-1.6
-1.0
-0.9
-1.8
-0.5
-1.7
-12.8423
2
N
N
O
ARG 137 H-donor
ARG 137 H-donor
ASP 349 H-donor
2.3
3
4
-11.8883
-11.9182
3.10
4.46
3.3
6-ring CB ARG 312 pi-H
O 26
O 25
O 14
O14
CG LYS 126
CG GLU`171
H-acceptor
H- donor
3.5
NH2ARG 137 H-donor
NH2 ARG 137 H-donor
NA
3.4
2.4
5
6
-11.5449
-11.5208
O 35 NE2 HIS 348 H-acceptor
3.34
3.68
-1.4
-0.0
6-ring
6-ring PHE300 pi-pi
7
8
9
NA
NA
O 18 CD ARG 439 H-acceptor
6-ring ARG 312 pi-H
N 19 OD2 ASP408 H-donor
3.30
-0.9
N
4.56
3.40
2.3
-0.9
-0.5
-1.6
-1.4
-2.4
-0.5
-0.0
-4.1
-0.0
10
11
-11.8106
-11.3226
O 25
6-ring
0 13
6-ring
6-ring
N 1
O
PRO
H-donor
CA PHE 177 pi-H
pi-H
2.2
12
-10.7830
ND2 ASN241 H-acceptor
CA PHE 157
H-pi
4.58
3.59
2.99
3.54
13
14
-10.9461
-11.1485
6-ring PHE300 pi-pi
ND2 ASN347 H-acceptor
6-ring 6-ring PHE157 H-acceptor
10

15
-10.1818
-11.8110
6-ring
6-ring PHE157
pi-pi
3.89
-0.0
16
17
18
NA
NA
N 1
ND2 ASN241 H-acceptor
3.15
3.55
-2.3
-0.0
6-ring
6-
pi-pi
ringPHE1570
19
20
-9.3442
N 1
ND2 ASN241 H-acceptor
3.42
3.17
3.74
3.58
-1.1
-1.6
-0.0
-0.0
-10.4988
O 34 OD2 ASP349 H-donor
6-ring
5-ring
6-ring PHE300 pi-pi
6-ring PHE300 pi-pi
NA
21
-10.4347
-10.5880
22
23
N 19 OD2 ASP349 H-donor
3.64
3.58
-1.0
-0.0
5-ring
6-ring PHE300 pi-pi
24
25
NA
NA
3.0. Conclusion
Twenty five analogs (1-25) of quinoline based schiff bases have been synthesized and evaluated
for their in vitroα-glucosidase inhibitory activity in the presence of reference drug acarbsoe. All
analogs displayed inhibitory actvity in range beween 6.20 ± 0.30 to 48.50 ± 1.30 µM. Here in
the present study analogs 4 with two OH-groups and analog 12 with F-group as substituents
emerged the most potent analogs among the series. The substitution effect on aromatic residue of
aldehyde was estimated through SAR study. Ligands Protein and analogs binding interaction was
confirmed through molecular docking study.
4.0 General Method
All nuclear magnetic resonance experiments had been carried out using on Avance Bruker 500
MHz. Elemental analysis was performed on Carlo Erba Strumentazion-Mod-1106, Italy.
Electron impact mass spectra (EI-MS) were recorded on a Finnigan MAT-311A, Germany. Thin
layer chromatography (TLC) was performed on pre-coated silica gel aluminum plates (Kieselgel
60, 254, E. Merck, Germany). Chromatograms were visualized by UV at 254 and 365 nm.
11

4.1. Syntheis of quinoline-6-carbohydrazide
Methyl quinoline-6-carboxylate (20 mmoL) were refluxed with excess amount of hydrazine
hydrate in absolute methano for six hrs to achieved quinoline-6-carbohydrazide. The reaction
completion was monitored by TLC. After completion of the reaction the reaction mixture in
round bottom flask placed in cold water till to crystals formation and then filtered to obatained
pure product.
4.2. Syntheis of N'-benzylidenequinoline-6-carbohydrazides
Quinoline-6-carbohydrazide (1 mmoL) were reacted with different substitueted aromatic
aldehydes (1 mmoL) in absolute ethanole (20 mL) as solvent. After complete dissolution of
reactants, the solution was acidified by few drops of glacial acetic acid and then refluxed the
reaction mixture for three hrs. After completion of the reaction solvent was evaporated through
rotavapour and the pure products (1-25) were crytalized from methanol.
4.2.1 N'-(2,5-dihydroxybenzylidene)quinoline-6-carbohydrazide (1)
1H NMR (500 MHz, DMSO-d6): 12.22 (s, 1H, NH), 10.35 (s, 1H, OH), 9.03 (dd, 1H, J = 1.5, J
= 4.0 Hz), 8.99 (s, 1H, OH), 8.65 (s, 1H, CH=N), 8.63 (d, 1H, J = 1.0 Hz), 8.54 (d, 1H, J = 8.0
Hz), 8.27 (dd, 1H, J = 2.0, J = 9.0 Hz), 8.17 (d, 1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0
13
Hz), 7.04 (d, 1H, J = 2.5 Hz), 6.80 - 6.76 (m, 2H); C NMR (150 MHz, DMSO-d6):163.1,
153.4, 152.1, 151.0, 146.9, 146.0, 137.5, 134.2, 130.1, 129.3, 129.1, 127.5, 122.1, 120.1, 119.6,
119.3, 116.1. HR-ESI-MS: m/z calcd for C17H13N3O3, [M+ H]+ 308.1035; Found 308.1417.
Anal. Calcd for C17H13N3O3, C = 66.44, H = 4.26, N = 13.67, O = 15.62, found C = 66.47, H =
4.27, N = 13.68.
4.2.2. N'-(2,3-dihydroxybenzylidene)quinoline-6-carbohydrazide (2)
1H NMR (500 MHz, DMSO-d6): 12.35 (s, 1H, NH), 11.11 (s, 1H, OH), 9.25 (s, 1H, OH), 9.04
(dd, 1H, J = 1.5, J = 4.0 Hz), 8.67 (s, 1H, CH=N), 8.64 (d, 1H, J = 1.0 Hz), 8.56 (d, 1H, J = 8.0
Hz), 8.27 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.18 (d, 1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0
13
Hz), 7.03 (d, 1H, J = 7.0 Hz), 6.90(d, 1H, J = 7.5 Hz), 6.79 (t, 1H, J = 8.0, J = 15.5 Hz); C
12

NMR (150 MHz, DMSO -d6):163.2, 152.2, 151.5, 147.3, 146.3, 146.1, 137.4, 134.3, 130.2,
129.4, 129.1, 127.4, 124.4, 122.5, 122.1, 119.5, 119.4. HR-ESI-MS: m/z calcd for C17H13N3O3,
[M+ H]+ 308.1035; Found 308.1173. Anal. Calcd for C17H13N3O3, C = 66.44, H = 4.26, N =
13.67, O = 15.62, found C = 66.48, H = 4.25, N = 13.69.
4.2.3 N'-(2,4-dihydroxybenzylidene)quinoline-6-carbohydrazide (3)
1H NMR (500 MHz, DMSO-d6): 12.15 (s, 1H, NH), 11.44 (s, 1H, OH), 9.99 (s, 1H, OH), 9.03
(dd, 1H, J = 1.5, J = 4.0 Hz), 8.61 (d, 1H, J = 1.0 Hz), 8.57 (s, 1H, CH=N), 8.54 (d, 1H, J = 8.0
Hz), 8.25 (dd, 1H, J = 2.0, J = 9.0 Hz), 8.16 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.5, J = 8.5
13
Hz), 7.37 (d, 1H, J = 8.5 Hz), 6.40 (dd, 1H, J = 2.0, J = 8.5 Hz), 6.35 (d, 1H, J = 2.0 Hz); C
NMR (150 MHz, DMSO -d6):163.3, 162.3, 162.1, 152.1, 147.2, 146.0, 137.6, 134.5, 133.4,
130.3, 129.3, 129.2, 127.3, 122.3, 110.9, 108.3, 103.5. HR-ESI-MS: m/z calcd for C17H13N3O3,
[M+ H]+ 308.1035; Found 308.1131. Anal. Calcd for C17H13N3O3, C = 66.44, H = 4.26, N =
13.67, O = 15.62, found C = 66.45, H = 4.28, N = 13.67.
4.2.4 N'-(3,4-dihydroxybenzylidene)quinoline-6-carbohydrazide (4)
1H NMR (500 MHz, DMSO-d6): 11.85 (s, 1H, NH), 9.34 (s, 2H, 2 x OH), 9.02 (dd, 1H, J = 1.5,
J = 4.0 Hz), 8.58 (d, 1H, J = 1.5 Hz), 8.54 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.32 (s, 1H, CH=N),
8.23 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.15 (d, 1H, J = 8.5 Hz), 7.66 (dd, 1H, J = 4.0, J = 3.0 Hz),
7.29 (d, 1H, J = 2.0 Hz), 6.99 (dd, 1H, J = 2.0, J = 8.0 Hz), 6.82 (d, 1H, J = 8.0 Hz). 13C NMR
(150 MHz, DMSO -d6):163.2, 152.3, 149.4, 147.4, 146.5, 146.2, 137.5, 134.3, 131.1, 130.2,
129.4, 129.0, 127.5, 123.1, 122.2, 117.2, 116.1; HR-ESI-MS: m/z calcd for C17H13N3O3, [M+
H]+ 308.1035; Found 308.1400. Anal. Calcd for C17H13N3O3, C = 66.44, H = 4.26, N = 13.67, O
= 15.62, found C = 66.45, H = 4.28, N = 13.68.
4.2.5 N'-(3,4-dimethoxybenzylidene)quinoline-6-carbohydrazide (5)
1H NMR (500 MHz, DMSO-d6): 11.97 (s, 1H, NH), 9.03 (t, 1H, J = 3.0, J = 4.0 Hz), 8.59 (s,
1H, CH=N), 8.55 (d, 1H, J = 8.0 Hz), 8.44 (s, 1H), 8.24 (d, 1H, J = 9.5 Hz), 8.16 (d, 1H, J = 9.0
Hz), 7.66 (dd, 1H, J = 4.5, J = 8.5 Hz), 7.39 (s, 1H), 7.26 (d, 1H, J = 8.0 Hz), 7.07 (d, 1H, J =
13
8.5 Hz), 3.85 (s, 3H, OCH3), 3.83 (s, 3H, OCH3); C NMR (150 MHz, DMSO -d6):163.4,
152.3, 152.1, 149.5, 146.5, 147.1, 137.4, 134.3, 130.3, 130.2, 129.3, 129.1, 127.5, 122.4, 122.2,
13

111.5, 108.9, 55.9, 55.9. HR-ESI-MS: m/z calcd for C19H17N3O3, [M+ H]+ 336.3645; Found
336.1498. Anal. Calcd for C19H17N3O3, C = 68.05, H = 5.11, N = 12.53, O = 14.31, found C =
68.07, H = 5.12, N = 12.55.
4.2.6 N'-(2-nitrobenzylidene)quinoline-6-carbohydrazide (6)
1H NMR (500 MHz, DMSO-d6): 12.45 (s, 1H, NH), 9.04 (d, 1H, J = 3.0 Hz), 8.94 (s, 1H,
CH=N), 8.65 (s, 1H), 8.56 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.27 (d, 1H, J = 9.0 Hz), 8.20 (dd, 2H, J
= 8.0, J = 12.5 Hz), 8.12 (d, 1H, J = 7.5 Hz), 7.88 (t, 1H, J = 7.0, J = 14.5 Hz), 7.73 (t, 1H, J =
13
7.0, J = 15.0 Hz), 7.68 (dd, 1H, J = 4.0, J = 8.0 Hz); C NMR(150 MHz, DMSO -d6):163.2,
152.2, 147.5, 147.3, 143.1, 137.5, 134.4, 134.3, 131.7, 130.2, 130.1, 129.3, 129.1, 128.1, 127.4,
123.9, 122.1. HR-ESI-MS: m/z calcd for C17H12N4O3, [M+ H]+ 321.0988; Found 320.1247.
Anal. Calcd for C17H12N4O3, C = 63.75, H = 3.78, N = 17.49, O = 14.98, found C = 63.76, H =
3.79, N = 17.50.
4.2.7 N'-(3-nitrobenzylidene)quinoline-6-carbohydrazide (7)
1H NMR (500 MHz, DMSO-d6): 12.36 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5 J = 4.0 Hz), 8.63 (s,
1H, CH=N), 8.60 (s, 2H), 8.56 (t, 1H, J = 1.0, J = 8.5 Hz), 8.30 - 8.20 (m, 3H), 8.18 (d, 1H, J =
8.5 Hz), 7.81 (t, 1H, J = 8.0, J = 16.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz); 13C NMR (150
MHz, DMSO -d6):163.4, 152.1, 148.3, 147.2, 146.4, 137.5, 134.3, 134.2, 132.3, 130.1, 129.5,
129.3, 129.1, 127.4, 126.1, 122.2, 121.3. HR-ESI-MS: m/z calcd for C17H12N4O3, [M+ H]+
321.0988; Found 321.1098. Anal. Calcd for C17H12N4O3, C = 63.75, H = 3.78, N = 17.49, O =
14.98, found C = 63.78, H = 3.79, N = 17.48.
4.2.8 N'-(4-nitrobenzylidene)quinoline-6-carbohydrazide (8)
1H NMR (500 MHz, DMSO-d6): 12.36 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5 J = 4.0 Hz), 8.63 (s,
1H, CH=N), 8.60 (s, 2H), 8.56 (t, 1H, J = 1.0, J = 8.5 Hz), 8.30 - 8.20 (m, 3H), 8.18 (d, 1H, J =
8.5 Hz), 7.81 (t, 1H, J = 8.0, J = 16.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz); 13C NMR(150
MHz, DMSO -d6):163.3, 152.3, 149.9, 147.1, 146.5, 138.9, 137.6, 134.2, 130.1, 129.2, 129.1,
127.4, 123.9, 123.9, 123.7, 127.7, 122.1. HR-ESI-MS: m/z calcd for C17H12N4O3, [M+ 2H]+
322.1066; Found 322.11584. Anal. Calcd for C17H12N4O3, C = 63.75, H = 3.78, N = 17.49, O =
14.98, found C = 63.76, H = 3.79, N = 17.49.
14

4.2.9 N'-(2-hydroxy-5-methoxybenzylidene)quinoline-6-carbohydrazide (9)
1H NMR (500 MHz, DMSO-d6): 12.31 (s, 1H, NH), 10.66 (s, 1H, OH), 9.04 (dd, 1H, J = 1.5, J
= 4.0 Hz), 8.70 (s, 1H, CH=N), 8.63 (d, 1H, J = 1.0 Hz), 8.55 (d, 1H, J = 8.0 Hz), 8.27 (dd, 1H, J
= 1.5, J = 8.5 Hz), 8.17 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.18 (d, 1H, J =
13
3.0 Hz), 6.95 (dd, 1H, J = 2.5, J = 8.5 Hz), 6.90 (d, 1H, J = 9.0 Hz), 3.76 (s, 3H, OCH3); C
NMR(150 MHz, DMSO -d6):163.2, 153.5, 153.1, 152.2, 147.3, 146.2, 137.4, 134.3, 130.2,
129.3, 129.1, 127.5, 122.2, 118.9, 118.3, 117.2, 113.1, 55.8. HR-ESI-MS: m/z calcd for
C18H15N3O3, [M+ H]+ 322.1192; Found 322.1334. Anal. Calcd for C18H15N3O3, C = 67.28, H =
4.71, N = 13.08, O = 14.94, found C = 67.30, H = 4.72, N = 13.09.
4.2.10 N'-(2-hydroxy-4-methoxybenzylidene)quinoline-6-carbohydrazide (10)
1H NMR (500 MHz, DMSO-d6): 12.23 (s, 1H, NH), 11.59 (s, 1H, OH), 9.04 (dd, 1H, J = 1.5, J
= 4.5 Hz), 8.62 (s, 2H, CH=N, H-6), 8.55 (d, 1H, J = 8.0 Hz), 8.26 (dd, 1H, J = 2.0, J = 9.0 Hz),
8.17 (d, 1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.5 Hz), 7.49 (d, 1H, J = 8.5 Hz), 6.57 (dd,
13
1H, J = 2.0, J = 8.5 Hz), 6.53 (d, 1H, J = 2.0 Hz), 3.80 (s, 3H, OCH3); C NMR (150 MHz,
DMSO -d6):164.4, 163.3, 162.1, 152.3, 147.1, 146.0, 137.5, 134.4, 133.3, 130.1, 129.4, 129.2,
127.3, 122.1, 109.9, 106.8, 103.1, 55.8. HR-ESI-MS: m/z calcd for C18H15N3O3, [M+ H]+
322.1192; Found 321.1379. Anal. Calcd for C18H15N3O3, C = 67.28, H = 4.71, N = 13.08, O =
14.94, found C = 67.29, H = 4.73, N = 13.10.
4.2.11 N'-(3-hydroxy-4-methoxybenzylidene)quinoline-6-carbohydrazide (11)
1H NMR (500 MHz, DMSO-d6): 11.91 (s, 1H, NH), 9.32 (s, 1H, OH), 9.03 (dd, 1H, J = 1.5, J =
4.0 Hz), 8.59 (s, 1H, CH=N), 8.54 (t, 1H, J = 7.5, J = 8.0 Hz), 8.36 (s, 1H), 8.24 (dd, 1H, J = 1.0,
J = 8.5 Hz), 8.15 (d, 1H, J = 9.0 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.5 Hz), 7.32 (s, 1H), 7.11 (t, 1H,
J = 6.5, J = 8.0 Hz), 7.01 (d, 1H, J = 8.5 Hz), 3.83 (s, 3H, OCH3); 13C NMR (150 MHz, DMSO -
d6):163.4, 152.2, 152.1, 147.3, 147.1, 146.5, 137.6, 134.2, 131.0, 130.1, 129.3, 129.2, 127.2,
122.5, 122.1, 115.6, 112.1, 55.9. HR-ESI-MS: m/z calcd for C18H15N3O3, [M+ H]+ 322.1192;
Found 322.1319. Anal. Calcd for C18H15N3O3, C = 67.28, H = 4.71, N = 13.08, O = 14.94, found
C = 67.27, H = 4.73, N = 13.09.
15

4.2.12 N'-(2-fluorobenzylidene)quinoline-6-carbohydrazide (12)
1H NMR (500 MHz, DMSO-d6): 12.22 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.77 (s,
1H, CH=N), 8.63 (s, 1H), 8.55 (t, 1H, J = 7.5, J = 8.5 Hz), 8.26 (d, 1H, J = 8.5 Hz), 8.17 (d, 1H,
J = 9.0 Hz), 8.02 (t, 1H, J = 7.0, J = 14.0 Hz), 7.67 (dd, 1H, J = 4.5, J = 8.5 Hz), 7.55 (dd, 1H, J
= 6.5, J = 13.5 Hz), 7.35 (dd, 2H, J = 7.0, J = 11.0 Hz). 13C NMR (150 MHz, DMSO -d6):163.3,
159.3, 152.3, 147.1, 143.5, 137.4, 134.3, 132.2, 130.6, 130.3, 129.3, 129.1, 127.4, 123.7, 122.3,
117.9, 115.2. HR-ESI-MS: m/z calcd for C17H12FN3O, [M+ H]+294.1043; Found 294.1504.
Anal. Calcd for C17H12FN3O, C = 69.62, H = 4.12, F = 6.48, N = 14.33, O = 5.45, found C =
69.65, H = 4.14, N = 14.35.
4.2.13 N'-(3-fluorobenzylidene)quinoline-6-carbohydrazide (13)
1H NMR (500 MHz, DMSO-d6): 12.21 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.62 (s,
1H, CH=N), 8.56 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.52 (s, 1H), 8.25 (d, 1H, J = 8.5 Hz), 8.17 (d,
1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.5 Hz), 7.63 (d, 1H, J = 7.5 Hz), 7.59 (d, 1H, J = 10.5
Hz), 7.55 (t, 1H, J = 6.5, J = 13.5 Hz), 7.32 (t, 1H, J = 7.5, J = 15.5 Hz); 13C NMR (150 MHz,
DMSO -d6):163.3, 163.1, 152.2, 147.4, 146.5, 137.3, 134.9, 134.3, 130.1, 130.1, 129.2, 128.9,
127.5, 124.3, 122.1, 117.6, 113.9. HR-ESI-MS: m/z calcd for C17H12FN3O, [M+ H]+294.1043;
Found 294.1277. Anal. Calcd for C17H12FN3O, C = 69.62, H = 4.12, F = 6.48, N = 14.33, O =
5.45, found C = 69.64, H = 4.15, N = 14.34.
4.2.14 N'-(4-fluorobenzylidene)quinoline-6-carbohydrazide (14)
1H NMR (500 MHz, DMSO-d6): 12.11 (s, 1H, NH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.61 (s,
1H, CH=N), 8.54 (d, 1H, J = 1.0 Hz), 8.53 (d, 1H, J = 3.5 Hz), 8.25 (d, 1H, J = 8.5 Hz), 8.16 (d,
1H, J = 8.5 Hz), 7.85 (t, 2H, J = 7.5, J = 13.5 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.34 (t, 2H,
J = 9.0, J = 17.5 Hz); 13C NMR (150 MHz, DMSO -d6):164.9, 163.1, 152.1, 145.4, 142.9, 136.8,
134.3, 130.6, 130.3, 130.3, 129.1, 129.0, 128.9, 127.6, 122.2, 115.3, 115.2. HR-ESI-MS: m/z
calcd for C17H12FN3O, [M+ H]+294.1043; Found 294.1329. Anal. Calcd for C17H12FN3O, C =
69.62, H = 4.12, F = 6.48, N = 14.33, O = 5.45, found C = 69.63, H = 4.13, N = 14.36.
4.2.15 N'-(pyridin-2-ylmethylene)quinoline-6-carbohydrazide (15)
16

1H NMR (500 MHz, DMSO-d6): 12.30 (s, 1H, NH), 9.04 (dd, 1H, J = 1.0, J = 4.0 Hz), 8.64 (s,
2H, CH=N, H-6),8.57 (d, 2H, J = 10.0 Hz), 8.26 (d, 1H, J = 8.5 Hz), 8.18 (d, 1H, J = 9.0 Hz),
8.04 (d, 1H, J = 7.5 Hz), 7.93 (t, 1H, J = 7.5, J = 15.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.5 Hz),
13
7.46 (t, 1H, J = 6.0, J = 11.5 Hz). C NMR (150 MHz, DMSO -d6):163.2, 153.3, 152.2, 148.9,
145.3, 138.8,137.5, 136.1, 134.3, 130.1, 129.2, 129.1, 127.4, 125.8, 123.5, 122.3. . HR-ESI-MS:
m/z calcd for C16H12N4O, [M+ H]+ 277.1089; Found 277.1041. Anal. Calcd for C16H12N4O, C =
69.55, H = 4.38, N = 20.28, O = 5.79, found C = 69.59, H = 4.39, N = 20.30.
4.2.16 N'-(pyridin-3-ylmethylene)quinoline-6-carbohydrazide (16)
1H NMR (500 MHz, DMSO-d6): 12.26 (s, 1H, NH), 9.03 (dd, 1H, J = 1.5, J = 4.5 Hz), 8.91 (s,
1H, CH=N),8.65 (d, 1H, J = 4.0 Hz), 8.62 (s, 1H), 8.57 (s, 1H), 8.55 (dd, 1H, J = 1.0, J = 8.0
Hz), 8.25 (d, 1H, J = 8.5 Hz), 8.20 (dd, 2H, J = 7.5, J = 16.0 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0
Hz), 7.53 (dd, 1H, J = 5.0, J = 7.0 Hz); 13C NMR (150 MHz, DMSO -d6):163.2, 152.2, 152.0,
150.9, 145.3, 142.9, 137.5, 137.3, 134.2, 130.2, 130.1, 129.3, 129.1, 127.4, 123.9, 122.3. HR-
ESI-MS: m/z calcd for C16H12N4O, [M+ H]+ 277.1089; Found. 277.1098. Anal. Calcd for
C16H12N4O, C = 69.55, H = 4.38, N = 20.28, O = 5.79, found C = 69.57, H = 4.41, N = 20.29.
4.2.17 N'-(pyridin-4-ylmethylene)quinoline-6-carbohydrazide (17)
1H NMR (500 MHz, DMSO-d6): 12.37 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.68 (s,
2H), 8.63 (s, 1H, CH=N),8.56 (d, 1H, J = 8.0 Hz), 8.51 (s, 1H), 8.25 (d, 1H, J = 8.5 Hz), 8.17 (d,
1H, J = 9.0 Hz), 7.72 (s, 2H), 7.67 (dd, 1H, J = 4.0, J = 8.5 Hz); 13C NMR (150 MHz, DMSO -
d6):163.0, 152.3, 149.5, 149.5, 145.6, 144.3, 143.0, 137.8, 134.6, 130.3, 129.6, 129.2, 127.7,
124.1, 124.1, 122.2. HR-ESI-MS: m/z calcd for C16H12N4O, [M+ H]+ 277.1089; Found
276.1009. Anal. Calcd for C16H12N4O, C = 69.55, H = 4.38, N = 20.28, O = 5.79, found C =
69.58, H = 4.40, N = 20.31.
4.2. 18 N'-(4-hydroxybenzylidene)quinoline-6-carbohydrazide (18)
1H NMR (500 MHz, DMSO-d6): 11.91 (s, 1H, NH), 9.97 (s, 1H, OH), 9.02 (t, 1H, J = 2.5, J =
4.0 Hz), 8.59 (s, 1H, CH=N), 8.53 (d, 1H, J = 8.0 Hz), 8.42 (s, 1H), 8.24 (t, 1H, J = 8.0, J = 9.0
Hz), 8.15 (d, 1H, J = 8.5 Hz), 7.65 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.62 (d, 2H, J = 8.5 Hz), 6.88(d,
13
2H, J = 8.5 Hz); C NMR (150 MHz, DMSO -d6):163.3, 160.5, 152.1, 145.3, 142.9, 137.3,
17

134.2, 130.3, 130.2, 130.0, 129.2, 129.1, 127.5, 126.3, 122.1, 115.9, 115.9. HR-ESI-MS: m/z
calcd for C17H13N3O2, [M+ H]+ 292.1086; Found 292.1468. Anal. Calcd for C17H13N3O2, C =
70.09, H = 4.50, N = 14.42, O = 10.98, found C = 70.11, H = 4.51, N = 14.44.
4.2.19 N'-(3-hydroxybenzylidene)quinoline-6-carbohydrazide (19)
1H NMR (500 MHz, DMSO-d6): 12.04 (s, 1H, NH), 9.66 (s, 1H, OH), 9.03 (dd, 1H, J = 1.5, J =
4.0 Hz), 8.61 (s, 1H, CH=N), 8.54 (d, 1H, J = 8.0 Hz), 8.43 (s, 1H), 8.25 (d, 1H, J = 9.0 Hz),
8.16 (d, 1H, J = 9.0 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.30 (d, 1H, J = 7.5 Hz), 7.27 (d, 1H,
13
J = 5.0 Hz), 7.15 (d, 1H, J = 7.5 Hz), 6.87(d, 1H, J = 7.0 Hz); C NMR (150 MHz, DMSO -
d6):163.3, 158.3, 152.2, 145.2, 142.8, 137.5, 134.9, 134.3, 130.4, 130.2, 129.1, 129.0, 127.4,
122.0, 121.5, 117.9, 114.8. HR-ESI-MS: m/z calcd for C17H13N3O2, [M+ H]+ 292.1086;Found
292.1528. Anal. Calcd for C17H13N3O2, C = 70.09, H = 4.50, N = 14.42, O = 10.98, found C =
70.10, H = 4.52, N = 14.43.
4.2.20 N'-(2-hydroxybenzylidene)quinoline-6-carbohydrazide (20)
1H NMR (500 MHz, DMSO-d6): 12.30 (s, 1H, NH),11.26 (s, 1H, OH), 9.04 (dd, 1H, J = 1.5, J
= 4.0 Hz), 8.72 (s, 1H, CH=N), 8.64 (s, 1H), 8.55 (d, 1H, J = 8.0 Hz), 8.27 (dd, 1H, J = 1.5, J =
8.5 Hz), 8.18 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.61 (d, 1H, J = 7.5 Hz),
13
7.35 (dd, 1H, J = 1.0, J = 8.0 Hz), 6.98 (dd, 2H, J = 8.0, J = 13.5 Hz); C NMR (150 MHz,
DMSO -d6):163.2, 160.9, 152.2, 145.3, 142.7, 137.4, 134.3, 132.2, 130.3, 130.1, 129.3, 129.1,
127.5, 122.1, 121.2, 118.3, 115.8. HR-ESI-MS: m/z calcd for C17H13N3O2, [M+ H]+ 292.1086;
Found 292.1334. Anal. Calcd for C17H13N3O2, C = 70.09, H = 4.50, N = 14.42, O = 10.98, found
C = 70.10, H = 4.52, N = 14.45.
4.2.21 N'-(thiophen-2-ylmethylene)quinoline-6-carbohydrazide (21)
1H NMR (500 MHz, DMSO-d6): 12.05 (s, 1H, NH), 9.02 (t, 1H, J = 2.5, J = 4.0 Hz), 8.72 (s,
1H, CH=N), 8.58 (s, 1H),8.54 (d, 1H, J = 8.0 Hz), 8.23 (d, 1H, J = 9.0 Hz), 8.16 (d, 1H, J = 9.0
Hz), 7.71 (d, 1H, J = 4.5 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.52 (d, 1H, J = 2.5 Hz), 7.18 (t,
1H, J = 4.5, J = 8.0 Hz); 13C NMR (150 MHz, DMSO -d6):163.4, 152.4, 145.2, 144.1, 137.6,
134.2, 130.1, 129.2, 129.0, 127.3, 127.1, 127.1, 125.3, 125.1, 122.2. HR-ESI-MS: m/z calcd for
18

C15H11N3OS, [M+ H]+ 282.0701; Found 282.0889. Anal. Calcd for C15H11N3OS, C = 64.04, H =
3.94, N = 14.94, O = 5.69, S = 11.40 found C = 64.05, H = 3.96, N = 14.97.
4.2.22 N'-(2,6-dimethylbenzylidene)quinoline-6-carbohydrazide (22)
1H NMR (500 MHz, DMSO-d6): 12.03 (s, 1H, NH), 9.03 (d, 1H, J = 3.0 Hz), 8.85 (s, 1H,
CH=N), 8.62 (s, 1H), 8.56 (d, 1H, J = 8.0 Hz), 8.26 (t, 1H, J = 7.5, J = 9.0 Hz), 8.17 (d, 1H, J =
8.5 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.5 Hz), 7.23 (t, 1H, J = 7.5, J = 15.0 Hz), 7.14 (d, 2H, J = 7.5
Hz), 2.52 (s, 3H, CH3), 2.49 (s, 3H, CH3); 13C NMR (150 MHz, DMSO -d6):163.3, 152.2, 145.2,
142.9, 138.4, 138.2, 137.5, 134.3, 130.5, 130.1, 129.4, 129.1, 127.4, 125.8, 125.3, 125.2, 122.1,
17.8, 17.8. HR-ESI-MS: m/z calcd for C19H17N3O, [M+ H]+304.1450; Found 304.1634. Anal.
Calcd for C19H17N3O, C = 75.23, H = 5.65, N = 13.85, O = 5.27 found C = 75.26, H = 5.67, N =
13.86.
4.2.23 N'-(furan-2-ylmethylene)quinoline-6-carbohydrazide (23)
1H NMR (500 MHz, DMSO-d6): 12.04 (s, 1H, NH), 9.03 (t, 1H, J = 2.5, J = 4.0 Hz), 8.59 (s,
1H, CH=N), 8.54 (d, 1H, J = 8.0 Hz), 8.40 (s, 1H),8.23 (d, 1H, J = 8.5 Hz), 8.16 (d, 1H, J = 8.5
13
Hz), 7.88 (s, 1H), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 6.99 (d, 1H, J = 2.5 Hz), 6.67 (s, 1H); C
NMR (150 MHz, DMSO -d6):163.2, 152.1, 148.8, 145.4, 143.6, 137.4, 134.3, 134.2, 130.1,
129.2, 129.1, 127.3, 122.3, 109.5, 109.2. HR-ESI-MS: m/z calcd for C15H11N3O2, [M+ H]+
266.093; Found 266.1123. Anal. Calcd for C15H11N3O2, C = 67.92, H = 4.18, N = 15.85, O =
12.06, found C = 67.94, H = 4.20, N = 15.88.
4.2.24 N'-(4-methoxybenzylidene)quinoline-6-carbohydrazide (24)
1H NMR (500 MHz, DMSO-d6): 11.96 (s, 1H, NH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.59 (s,
1H, CH=N), 8.54 (t, 1H, J = 7.0, J = 8.5 Hz), 8.46 (s, 1H), 8.24 (d, 1H, J = 8.5 Hz), 8.16 (d, 1H,
J = 9.0 Hz), 7.73 (d, 1H, J = 8.5 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.06 (d, 1H, J = 8.5 Hz),
13
3.83 (s, 3H, OCH3); C NMR (150 MHz, DMSO -d6):163.3, 163.1, 152.3, 145.5, 142.9, 137.6,
134.3, 130.4, 130.1, 130.0, 129.2, 129.1, 127.4, 125.8, 122.0, 114.1, 114.1, 55.9. HR-ESI-MS:
m/z calcd for C18H15N3O2, [M+ H]+306.1243; Found 306.1432. Anal. Calcd for C18H15N3O2, C =
70.81, H = 4.95, N = 13.76, O = 10.48, found C = 70.84, H = 4.96, N = 13.78.
4.2.25 N'-(3-methoxybenzylidene)quinoline-6-carbohydrazide (25)
19

1H NMR (500 MHz, DMSO-d6): 12.11 (s, 1H, NH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.61 (s,
1H, CH=N), 8.55 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.49 (s, 1H), 8.25 (d, 1H, J = 9.0 Hz), 8.16 (d,
1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.43 (t, 1H, J = 8.0, J = 16.0 Hz), 7.34 (d, 2H,
13
J = 6.0 Hz), 7.05 (d, 1H, J = 7.0 Hz), 3.84 (s, 3H, OCH3); C NMR (150 MHz, DMSO -
d6):163.3, 160.4, 152.3, 145.3, 142.8, 137.5 , 134.5, 134.4, 130.1, 129.4, 129.2,129.1, 127.3,
122.1, 121.2, 116.3, 113.1, 55.9. HR-ESI-MS: m/z calcd for C18H15N3O2, [M+ H]+ 306.1243;
Found 306.1450. Anal. Calcd for C18H15N3O2, C = 70.81, H = 4.95, N = 13.76, O = 10.48, found
C = 70.83, H = 4.97, N = 13.77.
4.3. α-glucosidase assay
The a-glucosidase inhibition assay had been carried out using Baker’s yeast a-glucosidase (EC
3.2.1.20) and p-nitrophenyl-α-D-glucopyranoside. The samples (5 mg/mL) were prepared by
dissolving all compounds (1–25) in DMSO. Test samples (10 mL) which had been prepared
were reconstituted in 100 mL of phosphate buffer (100 mM) at pH 6.8 in 96-well micro-plate
and incubated with 50 mL of Baker’s yeast a-glucosidase for 5 min before 50 mL of p-
nitrophenyl-a-D-glucopyranoside (5 mM) was added. After incubating for 5 min, the absorbance
was measured at 405 nm using Spectra Max plus384 (Molecular Devices Corporation,
Sunnyvale, CA, USA). Blank in which the substrate was changed with 50 mL of buffer were
analyzed to accurately determine the background absorbance. Positive control sample (acarbose)
was prepared to contain 10 mL DMSO instead of test samples.
4.4. Molecular docking
Blind docking (BD) approach was performed using MOE-dock module implemented in
Molecular Operating Environment (MOE) software packageof all the non-competitive type
synthesized derivatives against α-glucosidase enzyme. Due to the unavailability of
20

crystallographic structure of the corresponding enzyme, we used the homology modelling
structural coordinates described by Taha M et al [28]for α-glucosidase enzyme. Next, the whole
protein was considered as a binding site for the purpose of BD. Briefly, the homology model was
subjected for 3D protonation and energy minimization up to 0.05 Gradient using MMFF94s
forcefield implemented in MOE software. The 3D structures were built by using Molecular
Builder Module in MOE. All the derivatives were then docked using the whole protein as a
binding site and total 50 different conformations for each inhibitor allowed to generate. The
ligands be flexible during docking, so that to obtain minimal energy complex. Later, the docked
complexes were ranked based on the docking scores (S). Finally, the predicted ligand-protein
complexes were analyzed for molecular interactions usingPyMol v 1.7.
Acknowledgments
Dr. Sadia would like to thanks UiTM Malaysia for faculty support fund. Dr. Taha would like to
thanks Imam Abdulrahman Bin Faisal University for a research facility.
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26

Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies
Muhammad Tahaa, Sadia Sultanb,c, Syahrul Imranc, Fazal Rahimd, Khalid Zamand, Abdul Wadoode, Ashfaq Ur
Rehmane, Nizam Uddinf, Khalid Mohammed Khang
aDepartment of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman
Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
bFaculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, 42300 Bandar
Puncak Alam, Selangor D. E., Malaysia
cAtta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA Cawangan
Selangor Kampus Puncak Alam, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia.
dDepartment of Chemistry, Hazara University, Mansehra-21300, Pakistan
eDepartment of Biochemistry, Abdul Wali Khan University Mardan, Mardan-23200, Pakistan.
fDepartment of Chemistry, University of Karachi, Karachi 75270, Pakistan.
gH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
Karachi, Karachi-75270, Pakistan
O
O
N
N
N
H
N
H
F
N
N
OH
OH
IC50 = 7.40 ± 0.20 µM
IC50 = 6.20 ± 0.30 µM
Compund
FigD
12
Compound
FigA
4
Acarbose (Std) IC50 = 38.45 ± 0.80µM
 Correspondence and reprints
E-mail: E-mail: taha_hej@yahoo.com and mtaha@iau.edu.saTel: 00966502057370
27