Microwave Assisted Synthesis and Antimicrobial Potential of Quinoline-Based 4-Hydrazide-Hydrazone Derivatives

Article abstract of DOI:10.1002/jhet.3050

Quinoline is a benzo-fused pyridine which is a therapeutically important heterocycle in medicinal chemistry research and new drug development. A series of 12 new hydrazide-hydrazone motifs bearing quinoline core 4a–l was successfully synthesized by microwave irradiation technique. The synthesis involved four steps strategies which was initiated by ring-opening synthetic modification of isatin to quinoline-4-carboxylic acid through Pfitzinger approach. The structure of the reactive intermediates 1, 2, and 3 as well as the targeted quinoline 4a–l were confirmed by the result of physicochemical parameters and spectroscopic means which include FTIR, UV, ¹H and ¹³C NMR as well as DEPT 135 NMR. The in vitro antimicrobial screening of the targeted hydrazide-hydrazones 4a–l alongside with gentamicin (clinical standard) against six microorganisms was determined using agar diffusion. The result from the MIC test showed that this series of hydrazide-hydrazones exhibited remarkable efficacy as antimicrobial agents with 4e being the most active antibacterial agent with MIC value ranging from 3.13 to 0.39?μg/mL on the six organisms tested.

Full text of DOI:10.1002/jhet.3050

Month 2017
Microwave Assisted Synthesis and Antimicrobial Potential of Quinoline-
Based 4-Hydrazide-Hydrazone Derivatives
a
Olayinka O. Ajani,
King T. Iyaye,a Oluwatosin Y. Audu,b Shade J. Olorunshola,c Alice O. Kuye,c and
*
Ifedolapo O. Olanrewajua
aDepartment of Chemistry, Covenant University, CST, Canaanland, Km 10 Idiroko Road, P.M.B. 1023, Ota, Ogun State,
Nigeria
bDepartment of Chemistry, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
cDepartment of Biological Sciences, Covenant University, CST, Canaanland, Km 10 Idiroko Road, P.M.B. 1023, Ota,
Ogun State, Nigeria
*
E-mail: ola.ajani@covenantuniversity.edu.ng
Received August 28, 2017
DOI 10.1002/jhet.3050
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
O
O
H
O
N
N
H
N
N
H
O
NH
Isatin
4e
MIC = 0.39-3.13 µg/mL
N
N
3
Quinoline is a benzo-fused pyridine which is a therapeutically important heterocycle in medicinal chem-
istry research and new drug development. A series of 12 new hydrazide-hydrazone motifs bearing quinoline
core 4a–l was successfully synthesized by microwave irradiation technique. The synthesis involved four
steps strategies which was initiated by ring-opening synthetic modification of isatin to quinoline-4-
carboxylic acid through Pfitzinger approach. The structure of the reactive intermediates 1, 2, and 3 as well
as the targeted quinoline 4a–l were confirmed by the result of physicochemical parameters and spectroscopic
1
means which include FTIR, UV, H and 13C NMR as well as DEPT 135 NMR. The in vitro antimicrobial
screening of the targeted hydrazide-hydrazones 4a–l alongside with gentamicin (clinical standard) against
six microorganisms was determined using agar diffusion. The result from the MIC test showed that this se-
ries of hydrazide-hydrazones exhibited remarkable efficacy as antimicrobial agents with 4e being the most
active antibacterial agent with MIC value ranging from 3.13 to 0.39 μg/mL on the six organisms tested.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
α-methyleneketones [7]. Another method which has
become one of the most efficient processes for the
synthesis of quinolines is Povarov synthetic approach
which is an inverse electron demand aza-Diels–Alder
reaction of N-aryl imines, derived from aldehydes and
anilines, with electron rich olefins [8] and Skraup method
[9]. Quinoline skeletons are recurrently encountered
heterocyclic compounds in medicinal chemistry literature
with wide spread pharmacological diversity such as
anticancer [10] antioxidant [11], antileishmanial [12],
antibacterial [13], analgesic, anti-inflammatory [14],
antifungal [15], antimalarial [16], antitumor [17], and DNA
enzyme topoisomerase I inhibitory [18] among others.
Furthermore, in the recent time, the chemistry of
carbon–nitrogen double bond of hydrazone is fast
becoming the backbone of condensation reaction in
benzo-fused N-heterocycles [19]. Hydrazone containing
azomethine –NHN═CH protons constitute an important
class of compounds for new drug development [19]
which have been reported to possess, among others,
antimicrobial [20], antitubercular [21], and antiplatelet
[22]. Also, a recent review on pharmacological activities
The structure of un-substituted quinoline was confirmed
by the syntheses in which allylaniline was passed over
glowing lead oxide or from o-nitrocinnamaldehyde [1].
Quinoline is characterized by a double ring structure
composed of benzene and pyridine ring fused at two
adjacent carbon atoms, while the pyridine ring contains five
carbon atoms and a nitrogen heteroatom [2]. Due to wide
application of quinoline core in many medicinal and
industrial processes, various synthetic approaches have
been used for the synthesis of this valuable heterocyclic
system. These methods include the following: Pfitzinger
approach which is reaction of isatin with ketones and
aldehyde [3]; Doebner–Von Miller method, which is
composed of reaction of an aniline with α,β-unsaturated
carbonyl compounds [4]; Conrad–Limpach method which
is based on the condensation of anilines with β-ketoesters
[5]; Combe synthetic approach which involves the reaction
of β-diketones, with primary aryl amines like aniline [6]
and Friedlander synthetic approach which proceeded
by the condensation of 2-aminoaryl ketones with
© 2017 Wiley Periodicals, Inc.

O. O. Ajani, K. T. Iyaye, O. Y. Audu, S. J. Olorunshola, A. O. Kuye, and I. O. Olanrewaju
Vol 000
of hydrazone derivatives showed them to display
anticonvulsant, anti-inflammatory, antimalarial,
ethanol at temperature of 60°C by heating under reflux
for 1 h in the presence of catalytic amount of
concentrated sulphuric acid (Conc. H2SO4) to achieve a
solution which was worked-up by adding water and
extracted in two portions with diethyl ether. The organic
layer was combined and dried over anhydrous Na2SO4 to
trap any escaped moisture. The filtrate was evaporated
to dryness in order to afford ethyl 2-propylquinoline-4-
antioxidant, antidepressant, and antifungal [23]. In an
earlier review, which dealt with exploring biological
activities of hydrazone, it was unveiled that they
exhibited analgesic, central nervous system (CSN),
antiprotozoal, cardio-protective and anticancer activities
[24]. Due to occurrence of microorganisms' drug
resistance and emergence of new diseases which have
contributed to the alarming rate of global health threat,
there is a continuous need for the synthesis of new
heterocyclic compounds as potential antimicrobial agents.
Therefore, we have herein designed and synthesized 12
novel hydrazide-hydrazones of quinoline 4a–l in order to
investigate their antimicrobial potential for possible future
drug discovery.
carboxylate,
2
(Scheme 2a). Subsequently, the
hydrazinolysis of 2 was carried out by reacting it
under reflux for 1 h with equimolar quantity of
hydrazine hydrate in ethanolic environment to afford
2-propylquinoline-4-carbohydrazide,
3 in high yield
(Scheme 2b). Finally, new 12 derivatives of hydrazide-
hydrazone bearing quinoline core, 4a–l were synthesized
by microwave assisted condensation reaction of the NH2
free end of hydrazide of intermediate 3 with sp2
hybridized carbonyl center of various aliphatic and
alicyclic ketones in the presence of ethanol (Scheme 3).
The microwave assisted reaction was completed between
1 and 3 min. The thermodynamic justification for faster
reaction rate under microwave was explained in our
previous work [20].
RESULTS AND DISCUSSION
Chemistry. In the continuation of our research effort
on the design and discovery of biologically active
hydrazones [19,20], we have herein embarked upon the
microwave-assisted
synthesis
of
quinoline-based
Characterization.
Spectroscopic characterization of
hydrazide-hydrazone through an eco-friendly synthetic
approach in order to evaluate their antimicrobial
potentials for possible future drug discovery. First and
foremost, the reaction was initiated by the synthesis of
2-propylquinoline-4-carboxylic acid (1) according to the
Pfitzinger synthetic procedure earlier reported [3]. This
involved the ring-opening reaction of isatin under the
influence of aqueous KOH by heating under reflux,
followed by ketonization of the reactive intermediate with
pentan-2-one at a reflux temperature of 80–90°C for 13 h
to form the potassium salt of 2-propylquinoline-4-
carboxylic acid. The choice of pentanone as the required
ketone is to access 2-propyl substitution on the quinoline
nucleus. The resulting solution was then worked-up
by acidification with concentrated hydrochloric acid
(Conc. HCl) to a pH of 2, after which colored solid was
precipitated. It was cooled and the solid formed
was filtered by suction and air-dried to afford
2-propylquinoline-4-carboxylic acid 1 as red colored
crystalline compound (Scheme 1). Secondly, the
compound (1) was esterified via reaction with absolute
the newly synthesized hydrazide-hydrazones 4a–l was
1
carried out using UV–vis, IR spectral data, H NMR, 13C
NMR and DEPT 135. According to the spectroscopic
study, the electronic transition of UV–vis spectra for the
hydrazide-hydrazones of quinoline, 4a–l gave rise to
wavelength (λmax) ranging from 203 nm for 4a to
428 nm for 4 l with log εmax of 4.04 for both
(Experimental). The first set of wavelengths (λmax) in all
the synthesized compounds were found between 203 and
225 nm and they were as a result of л→л* transition
indicating the presence of C═C peculiar to benzene
nucleus. This indicated that all the hydrazide-hydrazones,
4a–l possessed benzene ring as one of their core system.
Considering 4a as a representative of the targeted
compounds, its first wavelength was 203 nm (log
εmax = 4.04) while some bathochromic shifts were
experienced at 225 (log εmax
= 4.08), 251 (log
εmax = 4.10), 254 (log εmax = 4.38), and 305 nm (log
εmax = 4.11). They were as a result of the combinatory
effect of л→n transition of C═O and C═N as well as
extensive conjugation of C═C moieties. The longest
Scheme 1. Pathway for the synthesis of 2-propylquinoline-4-carboxylic acid, 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Bioactivity of Quinoline-based Hydrazide-hydrazones
Scheme 2. Pathways for the synthesis of (a) ethyl 2-propylquinoline-4-carboxylate, 2. (b) and quinoline hydrazide, 2-propylquinoline-4-carbohydrazide,
3.
Scheme 3. Hydrazide-hydrazones of quinoline core, 4a–l.
wavelength of 428 nm (log εmax = 4.04) was observed in
compound 4 l. This might be due to the presence of
auxochromic character of C═N and additional C═C
conjugation contributed by the benzene of the coumarin
template. The infrared spectra of all the compounds, 4a–l
showed absorption bands because of the stretching
vibration of N–H of hydrazide, C–H of aromatic, C–H of
aliphatic, C═O of hydrazide and amide, C═C of aromatic
of aliphatic (CH3, CH2) deformation, C–N of hydrazide,
═C–H bending and aryl bonded hydrogen respectively. In
addition, some bands were peculiar to some compounds
alone and not for the entire targeted scaffolds. In terms of
the ranges of the bands of each functional group, the
highest N–H band was found in 4a, 4e, 4f, and 4h at
3415 cmꢀ1 while the lowest N–H band was found in 4d
at 3244 cmꢀ1. The C–H band of aromatic ranged from
3151 cmꢀ1 for 4b to 3010 cmꢀ1 for 4g and 4h. Carbonyl
bands were available for all the compounds with carbonyl
of amide in 4g being the highest (1715 cmꢀ1) while the
carbonyl of hydrazide of 4c had the lowest carbonyl
absorption frequency of 1668 cmꢀ1. In a similar manner,
the stretching vibrational frequency of C═C varied
and C═N of hydrazone, and imine at 3415–3244 cmꢀ1
3151–3010 cmꢀ1, 2981–2804 cmꢀ1, 1715–1668 cmꢀ1
,
,
1638–1603 cmꢀ1 and 1589–1575 cmꢀ1, respectively. The
absorption bands observed at bending vibrational
frequencies of 1467–1360 cmꢀ1, 1254–1123 cmꢀ1
,
987–965 cmꢀ1, and 774–722 cmꢀ1 depicted the presence
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

O. O. Ajani, K. T. Iyaye, O. Y. Audu, S. J. Olorunshola, A. O. Kuye, and I. O. Olanrewaju
Vol 000
between 1638 cmꢀ1 for compound (4c) to 1603 cmꢀ1 for
compound 4b while the highest absorption frequency for
C═N was 1589 cmꢀ1 for 4b and 4k and lowest being
1575 cmꢀ1 for 4i, 4j, and 4k. The deformed aliphatic
groups attached to benzene were found between
1467 cmꢀ1 for 4b–4k and 1360 cmꢀ1 for 4i. The
confirmatory evidence for the C–N of hydrazide was
responsible for the bands ranging from 1254 cmꢀ1 for 4f
to 1123 cmꢀ1 for 4c while the rest of the bands were at
the finger print region.
Furthermore, the physicochemical parameters of the
synthesized compounds 4a–l evaluated and documented
were molecular formula, molecular weight, percentage
yields, melting points, color, and elemental composition
values for carbon, hydrogen, and oxygen (Experimental).
The molecular weight of the compounds, 4a–l ranged
from 283.87 for 4a to 399.44 for 4l. The weights
were above 200 g/mol, which partially revealed the
the quinoline-based hydrazide-hydrazones, 4a–l. The
visual observation of the compounds showed that the
color varied in the order: red for 4f; yellow for 4l;
white for 4e; black for 4h and 4k, while the rest of the
compounds were brown. The result of elemental
analysis did not only correlate well with the
molecular masses of the compounds but also showed a
consistent minimum difference of not more than
0.24 between % calculated and % found for the
carbon, hydrogen and nitrogen of the prepared
compounds, 4a–l (Experimental).
Antimicrobial activity.
Antimicrobial sensitivity
testing of targeted hydrazide-hydrazones 4a–l was
carried out in vitro against six organisms using agar-well
diffusion method [25]. The media were inoculated with
test organisms and DMSO was used as negative control.
The positive control on bacteria was gentamicin. The
zones of inhibition (Z.O.I.) in millimeters were
measured after 24 h of incubation and duly recorded as
shown in Table 1. The choice of gentamicin as clinical
standard is because, at low concentrations, gentamicin
only inhibits growth of the bacteria through induction of
prokaryotic ribosomes to misread mRNA [19].
Gentamicin also prevents initiation of protein synthesis
and leads to death of microbial cells. Gentamicin
inhibits bacterial growth by inhibiting protein
biosynthesis just like Streptomycin and other
aminoglycoside antibiotics. Interestingly, it was observed
that majority of the compounds exhibited probable and
highly promising significant activities based on the large
zone of inhibition reported. In fact, many of these
hydrazide-hydrazone of quinoline derivatives 4a–l had
larger zones of inhibition against all the six organisms
when compared to gentamicin standard. Generally
bicyclic nature of the compounds, 4a–l, since
monocyclic aromatic has molecular weight <200 g/mol
(e.g. benzene 78 g/mol). The majority of the
a
=
compounds have arbitrarily high melting point values and
4e, 4f, and 4l did not even melt at 300°C. It is a clear
indication of the formation of hydrazide bond which
has similar thermal behavior as amide bond with
high tendency of hydrogen bonding character. This was
in agreement with our earlier finding [19] wherein
3-hydrazinoquinoxalin-2(1H)-one was reported to have
high melting point values (m.p.>360°C). The percentage
yields of the synthesized hydrazide-hydrazones 4a–l
ranged from 70% for 4d to 94% for 4l. The good to
excellent yields obtained showed that microwave
irradiation technique was cost-effective and highly
efficient in the complete conversion of the precursor to
Table 1
The sensitivity testing of hydrazide-hydrazones 4a–l with zone of inhibition (mm).
Organisms used and Z.O.I. (mm)
Sample Code
S. aureus
B. lichenformis
M. varians
E. coli
P. vulgaris
P. aeruginosa
4a
4b
4c
4d
4e
39.00 1.25
28.00 1.25
18.00 1.11
38.00 1.25
40.00 1.25
25.00 1.06
19.00 1.20
42.00 1.25
26.00 1.19
31.00 1.25
30.00 1.25
32.00 1.25
23.00 1.25
38.00 1.25
23.00 1.04
31.00 1.25
13.00 1.00
33.00 1.25
16.00 1.00
8.00 1.00
11.00 1.00
13.00 1.03
24.00 1.21
16.00 1.14
25.00 1.24
15.00 1.08
33.00 1.25
23.00 1.00
24.00 1.08
14.00 1.07
33.00 1.25
11.00 1.01
8.00 1.00
14.00 1.00
13.00 1.01
14.00 1.14
14.00 1.09
20.00 1.17
18.00 1.21
30.00 1.15
15.00 1.01
25.00 1.25
11.00 1.01
30.00 1.15
15.00 1.08
3.00 0.45
4.00 0.39
13.00 1.03
18.00 1.22
19.00 1.21
15.00 1.07
25.00 1.19
R
29.00 1.10
24.00 1.11
26.00 1.09
20.00 1.14
38.00 1.25
14.00 1.14
4.00 0.46
8.00 0.39
8.00 0.41
25.00 1.25
22.00 1.25
20.00 1.25
R
13.00 1.00
18.00 1.08
13.00 1.08
31.00 1.25
14.00 1.18
32.00 1.25
17.00 1.11
8.00 0.44
18.00 1.22
12.00 1.03
18.00 1.20
25.00 1.20
4f
4g
4h
4i
4j
4k
4l
Gent.
S. aureus, Staphylococcus aureus; B. lichenformi, Bacillus lichenformis; M. varians, Micrococcus varians; E. coli, Escherichia coli; P. vulgaris, Proteus
vulgaris; P. aeruginosa, Pseudomonas aeruginosa; Gent., Gentamicin (Clinical standard); Z.O.I., Zone of Inhibition. Values are mean SD of triplicate
determination.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Bioactivity of Quinoline-based Hydrazide-hydrazones
speaking, compound 4h showed the largest zone of
inhibition (42.00 1.25 mm) against Staphylococcus
aureus while 4g had the least zone of inhibition of
3.00 0.45 mm against Escherichia coli among all the
screened compounds.
were probably more active than gentamicin, because this
organism (P. aeruginosa) developed resistance against
gentamicin, but had broad spectrum of activity with
Z.O.I. ranging from 4.00
0.46 mm for 4g to
38.00 1.25 mm for 4e. In the overall, hydrazide-
The compound 4a–l inhibited the growth of S. aureus
effectively with Z.O.I. ranging from 18.00 1.11 mm for
4c to 42.00 1.25 mm for 4h while Z.O.I. of gentamicin
against the same organism was 23.00 1.25 mm. Thus,
compounds 4k competed favorably with gentamicin
while all other compounds showed better activity
than gentamicin with larger zones of inhibition
(i.e. Z.O.I. > 23 mm) except compounds 4c and 4g with
Z.O.I. of 18 1.11 mm and 19 1.20 mm, respectively
against S. aureus. The antimicrobial activity against
Bacillus lichenformis showed that 4a had largest Z.O.I. of
38.00 1.25 mm while the least growth inhibitor was 4g
with Z.O.I. of 8.00 1.00 mm. The Z.O.I. of gentamicin
against B. lichenformis was 15.00 1.08 mm. This helped
us to know that four compounds, 4d, 4g, 4h, and 4i had
Z.O.I. values which were lower than that of gentamicin
while the remaining eight compounds inhibited the growth
of B. lichenformis at Z.O.I. value larger than that of
gentamicin. With respect to Micrococcus varians,
compounds 4a and 4e were the most probable growth
inhibitors due to their large Z.O.I. values of
33.00 1.25 mm while 4 g was the least probable due to
hydrazone 4e had the best activity across the strains of
the Gram-negative and Gram-positive organisms used in
this present study.
Both community-associated and hospital-acquired
infections with S. aureus have increased in the past
20 years. Types and presentation of S. aureus infection
include the following: skin and soft tissue (impetigo)
infection, scalded skin syndrome (Ritter disease),
folliculitis, furuncle, bone infections (osteomyelitis) in
children [26], septic arthritis, toxic shock syndrome,
thrombophlebitis, deep tissue abscess, and infection among
other which in turn leads to high mortality rate [27]. Based
on all the information aforementioned on S. aureus, the
selectivity index (S.I.) of quinoline hydrazide-hydrazones
4a–l against the S. aureus was evaluated (Fig. 1). The
comparative study of activity potential of 4a–l with
gentamicin was considered because, in humans, gentamicin
has structurally different ribosomes from bacteria, thereby
allowing the selectivity of this antibiotic for bacteria. The
selectivity index of gentamicin was unity, while any
compounds with S.I. > 1, have a better selectivity index as
compared with gentamicin whereas those with the S.I. < 1
possessed lesser selectivity index than gentamicin
antibiotic. On this note, it is interesting to note that four
compounds 4a, 4d, 4e, and 4h exhibited a better selectivity
index when compared to gentamicin against S. aureus,
while the rest of the compounds were less selective than
gentamicin on S. aureus.
Based on the broad activity spectrum noticed during
the antibacterial screening, MIC of the targeted
compounds 4a–l was carried out against the six
organisms using serial dilution method [25], with
varying concentration from 50 to 0.39 μg/mL as shown in
Table 2. The most susceptible organism to the efficacy of
4a–l was S. aureus because 13 compounds inhibited the
growth of this organism at MIC value as low as
0.39 μg/mL except two compounds; 4j which inhibited
S. aureus growth at MIC value of 0.78 μg/mL and 4e
with MIC of 1.56 μg/mL against S. aureus growth.
Thus, hydrazide-hydrazones, 4a–l synthesized herein
could pave way for new drug development for
combating infectious diseases caused by S. aureus.
Compound 4a could not inhibit the growth
of P. vulgaris at MIC value ≤50 μg/mL. The MIC of
synthesized compounds 4a–l ranged from 1.56 to
25.00 μg/mL against B. lichenformis; 1.56 to 12.50 μg/
mL against M. varians; 0.78 to 25.00 μg/mL against
E. coli; 0.39 to 25.00 μg/mL against P. vulgaris; and
0.78 to 50.00 μg/mL against P. aeruginosa. Based on
small Z.O.I. value of 8.00
1.00 mm. The Z.O.I. of
gentamicin against M. varians was 18.00 1.21 mm. This
assisted in identifying that there were five compounds
having Z.O.I. values (from 20.00
1.17 to
33.00 1.25 mm) greater than that of clinical standard
(gentamicin) while seven compounds were having Z.O.I.
values (from 8.00 1.00 to 14.00 1.14 mm) less than
that of gentamicin as far as growth inhibitory potential
against M. varians was concerned.
Nevertheless, upon the screening against three Gram-
negative organisms (E. coli, Proteus vulgaris,
Pseudomonas aeruginosa), noticeable activities were
observed, except screening of 4a against P. vulgaris and
gentamicin against P. aeruginosa where resistance was
observed. According to screening against gram negative
E. coli, the largest and smallest Z.O.I. were observed to
be 30.00 1.15 mm for 4a and 4e and 3.00 0.45 mm
for 4g, respectively. The Z.O.I. of gentamicin against
E. coli was 25.00
1.19 mm, which implied that 4c
competed favorably with gentamicin while two
compounds 4a, 4e, inhibited E. coli growth at Z.O.I.
larger than that of gentamicin. The antimicrobial activity
against gram positive P. vulgaris depicted 4g as the most
effective with largest Z.O.I. of 32.00 1.25 mm while 4i
was the least active with smallest Z.O.I. of
8.00 0.44 mm. The in vitro screening of the samples
4a–l against P. aeruginosa showed that all compounds
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

O. O. Ajani, K. T. Iyaye, O. Y. Audu, S. J. Olorunshola, A. O. Kuye, and I. O. Olanrewaju
Vol 000
Figure 1. Result of the selectivity index of hydrazide-hydrazones (4a–l) against S. aureus. [Color figure can be viewed at wileyonlinelibrary.com]
Table 2
The minimum inhibitory concentration (MIC) test of hydrazide-hydrazones 4a–l (μg/mL).
Organism Used
Code No
S. aureus
B. lichenformis
M. varians
E. coli
P. vulgaris
P. aeruginosa
4a
4b
4c
4d
4e
4f
4g
4h
4i
0.39
0.39
0.39
0.39
1.56
0.39
0.39
0.39
0.39
0.78
0.39
0.39
6.25
25.00
1.56
6.25
1.56
1.56
3.13
12.50
3.13
12.50
6.25
1.56
6.25
1.56
6.25
3.13
3.13
3.13
3.13
12.50
3.13
3.13
3.13
3.13
25.00
12.50
0.78
3.13
3.13
Nil
6.25
6.25
1.56
0.39
12.50
6.25
25.00
6.25
3.13
12.50
6.25
12.50
25.00
1.56
6.25
0.78
6.25
1.56
3.13
12.50
25.00
3.13
6.25
1.56
50.00
3.13
12.50
25.00
3.13
4j
4k
4l
25.00
the result of visual screening of MIC values across the
gram positive and Gram-negative organisms used herein,
compound 4e emerged as the most potent antimicrobial
agent with MIC from 0.39 to 3.13 μg/mL. Hence, it is a
worthwhile adventure to explore these compounds
further to investigate their cytotoxicity profile so as to
further harness and identify their potential for possible
novel drug discovery. This is needful, especially, in a
time like this when drug resistance challenge has
become a strong toolbox for global health threat and
undesirable avenue for high mortality rate among
mankind and livestock.
effective, cheap, fast, and economical. It also promotes
environmental friendly synthetic approach because the
toxicity and hazardous discharges from chemical usage is
not experienced and the synthesis was carried out
successfully in a neat and green reaction medium. As
envisaged, most of the novel hydrazide-hydrazones of
quinoline were shown to have higher inhibitory potentials
than the antibiotic standard, gentamicin used in most
cases. 2-Propyl-(N0-(1,7,7-trimethylbicyclo[2.2.1]heptan-
2-ylidene)quinoline-4-carbohydrazide, 4e emerged as the
most active antibacterial agent with MIC values ranging
from 1.59 to 0.39 μg/mL on the six organisms tested.
CONCLUSION
EXPERIMENTAL
The quinoline group has been proven to have remarkable
utilities in medicinal chemistry as one of the most widely
used antibiotics and antimalarials in the world. The
microwave irradiation method showed to be very
All chemical compounds were pure and of analytical
grade. They were purchased from Sigma Aldrich, USA
and except for cyclopentanone and isatin which
were purchased BDH Chemicals, UK, but were made
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Bioactivity of Quinoline-based Hydrazide-hydrazones
available by Department of Chemistry, Covenant
University. Melting points were determined in open
capillary tubes on Stuart melting point apparatus and
were uncorrected. The Infrared spectra were run using the
Perkin Elmer FTIR Spectrophotometer (KBr pellet, 4000
to 400 cmꢀ1). The Ultraviolet–visible (UV–vis.)
spectrophotometric analyses of all the samples were run
in either dichloromethane (CH2Cl2), or Dimethyl
sulphoxide (DMSO) solvents using UV-Genesys 10s
v1.200 Spectrophotometer. The absorbance was plotted
against the wavelength λmax (nm) and the obtained molar
absorptivity was used to calculate Log εmax. The progress
of the reaction and the level of purity of the compounds
were routinely checked by Thin Layer Chromatography
(TLC) on silica gel plates using different eluting solvent
(solvent system) and the developed plates were visualized
under UV light and in the iodine tank. Furthermore, the
1H NMR and 13C NMR spectra were recorded on NMR
Bruker DPX 500 Spectrometer, manufactured by Bruker
BioSpin Corporation, California, USA, operating at the
machine frequencies of 500 and 125 MHz, respectively
using either CDCl3 or DMSO-d6, as solvent for sample
preparation prior to analyses. In addition, DEPT-135
NMR analysis was also evaluated for all the synthesized
compounds. Tetramethylsilane (TMS) was used as
internal standard with the deuterium signal of the solvent
as the lock and chemical shifts δ were recorded in ppm
and the coupling constants (J) were reported in Hertz
(Hz) where distinct multiplicities were observed.
Standard abbreviation was used for the multiplicity which
include singlet (s), doublet (d), triplet (t), quartet (q), and
multiplet (m). The microwave assisted syntheses were
carried out with the aid of CEM Discover Monomode
oven operating at frequency of 2450 MHz monitored by
a PC computer and temperature control was fixed at
140°C within the power modulation of 500 W. The
reactions were performed in sealed tube within ramp time
of 1 to 3 min while stirring was provided by an in situ
magnetic stirrer. In addition, pH was monitored and
confirmed during acidification using pH meter model
PHB4. All drying was conducted at reduced pressure with
DHG-9023A Vacuum Oven which was manufactured by
Protech Holding Limited, Zhengzhou, China. The
elemental analysis (C, H, and N) of the synthesized
compounds were performed using a Flash EA 1112
elemental analyzer which was manufactured by Eltra
GmbH, Haan, Germany. Results were found to be in good
agreement with the calculated values (Table 1).
homogeneity. The resulting mixture was then irradiated in
microwave oven for a period of 1 to 3 min as the case
may be, based on the result obtained from the monitored
progress of reaction using TLC spotting in
dichloromethane (DCM) as eluting solvent. The heated
solution was allowed to cool to ambient temperature and
filtered to afford the corresponding hydrazide-hydrazone
of quinoline (4a–l) in good to excellent yields after
column chromatograph.
N0–(Butan-2-ylidene)-2-propylquinoline-4-carbohydrazide
(4a). Microwave assisted reaction of 3 (3.0 g, 13 mmol)
with butan-2-one (1.16 mL, 13 mmol) for 2 min afforded
N0-(butan-2-ylidene)-2-propylquinoline-4-carbohydrazide,
4a as brown solid. Yield 3.25 g (82%); m.p. 258°C;
C17H21N3O (283.87): Anal. Found: C, 72.06; H, 7.47; N,
1
14.83% Calc.: C, 72.11; H, 7.52, N, 14.92%. H NMR
(δ, ppm in dmso-d6): 7.75–7.73 (d, J = 10.0 Hz, 2H,
Ar–H), 7.52 (s, 1H, Ar–H), 7.29–7.26 (dd, J1 = 10.0 Hz,
J2 = 12.5 Hz, 2H, Ar–H), 5.80 (s, 1H, NH), 3.73–3.72
(m, 2H, CH2), 3.31–3.25 (q, J = 8.0 Hz, 2H, CH2CH3),
3.17–3.11 (q, J = 8.20 Hz, 2H, CH2CH3), 2.40 (s, 3H,
CH3–C═N), 1.12–1.08 (t, J = 8.0 Hz, 3H, CH3CH2),
1.02–0.99 (t, J = 8.0 Hz, 3H, CH3CH2). 13C NMR
(δ, ppm in DMSO-d6): 173.2 (C═O), 158.4, 151.2, 141.9,
135.0, 132.3, 127.4, 120.8, 117.0, 116.8, 110.0, 41.3,
29.3, 25.3, 20.2, 15.1, 10.1 (CH3). DEPT 135 (δ, ppm in
DMSO-d6): Positive signals are 141.9 (CH), 135.0 (CH),
132.3 (CH), 117.0 (CH), 116.8(CH), 20.2 (CH3), 15.1
(CH3), 10.1 (CH3). Negative signals are 41.3, 29.3, and
25.3 (CH2). UV–vis.: λmax (nm)/ log εmax (molꢀ1 cmꢀ1):
203 (4.04), 225 (4.08), 251 (4.10), 254 (4.38), and 305
(4.11). IR (cmꢀ1): νN-H 3415, νC–H aliph. 2981, νC═C
1633, νC–N 1140, ν = C–H bending 982.
N0-(Pentan-2-ylidene)-2-propylquinoline-4-carbohydrazide
(4b). Microwave assisted reaction of 3 (3.0 g, 13 mmol)
with pentan-2-one (1.38 mL, 13 mmol) for 2 min afforded
N0-(pentan-2-ylidene)-2-propylquinoline-4-carbohydrazide,
4b as brown solid. Yield 3.16 g (76%); m.p. 261–262°C;
C18H23N3O (297.39): Anal. Found: C, 72.70; H, 7.80, N,
1
14.13% Calc.: C, 72.65; H, 7.74; N, 14.09%. H NMR
(δ, ppm in DMSO-d6): 7.77–7.75 (d, J = 10.0 Hz, 2H,
Ar–H), 7.75 (s, 1H, Ar–H), 7.28–7.26 (dd, J1 = 10.0 Hz,
J2 = 12.5 Hz, 2H, Ar–H), 4.76 (s, 1H, NH), 3.53–3.48
(q, J = 8.5 Hz, 2H, CH2CH3), 3.34–3.29 (q, J = 8.9 Hz,
2H, CH2CH3), 2.40 (s, 3H, CH3–C═N), 2.08 (m, 2H,
CH2), 1.86 (m, 2H, CH2), 1.27–1.24 (t, J = 8.90 Hz, 3H,
CH3CH2), 1.10–1.06 (t, J = 8.50 Hz, 3H, CH3CH2). 13C
NMR (δ, ppm in DMSO-d6): 173.1 (C═O), 158.8, 151.3,
141.9, 135.0, 132.3, 127.4, 120.8, 117.0, 116.8, 110.0,
41.3, 33.3, 29.3, 25.3, 20.2, 15.1, 10.1 (CH3) ppm.
DEPT 135 (δ, ppm in DMSO-d6): Positive signals are
141.9 (CH), 135.0 (CH), 132.3 (CH), 117.0 (CH),
116.8(CH), 20.2 (CH3), 15.1 (CH3), 10.1 (CH3).
Negative signals are 41.3, 33.3, 29.3, and 25.3 (CH2).
General procedure for microwave-assisted synthesis of
hydrazide-hydrazone
(4a–l).
2-Propylquinoline-4-
carbohydrazide, 3 (3.0 g, 13 mmol) was dissolved in
about 10 mL of ethanol in a 100 mL beaker covered with
watch glass. The corresponding ketone (13 mmol) was
added and the beaker was swirled thoroughly for proper
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

O. O. Ajani, K. T. Iyaye, O. Y. Audu, S. J. Olorunshola, A. O. Kuye, and I. O. Olanrewaju
Vol 000
UV–vis.: λmax (nm)/log εmax (molꢀ1 cmꢀ1): 225 (4.10),
250 (4.31), 265 (4.45), 275 (4.75), 317 (4.61). IR
(cmꢀ1): νN–H 3358, νC–H arom. 3151, νC–H aliph.
2925, νC–H aliph. 2805, νC═O 1683, νC═C 1603,
νC═N 1589, νCH3 deformation 1467, νC–N 1248,
ν = C–H bending 982, νAr–H 749.
44.2 (CH), 21.3 (CH3), 14.6 (2 × CH3), and 10.1 (CH3).
Negative signals are 41.3, 29.3, and 25.3 (CH2). UV–vis.:
λmax (nm)/log εmax (molꢀ1 cmꢀ1): 217 (4.24), 224 (4.05),
239 (4.26), 275 (4.62), 320 (4.45). IR (cmꢀ1): νN–H
3374, 3244, νC–H arom. 3036, νC–H aliph. 2980, νC–H
aliph. 2889, νC═C 1688, νC═C 1605, νC═N 1587, νCH3
deformation 1464, νC═N 1243, ν = C–H bending 965,
νAr–H 774.
N0-(Hepta-2-ylidene)-2-propylquinoline-4-carbohydrazide
(4c). Microwave assisted reaction of 3 (3.0 g, 13 mmol)
with heptan-2-one (1.86 mL, 13 mmol) for
1½ min afforded N0-(hepta-2-ylidene)-2-propylquinoline-
4-carbohydrazide, 4c as brown solid. Yield 3.87 g (85%);
m.p. 263–265°C; C20H27N3O (325.46): Anal. Found: C,
73.81; H, 8.36; N, 12.91% Calc.: C, 73.71; H, 8.27; N,
13.04%. 1H NMR (δ, ppm in DMSO-d6): 7.58–7.56
2-Propyl-(N0-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)
quinoline-4-carbohydraz ide (4e).
Microwave assisted
reaction of 3 (3.0 g, 13 mmol) with camphor (1.99 g,
13 mmol) for
min afforded 2-propyl-(N0-
3
(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)quinoline-
4-carbohydr azide, 4e as white solid. Yield 3.92 g, (77%);
m.p. > 300°C; C23H29N3O (363.50): Anal. Found: C,
76.00; H, 8.04; N, 11.56% Calc.: C, 75.88; H, 8.16; N,
11.66%. 1H NMR (δ, ppm in DMSO-d6): 7.74–7.72
(d, J = 10.0 Hz, 2H, Ar–H), 7.51 (s, 1H, Ar–H),
7.29–7.26 (dd, J1 = 10.0 Hz, J2 = 12.5 Hz, 2H, Ar–H),
5.84 (s, 1H, NH), 3.78–3.77 (d, J = 4.8 Hz, 2H,
CH2CH), 3.31–3.25 (q, J = 7.4 Hz, 2H, CH2CH2CH),
2.40 (s, 3H, CH3–C═N), 2.12 (m, 1H), 1.80 (m, 2H),
1.67 (m, 2H, CH2), 1.48 (t, J = 5.8 Hz, 2H, CH2CH2),
1.25 (s, 6H, (CH3)2–C), 0.99 (t, J = 6.2 Hz, 3H,
CH3CH2). 13C NMR (δ, ppm in DMSO-d6): 172.7
(C═O), 159.6, 151.0, 142.7, 134.9, 132.3, 127.4, 120.8,
117.0, 116.8, 110.4, 62.2, 44.0, 41.1, 29.8, 29.3, 25.3,
21.1, 15.1 (2 × CH3), 11.1 (CH3). DEPT 135 (δ, ppm in
DMSO-d6): Positive signals are 142.7 (CH), 134.9 (CH),
132.3 (CH), 117.0 (CH), 116.8 (CH), 44.0 (CH), 21.1
(CH3), 15.1 (2 × CH3), and 11.1 (CH3). Negative signals
are 62.1, 41.1, 29.8, 29.3, and 25.3 (CH2). UV–vis.: λmax
(nm)/log εmax (molꢀ1 cmꢀ1): 215 (3.34), 236 (3.11), 431
(3.00), 437 (3.00). IR (cmꢀ1): νN–H 3415, νC–H aliph.
2949, νC–H aliph. 2935, νC–H aliph. 2883, νC═O 1688,
νC═C 1620, νCH3 deformation 1461, νC–N 1245,
ν = C–H bending 966, νAr–H 728.
(d,
J = 10.30 Hz, 2H, Ar–H), 7.21–7.19 (dd,
J1 = 10.5 Hz, J2 = 10.9 Hz, 2H, Ar–H), 4.86 (s, 1H,
NH), 3.73–3.70 (q, J = 9.1 Hz, 2H, CH2CH3), 3.31–3.26
(q, J = 8.9 Hz, 2H, CH2CH3), 3.15–3.04 (m, 2H, CH2),
2.36 (s, 3H, CH3C═N), 1.79–1.47 (m, 6H, 3 × CH2),
1.26–1.23 (t, J = 8.9 Hz, 3H, CH3CH2), 0.96–0.93
(t, J = 8.5 Hz, 3H, CH3CH2). 13C NMR (δ, ppm in
DMSO-d6): 173.1 (C═O), 158.8, 151.3, 141.9, 135.0,
132.3, 127.4, 120.8, 117.0, 116.8, 110.0, 41.3, 33.3, 29.3,
28.5 (2 × CH2), 25.3, 20.2, 15.1, 10.1 (CH3). DEPT 135
(δ, ppm in DMSO-d6): Positive signals are 141.9 (CH),
135.0 (CH), 132.3 (CH), 117.0 (CH), 116.8(CH), 20.2
(CH3), 15.1 (CH3), and 10.1 (CH3). Negative signals are
41.3, 33.3, 29.3, 28.5 (2 × CH2), and 25.3 (CH2).
UV–vis.: λmax (nm)/log εmax (molꢀ1 cmꢀ1): 208 (3.85),
215 (3.90), 224 (3.98), 230 (4.11), 257 (4.46). IR (cmꢀ1):
νN–H 3411, νC–H aliph. 2957, νC–H aliph. 2931, νC–H
aliph. 2861, νC═O 1668, νC═C 1638, νCH3 deformation
1460, νC–N 1123, ν = C–H bending 982, νAr–H 725.
N0-(4-Methylpentan-2-ylidene)-2-propyl
quinoline-4-carbohydrazide (4d).
Microwave assisted
reaction of 3 (3.0 g, 13 mmol) with 4-methylpentan-
2-one (1.62 mL, 13 mmol) for
2 min afforded
N0-(4-methylpentan-2-ylidene)-2-propylquinoline-4-carbo-
hydrazide, 4d as brown solid. Yield 3.05 g (70.00%); m.p.
268°C; C19H25N3O (311.42): Anal. Found: C, 73.28; H,
N0-(2-Oxoindolin-3-ylidene)-2-propylquinoline-4-
carbohydrazide (4f).
Microwave assisted reaction of 3
(3.0 g, 13 mmol) with isatin (1.91 g, 13 mmol) for 3 min
afforded N0-(2-oxoindolin-3-ylidene)-2-propylquinoline-4-
carbohydrazide, 4f as red solid. Yield 4.72 g, (94%); m.
p. > 300°C; C21H18N4O (358.39): Anal. Found: C,
70.21; H, 4.94; N, 15.48% Calc.: C, 70.38; H, 5.06; N,
15.63%. 1H NMR (δ, ppm in DMSO-d6): 7.98–7.96
(d, J = 8.2 Hz, 1H, Ar–H), 7.83–7.81 (d, J = 8.4 Hz, 1H,
Ar–H), 7.74–7.72 (d, J = 10.0 Hz, 2H, Ar–H), 7.51 (s,
1H, Ar–H), 7.44–7.40 (m, 2H, Ar–H), 7.29–7.26 (dd,
J1 = 10.0 Hz, J2 = 12.50 Hz, 2H, Ar–H), 6.01 (s, 1H,
NH), 5.80 (s, 1H, NH), 3.15–3.13 (t, J = 8.5 Hz, 2H,
CH2CH2), 1.71–1.67 (m, 2H, CH2), 0.99 (t, J = 8.0 Hz,
3H, CH3CH2). 13C NMR (δ, ppm in DMSO-d6): 180.0
(C═O), 173.2 (C═O), 158.4, 151.2, 146.9, 141.9, 135.9,
135.3, 132.8, 131.9, 127.4, 126.6, 121.7, 120.4, 117.3,
1
8.09; N, 13.49% Calc.: C, 73.12; H, 8.15; N, 13.58%. H
NMR (δ, ppm in DMSO-d6): 7.74–7.72 (d, J = 10.0 Hz,
2H, Ar–H), 7.51 (s, 1H, Ar–H), 7.29–7.26 (dd,
J1 = 10.0 Hz, J2 = 12.5 Hz, 2H, Ar–H), 5.80 (s, 1H,
NH), 3.73–3.72 (d, J = 7.2 Hz, 2H, CH2CH), 3.15–3.11
(t, J = 8.5 Hz, 2H, CH2CH2), 2.40 (s, 3H, CH3–C═N),
1.82–1.79 (m, 1H, CH), 1.71–1.67 (m, 2H, CH2),
1.10–1.08 (d, J = 8.2 Hz, 6H, 2 × (CH3)2–CH),
0.99–0.97 (t, J = 8.0 Hz, 3H, CH3CH2). 13C NMR (δ,
ppm in DMSO-d6): 173.2 (C═O), 158.4, 151.2, 141.9,
138.1, 128.7, 125.7, 120.8, 117.2, 115.3, 106.1, 44.2,
41.3, 29.3, 25.3, 21.3, 14.6 (2 × CH3), 10.1 (CH3). DEPT
135 (δ, ppm in DMSO-d6): Positive signals are 141.9
(CH), 138.1 (CH), 128.7 (CH), 117.2 (CH), 115.3 (CH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Bioactivity of Quinoline-based Hydrazide-hydrazones
116.7, 110.2, 109.1, 29.7, 25.5, 10.1 (CH3). DEPT 135 (δ,
ppm in DMSO-d6): Positive signals are 141.9 (CH), 135.9
(CH), 135.3 (CH), 132.8 (CH), 131.9 (CH), 121.7 (CH),
120.4 (CH), 117.3 (CH), 116.7 (CH), and 10.5 (CH3).
Negative signals are 29.7 (CH2) and 25.5 (CH2). UV–
vis.: λmax (nm)/log εmax (molꢀ1 cmꢀ1): 212 (4.08), 225
(4.09), 236 (4.25), 257 (4.73), 314 (4.50). IR (cmꢀ1):
νN–H 3415, νN–H 3281, νC–H arom. 3053, νC–H arom.
3020, νC–H aliph. 2854, νC═O 1723, νC═O 1688,
νC═C 1614, νCH3 deformation 1463, νC–N 1254,
ν = C–H bending 985, νAr–H 752.
132.3, 127.4, 120.8, 117.0, 116.8, 110.4, 61.9, 41.2, 35.8
(2 × CH2), 29.6, 24.7, and 13.4 (CH3). DEPT 135 (δ,
ppm in DMSO-d6): Positive signals are 142.7 (CH),
134.9 (CH), 132.3 (CH), 117.0 (CH), 116.8 (CH), and
13.4 (CH3). Negative signals are 61.9, 41.2, 35.8
(2 × CH2), 29.6, and 24.7 (2 × CH2). UV–vis.: λmax
(nm)/log εmax (molꢀ1 cmꢀ1): 207 (3.79), 213 (3.79), 227
(4.13), 254 (4.39), 308 (4.11). IR (cmꢀ1): νN–H 3415,
νC–H arom. 3030, νC–H aliph. 2930, νC–H aliph. 2865,
νC═O 1688, νC═C 1605, νCN 1575, νCH3 deformation
1467, νCH2 deformation 1355, νC–N 1248, ν = C–H
965, νAr–H 725.
N0-(3-Oxoheptan-2-ylidene)-2-propylquinoline-4-
carbohydrazide (4g).
Microwave assisted reaction of 3
N0-Cyclohexylidene-2-propylquinoline-4-carbohydrazide
(4i). Microwave assisted reaction of 3 (3.0 g, 13 mmol)
with cyclohexanone (1.35 mL, 13 mmol) for
2½ min afforded N0-cyclohexylidene-2-propylquinoline-
4-carbohydrazide, 4i as brown solid. Yield 3.54 g (88%);
m.p. 257–258°C; C19H23N3O (309.39): Anal. Found: C,
73.59; H, 7.31; N, 13.77% Calc.: C, 73.76; H, 7.49; N,
(3.0 g, 13 mmol) with heptane-2,3-dione (1.79 mL,
13 mmol) for 3 min afforded N0-(3-oxoheptan-2-ylidene)-
2-propylquinoline-4-carbohydrazide, 4g as brown solid.
Yield 3.85 g, (81%); m.p. 290–291°C; C20H25N3O3
(339.43): Anal. Found: C, 71.01; H, 7.59; N, 12.55%
1
Calc.: C, 70.77; H, 7.42; N, 12.38%. H NMR (δ, ppm in
1
DMSO-d6): 7.75–7.73 (d, J = 10.2 Hz, 2H, Ar–H), 7.55
(s, 1H, Ar–H), 7.29–7.26 (dd, J1 = 6.4 Hz, J2 = 10.2 Hz,
2H, Ar–H), 5.80 (s, 1H, NH), 3.73–3.70 (t, J = 6.1 Hz,
2H, CH2CH2), 3.31–3.25 (q, J = 6.9 Hz, 2H, CH2),
3.15–3.04 (m, 2H, CH2), 2.36 (s, 3H, CH3–C═N),
1.80–1.75 (m, 4H, 2 × CH2), 1.12–1.08 (t, J = 6.1 Hz,
3H, CH3CH2), 1.02–0.99 (t, J = 6.4 Hz, 3H, CH3CH2).
13C NMR (δ, ppm in DMSO-d6): 173.3 (C═O), 172.5
(C═O), 159.6, 151.0, 142.7, 134.9, 132.3, 127.4, 120.8,
117.0, 116.8, 110.4, 62.2, 41.1, 29.8, 29.3, 25.3, 20.2
(CH3), 15.1 (CH3), 11.1 (CH3). DEPT 135 (δ, ppm in
DMSO-d6): Positive signals are 142.7 (CH), 134.9 (CH),
132.3 (CH), 117.0 (CH), 116.8 (CH), 20.2 (CH3), 15.1
(CH3), and 11.1 (CH3). Negative signals are 62.2, 41.1,
29.8, 29.3, and 25.3 (CH2). UV–vis.: λmax (nm)/log εmax
(molꢀ1 cmꢀ1): 215 (4.33), 224 (4.43), 240 (4.33), 253
(4.49), 257 (5.14). IR (cmꢀ1): νN–H 3411, νC–H
arom.3010, νC–H aliph. 2929, νC–H aliph. 2891, νC═O
1715, νC═O 1688, νC═C 1620, νCH3 deformation 1461,
νC–N 1244, ν = C–H bending 967, νAr–H 725.
13.58%. H NMR (δ, ppm in DMSO-d6): 7.75–7.73 (d,
J = 10.2 Hz, 2H, Ar–H), 7.55 (s, 1H, Ar–H), 7.29–7.26
(dd, J1 = 6.6 Hz, J2 = 10.2 Hz, 2H, Ar–H), 5.80 (s, 1H,
NH), 3.76–3.72 (t, J = 7.4 Hz, 4H, 2 × CH2CH2),
3.31–3.27 (t, J = 5.6 Hz, 2H, CH2), 3.17–3.13 (m, 2H,
CH2), 1.80–1.75 (m, 4H, 2 × CH2), 1.25–1.22 (m, 2H,
CH2), 1.02–0.99 (t, J = 6.2 Hz, 3H, CH3CH2). 13C NMR
(δ, ppm in DMSO-d6): 172.4 (C═O), 159.5, 151.0, 142.6,
135.0, 132.4, 127.4, 120.8, 117.2, 116.8, 110.4, 61.9,
41.2, 35.8 (2 × CH2), 29.6, 24.7, 20.7, 13.9 (CH3). DEPT
135 (δ, ppm in DMSO-d6): Positive signals are 142.6
(CH), 135.0 (CH), 132.4 (CH), 117.2 (CH), 116.8 (CH),
and 13.9 (CH3). Negative signals are 61.9, 41.2, 35.8
(2 × CH2), 29.6, 24.7, and 20.7. UV–vis.: λmax (nm)/log
εmax (molꢀ1 cmꢀ1): 209 (4.57), 272 (5.42), 323 (5.25).
IR (cmꢀ1): νN–H 3411, νC–H arom. 3025, νC–H aliph.
2929, νC–H aliph. 2875, νC═O 1688, νC═C 1607,
νC═N 1575, νCH3 deformation 1465, νCH21360, νC–N
1245, ν = C–H bending 987, νAr–H 722.
N0-Cycloheptylidene-2-propylquinoline-4-carbohydrazide
N0-Cyclopentylidene-2-propylquinoline-4-carbohydrazide
(4j). Microwave assisted reaction of 3 (3.0 g, 13 mmol)
with cycloheptanone (1.54 mL, 13 mmol) for
2½ min afforded N0-cycloheptylidene-2-propylquinoline-
4-carbohydrazide, 4j as brown solid. Yield 3.74 g (89%);
m.p. 261–263°C; C20H25N3O (323.43): Anal. Found: C,
74.19; H, 7.95; N, 13.08% Calc.: C, 74.27; H, 7.79; N,
12.99%. 1H NMR (δ, ppm in DMSO-d6): 7.75–7.73
(d, J = 10.2 Hz, 2H, Ar–H), 7.55 (s, 1H, Ar–H), 7.29–
7.26 (dd, J1 = 6.6 Hz, J2 = 10.2 Hz, 2H, Ar–H), 5.80 (s,
1H, NH), 3.73 (t, J = 7.8 Hz, 4H, 2 × CH2CH2), 3.31–
3.27 (t, J = 5.6 Hz, 2H, CH2), 3.17–3.13 (m, 2H, CH2),
1.80–1.75 (m, 4H, 2 × CH2), 1.40 (m, 2H, CH2), 1.25–
1.22 (m, 2H, CH2), 1.02–0.99 (t, J = 6.2 Hz, 3H,
CH3CH2). 13C NMR (δ, ppm in DMSO-d6): 172.4
(C═O), 159.4, 151.0, 142.5, 135.0, 132.2, 127.5, 120.8,
(4h). Microwave assisted reaction of 3 (3.0 g, 13 mmol)
with cyclopentanone (1.15 ml, 13 mmol) for
1½ min afforded N0-cyclopentylidene-2-propylquinoline-
4-carbohydrazide, 4h as black solid. Yield 3.68g, (89%);
m.p. 255°C; C18H21N3O (295.38): Anal. Found: C,
72.99; H, 6.97; N, 14.39% Calc.: C, 73.19; H, 7.17; N,
1
14.23%. H NMR (δ, ppm in DMSO-d6): 7.75–7.73 (d,
J = 10.2 Hz, 2H, Ar–H), 7.55 (s, 1H, Ar–H), 7.29–7.26
(dd, J1 = 6.6 Hz, J2 = 10.2 Hz, 2H, Ar–H), 5.80 (s, 1H,
NH), 3.76–3.72 (t, J = 7.4 Hz, 4H, 2 × CH2CH2),
3.31–3.27 (t, J = 5.6 Hz, 2H, CH2), 3.17–3.13 (m, 2H,
CH2), 1.80–1.75 (m, 4H, 2 × CH2), 1.02–0.99 (t,
J = 6.2 Hz, 3H, CH3CH2). 13C NMR (δ, ppm in
DMSO-d6): 172.5 (C═O), 159.6, 151.0, 142.7, 134.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

O. O. Ajani, K. T. Iyaye, O. Y. Audu, S. J. Olorunshola, A. O. Kuye, and I. O. Olanrewaju
Vol 000
117.2, 116.7, 110.6, 61.5, 41.2, 35.8 (2 × CH2), 29.6
(2 × CH2), 24.7, 20.7, 13.9 (CH3). DEPT 135 (δ, ppm in
DMSO-d6): Positive signals are 142.6 (CH), 135.0 (CH),
132.4 (CH), 117.2 (CH), 116.8 (CH), and 13.9 (CH3).
Negative signals are 61.9, 41.2, 35.8 (2 × CH2), 29.6
(2 × CH2), 27.7, 24.5, and 20.9. UV–vis.: λmax (nm)/log
εmax (molꢀ1 cmꢀ1): 209 (4.55), 251 (4.45), 296 (4.28),
314 (4.07). IR (cmꢀ1): νN–H 3412, νC–H arom. 3020,
νC–H aliph. 2925, νC–H aliph. 2877, νC═O 1685, νC═C
1607, νC═N 1575, νCH3 deformation 1465, νCH2 1362,
νC–N 1245, ν = C–H bending 985, νAr–H 722.
NH), 3.31–3.27 (t, J = 6.8 Hz, 2H, CH2CH2), 2.40 (s,
3H, CH3–C═N), 1.80–1.74 (m, 2H, CH2), 1.02–0.99 (t,
J = 6.8 Hz, 3H, CH3CH2). 13C NMR (δ, ppm in
DMSO-d6): 177.2 (C═O), 172.5 (C═O), 161.5, 159.6,
155.2, 151.0, 142.7, 139.1, 135.2, 134.9, 132.3, 129.2,
127.4, 120.8, 117.0, 116.8, 114.0 (2 × CH), 111.9,
110.4, 54.1, 29.7, 20.1 (CH3), 13.4 (CH3). DEPT 135
(δ, ppm in DMSO-d6): Positive signals are 161.5,
155.2, 142.7 (CH), 134.9 (CH), 132.3 (CH), 129.2
117.0 (CH), 116.8 (CH), 114.0 (2 × CH), 20.1 (CH3),
and 13.4 (CH3). Negative signals are 54.1 (CH2) and
N0-(1-(4-ethylphenyl)ethylidene)-2-propylquinoline-4-
29.7
(CH2).
UV–vis.:
λmax
(nm)/log
εmax
(molꢀ1 cmꢀ1): 215 (4.06), 221 (4.44), 251 (4.68), 317
(4.09), 428 (4.04). IR (cmꢀ1): νN–H 3410, νC–H
arom. 3010, νC–H aliph. 2925, νC–H aliph. 2890,
νC═O ester 1745, νC═O 1685, νC═C 1620, νC═N
1575, νCH3 deformation 1460, νC–N 1243, ν = C–H
968, νAr–H 725.
Antimicrobial activity assay. The antimicrobial assay of
the compounds 4a–l was investigated against six
organisms, namely S. aureus, B. lichenformis, M. varians,
E. coli, P. vulgaris, and P. aeruginosa. Antibacterial
sensitivity testing was carried out on using agar diffusion
method while MIC test was determined by serial dilution
method as described by a standard method [25] as shown
in the supplementary information.
carbohydrazide (4k).
Microwave assisted reaction of 3
(3.0 g, 13 mmol) with 4-ethylacetophenone (1.94 mL,
13 mmol) for 2 min afforded N0-(1-(4-ethylphenyl)
ethylidene)-2-propylquinoline-4-carbohydrazide, 4k as
black solid. Yield 4.25 g, (91%); m.p. 241–243°C;
C23H25N3O (359.46): Anal. Found: C, 76.78; H, 6.88; N,
1
11.81% Calc.: C, 76.85; H, 7.01; N, 11.69%. H NMR
(δ, ppm in DMSO-d6): 7.98–7.96 (d, J = 8.0 Hz, 2H,
Ar–H), 7.75–7.72 (d, J = 10.2 Hz, 2H, Ar–H), 7.61–7.59
(d, J = 8.2 Hz, 2H, Ar–H), 7.52 (s, 1H, Ar–H), 7.29–7.26
(m, 2H, Ar–H), 5.80 (s, 1H, NH), 3.31–3.25
(q, J = 7.6 Hz, 2H, CH2CH3), 3.17–3.11 (q, J = 6.8 Hz,
2H, CH2CH2), 2.40 (s, 3H, CH3–C═N), 1.80–1.74 (m,
2H, CH2), 1.12–1.08 (t, J = 7.6 Hz, 3H, CH3CH2), 1.02–
0.99 (t, J = 6.5 Hz, 3H, CH3CH2). 13C NMR (δ, ppm in
DMSO-d6): 172.5 (C═O), 159.6, 151.0, 146.6 (2 × CH),
142.7, 134.9, 132.3, 127.4, 124.1 (2 × CH), 120.8, 117.0,
116.8, 110.4, 54.1, 29.7, 25.4, 20.1 (CH3), 15.3 (CH3),
13.4 (CH3). DEPT 135 (δ, ppm in DMSO-d6): Positive
signals are 146.6 (2 × CH), 142.7 (CH), 134.9 (CH),
132.3 (CH), 124.1 (2 × CH), 117.0 (CH), 116.8 (CH),
20.1 (CH3), 15.3 (CH3), and 13.4 (CH3). Negative signals
are 54.1 (CH2), 29.7 (CH2), and 25.4 (CH2). UV–vis.:
λmax (nm)/ log εmax (molꢀ1 cmꢀ1): 209 (4.55), 236
(4.45), 269 (4.28), 314 (4.07). IR (cmꢀ1): νN-H 3356,
νC–H arom.3050, νC–H aliph. 2925, νC–H aliph. 2804,
νC═O 1684, νC═C 1620, νC═C 1605, νC═N 1589,
νCH3 deformation 1461, νC–N 1248, ν = C–H bending
984, νAr–H 745.
Acknowledgments. The World Academy of Sciences (TWAS)
was gratefully acknowledged by OOA for the sponsorship of
this present work under the TWAS Research Grant for
Individual Scientists in Basic Sciences Programme (grant no.:
14-069 RG/CHE/AF/AC_1).
DECLARATION OF INTEREST
The authors confirm that this article content has no
conflict of interest.
N0-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-2-
REFERENCES AND NOTES
propylquinoline-4-carbohydrazide (4l). Microwave assisted
reaction of 3 (3.0 g, 13 mmol) with 3-acetylcoumarin
(2.44 g, 13 mmol) for 3 min afforded N0-(1-(2-
oxo-2H-chromen-3-yl)ethylidene)-2-propylquinoline-4-
carbohydrazide, 4l as yellow solid. Yield 4.41 g, (85%);
m.p. > 300°C; C24H21N3O3 (399.44): Anal. Found: C,
72.22; H, 5.19; N, 10.71% Calc.: C, 72.16; H, 5.30; N,
[1] Kannappan, N.; Reddy, S. R.; Sen, S.; Nagarajan, R.;
Dashpute, S. J Appl Chem Res 2009, 9, 59.
[2] Kharb, R.; Kaur, H. Int Res J Pharm 2013, 4, 63.
[3] Sonawane, R.; Tripathi, R. Int Lett Chem Phys Astron 2013,
7, 30.
[4] Chen, Y. J.; Wu, Y. C.; Liu, L.; Li, H. J.; Wang, D. J Org Chem
2006, 71, 6592.
[5] Brouet, J. C.; Gu, S.; Peet, N. P.; Williams, J. D. Synth
Commun 2009, 39, 5193.
[6] Sloop, J. C. J Phys Org Chem 2009, 22, 110.
[7] Zhang, X. L.; Wang, Q. Y.; Sheng, S. R.; Wang, Q.; Xiao-Ling,
L. Synth Commun 2009, 39, 3293.
[8] Almansour, A.; Arumugam, N.; Kumar, R. S.; Menendez,
J. C.; Ghabbour, H. A.; Fun, H. K.; Kumar, R. R. Tetrahedron Lett
2015, 56, 6900.
1
10.52%. H NMR (δ, ppm in DMSO-d6): 8.64 (s, 1H,
Het–H), 7.96–7.94 (d,
J = 8.0 Hz, 1H, Ar–H),
7.75–7.72 (d, J = 10.2 Hz, 2H, Ar–H), 7.70–7.66 (m,
2H, Ar–H), 7.52 (s, 1H, Ar–H), 7.29–7.26 (dd,
J1 = 10.20 Hz, J2 = 12.50 Hz, 2H, Ar–H), 5.80 (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Bioactivity of Quinoline-based Hydrazide-hydrazones
[9] Pandeya, S. N.; Tyagi, A. Int J Pharm Pharm Sci 2011, 3, 53.
[20] Ajani, O. O.; Ajayi, O.; Adekoya, J. A.; Owoeye, T. F.;
Durodola, B. M.; Ogunleye, O. M. J Appl Sci 2016, 16, 77.
[21] Cihan-Üstündağ, G.; Şatana, D.; Özhan, G.; Çapan, G. J
Enzyme Inhib Med Chem 2016, 31, 369.
[10] Bingul, M.; Tan, O.; Gardner, C. R.; Sutton, S. K.; Arndt,
G. M.; Marshall, G. M.; Cheung, B. B.; Kumar, N.; Black, D. S.
Molecules 2016, 21, 916.
[11] Baptiste, N. J.; Kalluyara, B. Der Pharm Chem 2016, 8, 167.
[12] Gopinath, V. S.; Pinjari, J.; Dere, R. J.; Verma, A.;
Vishwakarma, P.; Shivahare, R.; Moger, M.; Goud, P. S. K.; Ramanathan,
V.; Bose, P.; Rao, M. V. S.; Gupta, S.; Puri, S. K.; Launay, D.; Martin, D.
Eur J Med Chem 2013, 69, 527.
[22] Tehrani, K. H. M. E.; Zadeh, M. E.; Mashayekhi, V.; Hashemi,
M.; Kobarfard, F.; Gharebaghi, F.; Mohebbi, S. Iran J Pharm Res 2015,
14, 1077.
[23] Kumar, P.; Rai, A.; Singh, M.; Kumar, D.; Sahdev, A. K.; Raj,
V. EC Pharm Sci 2016, 2, 278.
[13] Wang, X.; Xie, X.; Cai, Y.; Yang, X.; Li, J.; Li, Y.; Chen, W.;
He, M. Molecules 2016, 21, 340.
[14] Gupta, S. K.; Mishra, A. Antiinflamm Antiallergy Agents Med
Chem 2016, 15, 545.
[24] Verma, G.; Marella, A.; Shaquiquzzaman, M.; Akhtar, M.; Ali,
M. R.; Alam, M. M. J Pharm Bioallied Sci 2014, 6, 69.
[25] Russell, A. D.; Furr, J. R. J Appl Bacteriol UK 1977, 43,
253.
[15] Chung, P. Y.; Tang, J. C. O.; Cheng, C. H.; Bian, Z. X.; Wong,
W. Y.; Lam, K. H.; Chui, C. H. SpringerPlus 2016, 5, 271.
[16] Phopin, K.; Sinthupoom, N.; Treeratanapiboon, L.;
Kunwittaya, S.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V.
EXCLI J 2016, 15, 144.
[26] Ladhani, S.; Garbash, M. Pediatr Drugs 2005, 7, 77.
[27] Nair, N.; Biswas, R.; Götz, F.; Biswas, L.; Andrews-
Polymenis, H. L. Infect Immun 2014, 82, 2162.
[17] Afzal, O.; Kumar, S.; Haider, R. M.; Rahmat, A. M.; Kumar,
R.; Jaggi, M.; Bawa, S. Eur J Med Chem 2015, 97, 871.
[18] Arafa, R.; Hegazy, G. H.; Piazza, G. A.; Abadi, A. H. Eur J
Med Chem 2013, 63, 826.
[19] Ajani, O. O.; Obafemi, C. A.; Nwinyi, O. C.; Akinpelu, D. A.
Bioorg Med Chem 2010, 18, 214.
SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet