Potential anti-bacterial agents: Montmorillonite clay-catalyzed synthesis of novel 2-(3,5-substituted-1H-pyrazol-1-yl)-3-substituted quinolines and their in silico molecular docking studies

Article abstract of DOI:10.1039/c4ra10534f

A series of 2-(3,5-substituted-1H-pyrazol-1-yl)-3-substituted quinolines 5a-g, were obtained from 2-chloro-3-(1,3-dioxolan-2-yl) quinolines 2a-c and diketones 3a-c with great yields by utilizing Montmorillonite clay K-10 as a catalyst in an eco-friendly methodology. All the synthesized compounds were characterized by FTIR, ¹H-NMR, ¹³C-NMR and HRMS spectral techniques. Antibacterial screening of the compounds revealed that some of the compounds demonstrate moderate to good results. Amongst all, compound 2c displayed a good inhibitory profile against P. aeruginosa and B. subtilis, while compound 5c exhibited remarkable activity against S. aureus, B. subtilis and P. aeruginosa with an MIC value of 25 μg mL^-1. Moreover, compound 5c presented a MIC value of 50 μg mL^-1 against E. coli and K. pneumoniae, which was comparable to that of the standard. In addition, compound 5f was demonstrated good viability against S. aureus and P. aeruginosa with a MIC value of 25 μg mL^-1. Compounds 2c and 5f, however, showed relatively moderate inhibition against S. aureus, while the latter had a moderate activity against B. subtilis. To further demonstrate the antibacterial efficacy of 2c, 5c and 5f, molecular docking studies were done, confirming that compound 5c possesses good binding interaction with the peptide deformylase protein, with a binding energy of -8.1 kcal mol^-1 - more prominent than that of standard ampicillin (-7.5 kcal mol^-1) - while compounds 2c and 5f have moderate binding affinity. This journal is

Full text of DOI:10.1039/c4ra10534f

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: P. pasupala, R.
Subashini, K.R. Ethiraj and F. Nawaz Khan, RSC Adv., 2014, DOI: 10.1039/C4RA10534F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 15
RSC Advances
Dynamic Article Links►
Journal Name
View Article Online
DOI: 10.1039/C4RA10534F
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Potential anti-bacterial agents: Montmorillonite Clay catalyzed
synthesis of novel 2-(3, 5-substituted-1H-pyrazol-1-yl)-3-substituted
quinolones and their in-silico molecular docking studies
5
Pasupala Pavan, R. Subashini*, K. R. Ethiraj and Fazlur-Rahman Nawaz Khan*
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A series of 2ꢀ(3,5ꢀsubstitutedꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ3ꢀsubstituted quinolines 5(a-g), were obtained from 2ꢀchloroꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀ
10 yl)quinolines 2(a-c) and diketones 3(a-c) in great yields by utilizing Montmorillonite clay Kꢀ10 as a catalyst through ecoꢀfriendly
methodology. All the synthesized compounds were characterized by FTIR, 1HꢀNMR, 13CꢀNMR and HRMS spectral techniques.
Antibacterial screening of the compounds revealed that some of the compounds demonstrate moderate to good results. Amongst all,
compound 2c displayed good inhibitory profile against P. aeruginosa and B. subtilis while compound 5c exhibited remarkable activity
against S. aureus, B. subtilis and P. aeruginosa with an MIC value of 25µg/mL and moreover against E. coli and K .pneumonia the
15 compound 5c was representing a MIC value of 50µg/mL which was comparable to that of the standard. In addition, the compound 5f
was demonstrating good viability against S. aureus and P. aeruginosa with a MIC value of 25µg/mL. The compounds 2c and 5f
however showed relatively moderate inhibition against S. aureus, while the later had a moderate acitivity against B. subtilis respectively.
To further display the antibacterial efficacy of 2c, 5c and 5f molecular docking studies were done which confirmed that compound 5c
possess good binding interaction with that of peptide deformylase protein with a binding energy of ꢀ8.1 Kcal/mol which was more
20 prominent than standard Ampicillin (ꢀ7.5 Kcal/mol) while the compounds 2c and 5f have moderate binding affinity.
biologically active molecules relevant to the pharmaceutical and
agrochemical sectors. They have shown broad spectrum of
1Introduction
pharmacological and biological activities such as antiꢀ
microbial13, antiꢀtumor14, antiꢀfungal 15, antiꢀtubercular 16, antiꢀ
Heterocyclic compounds particularly, the functionalized
quinolines have exhibited considerable attention owing to their
18ꢀ19
55 leukemia17, antiꢀdepressant
hyperglycemic21properties.
,
antiꢀconvulsant20and antiꢀ
25 biological properties such as antiꢀasthmatic, antibacterial, antiꢀ
inflammatory and antiꢀhypertensive properties1.
The
Compounds incorporating the pyrazolyl structural unit are being
developed in a wide variety of therapeutic areas22. Pyrazolo [3,4ꢀ
b]quinoline derivatives are significant for their pharmacological
functionalized quinolines are widespread in many natural
products2 and find their applications in the synthesis of
pharmaceuticals and biologically active molecules3.
30 Subsequently, various procedures have been proposed for
developing highly functionalized quinoline frameworks which
has always been a fascinating theme to numerous organic and
medicinal chemists4. In addition, late literature survey on
heterocyclic systems either annulated or substituted quinoline
35 frame were signifying different biological activities. For
example, the mono triazolyl substituted quinolines possess antiꢀ
cancer activity5, quinolineꢀbased azetidinone and thiazolidinone
analogues were promising antimicrobial and antitubercular
activity6, 4ꢀarylchalcogenylꢀ7ꢀchloroquinolines presented good
40 antioxidant activity7, isoxazolylpyrimido[4,5ꢀb]quinolines and
isoxazolylchromeno[2,3ꢀd]pyrimidinꢀ4ꢀones exhibited good
antimicrobial, antiꢀinflammatory and analgesic activity8.
Particularly, the 2ꢀsubstituted quinoline ring systems were
reported to be possessing diversified therapeutic activities9ꢀ10. The
45 Cꢀ2 pyridinyl and pyridinyl vinyl substituted quinolones were
reported to possess very good antiꢀfungal activity11 and an
introduction of an aryl or indole moiety at Cꢀ2 of quinoline ring
resulted in potent PDE4 inhibitory properties12. Likewise,
pyrazoles then again are heterocyclic targets of considerable
50 importance and are available in an extensive number of
60 activities23.
Particularly,
they
display
potential
antiviral, antimalarial24and antiꢀinflammatory properties25. As of
late, the utilization of solid supported reagents has gained
considerable significance in organic synthesis attributable to their
simplicity of handling, reaction rates, greater selectivity, simple
65 workꢀup and reusability of the catalyst26. The effectiveness of
Montmorillonite Kꢀ10 catalysis in organic synthesis has been
demonstrated by their advantages of high atom efficiency,
simplified isolation of product, easy recovery and recyclable of
the catalysts27ꢀ29
.
By considering all the above aspects in
70 continued quinoline research interests30ꢀ34, we were intrigued to
synthesize novel molecules having substituted pyrazole ring in
the 2nd position of quinoline moiety by green chemistry approach
utilizing MKꢀ10 catalyst.
2Results and discussion
75 2.1 Chemistry
In the present study, synthesis of novel 2ꢀ(3, 5ꢀsubstitutedꢀ1Hꢀ
pyrazolꢀ1ꢀyl)ꢀ3ꢀ quinolines, 4, 5(a-g) is reported following the
schemes depicted in Scheme 1. At first, the 2ꢀchloroꢀ3ꢀ(1, 3ꢀ
dioxolanꢀ2ꢀyl) quinoline derivatives, 1(a-f) acquired from the
80 corresponding chloroformyl derivatives,35 were reacted with an
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 |1

RSC Advances
Page 2 of 15
View Article Online
DOI: 10.1039/C4RA10534F
excess of hydrazine hydrate in ethanolic solution in the presence
of catalytic amount of ammonia under reflux condition to offer
the 2ꢀhydrazinoꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)quinolines, 2(a-f) in
quantitative yields in a short reaction time (1ꢀ2 h) than the
existence of methyl groups at position 7 and 8 of quinoline
nucleus which may expect to increase lipophilicity of the
molecule.
5
reported procedure36 (Table 1). One of the compounds, 2b was 70 The same pattern was observed in biological effect for the series
crystallized, analysed successfully and reported37.
5(a-g), where, the compounds 5c and 5f were found to be better
active over all other members of the series. The compound 5c
was found to have same or better MIC values over the standard
utilizied for the study. In the compounds 5a, 5b and 5c the
Compounds 2 were then reacted with diketones, 3(a-c) in
ethanolic medium by utilizing different catalysts to offer the 2ꢀ
10 (3,5ꢀsubstitutedꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ3ꢀsubstituted quinolines, 5(a- 75 position 7 on quinoline nucleus was unsubstituted while, two
g). The reaction conditions were optimized by conducting the
model reaction of 2b and acetyl acetone, 3a and by utilizing
different catalysts,for example, conc. H2SO4, anhydrous AlCl3,
SnCl2.2H2O and MKꢀ10 under reflux conditions in EtOH. The
methyl groups existed in the 3’ and 5’ positions of the compound
5a. Likewise, in the compound 5c the methyl groups were
replaced with aromatic system at 3’ and 5’ positions. Compound
5c was found to have potential and exceptional antibacterial
15 results are listed in Table 2. The reaction did not continue in the 80 character with a MIC value of 25µg/mL against S. aureus,
absence of catalyst; while, the reaction did proceed with a 57ꢀ
83% yields in the presence of catalysts. On examining different
catalysts, the MKꢀ10 was chosen as the best catalyst for the
synthesis of 2ꢀ(3, 5ꢀdimethylꢀ1Hꢀpyrazolꢀyl)ꢀ3ꢀ(1,3ꢀdioxolanꢀ
P. aeruginosa, B. Subtilis and 50µg/mL against E. coli and
K. pneumonia respectively. The compound 5f, having methyl
groups at position 7 and 8 of quinoline nucleus and further more
at 3’ and 5’ positions in pyrazole moiety has astounding activity
20 2yl)ꢀ7ꢀmethyl quinolones,5d. The catalyst loading of MKꢀ10 has 85 against S. aureus, P. Aeruginosa with a MIC of 25 µg/mL.
been screened from 20 mg to 140 mg and proposed that 100 mg
of the catalyst the reaction was essential for the completion of the
reaction. The 2ꢀ(3, 5ꢀsubstitutedꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ3ꢀsubstituted
quinolines 5(a-g) were isolated in excellent yields (Table 3). It is
Remaining compounds were found to be not signifying any
promising antibacterial activity. This indicated that the
replacement of methyl to aromatic ring have resulted in
compounds with better antibacterial property which makes the
25 observed, that in the presence of conc. H2SO4, the deprotection of 90 compound optimum lipophilic in nature.
aldehyde protecting group have resulted in the formation of 2ꢀ(3,
5ꢀdimethylꢀ1Hꢀpyrazolꢀ1ꢀylꢀ7ꢀmethylquinolineꢀ3ꢀcarbaldehyde,4.
The plausible mechanism of formation of the desired compound,
5d is delineated in Fig. 1.
The assessment of the docking results were carried out by
simultaneously sorting the different complexes concerning the
anticipated binding energies (Table 5), (Fig 3). From the results
95 acquired from the docking analysis it was apparent that the
compound 5c have good binding interaction with that of peptide
deformylase with binding energy of ꢀ8.1 Kcal/mol which was
more noteworthy than the standard Ampicillin (ꢀ7.5 Kcal/mol).
The compounds 2c and 5f have moderate binding affinity with
30
The structures of all the compounds 4, 5(a-g) were affirmed by
from the FTꢀIR, 1HꢀNMR, 13CꢀNMR and mass and HRMS
spectra. The mass spectrum of 5d demonstrated a molecular ion
peak at m/z 310 [M + H]+, which indicates the addition reaction
35 of the acetyl acetone, 3a to the 1ꢀ(3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ7ꢀ 100 receptor possessing binding energies ꢀ7.3 and ꢀ6.9 Kcal/mol.
methylquinolinꢀ2ꢀyl)hydrazine, 2b. The appearance of three
methyl protons at δ 2.32 ppm is attributable to the ꢀCH3 group at
7 position of the quinoline system. The three methyl protons
3 Experimental
appeared as singlet each at δ 2.43 ppm and δ 2.47 ppm
40 attributable to the two methyl groups in the pyrazole moiety.
Likewise, the existence of four methylene protons at δ 4.08 ppm
indicates the dioxalanyl moiety and the peaks observed at δ 5.97,
δ 6.13, δ 7.45, δ 7.79 and δ 7.82 ppm are attributable to the five
The materials were purchased from SigmaꢀAldrich, Merck and
were utilized without any additional purification. All reactions
105 were observed by TLC (Thin layer chromatography). Melting
points were recorded on an Elchem digital melting point
1
apparatus in open capillaries and are uncorrected. The HꢀNMR
1
aromatic protons in HꢀNMR spectrum. The 13CꢀNMR spectrum
spectra was measured on a Bruker Avanceꢀ400 MHz instrument
at room temperature. Chemical shifts δ are in parts per million
110 (ppm) measured in CDCl3 or DMSOꢀd6 as solvent and relative to
TMS as the internal standard. Mass spectra were obtained using
ESI, LCMS, and HRMS spectrometry.
45 of compound 5d demonstrated peakscarbons at δ 10.9, δ 17.3, δ
22.7 and δ 66.4 ppm attributable to the aliphatic and peaks from δ
101.6 to δ 160 ppm are attributable to the aromatic carbons.
2.2Anti-bacterial evaluation
50
The structural activity relationship investigations of 2ꢀhydrazinoꢀ
3ꢀ(1,3ꢀdioxolanꢀ2yl)quinolines, (2a-c) and 2ꢀpyrazoloquinolinꢀ3ꢀ
(1,3ꢀdioxolanꢀ2ꢀyl)quinolones, (5a-f) were performed for their
antimicrobial activity against five separate bacterial organisms.
55 The antibacterial effect of the compounds was assessedutilizing
ampicillin as a standard and reported as minimum inhibitory
concentration (MIC) values. Graphical representation of the
antibacterial trend followed could be seen in Fig. 2. In the 2ꢀ
hydrazinoꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)quinoline series, from compound
60 2a to 2c the number of methyl groups was found to be increasing
at positions 7 and 8 and therefore amongst 2(a-c) the antibacterial
effects was found to be higher for compound 2c, against all the
tested bacteria. The compound 2c exhibited MIC value of
25µg/mL which is comparable to the standard employed against
65 P. aeruginosa and B. subtilis. This may be ascribed to the
115
3.1 General procedure of the synthesis of 2-chloro-3-(1,3-
dioxolan-2-yl)quinolines, 1(a-f)
A solution of 2ꢀchloroquinolineꢀ3ꢀcarbaldehydes, (10 mmol) in
120 benzene (50 mL) containing ethylene glycol (1.78 g, 1.6 mL, 28.5
mmol) and a crystal of tolueneꢀpꢀsulfonic acid was heated under
reflux for 5 h utilizing a DeanꢀStark apparatus until no more
water collected in the side arm. The cooled solution was treated
with saturated aqueous sodium carbonate (50 mL). Benzene
125 layer was separated, dried and evaporated to afford 1(a-f) which
were recrystallized from petroleum ether gave a yellowish solids.
The products were characterized by NMR, mass spectral
techniques.
2
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
2-Chloro-3-(1,3-dioxolan-2-yl)quinolines,1a
Pale
yellow
65 3.2 General procedure for the synthesis of compounds 2(a-f)
The 2ꢀhydrazinoꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl) quinolines, 2(a-f) were
powder, 65 % yield, mp 60ꢀ62 °C (Lit. 59ꢀ60 °C)36.IR
(KBrpellets, cmꢀ1) υ: 2899, 1621, 1567, 1330, 1100, 755. 1H
NMR (CDCl3, ppm, 400 MHz) δ: 4.13 (4H, m, CH2), 6.24 (1H, s,
CH), 7.55 (1H, t, J = 8 Hz, CH), 7.73 (1H, t, J = 8 Hz, CH), 7.84
prepared
by
refluxing
2ꢀchloroꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)
quinolines36, 1(a-f) (0.5 mmol) with excess of hydrazine hydrate
5
(3 ml) in ethanolic solution in the presence of catalytic amount of
(1H, d, J = 8 Hz, CH), 8.02 (1H, d, J = 8 Hz, CH), 8.40 (1H, s, 70 ammonia for 1ꢀ2 h. The completion of the reaction was
CH). 13C NMR (CDCl3,ppm, 100 MHz) δ: 2 x 66.2 (CH2ꢀCH2),
100.7 (CHꢀO), 124.8, 126.7, 127.1, 127.8, 128.9, 135.4, 141.7,
148.3, 149.2 (C=N). Mol. formula: C12H10ClNO2 requires 235;
monitored by TLC, excess solvent was removed and then poured
on to crushed ice. The solid separated was filtered and dried. The
compounds are pure enough to proceed further without any
additional purification.
10 ESIꢀMS m/z: 235 (M+).
75
2-Chloro-3-(1,3-dioxolan-2-yl)-7-methylquinolines,1b35 Pale
yellow powder, 85 % yield, mp 72ꢀ74 °C (Lit. 75ꢀ76 °C) 36. IR
(KBr pellets, cmꢀ1) υ: 2921, 1626, 1541, 1330, 1101, 810. 1H
15 NMR (CDCl3, ppm, 400 MHz) δ: 2.58 (3H, s, CH3), 4.13 (4H, m,
1-(3-(1,3-Dioxolan-2-yl)quinolin-2-yl)hydrazines,2a
Pale
brown solid, 68 % yield, mp 68ꢀ70 °C (Lit. 68 °C)36. IR (KBr
pellets, cmꢀ1) υ: 3389, 3290, 2886, 1627. 1H NMR (DMSOꢀd6,
ppm, 400 MHz) δ: 4.02 (4H, m, CH2), 4.47 (2H, s, NH2), 5.84
CH2), 6.24 (1H, s, CH), 7.42 (1H, d, J = 8 Hz, CH), 7.75 (1H, d, J 80 (1H, s, CH), 7.20 (1H, t, J = 8 Hz, CH), 7.40 (1H, s, CH), 7.53
= 8 Hz, CH), 7.83 (1H, s, CH), 8.37 (1H, s, CH). 13C NMR
(CDCl3, ppm, 100 MHz) δ: 22.0 (CH3), 2 x 65.5 (CH2ꢀCH2),
100.5 (CHꢀO), 124.8, 127.3, 127.6, 128.4, 129.5, 136.4, 141.7,
20 148.0, 149.2 (C=N). Mol formula: C13H12ClNO2 requires 249;
ESIꢀMS m/z: 250 (M+1).
(2H, m, CH), 7.71 (1H, d, J = 8 Hz, CH), 8.01 (1H, s, NH). 13C
NMR (DMSOꢀd6, ppm, 100 MHz) δ: 2 x 65.1 (CH2ꢀCH2), 100.0
(CHꢀO), 120.6, 2 x 122.1, 125.3, 125.9, 127.1, 133.4, 143.6,
156.7(C=N). Mol. formula: C12H13N3O2 requires 231; LCꢀMS
85 m/z: 232 (M+1).
2-Chloro-3-(1,3-dioxolan-2-yl)-7,8-dimethylquinolines,1c.
Pale yellow powder, 81 % yield, mp 107ꢀ109 °C. IR (KBr
25 pellets, cmꢀ1) υ: 3053, 2887, 1606, 1563, 1360, 1108, 781. 1H
1-(3-(1,3-Dioxolan-2-yl)-7-methylquinolin-2-yl)hydrazines,
2bReddish brown crystal, 78 % yield, mp 94ꢀ96 °C (Lit. 92ꢀ94
°C)36. IR (KBr pellets, cmꢀ1) υ: 3341, 3211, 2836, 1605. 1H
NMR (CDCl3, ppm, 300 MHz) δ: 2.54 (3H, s, CH3), 2.72 (3H, s, 90 NMR (DMSOꢀd6, ppm, 400 MHz) δ: 2.51 (3H, s, CH3), 4.07 (4H,
CH3), 4.10 (4H, m, CH2), 6.22 (1H, s, CH), 7.44 (1H, d, J = 9 Hz,
CH), 7.69 (1H, d, J = 9 Hz, CH), 8.65 (1H, s, CH). 13C NMR
(CDCl3, ppm, 75 MHz) δ: 13.3 (CH3), 20.7 (CH3), 2 x 65.4 (CH2ꢀ
30 CH2), 100.5(CHꢀO), 124.8, 125.1, 127.8, 129.9, 133.7, 136.6,
m, CH2), 4.61 (2H, s, NH2), 5.85 (1H, s, CH), 7.12 (1H, d, J = 8
Hz, CH), 7.55 (1H, d, J = 8 Hz, CH), 7.59 (1H, s, CH), 7.93 (1H,
s, CH), 8.10 (1H, s, NH). 13C NMR (DMSOꢀd6, ppm, 100 MHz)
δ: 21.9, 2 x 65.0 (CH2ꢀCH2), 101.8 (CHꢀO), 117.8, 121.2, 125.0,
138.9, 146.9, 147.9 (C=N). Mol. formula: C14H14ClNO2 requires 95 125.5, 127.5, 135.0, 140.5, 147.4, 156.5 (C=N). Mol. formula:
263.7; ESIꢀMS m/z: 264 (M+).
C13H15N3O2 requires 245; LCꢀMS m/z: 246 (M+1).
2-Chloro-3-(1,3-dioxolan-2-yl)-6-methylquinolines,1d
Pale
1-(3-(1,3-Dioxolan-2-yl)-7,8-dimethylquinolin-2-yl)hydrazines
, 2c Reddish brown crystal, 78 % yield, mp 117ꢀ119 °C. IR (KBr
100 pellets, cmꢀ1) υ: 3413, 3225, 2841, 1612. 1H NMR (DMSOꢀd6,
ppm, 400 MHz) δ: 2.34 (3H, s, CH3), 2.46 (3H, s, CH3), 4.07
(4H, m, CH2), 4.81 (2H, s, NH2), 6.21 (1H, s, CH), 7.33 (1H, d, J
= 8 Hz, CH), 7.54 (1H, d, J = 8 Hz, CH), 8.27 (1H, s, CH), 8.30
(1H, s, CH), 8.56 (1H, s, NH). 13C NMR (DMSOꢀd6, ppm,100
105 MHz) δ: 13.3, 20.7, 2 x 65.4 (CH2ꢀCH2), 100.5 (CHꢀO), 124.8,
125.1, 127.8, 129.9, 133.7, 136.6, 138.9, 146.9, 157.4 (C=N).
Mol. formula C14H14ClNO2 requires 259; LCꢀMS m/z: 260
(M+1).
yellow powder, 78 % yield, mp 52ꢀ54 °C (Lit. 48ꢀ50 °C)36 IR
35 (KBr pellets, cmꢀ1) υ: 2894, 1598, 1329, 1096, 823. 1H NMR
(CDCl3, ppm, 300 MHz) δ: 2.54 (3H, s, CH3), 4.20ꢀ4.13 (4H, m,
CH2), 6.23 (1H, s, CH), 7.62ꢀ7.57 (2H, m, CH), 7.95ꢀ7.92 (1H, d,
J = 8.55 Hz, CH), 8.32 (1H, s, CH). 13C NMR (CDCl3, 75 MHz)
δ: 21.5, 2 x 65.3 (CH2ꢀCH2), 100.3 (CHꢀO), 126.3, 126.5, 128.3,
40 135.9, 138.3, 139.5, 148.2, 149.2, 149.7 (C=N). Mol. formula:
C13H12ClNO2 requires 249.69: LCꢀMS m/z: 250 (M+1).
2-Chloro-3-(1,3-dioxolan-2-yl)-8-methylquinolines,1e
Pale
yellow powder, 87% yield, mp 86ꢀ88 °C (Lit. 88ꢀ90 °C)36. IR
45 (KBr pellets, cmꢀ1) υ: 2919, 2883, 1614, 1597, 1330, 1101, 765.
1H NMR (CDCl3, ppm, 400 MHz) δ: 2.78 (3H, s, CH3), 4.12
(4H, m, CH2), 6.26 (1H, s, CH), 7.44 (1H, t, J = 8 Hz, CH), 7.58
(1H, d, J = 8 Hz, CH), 7.68 (1H, d, J = 8 Hz, CH), 8.37 (1H, s,
CH). 13C NMR (CDCl3, ppm, 100 MHz) δ: 18.0, 2 x 65.0 (CH2ꢀ
50 CH2), 101.5 (CHꢀO), 119.1, 121.7, 122.1, 122.6, 126.3, 130.4,
133.2, 135.2, 146.1, 155.4 (C=N). Mol. formula: C13H12ClNO2
requires 249.7; LCꢀMS m/z: 250 (M+).
110 1-(3-(1,3-Dioxolan-2-yl)-6-methylquinolin-2-yl)hydrazines, 2d
Reddish brown solid, 73 % yield, mp 84ꢀ86 °C (Lit. 84ꢀ86 °C) 36
.
IR (KBr pellets, cmꢀ1) υ: 3331, 3221, 2829, 1611. 1H NMR
(DMSOꢀd6, ppm, 400 MHz) δ: 2.46 (3H, s, CH3), 4.07 (4H, m,
CH2), 4.47 (2H, s, NH2), 5.84 (1H, s, CH), 7.40 (1H, s, CH), 7.42
115 (1H, d, J = 8 Hz, CH), 7.66 (1H, d, J = 8 Hz, CH), 7.89 (1H, s,
CH), 8.21 (1H, s, NH). 13C NMR (DMSOꢀd6, ppm, 100 MHz) δ:
21.1, 2 x 64.9 (CH2ꢀCH2), 101.7 (CHꢀO), 118.7, 123.3, 125.8,
127.8, 132.0, 132.5, 134.7, 145.6, 156.0 (C=N). Mol. formula:
C13H15N3O2 requires 245; LCꢀMS m/z: 246 (M+1).
2-Chloro-3-(1,3-dioxolan-2-yl)-8-methoxyquinolines,1f Pale
55 yellow powder, 82 % yield, mp 119ꢀ121 °C. IR (KBr pellets,
cmꢀ1) υ: 2923, 1632, 1587, 1330, 1107, 805. 1H NMR (CDCl3,
300 MHz, ppm) δ: 3.92 (3H, s, OCH3), 4.10 (4H, m, CH2), 6.22
(1H, s, CH), 7.10 (1H, d, J = 9 Hz, CH), 7.37 (1H, t, J = 9 Hz,
CH), 7.91 (1H, d, J = 9 Hz, CH), 8.30 (1H, s, CH). 13C NMR
60 (CDCl3, ppm, 75 MHz) δ: 55.5, 2 x 65.5 (CH2ꢀCH2), 100.4 ,
105.5 (CHꢀO), 2 x 123.5, 127.9, 129.5, 135.3, 143.6, 146.5
(C=N), 158.2 (CꢀOCH3). Mol. formula: C13H12ClNO3 requires
265.7; ESIꢀMS m/z: 266 (M+).
120
1-(3-(1,3-Dioxolan-2-yl)-8-methylquinolin-2-yl)hydrazines, 2e
Reddish brown solid, 76 % yield, mp 97ꢀ99 °C (Lit. 98ꢀ100 °C)
36. IR (KBr pellets, cmꢀ1) υ: 3374, 3219, 2883, 1619. 1H NMR
(DMSOꢀd6, ppm, 300 MHz) δ: 2.48 (3H, s, CH3), 3.97 (4H, m,
125 CH2), 4.52 (2H, s, NH2), 5.86 (1H, s, CH), 7.11 (1H, t, J = 9 Hz,
CH), 7.40 (1H, d, J = 9 Hz, CH), 7.42 (1H, s, CH), 7.55 (1H, d, J
= 9 Hz, CH), 7.98 (1H, s, NH). 13C NMR (DMSOꢀd6, ppm, 75
MHz) δ: 18.0, 2 x 65.5 (CH2ꢀCH2), 100.5 (CHꢀO), 119.1, 121.7,
122.1, 122.6, 126.3, 130.4, 133.2, 135.2, 146.1, 155.4 (C=N).
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |3

RSC Advances
Page 4 of 15
View Article Online
DOI: 10.1039/C4RA10534F
Mol. formula: C13H15N3O2 requires 245; ESI m/z: 245 (M+).
1-(3-(1,3-Dioxolan-2-yl)-6-methoxyquinolin-2-yl)hydrazines,
2f Reddish brown solid, 69 % yield, mp 102ꢀ104 °C (Lit. 100ꢀ
102 °C)36. IR (KBr pellets, cmꢀ1) υ: 3433, 3219, 2831, 1621.1H
NMR (DMSOꢀd6, ppm, 400 MHz) δ: 3.90 (3H, s, OCH3), 4.13
(4H, m, CH2), 4.52 (2H, s, NH2), 5.98 (1H, s, CH), 7.42 (1H, s,
CH), 7.87 (1H, d, J = 8 Hz, CH), 7.93 (1H, d, J = 8 Hz, CH), 8.30
(1H, s, CH), 8.76 (1H, s, NH). 13C NMR (DMSOꢀd6, ppm, 100
MHz) δ: 55.9, 2 x 65.4 (CH2ꢀCH2), 100.3 (CHꢀO), 109.1, 119.1,
6.12 (s, 1H, CH), 6.71 (s, 1H, CH), 7.31 (m, 2H, CH), 7.41 (m,
65 5H, CH), 7.52 (m, 4H, CH), 7.56 (t, 1H, CH), 7.71 (m, 2H, CH),
8.03ꢀ8.05 (d, 1H, J = 8 Hz, CH). 13C NMR (DMSOꢀd6, 100 MHz,
ppm), δ: 2 x 66.3 (CH2ꢀCH2), 100.9 (CHꢀO), 103.6, 119.8, 124.9,
5
125.8, 2 x 126.7, 2 x 127.5, 127.8, 2 x 128.3, 2 x 128.9, 2 x
132.8, 133.4, 144.5, 145.7, 150.8, 161.4 (C=N). LCꢀMS m/z:
70 420 (M+1).Mol. formula: C27H21N3O2 requires 419.16.HRMS
[EI+] calcd for C27H21N3O2m/z 419.1634 [M+], found 419.1643.
10 2 x 127.7, 127.9, 136.4, 139.3, 148.3, 159.4 (C=N). Mol. formula
C13H12ClNO3 requires 261; ESIꢀMS m/z: 262 (M+1).
2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(1,3-dioxolan-2-yl)-7-
~
methylquinoline, 5d mp >300 °C, FTIR,
ν
/cm–1:2920, 2850,
75 1690, 1628. 1H NMR (DMSOꢀd6, 500 MHz, ppm),
δ
: 2.32 (s, 3H,
3.3 General procedure for the synthesis of compounds 4, 5(a-g)
Equimolar mixture of 2ꢀhydrazinoꢀ3ꢀ(1, 3ꢀdioxolanꢀ2ꢀ
15 yl)quinoline, 2(a-c) and diketones, 3(a-c) were taken in ethanol
and 100 mg of MKꢀ10 catalyst was added and refluxed on water
bath for 2ꢀ4 h. On completion of the reaction, the solution was
filtered to remove the catalyst, MKꢀ10 and then the excess
solvent was extracted using rotary evaporator to yield 2ꢀ(3,5ꢀ
20 substitutedꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ1ꢀ(1,3ꢀdioxolanꢀ2ꢀyl), 5(a-g) in
good yields. At the commencement of our work, conventional
approach of this synthesis was attempted by reacting compound
2b with acetyl acetone, 3a in the presence of conc. H2SO4 which
resulted in deprotection of aldehyde group and 2ꢀ(3, 5ꢀdimethylꢀ
25 1Hꢀpyrazolꢀ1ꢀyl)quinolineꢀ3ꢀcarbaldehyde, 4 was formed.
CH3), 2.43 (s, 3H, CH3), 2.47 (s, 3H, CH3), 4.08 (m, 4H, CH2),
5.97 (s, 1H, CH), 6.13 (s, 1H, CH), 7.45ꢀ7.51 (m, 2H, CH), 7.79
(s, 1H, CH), 7.82 (s, 1H, CH). 13C NMR (DMSOꢀd6, 125 MHz,
ppm),
δ: 10.9, 17.3, 22.7, 2 x 66.4 (CH2ꢀCH2), 101.6 (CHꢀO),
80 105.4, 119.7, 2 x 122.9, 127.1, 2 x 127.9, 133.8, 137.8, 143.6,
144.7, 149.0, 160.1 (C=N).
EIꢀMSm/z: 310 (M+1).
Mol.formula: C18H19N3O2 requires 309.14. HRMS [EI+] calcd for
C18H19N3O2m/z 309.1477 [M+], found 309.1473.
85 3-(1,3-dioxolan-2-yl)-7-methyl-2-(3-methyl-5-phenyl-1H-
~
pyrazol-1-yl)quinoline, 5e- mp >300 °C, FTIR,
ν
/cm–
1
1:2923,2849, 1687, 1621. H NMR (DMSOꢀd6, 400 MHz, ppm),
δ
: 2.43 (s, 3H, CH3), 2.61 (s, 3H, CH3), 4.10 (m, 4H, CH2), 6.11
(s, 1H, CH), 6.23 (s, 1H, CH), 7.25ꢀ7.33 (m, 4H, CH), 7.51 (m,
2-(3,5-dimethyl-1H-pyrazol-1-yl)-7-methylquinoline-3-
90 2H, CH), 7.70ꢀ7.72 (d, 1H, J = 8, CH), 7.90 (m, 2H, CH). 13C
NMR (DMSOꢀd6, 100 MHz, ppm), δ: 12.8, 21.3, 2 x 65.8 (CH2ꢀ
CH2), 101.1 (CHꢀO), 103.4, 118.6, 122.3, 125.9, 2 x 126.7, 127.8,
2 x 128.4, 2 x 129.1, 132.3, 133.7, 137.8, 145.1, 145.9, 147.1,
162.1 (C=N). LCꢀMS m/z: 372 (M+1).Mol. formula: C23H21N3O2
95 requires 371.16. HRMS [EI+] calcd for C23H21N3O2m/z 371.1634
[M+], found 371.1626.
~
carbaldehyde, 4 mp 227ꢀ229 °C, FTIR,
ν
/cm–1:2918, 2850,
1690, 1593, 1498. 1H NMR (CDCl3, 300 MHz, ppm),
δ
: 2.32 (s,
30 3H, CH3), 2.61 (s, 3H,CH3), 2.66 (s, 3H, CH3), 6.15 (s, 1H, CH),
7.45ꢀ7.47 (d, 1H, J = 6 Hz, CH), 7.85 (m, 2H, CH), 8.75 (s, 1H,
CH), 10.20 (s, 1H, ꢀCHO). 13C NMR (CDCl3, 75 MHz, ppm),
δ:
13.4, 22.1, 29.6, 108.9 (CHꢀO), 124.2, 124.3, 127.8, 2 x 128.9, 2
x 129.7, 139.3, 142.3, 142.6, 148.1 (C=N), 163.2 (C=O). GCꢀMS
35 m/z: 265 (M+).Mol. formula: C16H15N3O requires 245.12.
2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(1,3-dioxolan-2-yl)-7,8-
~
dimethylquinoline, 5f- mp >300 °C, FTIR,
100 1691, 1634. 1H NMR (DMSOꢀd6, 400 MHz, ppm),
ν
/cm–1:2927, 2841,
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(1,3-dioxolan-2-
~
yl)quinoline, 5a mp >300 °C, FTIR,
ν
/cm–1:2917, 2845, 1689,
δ
: 2.24 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.72 (s, 3H, CH3),
4.08 (m, 4H, CH2), 6.01 (s, 1H, CH), 6.16 (s, 1H, CH), 7.36ꢀ7.41
(m, 2H, CH), 7.79 (s, 1H, CH). 13C NMR (DMSOꢀd6, 100 MHz,
1624. 1H NMR (DMSOꢀd6, 500 MHz, ppm),
δ
: 2.20 (s, 3H,
40 CH3), 2.30 (s, 3H,CH3), 4.00ꢀ4.06 (m, 4H, CH2), 6.10 (s, 1H,
CH), 6.24 (s, 1H, CH), 7.70ꢀ7.715 (d, 1H, J = 7.5 Hz, CH), 7.96ꢀ
8.11(d, 1H, J = 7.5, CH), 8.16ꢀ8.26 (m, 2H, CH), 8.72 (s, 1H,
ppm), δ: 11.3, 12.8, 16.9, 17.7, 2 x 65.8 (CH2ꢀCH2), 101.2 (CHꢀ
105 O), 104.8, 117.8, 121.3, 124.7, 127.2, 133.3, 135.6, 136.5, 143.4,
147.3, 152.8, 160.1 (C=N). LCꢀMS m/z: 324 (M+1).Mol.
formula: C19H21N3O2 requires 323.16. HRMS [EI+] calcd for
C19H21N3O2m/z 323.1634 [M+], found 323.1647.
CH). 13C NMR (DMSOꢀd6, 125 MHz, ppm),
δ: 11.4, 17.0, 2 x
66.6 (CH2ꢀCH2), 103.5(CHꢀO), 107.2, 116.8, 2 x 125.0, 2 x
45 127.3, 2 x 129.7, 135.8, 141.3, 143.1, 156.5, 167.8 (C=N). Mol.
formula: C17H17N3O2 HRMS [EI+] calcd for C17H17N3O2m/z
295.1321 [M+], found 295.1312.
110 3-(1,3-dioxolan-2-yl)-7,8-dimethyl-2-(3-methyl-5-phenyl-1H-
~
pyrazol-1-yl)quinoline, 5g- mp 243 °C, FTIR,
2845, 1689, 1632. H NMR (DMSOꢀd6, 400 MHz, ppm),
ν
/cm–1:2929,
3-(1,3-Dioxolan-2-yl)-2-(3-methyl-5-phenyl-1H-pyrazol-1-
1
~
50 yl)quinoline, 5b mp >300 °C, FTIR,
ν
/cm–1:2909, 2834, 1676,
δ
: 2.26
(s, 3H, CH3), 2.47 (s, 3H, CH3), 2.68 (s, 3H, CH3), 4.10 (m, 4H,
CH2), 5.96 (s, 1H, CH), 6.42 (s, 1H, CH), 7.10ꢀ7.19 (m, 2H,
115 CH), 7.30 (s, 1H, CH), 7.44ꢀ7.84 (m, 3H, CH), 8.30 (s, 1H, CH),
1612. 1H NMR (DMSOꢀd6, 400 MHz, ppm),
δ
: 2.81 (s, 3H,
CH3), 4.08 (m, 4H, CH2), 6.19 (s, 1H, CH), 6.41 (s, 1H, CH),
7.39ꢀ7.42 (m, 3H, CH), 7.51ꢀ7.56 (m, 3H, CH), 7.70ꢀ7.78 (m, 3H,
CH), 8.22ꢀ8.26 (d, 1H, J = 8, CH). 13C NMR (DMSOꢀd6, 100
8.59 (s, 1H, CH). 13C NMR (DMSOꢀd6, 100 MHz, ppm),
δ: 13.6,
18.8, 19.3, 2 x 66.7 (CH2ꢀCH2), 101.4 (CHꢀO), 106.2, 119.1, 2 x
124.3, 125.7, 3 x 127.9, 2 x 128.3, 2 x 129.9, 134.1, 2 x 135.7,
136.8, 143.2, 151.9, 159.6 (C=N). HRMS [EI+] calcd for
120 C24H23N3O2m/z 385.1790 [M+], found 385.1781.
55 MHz, ppm), δ: 18.9, 2 x 66.7 (CH2ꢀCH2), 101.1(CHꢀO), 105.6,
120.5, 126.1, 3 x 126.9, 3 x 128.2, 2 x 129.0, 129.5, 2 x 133.4,
135.7, 143.1, 145.2, 151.6, 159.9 (C=N). LCꢀMS m/z: 358
(M+1).Mol. formula: C22H19N3O2 requires 357.14. HRMS [EI+]
calcd for C22H19N3O2m/z 357.1477 [M+], found 357.1469.
4 Antibacterial activity
60
3-(1,3-dioxolan-2-yl)-2-(3,5-diphenyl-1H-pyrazol-1-
Cultures of bacteria were grown on nutrient broth (Hi Media) at
~
/cm–1:2912, 2852, 1668,
°
yl)quinoline, 5c mp 246 °C, FTIR,
ν
125 37 C for 12–14 h and were maintained on respective agar slants
1612. 1H NMR (DMSOꢀd6, 400 MHz, ppm),
δ
:4.02 (m, 4H, CH2),
°
at 4 C. All the compounds 2(a–c) and 5(a–g) were tested for
4
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
their minimum inhibition concentrations (MIC) by dissolving in
1. S. Eswaran, A. V. Adhikari, N. K. Pal and I. H. Chowdhury,
Bioorg. Med. Chem. Lett.,2010,20, 1040ꢀ1044.
2. J. P. Michael,Nat. Prod. Rep., 2008,25, 166ꢀ187.
100% DMSO to obtain a concentration range of 25, 50, 75, 100
µg/cm3 and screened for their antibacterial activities against
Gramꢀpositive S. aureus ATCC 700699, B. subtilis MTCC 430, 65 3. S. Bawa, S. Kumar, S. Drabu and R. Kumar, J. Pharm.
5
and Gramꢀnegative E. coli ATCC 11105, Klebsiella ATCC 10273
and P. aeruginosa ATCC 27853 by agar well technique38. The
standard antibacterial ampicillin was also tested under similar
conditions for comparison.
Bioall. Sci., 2010,2, 64ꢀ71.
4. F. Xiao, Y. Chen, Y. Liu and J. Wang, Tetrahedron., 2008,
64,2755ꢀ2761.
5. A. R. Ellanki, A. Islam, V. S. Rama, R. P. Pulipati, D.
Rambabu, G. R. Krishna,C. M. Reddy, K. Mukkanti, G. R.
Vanaja, M. K. Arunasree, S. K. Kumar and M. Pal, Bioorg.
Med. Chem. Lett.,2012,22, 3455ꢀ3459.
70
10 4.1 Determination of minimum inhibitory concentration (MIC)
The concentration of test cultures was adjusted to 0.5 McFarland
standards by using a spectrophotometer Test organisms were
6. M. M. Bhupendra and J. Smita, Med. Chem. Res., 2013, 22,
647ꢀ658.
lawn cultured on the MHA plates. Agar surface was bored by 75 7. L. Savegnago, A. I. Vieira, N. Seus, B. S. Goldani, M. R.
15 using a sterilized cork borer and 100 mm3 of each dilution was
poured in the wells. All test plates were incubated at 37 °C for 24
h. The minimum concentration of each compound showing a
clear zone of inhibition was considered to be MIC. The
experiments were performed in triplicate 39ꢀ40 (Table 4).
20
Castro, E. J. Lenardo and D. Alves, Tetrahedron Lett.,
2013,54, 40ꢀ44.
8. E. Rajanarendar, M. N. Reddy, S. Rama Krishna, K. Rama
Murthy, Y. N. Reddy and M. V. Rajam, Eur. J. Med. Chem.,
2012,55, 273ꢀ283.
9. M. Kidwai and N. Negi, Monatsh. Chem., 1997, 128, 85ꢀ89.
10. S. R. Inglis, R. K. Jones, G. W. Booker and S. M. Pyke,
Bioorg. Med. Chem. Lett., 2006,16,387ꢀ390.
11. V. V. Kouznetsov, C. M. M. Gómez, M. G. Derita, L.
Svetaz, Esther delOlmo and S. A. Zacchino, Bioorg. Med.
Chem., 2012,20, 6506ꢀ6512.
12. K. Shiva Kumar, S. Kiran Kumar, B. Y. Sreenivas, D. R.
Gorja, R. Kapavarapu, , D. Rambabu, G. Rama Krishna, C.
Malla Reddy, M. V.BasaveswaraRao, K. V. L. Parsaand
Manojit Pal, Bioorg. Med. Chem., 2012,20, 2199ꢀ2207.
13. E. Akbas and I. Berber, Eur. J. Med. Chem., 2005,40, 401ꢀ
405.
14. S. Manfredini, R. Bazzanini, P. G. Baraldi, M. Guarneri, D.
Simoni, M. E. Marongiu, A. Pani, P. L. Colla andE.
Tramontano, J. Med. Chem., 1992,35, 917ꢀ924.
15. X. Liu, J. Zhu, C. Pan, B. Song and B. Li, Frontiers of
Chemistry in China., 2008, 3(4), 418ꢀ421.
16. D. Castagnolo, A. De Logu, M. Radi, B. Bechi, F. Manetti,
M. Magnani, S. Supino, R. Meleddu, L. Chisu and M. Botta,
Bioorg. Med. Chem., 2008,16, 8587ꢀ8591.
17. C. W.Noelland C. Cheng, J. Med. Chem.,1969,12, 545ꢀ546.
18. M. AbdelꢀAziz, G. E. A. AbuoꢀRahma and A. A. Hassan,
Eur. J. Med. Chem.,2009,44, 3480ꢀ3487.
80
85
90
95
4.2 Molecular docking analysis for antibacterial efficacy
The binding affinity of compounds 1ꢀ(3ꢀ(1,3ꢀDioxolanꢀ2ꢀyl)ꢀ7,8ꢀ
dimethyl quinolinꢀ2ꢀyl) hydrazine 2c, 3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ
25 (3,5ꢀdiphenylꢀ1Hꢀpyrazolꢀ1ꢀyl)quinoline 5c, 2ꢀ(3,5ꢀdimethylꢀ1Hꢀ
pyrazolꢀ1ꢀyl)ꢀ3ꢀ(1,3 dioxo lanꢀ2ꢀyl)ꢀ7,8ꢀdimethylquinoline,5f
with peptide deformylase were calculated by using Autodock
.v.1.5.6. The peptide deformylase was taken from protein data
bank (ID: 1BS6). Rapid energy evaluation was achieved by pre
30 calculating atomic affinity potential for each ligand seperately
and the energy of interaction of each atom in the ligand was
encounteredFinally grid maps were calculated for each ligand
seperately and docking analysis were carried out by using
Lamarckian Genetic Algorithm. Autodock was run several times
35 to get various docked confirmations which were used further for
predicting docking energy. For each ligand 5 best poses were
generated and scored by using Autodock 4.2 scoring functions41.
Peptide deformylase is an enzyme which involves in the
deformylation of mitrochondrial proteins in bacteria. Inhibition 100
40 of peptide deformylase results in membrane delocalization which
subsequently leads to bacterial death.
19. D. Secci, A. Bolasco, P. Chimenti and S. Carradori, Curr.
Med. Chem., 2011,18, 5114ꢀ5144.
20. Z. Ozdemir, H. B.Kandilci, B. Gumusel, U. Calis and A. A.
Bilgin, Eur. J. Med. Chem., 2007,42, 373ꢀ379.
21. K. L. Kees, J. J. Jr. Fitzgerald, K. E. Steiner, J. F. Mattes, B.
Mihan, T. Tosi, D. Mondoro and M. L. McCaleb, J. Med.
Chem.,1996,39, 3920ꢀ3928.
105
Conclusions
A facile and efficient method has been developed for the
45 synthesis of 2ꢀ(3, 5ꢀdisubstitutedꢀ1Hꢀpyrazolꢀyl)ꢀ3ꢀ(1,3ꢀdioxolanꢀ
2yl)quinolines 5(a-g) by refluxing equimolar mixture of
2ꢀhydrazinoꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)quinolines,
2(a-c)
and
110
diketones, 3(a-c) in ethanol using Montmorillonite clay 10 as an
efficient catalyst. Also the synthesis of 2ꢀhydrazinoꢀ3ꢀ(1,3ꢀ
50 dioxolanꢀ2ꢀyl) quinolines, 2(a-c) has been succeeded within
lesser time using NH3. The synthesized compounds were
evaluated for in vitro antibacterial activity out of which 2c, 5c, 5f
showed good to moderate efficacy against the tested strains when
compared to that of standard ampicillin and in addition to this
55 SAR analysis and docking studies were also in good agreement
with the above results.
22. D. Sureshbabu and A. Nefzi, Eur. J. Med. Chem.,2011, 46,
5258ꢀ5275.
23. K. Karnakar, N. S. Murthy, K. Ramesh, G. Satish, B. N.
Jagdeesh and Y. V. D. NageshwarTetrahedron Lett., 2012,
53, 2897ꢀ2903.
24. R. G. Stein, J. H. Biel and T. Singh, J. Med. Chem.,1970, 13,
153ꢀ155.
25. R. Mekheimer, Pharmazie., 1994, 49(7), 486ꢀ489.
26. C. Gil and S. Brase, J. Comb. Chem., 2009, 11, 175ꢀ197.
115
120 27. M. Kowalska and D. L. Cocke, Chemosphere., 1998, 36,
547ꢀ552.
Notes and references
28. V. P. Evangelou, M. Marsi and M. M. Vandiviere, Plant and
Soil., 1999,213, 63ꢀ74.
29. O. Y. Kwon, K. W. Park and S. Y. Jeong, Bull. Korean
*Organic Chemistry Division, School of Advanced Sciences, VIT
University, Vellore-632014, Tamilnadu, India. Tel: 0416 220 2352;0416
60 220 2334; E-mail: nawaz_f@yahoo.co.in; dr.subashini.r@gmail.com.
125
Chem. Soc., 2001, 22, 678ꢀ684.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |5

RSC Advances
Page 6 of 15
View Article Online
DOI: 10.1039/C4RA10534F
30. R. Subashini, FꢀR.N. Khan, Monatsh.Chem., 2012, 143,
485ꢀ489
31. S.M. Roopan, FꢀR.N. Khan, Chem. Papers 2010, 64 , 812ꢀ
817
5
32. SM Roopan, FꢀR.N Khan, Med. Chem. Res., 2011, 20, 732ꢀ
737
33. V.R. Hathwar, S.M. Roopan, R. Subashini, F.N. Khan,
T.N.G. Row. J. Chem..Sci., 2010, 122, 677ꢀ685
34. S.M. Roopan, FꢀR.N. Khan, B.K. Mandal, Tetrahedron
Lett., 2010, 51, 2309ꢀ2311
10
35. O. MethꢀCohn, B. Narine and B. Tarnowski, J. Chem. Soc.,
Perkin Trans. 1., 1981, 1, 1520ꢀ1530.
36. A. Afghan, M. M. Baradarani and J. A. Joule, Arkivoc.,
2009, 2, 20ꢀ30.
15 37. R. Subashini, R. H. Venkatesha, P. Nithya, K. Prabakaran
and F. N. Khan, Acta Crystallogr.Sect. E, 2009, 65, o407ꢀ
o408.
38. F. N. Khan, P. Deepika, R. Subashini and S. M. Roopan,
Indian J. Heterocyl. Chem., 2009, 19, 79.
20 39. J. L. Rios, M. C. Recio and A. J. Vilar, J. Ethnopharmacol.,
1988,23, 127ꢀ149.
40. K. Gaurav, L. Karthik and K. V. BhaskaraRao, Journal of
Pharmacy Research., 2010, 3, 539ꢀ542.
41. G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K.
25
Belew, D. S. Goodsell and A. J. Olson, J. Comput.
Chem., 2009, 16, 2785ꢀ2791.
6
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
FIGURE CAPTIONS
Scheme 1: Scheme 1. Synthesis of 2ꢀhydrazinoꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)quinolines, 2(a-f)
Scheme 2: Synthesis of 2ꢀ(3, 5ꢀsubstitutedꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ3ꢀsubstituted quinolines4 and 5(a-g)
Fig. 1: Plausible mechanism for the synthesis of 3ꢀ(1, 3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ(3, 5ꢀdi methylꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ7ꢀ
methyl quinoline, 5d
Fig. 2: Antibacterial activity of compounds 2(a-c), 5(a-g) and SꢀAmpicillin (standard)
Fig3: The binding interactions of various ligands with peptide deformylase. [A] The binding affinity of 2c with
receptor in ribbon view. [B] Interaction of 2c with the molecular surface of the receptor. [C] The binding
affinity of 5c with receptor in ribbon view. [D] Interaction of 5c with the molecular surface of the receptor.
[E] The binding affinity of 5f with receptor in ribbon view. [F] Interaction of 5f with the molecular surface
of the receptor. [G] The binding affinity of Ampicillin with receptor in ribbon view. [H] Interaction of
Ampicillin with the molecular surface of the receptor.
1
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 8 of 15
View Article Online
DOI: 10.1039/C4RA10534F
O
O
O
O
i
N
NHNH2
N
Cl
R
R
2 (a-f)
1 (a-f)
Reagents and Conditions: (i) NH2NH2.H2O, EtOH/NH3EtOH, reflux, 80 °C
Scheme 1. Synthesis of 2-hydrazino-3-(1, 3-dioxolan-2-yl)quinolines, 2(a-f)
2
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 9 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
O
O
O
O
R
7-CH3
H
H
H
7-CH3
7-CH3
7,8-CH3 -CH3
R1
-CH3
-CH3
-C6H5
-C6H5
-CH3
-C6H5
R2
-CH3
-CH3
-CH3
-C6H5
-CH3
-CH3
-CH3
-CH3
+
R2
R1
4
N
NHNH2
R
5a
5b
5c
5d
5e
5f
3 (a-c)
ii)
2
i)
O
CHO
O
N
5g 7,8-CH3 -C6H5
N
N
N
N
N
R
R2
R
R2
4
5 (a-g)
R1
R1
°
°
Reagents and Conditions: (i) Conc. H2SO4, EtOH, reflux, 80 C (ii) MKꢀ10, EtOH, reflux, 80 C
Scheme 2. Synthesis of 2-(3,5-substituted-1H-pyrazol-1-yl)-3-substituted
quinolines 4 and 5(a-g)
3
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 10 of 15
View Article Online
DOI: 10.1039/C4RA10534F
Fig. 1Plausible mechanism for the synthesis of 3ꢀ(1, 3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ(3, 5ꢀdi
methylꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ7ꢀmethyl quinoline, 5d
4
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 11 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
Fig. 2 Antibacterial activity of compounds 2(a-c), 5(a-g) and SꢀAmpicillin (standard)
5
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 12 of 15
View Article Online
DOI: 10.1039/C4RA10534F
Fig. 3:The binding interactions of various ligands with peptide deformylase. [A] The
binding affinity of 2c with receptor in ribbon view. [B] Interaction of 2c with the
molecular surface of the receptor. [C] The binding affinity of 5c with receptor in
ribbon view. [D] Interaction of 5c with the molecular surface of the receptor. [E] The
binding affinity of 5f with receptor in ribbon view. [F] Interaction of 5f with the
molecular surface of the receptor. [G] The binding affinity of Ampicillin with
receptor in ribbon view. [H] Interaction of Ampicillin with the molecular surface of
the receptor.
Table 1.Synthesis of 2ꢀhydrazinoꢀ3ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)quinolines2(a-f)a
S. No.
R
Product
Time / h
Reported
Yield %
Experimental
Yieldb %
85
1
2
3
4
5
6
H
2a
2b
2c
2d
2e
2f
1.5
2
2
1.5
1
2
80
85
ꢀ
80
80
85
7ꢀCH3
7,8ꢀCH3
6ꢀCH3
8ꢀCH3
6ꢀOCH3
89.3
81.2
85.2
84
89
Reagentsa:1(aꢀf)ꢀ1 mmole, NH2NH2.H2O (excess), EtOH, 2ꢀ3 drops ofNH3,80 ºC; isolated
b
yield
Table 2. Screening of the catalyst and its amount of the cyclization reactiona
6
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 13 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
S. No.
1
Catalyst
Product Yieldb/% S. No.
MKꢀ10
(mg)
Nil
Time/ h Yieldb/ %
No catalyst
ꢀ
1
48
ꢀ
5d
2
3
4
5
6
7
8
20
40
60
24
18
10
6
3
3
36
40
55
62
83
84
85
2
3
4
5
Conc.H2SO4
AlCl3
57
64
61
83
4
80
5d
5d
5d
100
120
140
SnCl2.2H2O
MKꢀ10
3
Reagentsa: MKꢀ10, EtOH, reflux; bisolated yield
Table 3.Synthesis of 2ꢀ(3,5ꢀsubstitutedꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ3ꢀsubstituted quinolines, 5(a-g)a
S. No.
R
H
H
R1
R2
Product
Time / h
Yieldb / %
1
2
3
4
5
6
7
CH3
C6H5
C6H5
CH3
C6H5
CH3
C6H5
CH3
CH3
C6H5
CH3
CH3
CH3
CH3
2.5
3
3.5
3
3.5
2.5
3
85
79
75.5
83
81
5a
5b
5c
5d
5e
5f
H
7ꢀCH3
7ꢀCH3
7,8ꢀCH3
7,8ꢀCH3
82.6
79
5g
Reagentsa: 2(aꢀc) (1 mmole), 3(aꢀc) (1 mmole), MKꢀ10 (100 mg), EtOH, 80 °C; isolated
yield
b
Table 4. Determination of minimum inhibitory concentration
Test strains
MIC (µg cmꢀ3)
2a
2b
2c 5a 5b 5c
5d
5e
5f
5g
S
N
S. aureus
K. pneumonia
B. subtilis
100
50
50 75
25
ꢀ
75
25
ꢀ
25
ꢀ
50
ꢀ
50
75
ꢀ
50
50
ꢀ
50
75
50
50
50
50
50
50
75
50
25
75
100
50
50
25
50
25
ꢀ
ꢀ
ꢀ
ꢀ
100 25 50 50 25
E. coli
50
75
75
ꢀ
ꢀ
50
100
75
P. aeruginosa
75
25 75 75 25
75
SꢀStandard (Ampicillin), NꢀNegative Control (DMSO)
7
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 14 of 15
View Article Online
DOI: 10.1039/C4RA10534F
Table 5.Binding affinity of synthesized ligands 2c, 5c and 5f and standard Ampicillin with
peptide deformylase.
Binding Energies (kcal/mol)
Ligand
Conformations
1
2
3
4
5
2c
5c
5f
ꢀ6.8
ꢀ7.3
ꢀ6.4
ꢀ6.7
ꢀ6.4
ꢀ6.9
ꢀ6.2
ꢀ6.5
ꢀ7.0
ꢀ7.8
ꢀ6.9
ꢀ7.5
ꢀ6.6
ꢀ7.5
ꢀ6.0
ꢀ6.2
ꢀ7.3
ꢀ8.1
ꢀ6.7
ꢀ7.0
Standarda
aAmpicillin
8
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 15 of 15
RSC Advances
View Article Online
DOI: 10.1039/C4RA10534F
Potential anti-bacterial agents: Montmorillonite Clay catalyzed synthesis of
novel 2-(3, 5-substituted-1H-pyrazol-1-yl)-3-substituted quinolones and their
in-silico molecular docking studies
Pasupala Pavan, R. Subashini*, K. R. Ethiraj and F. Nawaz Khan*
Graphical Abstract