Design and synthesis of some novel 7-substituted thiosemicarbazinyl-quinolines via Ullmann coupling reaction and examination of their antimicrobial activities

Article abstract of DOI:10.1007/s11164-017-3136-8

Abstract: The present work demonstrates functionalization of 4,7-dichloro quinoline via a modified Ullmann coupling reaction concept of varying oxidation state and reaction conditions. Based on these conditions, novel 2-(4-morpholino quinolin-7-yl)-N-substituted phenyl hydrazinyl carbothioamide derivatives have been synthesized. Structures of the final synthesized compounds including intermediates were confirmed by IR, ¹H NMR and ¹³C NMR spectral studies. Examination of biological profiles was carried out against various strains of micro-organisms. SAR and HOMO–LUMO calculations were carried out for judicious design. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-017-3136-8

Res Chem Intermed
DOI 10.1007/s11164-017-3136-8
Design and synthesis of some novel 7-substituted
thiosemicarbazinyl-quinolines via Ullmann coupling
reaction and examination of their antimicrobial
activities
Jankiben J. Patel1 Anuj P. Patel1
•
•
Kishor H. Chikhalia1
Received: 6 June 2017 / Accepted: 28 August 2017
Ó Springer Science+Business Media B.V. 2017
Abstract The present work demonstrates functionalization of 4,7-dichloro quinoline via a
modified Ullmann couplingreaction concept of varyingoxidation state andreaction conditions.
Based on these conditions, novel 2-(4-morpholino quinolin-7-yl)-N-substituted phenyl
hydrazinyl carbothioamide derivatives have been synthesized. Structures of the final synthe-
1
sized compounds including intermediates were confirmed by IR, H NMR and 13C NMR
spectral studies. Examination of biological profiles was carried out against various strains of
micro-organisms. SAR and HOMO–LUMO calculations were carried out for judicious design.
Graphical Abstract
&
Kishor H. Chikhalia
Chikhalia_kh@yahoo.com
1
Department of Chemistry, School of Science, Gujarat University, Ahmedabad, Gujarat 380 009,
India
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J. J. Patel et al.
Keywords 4,7-Dichloro quinoline Á Thiosemicarbazide Á Ullmann
coupling reaction Á Antimicrobial activity Á HOMO–LUMO/FMO
Introduction
Major challenges over the next few years will be the development of drugs with
significantly improved resistance profiles for microbial infections, such as bacterial
and fungal [1–3]. The optimization of the current antimicrobial drug systems and
the development of novel drugs are still issues in microbial chemotherapy [4]. It is
believed that new antimicrobial agents will stay in demand because of the
expanding global spread of drug-resistant pathogens [5, 6]. Infection with
Staphylococcus aureus, S. pyogenes, Salmonella typhimurium and Escherichia coli
might have resulted in massive destruction of host tissue and life-threatening
diseases. These bacterial parasites cause food poisoning, rheumatic fever and
diarrhea which affect millions of individuals in developing countries. According to
the available worldwide reports, more than 50 million people are infected by life-
threatening disease,with 25,000 patients dying every year [7]. Because of this, we
decided to synthesize some hitherto unreported quinoline derivatives. One of the
most repeatedly encountered heterocycles in medicinal chemistry is quinoline,
because of its broad range of pharmacological activities. As medicines, many of its
derivatives display anticancer [8], antitumor [9], antimalarial [10, 11], antifungal
[12], antibacterial [13] and anti-HIV properties [14]. Recent developments in
antimicrobial quinoline chemistry have been briefly reviewed, covering five
important topics: (1) historical aspects of quinoline-based antimicrobial drug
development; (2) increasing resistance problems and the reasons for developing new
antimicrobial agents; (3) molecular quinoline-based hybrids in the design and
development of novel antimicrobial agents; (4) structural evolution of quinolones as
effective agents in the treatment of microbial infections; and (5) the design and
synthesis of new quinoline-based molecules as potential antimicrobial agents.
Consequently, the quinoline skeleton has been chosen for the design of new
bioactive molecules by a large number of researchers. Furthermore, various types of
hydrazones have attracted continued interest in the medicinal field owing to their
varied biological activities [15]. Although a large number of antibiotics and
chemotherapeutics are available for medical use, in recent decades, antimicrobial
resistance has created a substantial need for new classes of antibacterial agents
[16, 17]. Derivatives of thiosemicarbazide play a vital role in the field of chemistry
by regulating various pharmacological activities [18]. A literature survey has
revealed that thiosemicarbazide derivatives were found to possess antibacterial
activity against S. aureus and E. coli. Diverse parasitic bacteria such as S. aureus, S.
pyogenes, Salmonella typhimurium, and E. coli have significant impacts on the
mucosal health of humans. Amoxicillin, Norfloxacin, and Ciprofloxacin are the
most common drugs used for bacterial infections but are associated with severe side
effects. Toxicity and resistance to the drugs also play an important role in the failure
of treatment [19, 20]. Encouraged by these observations, we decided to synthesize
some new quinolinyl compounds and screen them for their possible antimicrobial
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Design and synthesis of some novel 7-substituted…
activities. As part of our continuing research program in the synthesis of new
antimicrobial agents, we wish to know the key players of inhibition towards the
strains. The constructed target molecule contains a hydrazinyl bridge through
carbothioamide linkage, which we believe to be the important key part for obtaining
the desired biological response. In addition to this, its functionalization with various
motifs has relevance to drug development and medicinal chemistry.
In the present study, the Ullmann coupling method [21] was carried out for the
condensation of thiosemicarbazide and quinoline. the SNAr reaction of 4,7-dichloro
quinoline reveals that the 4th position is more feasible compared to the 7th position.
So, morpholine was entered first in the 4th position and then we explored the 7th
position for Ullmann coupling. The literature survey revealed that urea, thiourea and
thiosemicarbazide derivatives of quinoline show good activity towards different
strains. In an advancement from our previous work, we stimulated an interest in club
thiosemicarbazide with quinoline. The morpholine–quinoline combination is found
in the structure of many well known antimicrobial drugs like Ciprofloxacin,
Norfloxacin, Ofloxacin, Pefloxacin. etc. In our previous study, our group introduced
various piperazine and morpholine derivatives to the s-triazine core and identified
the compounds with good antibacterial profile [22, 23]. Prompted by these
observations, we have looked for combinations of the above-mentioned bioactive
components (quinoline and morpholine) with significant activities in a compact
system in order to identify new candidates which may be of value in designing new
biologically active agents. In this context, a novel hybrid series of quinoline
molecules with combinations of different bioactive compounds, such as morpholine
and thiosemicarbazide, which are structurally related to antimicrobial lead
compounds, i.e., Linezolid (I) having a morpholine nucleus [24], Triapine (II)
having a thiosemicarbazide group [25] and Chloroquine (III) with a quinoline
moiety [26] are reported.
Chemistry
The quinoline derivatives were synthesized from 4,7-dichloro quinoline and
different nucleophiles (Scheme 1). The nucleophile can selectively relocate
different chlorines by controlling the reaction temperature and the nature of the
reactive group, and vice versa [27]. The first chlorine at the 4th position can be
replaced when the temperature is maintained at 0–5 °C [28], the second chlorine
between 30 and 40 °C [29] and, due to the reactivity; the temperature can be up to
80–90 °C. As commercially available and currently used antibiotics, Linezolid
possesses a morpholine motif inits structure and quinoline itself is a potent bioactive
scaffold. Based on these observations, we tried to achieve our goal by the
condensation of 4,7-dichloro quinoline with morpholine in equimolar ratio, yielding
4-morpholino-7-chloroquinoline, which was then subjected to further Ullmann
coupling reaction by employing optimized reaction conditions along with hydrazine
hydrate. In addition, a wide range of different isothiocyanates were condensed at
reflux temperature. In addition, Serda et al. [30] designed two novel anticancer
agents (IV and V) by combining quinoline and thiosemicarbazide, at the 2nd, 5th
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J. J. Patel et al.
and 8th positions of quinoline, but here we explored only the 7th position with the
same substituent.
Hence, in the present study, the first step comprises the formation of intermediate
1 in very good yield by nucleophilic substitution on the 4th chlorine atom of 4,7-
dichloro quinoline by morpholine. The synthesis of 4-(7-chloroquinolin-4-yl)
morpholine intermediate 1 was achieved in 80–90% of yield by the reaction
between 4,7-dichloroquinoline and morpholine in the presence of dichloromethane
at 0–5 °C temperature. The characteristic band appeared at 1335 cm-1, confirming
the presence of 3°-amine C–N–C stretching in the FT-IR spectra of compound 1.
urthermore, one strong peak was found at 1165 cm-1, which indicates the presence
of C–O–C stretching of the morpholine motif.
Subsequently, coupling of compound 1 with the hydrazine hydrate by the
Ullmann coupling method was carried out under basic conditions. An appropriate
Cu catalyst and ligand in 1,4-dioxane solvent at 80–90 °C formed the corresponding
compound 2, and this reaction proceeded in good yield. The synthesis of compound
2 was confirmed on the basis of IR spectra analysis in which a very strong peak was
obtained at 3336 cm-1 to confirm the presence of –NH–NH– stretching in
compound 2. Previously, in our research group, a plausible mechanism for the Cu(0)
catalyzed by the Ullmann coupling reaction was presented [31], but here we propose
the mechanism for the Cu(I) catalyst. The plausible mechanism for the Cu(I)-
catalyzed Ullmann coupling reaction is demonstrated in Scheme 2. Subsequently,
compound 2 was treated with different isothiocyanates, 3a–j, to achieve the desired
products, 4a–j, in the presence of THF for 3–4 h. The confirmation of synthesis
compounds 4a–j was proved on the basis of IR and 1H NMR spectral analysis, and
the purity was examined by elemental analysis. Here, we also report the log
P values of the synthesized title compounds which are used in QSAR studies and
rational drug design as a measure of molecular hydrophobicity, which affects drug
bioavailibity, adsorption, hydrophobic drug–receptor interactions, and metabolism
of molecules, as well as the toxicity of the compound; their log P values must not be
more than 5.0.
In the proposed catalytic cycle, the first step is a nucleophilic substitution
reaction between Copper(I) chloride (A) and nucleophile hydrazine in the presence
of base. The halide on copper(I) is exchanged with the nucleophile hydrazine and
123

Design and synthesis of some novel 7-substituted…
Where, R=
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
2-Cl
3-Cl
4-Cl
2-CH3
3-CH3
4-CH3
2-F
3-F
4-F
4j
Synthesis of final quinoline derivatives, Reagents and condition: (i) Dichloromethane, 0-5°C, 1-2 h (ii) CuCl,
K2CO3, 1,4-Dioxane (iii) Reflux, THF, 3-4 h.
Scheme 1 Synthesis of target compounds
obtained intermediate (B) and then, after an oxidative addition of 4-(7-chloro-
quinolin-4-yl)morpholine 1 to copper(I) to form a copper(III) intermediate (C),
which on a reductive elimination step releases the coupling product 4-(7-hydrazinyl
quinolin-4-yl)morpholine 2, the active Cu(I) catalyst is regenerated. Previously,
123

J. J. Patel et al.
Chen et al. [32] proposed a catalytic mechanism for Cu(I) to Cu(III). Analogous
reports favor the mechanism in which the nucleophile reacts first with the
copper(I) halide catalyst before the oxidative addition [33].
Medicinal chemistry
In vitro evaluation of antimicrobial activity
In order to study the antimicrobial properties of the novel hybrid quinoline–
thiosemicarbazide derivatives, several bacterial (S. aureus MTCC 96, S. pyogenus
MTCC 442, Pseudomonas aeruginosa MTCC 741, E. coli MTCC 443) and fungal
(Candida albican MTCC 227, Aspergillus niger MTCC 282, A. clavatus MTCC
1323) species were selected and the minimum inhibitory concentration (MIC) of
each compound was determined by the agar streak dilution method [34]. A stock
solution of the tested compound (100 lg/ml) in dimethyl sulfoxide was prepared
and graded quantities of the test compounds were incorporated in a specified
quantity of molten sterile agar, i.e. nutrient agar for the evaluation of antibacterial
and sabouraud dextrose agar for antifungal activity, respectively. The medium
containing the test compound was poured into a Petri dish to a depth of 4–5 mm and
allowed to solidify under aseptic conditions. A suspension of the respective
microorganism of approximately 105 CFU/ml was prepared and applied to the
plates with serially diluted compounds with concentrations in the range of
3.125–100 lg/ml in dimethyl sulfoxide and incubated at 37 1 °C for 24 h. The
lowest concentration of the substance which prevented the development of visible
growth is considered to be the MIC value [35].
Where, 1= 4-(7-Chloroquinolin-4-yl)morpholine & 2= 4-(7-Hydrazinyl quinolin-4-yl)morpholine
Scheme 2 Plausible mechanism for Cu(I)-catalyzed Ullmann coupling reaction
123

Design and synthesis of some novel 7-substituted…
Material and methodology
Melting points were determined in open capillaries on a Veego electronic apparatus,
VMP-D, and are uncorrected. IR spectra of synthesized compounds were recorded
on a Shimadzu 8400-S FT-IR spectrometer using KBr pellets. Thin layer
chromatography was performed on object glass slides (2 9 4 cm) coated with
silica gel-G, and spots were visualized under UV irradiation and also by ninhydrin
1
solution to prove the presence of the –NH2 function group. H NMR spectra were
recorded on a the Varian 400 MHz model spectrometer, using dimethyl sulfoxide as
a solvent, chemical shifts (d) were reported in parts per million (ppm) with reference
to tetramethylsilane as internal standard. and coupling constants (J) were reported in
Hertz (Hz). 13C NMR spectra were obtained on a Bruker 100 MHz AC-300
spectrometer in dimethyl sulfoxide. Elemental analysis (C, H, N) was performed
using a Heraeus Carlo Erba 1180 CHN analyzer (Hanau, Germany). The log
P values of the compounds were determined by the ChemBioDraw Ultra 12.0
program.
Experimental
4-(7-Chloroquinolin-4-yl)morpholine (1)
To a stirred solution of 4,7-dichloroquinoline (2.0 g, 0.0101 mol) in dichlor-
omethane (10 ml), morpholine (0.8 ml, 0.0091 mol) in dichloromethane (5 ml) was
added dropwise at 0–5 °C. After the completion of the addition,the reaction mixture
was subjected for stirring for 1 h at room temperature. Progress of the reaction was
monitored by TLC using ethyl aceatate:hexane (6:4) as a solvent system. After the
completion of the reaction. the reaction mixture was poured into cold water
followed by the solvent extraction. The organic layer was separated and
concentrated using a rotary evaporator to obtain the solid, which was then
crystallized from ethanol to obtain the title compound 1. White solid, yield = 88%,
M.P. = 196–198 °C. IR = 1170 cm-1(–C–O–C– stretching), 1330 cm-1(–C–N–
C- stretching) in morpholine ring.
4-(7-Hydrazinyl quinolin-4-yl)morpholine (2)
To a solution of 4-(7-chloroquinolin-4-yl) morpholine 1 (2.0 g, 0.00804 mol) in 1,4-
dioxane (10 ml), hydrazine hydrate (0.5 ml, 0.00804 mol) in 5 ml, 1,4-dioxane was
added and stirred at room temperature for 20 min, then CuCl(0.076 g,
0.000402 mol), K2CO3 (2.22 g, 0.0161 mol in 5–7 ml of 1,4-dioxane was added
at 30–35 °C and stirred for 1 h. The temperature was gradually raised to 80 °C and
refluxed for 4–5 h. Progress of the reaction was monitored by TLC using ethyl
acetate:hexane (2:8) as a solvent system. After the completion of the reaction, the
reaction mixture was poured into cold water followed by solvent extraction. The
organic layer was concentrated with a rotary evaporator to obtain the solid product,
123

J. J. Patel et al.
which was then recrystallized from ethanol to obtain a white solid, yield = 75%,
M.P. = 210–212 °C. IR = 3339 cm-1 (–NH stretching in –NH–NH–), 890 cm-1
(–C–N stretching in quinoline).
General procedure for 2-(4-morpholino quinolin-7-yl)-N-phenyl hydrazinyl
carbothioamide (4a–j)
To a stirred solution of phenyl isothiocyanates 3a–j (1.1 g, 0.008192 mol) in THF
(10.0 ml), 4-(7-hydrazinyl quinolin-4-yl) morpholine 2 (2.0 g, 0.008186 mol) was
added at 5–10 °C. The reaction mixture was then stirred at room temperature for
1 h. The temperature was gradually raised and then refluxed for 3–4 h. Progress of
the reaction was monitored by TLC using hexane:ethyl acetate (6:4) as eluent. After
the completion of reaction the reaction mixture was poured into cold water, filtered,
washed with copious quantity of water and dried. It was then crystallized from
ethanol to obtain the title compound 4a–j. Similarly, other derivatives were
synthesized; their physical and analytical data are mentioned in Table 1.
IR = 3273 cm-1 (–CS–NH– stretching), 1569 cm-1 (–C=S– stretching).
Results and discussion
Antimicrobial activity
The antimicrobial activities of quinoline and thiosemicarbazide are known.
Keeping this in mind, the active pharmacophore thiosemicarbazide was annelated
to the 7th position of the basic quinoline motif. It is worth mentioning here that
the presence of morpholine at the 4th position of quinoline was regarded as an
important predictor for the escalation and generation of activity. In this context,
we have clubbed quinolinyl-thiosemicarbazide and morpholine into one hybrid
and evaluated their antibacterial and antifungal potency against various species of
bacteria and fungi i.e., bacteria S. aureus MTCC 96 lg/ml, S. pyogenus MTCC
443 lg/ml, P. aeruginosa MTCC 741 lg/ml, E. coli MTCC 442 lg/ml, C.
albicans MTCC 227 lg/ml, A. niger MTCC 282 lg/ml and A. clavatus MTCC
1323 lg/ml.
The antibacterial potency in terms of MIC values are summarized in Table 2.
Results of MIC values of the compounds are observed in the varied range
(62.5–500 lg/ml) of antibacterial activity against all the tested bacterial strains
shown in Table 2. For Gram-negative strains, compounds 4b and 4h with
electron-withdrawing groupd like 2-Cl and 2-F to phenyl nucleus appeared with
MIC 50 and 25 against P. aeruginosa and E. coli, respectively. Against Gram-
positive bacteria, S. aureus unsubstituted phenyl 4a with MIC 62.5 lg/ml and 4c
and 4i with electron-withdrawing groups like 3-Cl and 3-F with MIC 100 lg/ml,
while 4e and 4f with electron-donating groups like 2- and 3-CH3 to the phenyl
nucleus appeared with MIC 100 lg/ml against both the Gram-positive bacterias
(S. aureus and S. pyogenus), while 4b with electron-withdrawing group –Cl at the
2nd positon of the phenyl nucleus appeared with MIC 62.5 lg/ml against S.
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Design and synthesis of some novel 7-substituted…
Table 1 Physical and analytical data of compounds 4a–j
Comp. no. -R
Molecular formula M.P. (°C) Yield (%) Log P Elemental analysis
% C % H % N
4a
4b
4c
4d
4e
4f
H
C
20H21N5OS
264
69
55
70
65
52
59
64
58
65
72
3.08
3.64
3.64
3.64
3.57
3.57
3.57
3.24
3.24
3.24
R
F
63.30 5.58 18.46
63.27 5.55 18.43
58.03 4.87 16.92
58.05 4.90 16.89
58.03 4.87 16.92
58.00 4.84 16.90
58.03 4.87 16.92
58.01 4.89 16.95
64.10 5.89 17.80
64.06 5.86 17.76
64.10 5.89 17.80
64.13 5.85 17.83
64.10 5.89 17.80
64.07 5.91 17.75
60.44 5.07 17.62
60.41 5.03 17.59
60.44 5.07 17.62
60.40 5.09 17.60
60.44 5.07 17.62
60.47 5.02 17.58
2-Cl
3-Cl
4-Cl
C20H20N5OSCl
270–272
276
R
F
C
20H20N5OSCl
20H20N5OSCl
R
F
C
262
R
F
2-CH3 C21H23N5OS
3-CH3 C21H23N5OS
4-CH3 C21H23N5OS
266–268
272
R
F
R
F
4g
4h
4i
278
R
F
2-F
3-F
4-F
C20H20N5OSF
282
R
F
C20H20N5OSF
286–288
290
R
F
4j
C20H20N5OSF
R
F
pyogenus Gram-positive bacteria. The remaining compounds appeared with
moderate to good activity profiles.
The antifungal potency in terms of MIC values are summarized in Table 2.
Results of the MIC values of the compounds are observed in a varied range
(100 [ 1000 lg/ml) against studied fungal strains. In analogues to antibacterial
activity, compounds bearing electron-withdrawing groups, particularly 4b with 2-Cl
and 4h with 2-F substituent to the phenyl nucleus, appeared with better activity
compared to the others.
SAR study
The structural similarity in terms of substituents of several of the antimicrobial
(Linezolid, Triapine, Ciprofloxacin and Nystatin) and the synthesized quinoline–
thiosemicarbazide hybrids have permitted a systematic comparison of the SAR
relationships. The numbers and sites of attachment of the morpholine, various
aromatic amines and thiosemicarbazide substituents profoundly affect the ability
of these compounds to inhibit in vitro bacterial and fungal infections. SAR reveals
the introduction of various groups attached to the aromatic amine and, according
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J. J. Patel et al.
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Design and synthesis of some novel 7-substituted…
to the attachment, the activity could be defined where it is increased/decreased.
The physiological properties such as lipophilicity or hydrophobicity might be
concerned with their activities. Here, we found out some log P values of the
compounds. The log P value of a compound, which is the logarithm of its partition
coefficient between n-octanol and water, is a well-established measure of the
compound’s hydrophobicity and it must be less than 5.0.
cðnÀoctanolÞ
log P ¼ log
cðwaterÞ
In all cases, we observed that the log P values of the synthesized compounds
were obtained less than 5.0, being around 3.0–4.0, which is indicated in Table 1.
From that, we considered that the hydrophobicity of the design molecules are very
good and the study of SAR obtained is positive. Halogens are very reactive due to
their high electronegativity and high effective nuclear charge. From that we can
conclude that sufficient quantities of halogens can be dangerous to micro-
organisms [36]. On the whole, halogen-substituted –Cl substituent compounds 4b,
4c, and 4d (log P = 3.64) increases the lipophilicity of the compounds. Hence, it
could be concluded that the more hydrophobic the substituent, the more effective
is its antimicrobial property. From the results, we can see that compounds which
contain –F as substituent 4h, 4i and 4j (log P = 3.24) gave the best absorptions,
or we can say have a very good hydrophobicity. Compound 4a also appeared with
the best hydrophobicity because of not having any substituent. Furthermore, from
the lipophilicity point of view, it can be concluded that compounds with greater
lipophilicity (greater log P value) displayed higher activities in terms of lower
MICs and higher inhibition zones due to their higher lipophilic nature. This
clearly demonstrates the importance of lipophilicity for the antimicrobial
activities of the resultant scaffolds.
Graphical illustration of antibacterial activity of synthesized compounds
(4a–j):
600
S.aureus
S.pyogenus
P.aeruginosa
E.coli
500
400
300
200
100
0
Graphical illustration of antifungal activity of synthesized compounds (4a–
j):
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J. J. Patel et al.
1200
1000
800
600
400
200
0
C.albicans A.niger
A.clavatus
Frontier molecular orbital analysis (HOMO–LUMO concept)
Molecular orbitals (HOMO and LUMO) and their properties such as energy are a
very useful tool for physicists and chemists [37]. The calculated HOMO and LUMO
energies show that charge transfer occurs within the molecule. They are also very
important parameters for quantum chemistry. Both HOMO amd LUMO are the
main orbitals taking part in chemical stability [38]. This electronic absorption
corresponds to the transition from the ground state to the first excited state, and is
mainly described by one electron excitation from the highest occupied molecular
orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO). The HOMO–
LUMO energy gap of the compound reveals that the energy gap reflects the
biological activity of the molecule. [39–41] The HOMO represents the ability to
offer an electron and LUMO as an electron-acceptor represents the ability to gain an
electron. The atomic orbital compositions for 4a, 4b and 4e of the frontier molecular
orbitals are sketched in Fig. 1.
The HOMO is located over quinoline and the N-atom of morpholine and the
HOMO ? LUMO transition implies an electron density transfer to the substituted
thiosemicarbazide’s aromatic ring from the quinoline and the N-atom of the
morpholine analogues. The energy gap between HOMO and LUMO explains the
biological activity of the molecule, which is due to the change in partial charge
and to the change in total dipole moment. The energy of the HOMO directly
relates to the ionization potential while the energy of the LUMO directly relates to
the electron affinity. The calculated HOMO and LUMO energies is given in
Table 3.
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Design and synthesis of some novel 7-substituted…
LUMO PLOT
(First excited state)
ELUMO = -0.882 eV
∆E(HOMO-LUMO) = -0.691 eV
e-
EHOMO = -1.573 eV
HOMO PLOT
(Ground state)
LUMO PLOT
(First excited state)
ELUMO = 0.332 eV
∆E(HOMO-LUMO) = -1.879 eV
e-
EHOMO = -1.547 eV
HOMO PLOT
(Ground state)
LUMO PLOT
(First excited state)
ELUMO = -0.902 eV
∆E(HOMO-LUMO) = -0.702 eV
e-
EHOMO = -1.604 eV
HOMO PLOT
(Ground state)
Fig. 1 Atomic orbital compositions of the FMO for Compound 4a, 4b and 4e
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J. J. Patel et al.
Table 3 Energy gap of HOMO–LUMO of the compounds
Compound
EHOMO (eV)
ELUMO (eV)
DE = EHOMO–LUMO (energy gap) (eV)
4a
4b
4e
-1.573
-1.547
-1.604
-0.882
0.332
-0.691
-1.879
-0.702
-0.902
Conclusion
Design of the 4,7-disubstituted quinoline motif was achieved by the gradual SNAr
concept. Selectivity was studied and annelated the groups, and accordingly
substitution of the 4th position of the basic pharmacophore was routine chemistry
but the 7th position was activated by a modified Ullmann coupling concept. The
results obtained confirm that the nature of the substituents and the substitution
pattern on the quinoline ring clubbed with morpholine and thiosemicarbazide motifs
may have a considerable impact on the biological activities of the target product.
Out of 10 screened compounds, 4a, 4b, 4e, 4f and 4h exhibited good in vitro
antibacterial activity compared to the others. In general, we ascertained that some of
the compounds containing electron-donating groups, like methyl, on the phenyl ring
of the amine showed good activity against Gram-negative strains, while electron-
withdrawing groupd like chloro, fluoro and the unsubstituted phenyl ring also
showed good activity against Gram-negative strains as well as antifungal strains
compared to the other synthesized compounds. As per the electronic effect, hyper-
conjugation of the methyl group favors the increase in activity of the lead molecule.
The structural variations such as the methyl group at the o- and m-positions to the
aromatic phenyl nucleus of thiosemicarbazide annelated to the quinoline residue
resulted in an increase in activity due to the crowding effect of the methyl group.
Based on a computational study of HOMO–LUMO, it is concluded that, the lower
the value of energy gap, the better the biological activity against various strains. i.e.,
4b. The biological profile of the chosen pharmacophore is such that it is worth
proceeding with further research on the functionalisation and annelation of other
bioactive motifs with anticipation of the development of chemistry and biological
profiles.
Acknowledgements We are grateful to Prof. N.K. Shah, Head of the Chemistry Department, School of
Sciences, Gujarat University for giving support and facilities. The authors also express their sincere
thanks to the Center of Excellence, Department of Chemistry, Saurashtra University, Rajkot for spectral
analysis. The authors wish to offer their deep gratitude to Department of Microbiology, School of
Sciences, Gujarat University, Ahmedabad for carring out the biological screenings. They are also grateful
to GUJCOST, Ghandhinagar for financial support.
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