Novel 4-(1H-1,2,3-triazol-4-yl)methoxy)cinnolines as potent antibacterial agents: Synthesis and molecular docking study

Article abstract of DOI:10.1080/00397911.2020.1728333

A new series of cinnoline-1,2,3-triazole derivatives were designed and synthesized by adopting Cu(1) catalyzed regeoselective1,3-dipolar cycloaddition reaction of terminal alkyne and azide. The in vitro antibacterial activity of all these compounds revealed that compounds 9d, 10a, 10b, and 10c are more potent antibacterial agents. Among the series, compound 4-(3-(4-((cinnolin-4-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)morpholine (10b) exhibited the most potent antibacterial activity against all tested gram-positive and gram-negative bacterial strains. Furthermore, molecular docking studies were also performed to understand the binding interactions of the most active analogs 9d, 10a, 10b, and 10c with Elastase of Pseudomonas aeruginosa (PDB: 1U4G). The results indicated that these classes of compounds have potential antibacterial activity, especially the compound 10b may serve as a promising antibacterial lead compound that could be further optimized for the further development of antibacterial drugs.

Full text of DOI:10.1080/00397911.2020.1728333

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Novel 4-(1H-1,2,3-triazol-4-yl)methoxy)cinnolines
as potent antibacterial agents: Synthesis and
molecular docking study
Mohan Babu Bommagani, Sudhakar Mokenapelli, Jayaprakash Rao
Yerrabelli, Sathish Kumar Boda & Prasad Rao Chitneni
To cite this article: Mohan Babu Bommagani, Sudhakar Mokenapelli, Jayaprakash Rao
Yerrabelli, Sathish Kumar Boda & Prasad Rao Chitneni (2020): Novel 4-(1H-1,2,3-triazol-4-
yl)methoxy)cinnolines as potent antibacterial agents: Synthesis and molecular docking study,
Synthetic Communications, DOI: 10.1080/00397911.2020.1728333
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https://doi.org/10.1080/00397911.2020.1728333
Novel 4-(1H-1,2,3-triazol-4-yl)methoxy)cinnolines as
potent antibacterial agents: Synthesis and molecular
docking study
Mohan Babu Bommagani, Sudhakar Mokenapelli , Jayaprakash Rao Yerrabelli,
Sathish Kumar Boda, and Prasad Rao Chitneni
Natural Products Laboratory, Department of Chemistry, Osmania University, Hyderabad, Telangana, India
ABSTRACT
ARTICLE HISTORY
Received 22 September 2019
A new series of cinnoline-1,2,3-triazole derivatives were designed
and synthesized by adopting Cu(1) catalyzed regeoselective1,3-
dipolar cycloaddition reaction of terminal alkyne and azide. The
in vitro antibacterial activity of all these compounds revealed that
compounds 9d, 10a, 10b, and 10c are more potent antibacterial
agents. Among the series, compound 4-(3-(4-((cinnolin-4-yloxy)-
methyl)-1H-1,2,3-triazol-1-yl)propyl)morpholine (10b) exhibited the
most potent antibacterial activity against all tested gram-positive
and gram-negative bacterial strains. Furthermore, molecular docking
studies were also performed to understand the binding interactions
of the most active analogs 9d, 10a, 10b, and 10c with Elastase of
Pseudomonas aeruginosa (PDB: 1U4G). The results indicated that
these classes of compounds have potential antibacterial activity,
especially the compound 10b may serve as a promising antibacterial
lead compound that could be further optimized for the further
development of antibacterial drugs.
KEYWORDS
Anti-bacterial activity;
cinnolines; click reaction;
molecular docking
studies; triazoles
GRAPHICAL ABSTRACT
Introduction
Bacterial infections are one of the most common causes of chronic infections and mortal-
ity against human health throughout the world. Antimicrobial agents, the “miracle drugs,”
are considered to be the principal agents to combat infectious diseases. Moreover, antibi-
otics have become less effective against certain illnesses because of their toxic reactions
and also due to the surfacing of drug-resistant bacteria. For the last two decades, rapid
progress in synthetic organic chemistry is associated with a search for new drug-like
CONTACT Chitneni Prasad Rao
prasadraoou@yahoo.com
Natural Products Laboratory, Department of Chemistry,
Osmania University, Hyderabad 500007, Telangana, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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B. M. BABU ET AL.
Figure 1. Some of the biologically active cinnoline derivatives.
compounds with desired properties. The discovery, development, and application of nat-
ural drugs have been carried out for thousands of years. One of the most fruitful para-
digms for the discovery of new bioactive chemical entities is to start with established
structural cores, known to be part of other bioactive molecules.[1] Cinnoline moiety, most
commonly found in fluorescent chemicals, biologically active molecules, and other func-
tional materials.[2–4] None of the cinnoline (1,1,2-diazanaphtalene or benzo[c] ꢀ 1,2-dia-
zine), derivatives are found in nature. Hence, cinnolines were designed as analogs to
quinoline and isoquinoline derivatives as they are isosteric to quinoline and isoquinolines.
Richter and coworkers synthesized cinnoline derivatives for the first time in 1883.[5] Later
on, its biological properties have been reported in the literature.[6,7] Recently, a series of
cinnoline derivatives were reported as phosphodiesterase 10A (PDE10A) inhibitors[8] and
HNE inhibitors.[9] Cinnolines are known to exhibit antibacterial,[10] anti-inflammatory
(IV),[11] antithrombotic,[12] anti-antimalarial,[13] anti-leukemic,[14] anti-tumor (V),[15] and
CNS activities[16] (Figure 1). Owing to the significant biological activity, the chemistry of
cinnoline has gained the enormous interest of medicinal chemists.
On the other hand, triazole derivatives have also gained much attention in heterocyc-
lic chemistry due to their interesting chemical and structural properties and have been
over the past years found to be wide applications in medicinal chemistry.[17] The 1,2,3-
triazole heterocyclic scaffold plays an important role in agrochemical and pharmaceuti-
cals containing anti-inflammatory,[18] anti-proliferative,[19] antiviral,[20] anti-HIV,[21]
anticancer,[22] fungicidal,[23] and insecticidal[24] activity (Figure 2). Therefore, the
amenable biological importance of these cinnolines and the medicinal importance of
triazole heterocyclic moiety directed our attention to design and synthesize the cinno-
line-4-substituted-1,2,3-triazole hybrid derivatives to evaluate their antibacterial activity.
Results and discussion
Chemistry
The present investigation focuses on the development of novel 4-(1H-1,2,3-triazol-4-
yl)methoxy)cinnoline conjugates, starting from commercially available 2-aminobenzoic

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3
Figure 2. Some of the biologically active 1,2,3-triazole derivatives.
Scheme 1. Synthesis of alkyne partners 4a–d.
acid derivatives 1a–d using 1,3-dipolar cycloaddition adopted with “Click reaction” as
the key step.[25] Initially, the alkyne coupling partners 4a–d were prepared in a stepwise
manner starting from 2-aminobenzoic acid derivatives 1a–d which were treated with a
solution of methyllithium to provide 2-aminoacetophenones 2a–d in moderate to good
yields.[26] The aminoketones 2a–d were further converted into the desired 4-hydroxy-
cinnolines 3a–d in good yields by diazotization/cyclization reaction.[27] Propargylation
of the free hydroxyl group in 3a–d with propargyl bromide in the presence of anhyd-
rous K2CO3 in acetonitrile provided propargyl-cinnolines 4a–d (Scheme 1).
The azide coupling partners (azidomethyl)benzenes 6a–d and 4-(3-azidopropyl)morpho-
line (8) were prepared from corresponding amines 5a–d and 7 using 1 H-imidazole-1-sulfonyl
azide hydrochloride in the presence of CuSO4ꢁ5H2O in MeOH as shown in Scheme 2.[28,29]
Finally, the “Click reaction” was employed as the key step for the preparation of
target compounds as outlined in Scheme 3. The reaction of azides 6a–d and 8 with
4-(prop-2-yn-1-yloxy)cinnolines 4a–d individually was carried out in the presence of
catalytic amount of CuSO4ꢁ5H2O and sodium ascorbate in H2O:t-BuOH (1:1 ratio) to

4
B. M. BABU ET AL.
Scheme 2. Synthesis of azide partners 6a–d and 8.
Scheme 3. Synthesis of cinnoline-1,4-disubstituted-1,2,3- triazoles 9a–o and 10a–d.
render the corresponding cinnoline-4-substituted-1,2,3-triazole conjugates 9a–o and
10a–d as final products in moderate to good yields in the range of 38.9% to 68.9%. The
plausible reaction mechanism for the formation of triazole ring was shown in Figure 3
although it is a known plausible reaction mechanism for triazole formation in
literature.[30]
1
All the synthesized compounds were well characterized by H NMR, 13C NMR, and
Mass spectral analysis. The structure of 4-(prop-2-yn-1-yloxy-)cinnolines (4a) is
1
explored in H NMR spectra, the characteristic propargylic protons appeared at showed
at d 2.51 ppm as triplet and methylene protons appeared as doublet at d 5.47 ppm,
whereas the compound 9a, the triazole proton of 9a appeared as a singlet at d
7.80 ppm, –OCH2 appeared as singlet at d 5.76 ppm and N-CH2 appeared as singlet at
d 5.55 ppm, then again 13C NMR showed carbon signals between d 51.67 and d
171.13 ppm that explored the presence of cinnoline as well as a –OCH2 and 1,2,3-
triazole ring. Moreover, the Mass spectral analysis showed that the molecular ion peak
corresponding to the molecular mass of compound 9a. Similarly, for compound 10a,
the characteristic proton of the newly formed triazole ring is appeared as a singlet at d

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5
Figure 3. Plausible mechanism of 1,3-dipolar cycloaddition product formation.
7.51 ppm, whereas the –OCH2 which was attached cinnoline ring resonated at d
4.39 ppm, and the marpholine part of –OCH2’s appeared at d 3.63 ppm. Besides the 13C
NMR, Mass spectral analysis data confirmed that the formation of compound 10a from
the reaction of 4a and compound 8 in t-Butanol and water 1:1 ratio in the presence
of CuSO4.
Biological activity
Antibacterial activity
Inoculation of Pseudomonas aeruginosa (gram-negative), Escherichia coli (E. coli) (gram-
negative), Bacillus subtilis (gram-positive), and Staphylococcus aureus (gram-positive) all
microbes obtain from Microbial Type Culture Collection –MTCC. In auto calved LB
broth media and Incubate overnight at 37ꢂC in a shaker for Bacterial growth. From
that, 0.3 mL of bacterial culture was taken and inoculated using spreader on freshly pre-
pared auto calved agar plates, i.e., Petri dishes. After drying the plates, a 5-mm sample
disc, which was dissolved in DMSO solvent, was kept on microbial plate along with
positive controls NX (Norfloxacin) for Staphylococcus and Pseudomonas, and OF
(ofloxacin) for Bacillus and E. coli, which were incubated overnight at 37ꢂC in BOD
incubator. After overnight incubation, zone of inhibition is measured using a measur-
ing scale.

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B. M. BABU ET AL.
Table 1. Anti-bacterial activity of compounds 9a–o and 10a–d.a
Gram-positive bacteria
Gram-negative bacteria
Compound
Bacillus subtilis
Staphylococcus aureus
Pseudomonas Aeruginosa
Escherichia coli
9a
9b
–
–
–
–
–
–
–
–
9c
9d
9e
–
4.1
–
–
4.5
–
–
3.8
–
–
4.2
–
9f
9g
9h
–
3.1
–
–
–
–
–
–
–
–
4.0
–
9i
9j
–
–
–
–
–
–
–
–
9k
9l
3.0
–
3.0
–
–
–
–
–
9m
9n
9o
–
3.0
–
–
–
–
–
–
–
–
–
–
10a
10b
10c
10d
3.5
5.2
4.0
3.9
6.1
4.2
5.5
4.6
3.5
6
4.0
5.6
3.1
–eth]
6.4
3.7
4.8
3.8
–
Norfloxacin
7
aZone of inhibition (mm) 10 mg/mL concentrations.
All the synthesized compounds were screened for their ability in in vitro assays for
their anti-bacterial[31] activity against two different gram-positive bacterial strains [B.
subtilis; S. aureus] and two gram-negative bacterial strains [P. aeruginosa; E. coli]. The
strains used for the activity procured from IMT, Chandigarah. Cultures of test organ-
isms were maintained on nutrient agar (bacterial) subcultured in Petri dishes prior to
testing. The compounds are tested at concentrations of 10 mg/mL using DMSO as a
solvent. The zone of inhibition (in mm) was compared with standard drug Norfloxacin.
The results are given in Table 1. Among all, the compounds 9d, 10a 10b, and 10c have
shown an excellent zone of inhibition against P. aeruginosa bacterial strain, and these
compounds also have shown good bacterial activity. The compound 9d has shown
4.0 mm zone of inhibition against E. coli bacterial strain. Remaining derivative com-
pounds have shown moderate antibacterial activity. Morpholine moiety containing
Cinnoline-triazole conjugates as the side chain exhibited enhanced activity when com-
pared to other molecules.
Molecular docking studies
Exploration of the molecular interaction of the compounds was performed through
molecular docking studies. To study the molecular interaction of compounds, crystallo-
graphic data of Elastase of P. aeruginosa (PDB:1U4G) was retrieved from Protein Data
Bank (DOI: 10.2210/pdb1U4G/pdb). The docking study of antibacterial active com-
pounds 9d, 10a, 10b, and 10c with Elastase revealed the high docking score
(LibDock)[32] and binding affinity, in the range of 110.706–129.425, as compared to
known antibiotic drug. Norflaxacin 135.922 (Table 2). The best conformations with H-
bond interactions obtained for docked compounds are shown in Figure 4. These results
indicate that most of the compounds bound within the binding site pocket of reference

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Table 2. Details of LibDock score and ligand interaction data revealed through molecular docking of
title derivatives on Elastase of Pseudomonas aeruginosa (PDB: 1U4G).
Compound
Lib Dock score
110.706
Interacting atoms
Bond distance
No. of H-bonds
1
9a
A:ARG198:HH12–16a:O11
16a:H32–A:ARG198:HH12
16a:H29–A:GLY187:CA
16a:H31–A:HIS140:ND1
A:ARG198:HH12–19a:O11
19a:H35–A:TYR114:HA
19a:C3–A:VAL137:HG23
A:GLY187:HN–19b:O24
A:ARG198:HH12–19b:N21
19b:H36–A:ARG198:HH22
19b:H44–A:GLY187:HA2
19b:O24–A:GLY187:N
A:HIS140:HD1–19c:Br27
A:ARG198:HH12–19c:O11
19c:H29–A:GLY187:CA
19c:H29–A:GLY187:HA1
19c:H37–A:TYR114:HA
19c:H41–A:HIS144:CG
A:GLY187:HN–Nor:N6
2.360000
1.606000
2.191000
2.083000
2.322000
1.696000
2.043000
2.467000
2.261000
1.553000
1.461000
2.285000
2.320000
2.000000
1.985000
1.372000
1.541000
2.139000
2.369000
2.410000
0.860000
1.740000
10a
10b
116.347
129.425
1
2
10c
123.732
135.922
2
3
Norflaxacin
A:ASN112:HD22–Nor:O2
A:ASN112:HD22–Nor:O3
Nor:H41–A:HIS140:NE2
Figure 4. Receptor-ligand hydrogen bonds (green color) and bumps (pink color) of compounds 9d,
10a, 10b, 10c and norfloxacinwith active site residues of Elastase of Pseudomonas aeruginosa
(PDB: 1U4G).
and similar binding pattern with binding site amino acid residues. All the docked com-
pounds have a significant binding affinity on selected target infers that these com-
pounds are very active and can be potential leads against antibacterial. Docking analysis
of all the compounds with the Elastase of P. aeruginosa revealed that the compound
10b fitted well in the active site pocket, showing the best docking score of 129.425,
which is closest to Norflaxacin which has a docking score of 135.922. From Figure 4, it
is revealed that two hydrogen bonds and three close contacts are formed between com-
pound 10b with the protein. The first hydrogen bond is formed with the amino acid
Gly187 of the Elastase. This bond is formed between the hydrogen atom of nitrogen

8
B. M. BABU ET AL.
molecule of the amino acid Gly187 with the 24th oxygen atom of the compound 10b
(GLY187:HN-10b:O24) with a hydrogen bond distance of 2.467 Å, and the second
hydrogen bond formed in between ARG198:HH12-10b:N21 with a hydrogen bond dis-
tance 2.261 Å. In addition to that, the compound 10b also formed three close contacts
with Arg198 and Gly187 amino acid residues of the target protein.
Conclusions
In conclusion, we have developed simple and efficient method for the synthesis of
novel 4-((1-alkyl-1H-1,2,3-triazol-4-yl)methoxy)cinnolines 9a–o and 10a–d. All the
synthesized compounds are screened for their antibacterial activity. Among the series
of compounds, halogen-containing groups and electron-donating group (–OCH3) on
either of cinnoline/aromatic moiety derivatives (9d, 9g, and 9k) have enhanced the
anti-bacterial activity. Moreover, it is clear that the morpholine side chain containing
cinnoline-triazole derivatives (10a–c) has more potent anti-bacterial activity. Molecular
docking analysis of these compounds also well supported the experimental screening
results of four different bacterial strains. Among all those compounds, 10a fitted well in
the active site pocket of Elastase of P. aeruginosa, showing the best docking score of
129.425. The potent antibacterial activity of these cinnoline-triazole derivatives
suggests that they are potential candidates for further development of new anti-
biotic drugs.
Experimental
Instrumentation and chemicals
All chemicals used were of laboratory grade and used without further purification.
Melting points of compounds were determined in open capillary tubes in a silicon oil
bath using a Veego melting point apparatus and are uncorrected. The purity of com-
pounds was monitored using TLC on silica F254 coated aluminum plates (Merck) as
1
adsorbent and U.V. light and iodine as visualizing agents. H and 13C NMR spectra
were recorded on Varian mercury TH-300 operating at 400 MHz (1H NMR) and
101.6 MHz (13C NMR) using CDCl3 and DMSO-d6 as solvents and TMS as an internal
standard (Chemical shift in ppm).
General procedure for synthesis of 4-(1H-1,2,3-triazol-yl)methoxy)cinnoline
conjugates (9a–o and 10a–d)
To the stirred suspension of 4-(prop-2-yn-1-yloxy)cinnoline (4a–d) (0.81 mmol) in
H2O:t-BuOH (1:1 ratio) in 50 mL round bottom flask, azidomethyl benzene (6a–d/8)
were added (1.22 mmol), followed by addition of sodium ascorbate (4.07 mmol), and
CuSO4.5H2O (1.63 mmol). The resulting mixture was stirred at room temperature for
6–6 h, then the reaction mixture was diluted with H2O (10 mL) and extracted into
DCM (3 ꢃ 10 mL). The combined organic layers were dried over MgSO4, filtered off,
concentrated, and purified using Flash chromatography to afford respective desired
compounds 9a–o/10a–d in moderate to good yields.

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4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)cinnoline (9a)
Yield (46.5%), m.p. 120–130 ꢂC. Brown solid.1H NMR (400 MHz, CDCl3) d 8.24 (s, 1 H,
Ar), 8.11 (d, J ¼ 8.0 Hz, 1 H, Ar), 7.96 (d, J ¼ 8.8 Hz, 1 H, Ar), 7.83 (d, J ¼ 7.2 Hz, 2 H,
Ar), 7.49 (t, J ¼ 7.6 Hz, 1 H, Ar), 7.33 (t, J ¼ 7.2 Hz, 3 H, Ar), 7.26 (d, J ¼ 6.8 Hz, 2 H,
Ar), 5.76 (s, 2 H, –OCH2), 5.55 (s, 2 H, –NCH2).13C NMR (100 MHz, CDCl3) d 171.1,
142.7, 140.5, 140.4, 134.1, 134.0, 129.2, 128.9, 128.1, 125.7, 125.1, 124.6, 122.5, 115.6,
54.4, 51.6. ESI-MS: m/z 318.0 [M þ H]þ. Anal. Calcd for (C18H15N5O). C: 68.13; H:
4.76; N: 22.07. Found. C: 68.20; H: 4.41; N: 22.20%.
1
Full experimental details: characterization data and copies of H, 13C NMR and MS
spectra for all novel synthesized compounds have been submitted along with the manu-
script. This material can be found via the “Supplementary Content” section of this
article’s webpage.
Acknowledgments
Authors, Mohan Babu thanks to, Head Department of Chemistry, CFRD Osmania University,
Hyderabad, Telangana, India for providing facilities.
ORCID
Sudhakar Mokenapelli
Prasad Rao Chitneni
http://orcid.org/0000-0001-9575-4830
http://orcid.org/0000-0003-0062-9856
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