Synthesis and anti-inflammatory activity of triazole-based macrocyclic amides through click chemistry

Article abstract of DOI:10.1080/00397911.2016.1254800

Triazole-based macrocyclic amides 1–12 with amide group as the intrannular functionality has been synthesized through click chemistry. Triazole-based macrocyclic amides 1–12 show good anti-inflammatory activity even at low concentration (50 μg/mL) when co

Full text of DOI:10.1080/00397911.2016.1254800

Synthetic Communications
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Synthesis and Anti-Inflammatory Activity of
Triazole Based Macrocyclic Amides through Click
Chemistry
Ramasamy Anandhan, Ayyavoo Kannan & Perumal Rajakumar
To cite this article: Ramasamy Anandhan, Ayyavoo Kannan & Perumal Rajakumar (2016):
Synthesis and Anti-Inflammatory Activity of Triazole Based Macrocyclic Amides through Click
Chemistry, Synthetic Communications, DOI: 10.1080/00397911.2016.1254800
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Date: 07 February 2017, At: 06:23

Synthesis and anti-inflammatory activity of triazole based macrocyclic amides
through click chemistry
Ramasamy Anandhan1, Ayyavoo Kannan1, Perumal Rajakumar1
1Department of Organic Chemistry, University of Madras, Chennai, Tamil Nadu, India
Corresponding author E-mail:
perumalrajakumar@gmail.com/ananthanramasamy@gmail.com
Abstract
Triazole based macrocyclic amides 1-12 with amide group as the intrannular
functionality has been synthesized through click chemistry. Triazole based macrocyclic
amides 1–12 show good anti-inflammatory activity even at low concentration (50 µg/mL)
when compared to that of the reference drug prednisolone. BINOL based chiral
macrocyclic amides and pyridine based macrocyclic amides show better anti-
inflammatory activity than the other synthesized macrocyclic amides.
Graphical Abstract
KEYWORDS: click chemistry, macrocyclic amides, anti-inflammatory, NSAIDs
1

1. INTRODUCTION
Cyclophane amides are biologically active supramolecular motifs[1] used as molecular
clefts,[2] molecular receptors[3] and for molecular recognition. [4]In particular cyclophane
amides[5] can form complexes with fluoride, chloride, bromide and phosphate anions, and
also can exhibit antimicrobial activity with various human pathogenic bacteria and plant
pathogenic fungi. Incorporation of chiral unit into cyclophanes is an essential
phenomenon in the field of chiral separations and analysis,[6] asymmetric synthesis,[7]
supramolecular material science,[8] host–guest chemistry[9] and chiral biomolecules such
as proteins, nucleic acids and carbohydrates. On the other hand, the synthesis of amide
functionalized cyclophaneshas received considerable attention due to their biological
importance includinganti-inflammatory,[10] cytotoxic,[11] and anticonvulsant activities.[12]
NSAIDs (NonSteroidal Anti-Inflammatory Drugs) such as aspirin, ibuprofen, naproxen
and fenbufenare commonly used for the treatment of pain, fever, and inflammation
particularly arthritis.[13] Such common NSAIDs gives only temporary relief[14] and have
many side effects such as dyspepsia, gastrointestinal bleeding, perforation in addition to
renal failure and distinct salicylate intoxication.[15] To overcome such side effects, 1,2,3-
triazoleas drug delivery system has been developed to enhance the activity of NSAIDs
and limit their side effects, which promise to be safer than their traditional NSAID
counterparts over the years.[16] During recent times considerable attentionhas been
focused on the synthesize and anti-inflammatory activity of various novel
‘clickable’’1,2,3-triazole based cyclophanes. The main challenge in preparing
macrocyclic compound using “click” cyclization is to find a macrocyclic amenable to
2

efficient end-group modification at opposite ends of azides and alkynes. 1,2,3-Triazole
can serve as hydrogen bond acceptors and can function as an effective amide mimicin
various biological applications.[17] “Click” reaction results from the ligation of azides and
alkynes to give a 1,2,3-triazole moiety and has great potentialfor the synthesis of
macrocyclic molecules. On the other hand, during recent years Cu(I) has been utilizedas
an efficient protocol to generate macrocycles of different sizes by the formation of 1,2,3-
triazole ring system.[18] In particular, the synthesis and in vitro anti-arthritic[19] andanti-
inflammatory activities of amide based cyclophanes has been reported from our
laboratory.[20] Recently, our research focus on the utility of Cu(I) catalyzed click
chemistry for the synthesis of macrocylic amides. Therefore, we wish to report herein the
synthesis and In-vitro anti-inflammatory activity of triazole based macrocyclic amides 1-
12 by click chemistry approach (Figure 1).
RESULTS AND DISCUSSION
2-Aminothiophenol 13 on S-alkylation with propargyl bromide in the presence of KOH
and catalytic amount of TBAB (10 mg) in a mixture of toluene/H2O (1:1) afforded S-
propargyloxy-2-aminothiophenol 14 in 83% yield. Further, reaction of 2.1 equiv. of S-
propargyloxy-2-aminothiophenol 14 with one equiv. of isophthaloyl chloride 15,
pyridine-2,6-dicarboxylic acid chloride 16, thiophenedicarboxylic acid chloride 17 and
(S)-BINOL diacid chloride 18 in the presence of triethylamine in DCM for 12 h at room
temperature afforded the precyclophane amides 19, 20, 21 and 22 in 65%, 71%, 64% and
68% yields, respectively.
3

The 1H NMR spectrum of the precyclophane amide 20 displayed a triplet at δ 2.00 for
acetylenic protons and singlet at δ 10.70 for amide NH protons in addition to the signals
for the other aliphatic and aromatic protons. In the 13C NMR spectrum, the amide
precyclophane 20 showed the acetylenic carbons at δ 72.4 and 79.0 and the amide
carbonyl carbon at δ 160.4 in addition to the signals for the other aliphatic and aromatic
carbons. The mass spectrum (ESI-MS) of 20 showed the molecular ion peak at m/z 457.
Further, the structure of the precyclophane amide 20 was also confirmed from elemental
analysis. Similarly, the structure of precyclophane amides 19, 21 and 22 was confirmed
from the spectral and analytical data.
Triazole based macrocylic amides1-6 were synthesized in 72%, 71%, 58%, 55%, 75%
and 73% yields, respectively by treating one equiv. of precyclophane amide 19 and 20
with one equiv. of 1,4-xylenediazide 23, 1,4-dimethoxy-2,5-xylenyldiazide 24 and 1,3-
azidomethylprydine 25 in the presence of 5 mol % CuSO4.5H2O with 10 mol % sodium
ascorbate (Scheme 2). In 1H NMR spectrum, macrocyclic amide 4 showed sharp singlets
at δ 3.57, 4.00 and 5.21 for O-methyl, S-methylene and N-methylene protons respectively
and a singlet at δ 10.71 for the amide NH proton in addition to the signals for fifteen
aromatic protons. The 13C NMR spectrum of macrocyclic amide 4 showed O-methyl, S-
methylene and N-methylene carbons at 28.6, 46.5 and 53.9 respectively and amide
carbonyl at δ 159.6 in addition to the signals for fourteen aromatic carbons. The mass
spectrum (ESI-MS) of 4 showed the molecular ion peak at m/z 705 (M+). Further, the
structure of the macrocyclic amide 4 was also confirmed from elemental analysis.
4

In 1H NMR spectrum, macrocyclic amide 5 showed sharp singlets at δ 4.18 and 5.43 for
S-methylene and N-methylene protons respectively and a singlet at δ 9.29 for the amide
NH proton in addition to the signals for the other aliphatic and aromatic protons. The 13C
NMR spectrum of macrocyclic amide 5 showed S-methylene and N-methylene carbons at
32.6 and 55.0 respectively and amide carbonyl carbon at δ 163.5 in addition to the
signals for the other aliphatic and aromatic carbons. The mass spectrum (ESI-MS) of 5
showed the molecular ion peak at m/z 646 (M+). Further, the structure of the macrocyclic
amide 5 was also confirmed from elemental analysis. Similarly, the structure of
macrocyclic amide 1, 2, 3, and 6 was confirmed from spectral and analytical data.
Next, we focussed our attention on the synthesis of thiophene based macrocyclic amides
7, 8 and 9. Reaction of the precylophane 21 with one equivalent of 1,4-xylenediazide 23,
1,4-dimethoxy-2,5-xylenyldiazide 24 and 1,3-azidomethylprydine 25 gave
themacrocyclic amide 7, 8 and 9 in 72%, 63% and 77% yields, respectively (Scheme 3).
In 1H NMR spectrum, the macrocyclic amide 8 showed sharp singlets at δ 3.71, 4.12 and
5.30 for O-methyl, S-methylene and N-methylene protons respectively and a singlet at δ
9.22 for the amide NH proton in addition to the signals for the other aliphatic and
aromatic protons. The 13C NMR spectrum of macrocyclic amide 8 showed O-methyl, S-
methylene and N-methylene carbons at 29.7, 49.5 and 56.2 respectively and amide
carbonyl carbon at δ 158.6 in addition to the signals for the other aliphatic and aromatic
carbons. The mass spectrum (ESI-MS) of 8 showed the molecular ion peak at m/z 711
(M+). Further, the structure of the macrocyclic amides 8 was also confirmed from
5

elemental analysis. Similarly, the structure of other triazole based macrocyclic amides 7
and 9 was also confirmed from the spectral and analytical data.
Incorporation of chiral (S)-BINOL unit in the cyclophanes amide would be more
promising with reference to the biological application.[21] Triazole based chiral
macrocyclic amides 10-12 were obtainedin 63%, 59% and 69% yields, respectively by
the reaction of one equiv. of the chiral precyclophane amide 20 with one equiv. of 1,4-
xylenyldiazide 21 1,4-dimethoxy-2,5-xylenyldiazide 22 and 1,3-azidomethylprydine 25
under click reaction conditions (Scheme4).
In the 1H NMR spectrum, the triazole based macrocyclic amide 10 showed sharp singlets
at δ 3.42 and 5.15 for S-methylene and N-methylene protons respectively, a pair of
doublets at δ 4.46 and 4.53 for O-methylene protons attached to the S(-)-BINOL unit and
a singlet at δ 8.72 for amide NH protons in addition to the signals for the aromatic
protons. The 13C NMR spectrum of the triazole based chiralmacrocyclic amide 10
showed S-methylene, N-methylene and O-methylene carbons attached to the S(-)-BINOL
unit at 29.7, 53.2 and 69.71 respectively, amide carbonyl at δ 166.2 in addition to the
signals for nineteen aromatic carbons. The mass spectrum (ESI-MS) of 10 showed the
molecular ion peak at m/z 880 (M+). Further, the structure of the triazole based
chiralmacrocyclic amide 10 was also confirmed from elemental analysis. Similarly, the
structures of the triazole based macrocyclic amides 11 and 12 were also confirmed from
the spectral and analytical data.
6

ANTI-INFLAMMATORY ACTIVITY
The lysosomal enzymes released during inflammation produce a variety of disorders. The
extracellular activity of these enzymes is related to acute or chronic inflammation. Since
the HRBC membranes are similar to lysosomalmembrane components, the prevention of
hypotonicity induced HRBC membrane lysis is taken as a measure of anti-inflammatory
activity of drug. The triazole based cyclophane amides 1-12 were screened for in-vitro
anti-inflammatory activity.Percentage stabilization of the membrane in the presence of
macrocyclic amides 1-12 at various concentration levels of 2.5, 5, 10, 50, 100, 400, 800
and 1000 µg/mL is shown in Figure 2. The anti-inflammatory activities of all the
macrocyclic amides are concentration dependent. All the cyclophane amides 1-12
showed better anti-inflammatory activity at lower concentration of 50 µg/mL than at all
other concentrations. Chiral BINOL macrocyclic amides and thiophene macrocyclic
amides showed better anti-inflammatory activity than the other cyclophanes amides.
Anti-inflammatory of activity BINOL amides could be due to their binding on to the
erythrocyte membrane with subsequent alteration of the charges. In particular chiral (S)-
BINOL macrocyclic amides 10, 11, and 12 exhibits better anti-inflammatory activity than
all other macrocyclic amides at all concentrations which shows that their binding on to
the membrane of the erythrocyte is very effective which could be due to the presence of
rigid chiral BINOL unit and more number of triazoles units. This might have prevented
physical interaction with aggregating agents or promote dispersal by mutual repulsion of
like charges which are involved in the haemolysis of red blood cells.
7

EXPERIMENTAL SECTION
Materials And Methods
All reagents were commercially available and used as such unless otherwise stated. The
diacid chlorides 15, 16,17 and 18 were prepared from corresponding diacid, as reported
earlier from our laboratory.[22] All melting points are uncorrected. 1H NMR and 13C NMR
spectra were recorded with BRUKER 300MHz instruments in deuterated chloroform
(CDCl3) with Tetramethylsilane (TMS) as internal standard. Elemental analyses were
carried out using a Perkin- Elmer CHNS 2400 instrument. Column chromatography was
performed on silica gel (ACME, 100–200 mesh). Routine monitoring of the reaction was
made using thin layer chromatography developed on glass plates coated with silica gel-G
(ACME) of 25 mm thickness and visualized with iodine.
General Procedure For The Cu (I) Catalyzed Click Reaction
A mixture of azide (1.0 mmol, 1 equiv.), alkyne (1.0 mmol, 1 equiv.) was dissolved in
THF/H2O (1:1; 20 mL) and added NaAsc (0.4 mmol, 0.4 equiv.) followed by the addition
of CuSO4.5H2O (0.2 mmol, 0.2 equiv.). The reaction mixture was stirred overnight at
room temperature. The solvent was evaporated and the crude product obtained was
dissolved in EtOAc (2 X 100 mL), washed with brine solution (50 mL), dried over
Na2SO4 and concentrated to give a residue, which was purified by column
chromatography (SiO2).
Triazole Based Cyclophane Amide 1
8

Yield: 72%; 1H NMR (300 MHz, CDCl3): δ 4.14 (s, 4H), 5.45 (s, 4H), 6.89 (s, 1H), 6.97
(s, 4H), 7.17 (t, J = 7.5 Hz, 2H), 7.26 (s, 3H), 7.41 (s, 2H), 7.72-7.77 (m, 2H), 8.07 (dd, J
= 6.3 Hz, J = 1.5 Hz, 2H), 8.39-8.42 (m, 2H), 9.41 (s, 2H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 32.0, 53.5, 119.7, 121.8, 122.5, 124.7, 125.4, 128.0, 130.7, 134.8, 134.9,
136.5, 140.3, 163.4 ppm. MS (EI): m/z= 644 [M+]. Elemental Anal.Calcd for
C34H28N8O2S2: C, 63.33; H, 4.38; N, 17.38 %. Found: C, 63.19; H, 4.32; N, 17.40 %.
CONCLUSION
In conclusion, the triazole based macrocyclic amides 1-12 with amide group as the
intrannular functionality have been synthesised through click chemistry. All the triazole
based cyclophane amides 1-12 show good anti inflammatory activity even at low
concentration of 50 µg/mL than the reference drug prednisolone. The BINOL based
chiral macrocyclic amides and thiophene based macrocyclic amides show better anti-
inflammatory activity than the other macrocyclic amides.
ACKNOWLEDGMENTS
The authors thank CSIR, New Delhi, India, for financial assistance and DST-FIST for
providing NMR facility to the department and Prof. D. Chamundeeswari, Ph.D.,
Department of Pharmacognozy, College of Pharmacy, Sri Ramachandra University,
Chennai-600 116, for the in vitro anti-inflammatory studies.
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12

Table 1. In vitro anti-inflammatory activity of cyclophanes amideson HRBC membrane
stabilization
Cyclophanes
amides
Activity (% prevention of lysis)
5
10
50
100
400
800
1000
μg/mL
μg/mL
μg/mL
μg/mL
μg/mL
μg/mL
μg/mL
46.24 ± 57.34 ± 82.95 ± 80.05 ± 79.41 ± 80.00 ± 80.05 ±
0.80 1.00 0.77 0.81 0.43 0.55 1.01
47.19 ± 65.00 ± 84.80 ± 84.00 ± 81.00 ± 80.00 ± 80.80 ±
1.10 0.63 0.52 0.90 0.80 1.04 0.83
65.25 ± 65.84 ± 91.01 ± 87.63 ± 88.14 ± 90.32 ± 90.84 ±
0.99 0.55 0.41 0.35 0.71 0.78 0.55
67.97 ± 80.27 ± 93.00 ± 89.22 ± 84.05 ± 84.98 ± 84.27 ±
0.77 0.80 0.99 0.92 0.65 0.74 0.87
48.52 ± 56.79 ± 85.74 ± 83.11 ± 80.70 ± 81.90 ± 72.17 ±
0.27 0.74 0.33 0.98 0.66 0.49 0.77
49.54 ± 79.67 ± 85.14 ± 85.08 ± 82.52 ± 84.39 ± 79.67 ±
0.41 0.45 0.70 0.54 0.61 1.08 0.73
70.25 ± 88.54 ± 96.74 ± 91.00 ± 91.14 ± 88.48 ± 89.4 ±
0.78 0.90 0.47 0.93 0.63 1.01 0.33
63.52 ± 81.41 ± 95.84 ± 89.19 ± 93.37 ± 93.52 ± 94.41 ±
0.41 0.86 0.51 0.38 0.54 0.75 0.86
71.97 ± 90.00 ± 95.08 ± 93.82 ± 93.46 ± 91.69 ± 91.00 ±
0.76 0.40 0.54 0.49 0.92 1.11 0.30
1
2
3
4
5
6
7
8
9
13

70.24 ± 80.42 ± 95.28 ± 93.94 ± 89.87 ± 91.39 ± 93.42 ±
0.58 0.82 0.36 0.27 0.59 0.62 0.82
76.10 ± 82.54 ± 98.21 ± 94.63 ± 95.67 ± 96.23 ± 95.54 ±
0.60 0.81 0.30 0.25 0.51 0.66 0.81
77.64 ± 87.27 ± 98.74 ± 94.22 ± 96.05 ± 95.98 ± 95.27 ±
10
11
12
0.91
15.27 ± 25.16 ± 40.05 ± 59.34 ± 86.37 ±
0.76 0.76 0.76 0.76 0.76
0.92
0.49
0.32
0.60
0.81
-
0.92
-
Prednisolone
14

Scheme 1. Reagents and conditions: (i) Propargyl bromide (1.2 equiv), KOH,
TBAB(cat), Toluene-H2O (1:1), reflux, 5 h, 14 (83%); (ii) TEA, DCM (dry), 12 h. 19
(65%), 20 (71%), 21 (64%) and 22 (68%).
15

Scheme 2. Reagents and conditions: (i) 1,4-xylenediazide 23, 1,4-dimethoxy-2,5-
xylenyldiazide 24 and 1,3-azidomethylprydine 25, CuSO4 (5 mol %), sodium ascorbate
(10 mol %), H2O/THF (1:1) r.t., 10 h; 1 (72%), 2 (71%), 3 (58%), 4 (55%), 5 (75%) and
6 (73%).
16

Scheme 3. Reagents and conditions: (i) 1,4-xylenediazide 23, 1,4-dimethoxy-2,5-
xylenyldiazide 24 and 1,3-azidomethylprydine 25, CuSO4 (5 mol %), sodium ascorbate
(10 mol %), H2O/THF (1:1) r.t., 10 h; 7 (72%), 8 (63%) and 9 (77%).
17

Scheme 4. Reagents and conditions: (i) 1,4-xylenediazide 23, 1,4-dimethoxy-2,5-
xylenyldiazide 24 and 1,3-azidomethylprydine 25, CuSO4 (5 mol %), sodium ascorbate
(10 mol %), H2O/THF (1:1) r.t., 10 h; 10 (63%), 11 (59%) and 12 (69%).
18

Figure 1. Structure of triazole based macrocyclic amides 1-12
19

Figure 2. Anti-inflammatory activity of macrocyclic amides 1-12
20