Synthesis, study of antileishmanial and antitrypanosomal activity of imidazo pyridine fused triazole analogues

Article abstract of DOI:10.1039/d0ra07881f

Four groups, thirty-five compounds in total, of novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3-carboxamides were designed and synthesized using substituted pyridine, propargyl bromide, 2-azidoethyl 4-methyl benzenesulfonate and substituted acetylenes. These compounds were characterized using 1H NMR, 13C NMR, LCMS and elemental analyses and a crystal structure was obtained for one of the significantly active compounds, 8f. All the synthesized and characterized compounds were screened in vitro for antileishmanial and antitrypanosomal activity against Leishmania major and Trypanosoma brucei parasites, respectively. Among the tested analogues, fivecompounds (8d, 8f, 8j, 10b and 10d) exhibited significant antileishmanial activity while three compounds (10b, 11a and 11b) showed substantial activity against T. brucei parasite. In silico ADME prediction studies depicted that the essential compounds obeyed Lipinski's rule of five. The predictedin silico toxicity profile suggested that the tested compounds would be non-toxic, which was confirmed experimentally by the lack of cytotoxicity against HeLa cells. Finally, a molecular docking study was also performed, for 10d the most active antileishmanial compound, to study its putative binding pattern at the active site of the selected leishmanial trypanothione reductase target.

Full text of DOI:10.1039/d0ra07881f

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Synthesis, study of antileishmanial and
antitrypanosomal activity of imidazo pyridine fused
Cite this: RSC Adv., 2020, 10, 38328
triazole analogues†
a
a
b
Adinarayana Nandikolla,
Singireddi Srinivasarao, Banoth Karan Kumar,
b
a
c
Sankaranarayanan Murugesan, Himanshu Aggarwal,
Terry K. Smith and Kondapalli Venkata Gowri Chandra Sekhar
Louise L. Major,
c
a
*
Four groups, thirty-five compounds in total, of novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-
-carboxamides were designed and synthesized using substituted pyridine, propargyl bromide, 2-
azidoethyl 4-methyl benzenesulfonate and substituted acetylenes. These compounds were
3
1
13
characterized using H NMR, C NMR, LCMS and elemental analyses and a crystal structure was
obtained for one of the significantly active compounds, 8f. All the synthesized and characterized
compounds were screened in vitro for antileishmanial and antitrypanosomal activity against Leishmania
major and Trypanosoma brucei parasites, respectively. Among the tested analogues, five compounds
8d, 8f, 8j, 10b and 10d) exhibited significant antileishmanial activity while three compounds (10b, 11a
and 11b) showed substantial activity against T. brucei parasite. In silico ADME prediction studies depicted
that the essential compounds obeyed Lipinski's rule of five. The predicted in silico toxicity profile
suggested that the tested compounds would be non-toxic, which was confirmed experimentally by the
lack of cytotoxicity against HeLa cells. Finally, a molecular docking study was also performed, for 10d the
most active antileishmanial compound, to study its putative binding pattern at the active site of the
selected leishmanial trypanothione reductase target.
(
Received 15th September 2020
Accepted 13th October 2020
DOI: 10.1039/d0ra07881f
rsc.li/rsc-advances
(
CL), (b) mucocutaneous leishmaniasis (ML), (c) visercal leish-
1
. Introduction
maniasis (VL) and (d) post-kala-azar dermal leishmaniasis
3
Leishmaniasis is one of the most neglected tropical diseases as (PKDL). The current drugs used for treating leishmaniasis
identied by the WHO. Over twenty species of protozoan include sodium stibogluconate, itraconazole, paromomycin,
1
parasites cause the disease and it is transmitted to its miltefosine, amphotericin B, pentamidine, sitamaquine and
4
mammalian host via the bite of ninety different sandy species. rifampicin. Most of these drugs were discovered in the middle
Mostly leishmaniasis affects the developing countries and of the last century and use of them is constantly leading to
underprivileged people across the globe. Leishmaniasis was problematic resistance in several Leishmania species. A recent
discovered by William Leishman and Charles Donovan in the pilot study conducted in India with thirty-eight patients, proved
2
year 1900 and was observed in the spleen of the patient. If the efficacy of the miltefosine–paromomycin combination in
a person is infected with Leishmania, treatment is not easy and if treating PKDL, whose current treatment is lengthy, costly, time
5
it affects immunocompromised patients co-infected with HIV, consuming and associated with a variety of side-effects.
then the treatment becomes much harder and risky. Leishmania Human African trypanosomiasis also known as “sleeping sick-
is categorized into four classes: (a) cutaneous leishmaniasis ness” is a vector-borne disease mainly caused by infection with
protozoan parasites belonging to the genus Trypanosoma either
Trypanosoma brucei gambiense or Trypanosoma brucei rhode-
siense. Out of this, Trypanosoma brucei gambiense is found in
a
Department of Chemistry, Birla Institute of Technology and Science, Pilani,
Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad
– 500078,
twenty-four countries in west and central Africa. This form,
currently accounts for 98% of reported cases of sleeping sick-
Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of ness and causes a chronic infection. A person can be infected
Telangana, India. E-mail: kvgc@hyderabad.bits-pilani.ac.in; kvgcs.bits@gmail.com;
Tel: +91 40 66303527
b
Technology and Science Pilani, Pilani Campus, Pilani-333031, Rajasthan, India
for months or even years without major signs or symptoms of
the disease. Unlike the above, Trypanosoma brucei rhodesiense is
found in thirteen countries in eastern and southern Africa.
Nowadays, this form represents under 2% of reported cases and
causes an acute infection. First signs and symptoms are
c
Schools of Biology & Chemistry, BSRC, The University, St. Andrews, Fife, Scotland
KY16 9ST, UK
†
Electronic supplementary information (ESI) available. CCDC 1991585. For ESI
and crystallographic data in CIF or other electronic format see DOI:
0.1039/d0ra07881f
1
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Fig. 1 Imidazo-[1,2-a]-pyridine based drugs.
1
5
observed within few months or weeks aer infection. In general, minodronic acid (to treat anxiety, heart failure, osteoporosis),
16
it involves two stages, in the rst stage (also called haemo- and Soraprazan (anti-ulcer). It is also present in some bio-
lymphatic stage), the trypanosomes multiply in subcutaneous logically active derivatives such as GSK812397 (CXCR4 antago-
17
18
tissues, blood and lymph. This entails bouts of fever, head- nist), PI3K-a inhibitors, positive allosteric modulators of
19
20
aches, enlarged lymph nodes, joint pains and itching. In the mGlu2 receptors, TNF-a inhibitors (Fig. 2).
second stage (known as the neurological or meningo-encephalic Castera-Ducrosteam reported imidazo-[1,2-a]-pyridine based
stage), the parasites cross the blood–brain barrier to infect the analogues as antileishmanial agents. From this work, forty-four
central nervous system. This is where more obvious signs and compounds are tested for Leishmania donovani promastigotes.
symptoms of the disease appear: changes of behaviour, confu- Four selective hit compounds exhibited IC50 values 12.6, 18.2,
sion, sensory disturbances and poor coordination as well as 14.0 mM, and compound A (Fig. 3) with an IC 1.8 mM, was the
5
0
21
disturbance of the sleep cycle. They are transmitted to humans most active one of the series. Cyril Fersing's team reported
by tsetse y (Glossina genus) bites. It is endemic in thirty-seven twenty-nine compounds with good antileishmanial activity
sub-Saharan African countries where it has threatened millions against L. donovani, L. infantum and L. major forms of promas-
of people. Without treatment, the disease is considered fatal as tigote and amastigote. Compound B (Fig. 3), showed IC50 ¼ 1–
tsetse ies transmit the disease. Since the number of new 2.1 mM and has low cytotoxicity against the human HepG2 cell
human African trypanosomiasis cases reported between 2000 line (CC50 > 100 mM). The IC50 values of the compound C (Fig. 3)
and 2018 dropped by 95%, the WHO neglected tropical diseases were 1.2 and 2.3 mM against L. donovani of promastigote and
22
road map targeted its elimination as a public health problem by intramacrophase of amastigotes, respectively. John J. Allocco
6
2020 and eradication by 2030.
team did the work on whole-cell growth inhibitors of casein
The imidazo-[1,2-a]-pyridine moiety already exists in several kinase 1 (CK 1) of the L. major and T. brucei parasites. The
pharmacologically signicant molecules. This core moiety is compounds D and E (Fig. 3) showed growth inhibition with IC50
found in many pharmaceutical compounds that display values of 0.5 and 0.2 mM against L. major while in vitro CK1
benzodiazepine receptor agonism, antifungal, antitumor, anti- activity with IC50 values of 9.0 and 8.0 nM respectively was
7–9
23
viral, antibacterial, analgesic, and anti-HIV properties. The observed. Marhadour et al. reported that the diarylimidazo-
imidazo-[1,2-a]-pyridine core is present in some established [1,2-a]-pyridines exhibited low cytotoxicity against the HeLa
10
drugs (Fig. 1), such as alpidem (anxiolytic), zolpidem cells. Compound F was the most potent one against the pro-
1
1
12
24
(
(
hypnotic), saripidem (sedative and anxiolytic), zolimidine mastigote form of L. major with IC50 of 4.0 mM (Fig. 3).
1
3
14
anti-ulcer),
olprinone (to treat acute heart failure),
Fig. 2 Biologically active imidazo-[1,2-a]-pyridine derivatives.
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Fig. 3 Imidazo-[1,2-a]-pyridine based derivatives as antileishmanial agents.
Several triazole containing drugs are currently available in activity against the promastigotes and amastigotes of Leish-
the market. They exhibit pharmacological activities such as mania donovani. In this work, compound H (Fig. 5) showed the
3
6
antileishmanial, anticancer, antimalarial, antitubercular, best activity with IC50 values 7.76 mM and 6.08 mM respectively.
25–28
etc.
Mubritinib is used for breast, bladder, kidney, and Tahghighi et al. reported fourteen thiadiazol-2-amine contain-
prostate cancers. The compound carboxyamidotriazole or CAI ing triazole analogues. From this work, compound I (Fig. 5) was
the most active one against the promastigotes forms of L. major
tert-Butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) is with IC50 12.2 mM. Guimar ˜a es team synthesized lapachone
used as an anti-HIV reverse transcriptase inhibitor. Cefatrizine based 1,2,3-triazoles and evaluated in different resistant strains
and tazobactam are used as antibiotics, while runamide is of L. infantum and L. amazonensis. Compound J (Fig. 5) showed
29
30,31
is an anticancer drug currently in phase III clinical trials.
37
32
33
34
used as an anticonvulsant (Fig. 4).
activity in wild type with IC50 ꢀ 1.00 mM and 1.11 mM against L.
Casemate et al. reported sixteen 1,4-diaryl-1,2,3-triazole infantum and L. amazonensis; in antimony-resistant (2700R)
analogues. From this work, two compounds showed best in strain IC50 of 1.04 mM and 1.03 mM was observed in both L.
38
vitro activity against L. amazonensis promastigotes with IC50 infantum and L. amazonensis respectively.
Mohammad
values of 1.1 mM and 3.71 mM. Compound G (Fig. 5) showed Masood's team reported eighteen amino acid-triazole derivatives.
activity against both L. amazonensis and L. infantum with IC50 From this work, compound K (Fig. 5) showed moderate activity
35
values of 7.23 mM and 5.2 mM. Dwivedi team reported eighteen against the promastigote form of L. donovani (Dd8 strain) with
39
triazole based benzylquercetin glycoconjugates that showed IC50 88.33 mM. Chris Marie team synthesized hydroquinone-
Fig. 4 Triazole containing drugs.
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Fig. 5 Triazole based antileishmanial analogues.
triazole based eleven compounds and compound L with IC50 23 monitored anti-leishmanial activity against both promastigote
mM against L. major promastigote form was the most active one. and amastigote forms of Leishmania major. In this work,
Further, these compounds were found to be non-toxic against compound P (Fig. 6) displayed signicant activity against pro-
40
44
human embryonic kidney cells (Fig. 5).
mastigote form of L. major with IC50 10.73 mM. Chandar et al.
Piperazine is another attractive scaffold that has a multitude synthesized various piperazine linked phenyl derivatives and
of pharmacological effects and is also used as a linker in several tested them against promastigote and amastigote forms of L.
drug molecules. It is present in numerous marketed drugs such infantum. Compound Q with IC50 values of 3.61 and 44.14 mM
45
as ranolazine (antianginal), imatinib (anticancer), buspirone against both the forms was the most active compound (Fig. 6).
(antidepressant), cinnarazine (antihistamine), upentixol
In the current work, we focused mainly on our efforts towards
(
antipsychotic), sildenal (erectile dysfunction), to name a synthetic approach implicating the combination of the pharma-
41
a few. Literature reports indicate that piperazine is used as cophore units of imidazo[1,2-a]pyridine, piperazine and triazole
a linker in obtaining signicantly active antileishmanial (Fig. 7) into one framework. Both imidazo[1,2-a]pyridine and the
compounds. Especially acyl group adjacent to the piperazine N 1,2,3-triazole moiety were linked together by carbonyl piperazine.
was noticed in several active compounds. Alireza et al. synthe-
sized
piperazine derivatives. From this work, compounds M and N
Fig. 6) exhibited good activity with IC50 94 and 77.6 mM values
against L. major's promastigote form. Carlos Barea et al.
synthesized 2-cyano-3-(4-phenylpiperazine-1-carboxamido) qui-
noxaline 1,4-dioxide derivatives. Compound O (Fig. 6) with IC50
1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole-2-yl]-4-benzoyl 2. Results and discussion
2
.1 Synthesis
4-Methyl pyridine-2-amine (1a) and 5-chloropyridin-2-amine
1b) on treatment with ethyl 2-chloro-3-oxobutanoate in DME
(
42
(
under reux for 24 h yielded ethyl-2,7-dimethylimidazo[1,2-a]
pyridine-3-carboxylate (2a) and ethyl-6-chloro-2-methylimidazo
[1,2-a]pyridine-3-carboxylate (2b) respectively. Further reac-
5
.7 mM against axenic forms of Leishmania infantum emerged
46
43
from this work to be the most active compound. Fardmog-
hadam et al. reported furan and thiophene containing 1,3,4-
thiadiazole and arylpiperazine based compounds and
ꢁ
tion of ethyl ester with LiOH in ethanol and water at 70 C for
46
12 h afforded substituted carboxylic acids (3a–b). The acids 3a
and 3b on coupling with 1-Boc-piperazine using EDC$HCl,
Fig. 6 Piperazine linked antileishmanial derivatives.
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Fig. 7 Design of the titled compounds 7a–j, 8a–p, 10a–d, and 11a–e.
Scheme 1 Preparation of intermediate compounds 5a and 5b. Reagents and conditions: (i) 1a/1b (1.0 eq.), ethyl 2-chloro-3-oxobutanoate (1.5
ꢁ
eq.), 1,4-dioxane, reflux, 36 h; (ii) LiOH (2.0 eq.), EtOH, water, 75 C, 22 h; (iii) 1-Boc-piperazine (1.1 eq.), EDC$HCl (1.5 eq.), hydroxybenzotriazole
ꢁ
(
1.5 eq.), DIPEA (3 eq.) DMF, rt, 16 h; (iv) 4 M dioxane–HCl (2V) DCM, 0 C to rt, 4 h.
HOBt, and DIPEA in DMF at rt for 12 h yielded 4a and 4b, 5a and 5b with propargyl bromide, potassium carbonate, and
respectively. The key intermediate 5a and 5b were prepared by a catalytic amount of potassium iodide in acetone and water at
ꢁ
ꢁ
BOC deprotection of 4a and 4b using 4 M dioxane–HCl at 0 C to 50 C for 24 h yielding 6a and 6b. Further, 6a and 6b on the
rt for 4 h, as shown in Scheme 1. We prepared the title treatment with various substituted azides using CuSO $5H O
4
2
ꢁ
compounds 7a–j and 8a–p in two steps, as shown in Scheme 2. and sodium ascorbate in DMF and water at rt to 55 C for 12 h
First, we performed the S 2 reaction, involving the reaction of afforded the title compounds 7a–j and 8a–p.
N
Scheme 2 Preparation of title compounds 7a–j and 8a–p. Reagents and conditions: (v) 5a/5b (1.0 eq.), propargyl bromide (80% in toluene) (1.5
ꢁ
$
eq.), K CO
2 3
(4 eq.), DMF, 100 C, 12 h; (vi) substituted azides (1.5 eq.), CuSO
4
2
5H O, (10 mol%), sodium ascorbate (10 mol%), DMF : water (8 : 2), rt,
7
–12 h.
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Scheme 3 Preparation of title compounds 10a–d and 11a–e. Reagents and conditions: (vii) 5a/5b (1.0 eq.), 2-azidoethyl 4-methyl-
ꢁ
$
benzenesulfonate (1.5 eq.), K
ascorbate (10 mol%), DMF : water (8 : 2), rt, 7–12 h.
2
CO (4 eq.), DMF, 100 C, 12 h; (viii) substituted terminal alkynes (1.5 eq.), CuSO 5H O, (10 mol%), sodium
3
4
2
We prepared the compounds 10a–d and 11a–e in two steps, compound 10d showed comparable IC50 value (15.1 mM) as
as shown in Scheme 3. Compounds 5a and 5b on treatment with standard drug miltefosine (12.6 mM). Apart from this, around
2
-azidoethyl 4-methylbenzenesulfonate using
K
2
ꢁ
CO
3
and nine compounds (7d, 8c, 8e, 8h, 8k, 8l, 8n, 8o, and 11b)
a catalytic amount of KI in acetone and water at 50 C for 24 h exhibited moderate activity against the tested strain of L. major
yielded 9a and 9b. Finally, 9a and 9b on treatment with various with IC50 values in the range of 63 to 91 mM. The remaining
substituted acetylenes using CuSO $5H O and sodium ascor- compounds were found weakly active against the tested forms
bate in DMF and water at rt to 55 C for 12 h afforded the of the parasite in comparison to the standard drug. Finally,
compounds 10a–d and 11a–e. All the nal compounds were among the four tested series, the majority of 8a–p and 10a–
puried by column chromatography using 65–95% ethyl acetate d compounds possessed signicant activity against the tested
4
2
ꢁ
in hexane and 2–6% methanol in CH
2
Cl
2
as eluents.
strain of promastigote of L. major and 7a–j, 11a–e series
1
The H NMR of nal compounds 7a–j, 8a–p, 10a–d, and 11a–e compounds exhibited weak activity against L. major. On the
showed one singlet and one multiplet between d 3.0–4.00 ppm other side, among the tested thirty-ve compounds, three
due to methylene protons between the piperazine-triazole compounds (10b, 11a, and 11b) showed signicant activity
nucleus and piperazine (methylene groups) respectively. against the T. brucei parasite with IC50 values of 5.5, 7.4, and 0.7
Another singlet was observed in the range d 2.00–2.65 ppm due to mM, respectively. The later compound 11b showed only a ten-
methyl protons attached to the imidazole ring. In the aromatic fold high IC50 value than that of standard drug melarsoprol
region, one singlet appeared between d 8.50–9.50 ppm due to the (0.05 mM). Apart from this, around twelve compounds (7j, 8c,
single proton of the triazole nucleus of the compounds 7a–j, 8a– 8d, 8f, 8h, 8i, 8j, 8l, 8n, 8o, 8p, 10a) exhibited moderate anti-
p, 10a–d, and 11a–e conrming the formation of products. All the trypanosomal activity with IC50 values in the range of 23 to 53.9
synthesized compounds were conrmed by mass spectrometry, mM. Around ve compounds (7c, 7d, 8e, 8k, and 10c) possessed
1
13
H and C NMR, and elemental analyses.
weak activity with IC50 values in the range of 61 to 95.9 mM
against the tested T. brucei parasite in the in vitro assay. The
remaining compounds were found largely inactive against the
2
.2 Cytotoxicity evaluation
Initially, all the synthesized nal compounds were evaluated for tested forms of the parasite in comparison to the standard drug.
cytotoxicity against HeLa cell lines at 100 mM by an Alamar blue In summary, compound 10b showed signicant, and ve
assay, which showed most of these compounds were non-toxic to compounds (8c, 8h, 8l, 8n, and 8o) exhibited moderate activity
HeLa cells at tested concentration. Compounds that showed against both the tested strains of L. major and T. brucei.
cytotoxicity against HeLa cells were further evaluated to determine
2.4 Structure–activity relationship (SAR) description
cytotoxic concentration (CC50) value. Among the tested deriva-
Electron withdrawing groups especially at the para position of the
phenyl group attached to triazole nucleus (8d, 8f), enhanced the
antileishmanial activity. In contrast, a majority of the compounds
substituted with electron-withdrawing groups at the ortho, meta,
and ortho, meta disubstitution (8h, 8k, 8l, 8n, 8o) showed moderate
antileishmanial activity against the tested L. major. Concerning the
antitrypanosomal activity, compounds substituted with bulky
group/long chain at the triazole nucleus (10b and 11b) showed
signicant activity among all the tested series of compounds.
Electron-withdrawing groups, especially at the para position of the
phenyl group attached to the triazole nucleus (7c, 7d, 8e, 8k),
resulted in a weak antitrypanosomal activity.
tives, only compounds 8d and 10b showed moderate cytotoxicity
(CC50 58.09 and 62.67 mM, respectively) against HeLa cells.
2.3 In vitro antileishmanial and antitrypanosomal activity of
the titled compounds
In the current study, the effect of all synthesized title
compounds on promastigotes of L. major and trypanocidal
properties on bloodstream-form T. brucei was evaluated in vitro
initially as a single point. All compounds with IC50 below 75 mM
were further tested in replicates of four to obtain a mean and
standard deviation. The antileishmanial and antitrypanosomal
activities of these novel compounds are shown in Table 1.
Among the tested four series of thirty-ve compounds, ve
compounds (8d, 8f, 8j, 10b, and 10d) showed signicant inhi-
2.5 In silico prediction of ADME and toxicity parameters
bition on the growth of promastigote forms of L. major with IC50 Lipinski's rule of ve parameters (mol. weight, donor HB, acceptor
values in the range of 15 to 47 mM. The most signicantly active HB, and log P) of all the titled compounds are satised compared
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a
Table 1 Antileishmanial and antitrypanosomal results of the title compounds
S. no.
Comp. code
R
L. major (IC50, mM)
T. brucei (IC50, mM)
CC50, mM
SI (L. major)
SI (T. brucei)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
10a
10b
10c
10d
11a
11b
245.7
>500
288.3
131.10
>500
95.90
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
58.09
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
62.67
>100
>100
>100
>100
>100
>100
>100
>0.41
—
>0.76
—
>1.04
>1.53
—
—
>0.39
—
4-NO
2
4-CF
4-C
4-Br
3-NO
3
>0.35
>1.49
>0.67
>0.40
>0.56
>0.47
>0.58
>0.88
>0.52
>0.40
>1.48
1.57
>1.13
>2.92
>0.40
>1.43
>0.89
>2.22
>1.38
>1.09
>0.47
>1.43
>1.43
>0.99
>0.57
1.63
2
H
5
74.6 ꢂ 1.4
63.2 ꢂ 2.0
149.2
>500
2
>250
179.8
211.3
173.8
114.0
192.4
>250
62.8 ꢂ 2.4
34.5 ꢂ 0.6
88.6
>500
259.30
>500
>500
3-OMe
2-Cl
3-Cl, 4-F
4-OMe, 2-NO
H
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
2
47.7 ꢂ 9.8
>2.4
>0.86
—
>4.3
1.86
>1.06
>1.73
—
>2.98
>1.34
>2.36
>1.66
>2.03
—
>1.85
>2.42
>2.11
>1.44
6.83
>1.40
—
116.10
4-NO
4-CF
2
>500
3
23.2 ꢂ 1.5
29.1 ꢂ 1.3
94.30
4-C
4-F
2 5
H
4-Br
3-NO
3-CF
33.6 ꢂ 0.6
28.7 ꢂ 3.1
2
>250
>500
3
73.6 ꢂ 2.0
111.8
47.1 ꢂ 0.9
73.1 ꢂ 2.8
91.48
212.20
70.9 ꢂ 2.8
60.9 ꢂ 1.0
100.7
24.2 ꢂ 1.0
50.9 ꢂ 5.7
26.5 ꢂ 1.5
61.2 ꢂ 2.5
33.5 ꢂ 2.7
>500
3-OMe
3-Cl
2-F
2-Cl
3-Cl, 4-F
3,5-CH
3,4-CH
4-OMe, 2-NO
n-Propyl
n-Nonyl
Cyclopropyl
4-t-Butyl phenyl
n-Propyl
n-Nonyl
Cyclopropyl
Phenyl
4-t-Butyl phenyl
3
53.90
3
40.9 ꢂ 2.0
46.3 ꢂ 1.6
40.5 ꢂ 2.7
5.5 ꢂ 0.5
71.3
2
176.1
38.5 ꢂ 0.9
250.6
>0.40
>6.37
>0.21
>1.63
>0.19
>0.35
>1.49
15.1 ꢂ 1.0
475.1
>500
7.4 ꢂ 0.9
0.72 ꢂ 0.57
131.9
>500
>500
>3.09
>6.12
>0.76
—
62.0 ꢂ 2.7
11c
11d
11e
Miltefosine
Melarsoprol
>500
>250
171.1
>0.76
12.6 ꢂ 0.5
—
—
0.05 ꢂ 0.01
a
The values are either a single IC50 determination (for compounds with IC50 > 75 mM) or mean ꢂ standard deviations (n ¼ 4) (for compounds with
IC50 < 75 mM).
with the marketed approved drugs. The solvent-accessible 10d, while in compound 8p, it is 48%. For the rest of the nal
surface area, aqueous solubility pattern, brain/blood partition compounds, it lies between 84–55% (Table 2).
coefficient, and the number of rotatable bonds of the titled
compounds were found to be in the prescribed range as that of
2.6 In silico predicted toxicity prole of the titled compounds
marketed drugs. The Caco-2 permeability of all the compounds
except few compounds (7b, 7f, 7j, 8b, and 8g) was found to be
moderate when compared to the marketed drugs. Percent of
human oral absorption was 100% in the compounds 10b and
The results of anticipated toxicity studies of the nal
compounds (7a–j, 8a–p, 10a–d, and 11a–e) revealed that the
tested compounds are non-toxic. Cancer-causing properties like
mutagenicity and tumorigenicity of these agents were found to
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a
Table 2 Results of in silico predicted ADME parameters of the titled analogues
Acceptor
% Human
S. no.
Comp. code
Mol. wt.
SASA
Donor HB
HB
log Po/w
log S
P
Caco
log BB
Rotor
oral absorption
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
10a
10b
10c
10d
11a
11b
11c
11d
11e
415.50
460.49
483.50
443.55
494.39
460.49
445.52
449.94
467.93
490.52
435.92
480.91
503.91
463.97
453.91
514.81
480.91
503.91
465.94
470.36
453.91
470.36
488.35
463.97
463.97
510.94
395.51
479.67
393.49
485.63
415.93
500.09
413.91
449.94
506.05
757.26
797.80
812.89
821.72
786.30
797.65
795.51
778.99
789.71
823.13
748.21
789.14
802.61
812.97
757.74
777.17
788.44
800.22
787.38
774.46
757.34
770.05
782.52
813.29
805.29
814.65
770.01
957.13
697.95
866.91
734.35
947.49
689.03
764.40
882.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
8.50
3.07
2.39
4.12
3.79
3.66
2.38
3.20
3.57
3.84
2.59
3.25
2.56
4.28
4.01
3.50
3.84
2.56
4.26
3.38
3.82
3.54
3.79
4.03
3.90
3.87
2.77
2.69
4.96
2.23
4.46
2.78
5.13
2.40
3.41
4.73
ꢃ4.41
ꢃ4.49
ꢃ5.98
ꢃ5.47
ꢃ5.30
ꢃ4.49
ꢃ4.58
ꢃ5.07
ꢃ5.50
ꢃ4.42
ꢃ4.54
ꢃ4.63
ꢃ6.09
ꢃ5.61
ꢃ4.93
ꢃ5.43
ꢃ4.63
ꢃ6.05
ꢃ4.74
ꢃ5.36
ꢃ4.88
ꢃ5.21
ꢃ5.68
ꢃ5.78
ꢃ5.63
ꢃ4.57
ꢃ3.90
ꢃ6.47
ꢃ2.86
ꢃ5.90
ꢃ3.53
ꢃ6.59
ꢃ3.00
ꢃ4.43
ꢃ6.49
245.81
34.87
256.96
256.76
245.73
33.53
282.14
274.69
283.04
56.64
256.45
34.89
256.02
291.36
256.01
257.36
33.38
243.67
281.53
282.23
304.91
307.83
281.51
242.65
243.04
56.18
263.71
245.83
257.06
302.69
326.11
246.81
256.07
329.49
270.88
ꢃ0.38
ꢃ1.49
ꢃ0.12
ꢃ0.48
ꢃ0.22
ꢃ1.52
ꢃ0.40
ꢃ0.20
ꢃ0.07
ꢃ1.30
ꢃ0.18
ꢃ1.31
0.06
3.00
4.00
3.00
4.00
3.00
4.00
4.00
3.00
3.00
5.00
3.00
4.00
3.00
4.00
3.00
3.00
4.00
3.00
4.00
3.00
3.00
3.00
3.00
3.00
3.00
5.00
6.00
12.00
4.00
5.00
6.00
12.00
4.00
4.00
5.00
87.72
55.57
94.18
92.25
91.14
55.23
89.53
91.50
93.32
60.54
89.11
56.61
82.16
94.52
90.53
79.61
56.24
81.63
90.56
93.17
92.11
93.66
94.37
92.49
92.29
48.54
86.02
100.00
83.11
100.00
88.23
73.90
84.08
91.95
85.20
9.50
8.50
8.50
8.50
9.50
9.25
8.50
8.50
10.25
8.50
9.50
8.50
8.50
8.50
8.50
9.50
8.50
9.25
8.50
8.50
8.50
8.50
8.50
8.50
10.25
9.00
9.00
9.00
9.00
9.00
9.00
9.00
9.00
9.00
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
ꢃ0.23
ꢃ0.08
ꢃ0.02
ꢃ1.32
0.04
ꢃ0.22
0.02
ꢃ0.01
0.04
0.11
ꢃ0.26
ꢃ0.25
ꢃ1.12
ꢃ0.55
ꢃ1.11
ꢃ0.31
ꢃ0.44
ꢃ0.21
ꢃ0.93
ꢃ0.12
ꢃ0.11
ꢃ0.36
a
Comp. code – compound code; mol. wt. – molecular weight (130–725); SASA – solvent accessible surface area (300–1000); donor HB – hydrogen
bond donor (0–6); acceptor HB – hydrogen bond acceptor (0–20); log Po/w – partition co-efficient (octanol/water) (ꢃ2.0 to 6.50); log S – solubility
ꢃ3
ꢃ1
compound (ꢃ6.5 to 0.5 mol dm ); PCaco – Caco-2 cell permeability in nm s (<25 poor, >500 good); log BB – brain/blood partition coefficient
ꢃ3.0 to 1.2); rotor – number of rotatable bonds (0 to 15); % human oral absorption – percentage human oral intestional absorption (up to 100).
(
be nil. The rest of the features like reproductive effect and toxicity parameters of the designed compounds displayed
irritant effects were also found to be none. With these satis- productive results. The results disclosed that these compounds
factory results, we conclude that all the predicted ADME and might not face any problems during clinical trials.
Table 3 In-depth analysis of the significantly active compound 10d and co-crystal ligand of PDB-2JK6
P–P
Hydrogen bond with
distances ( A˚ )
interactions with
distances ( A˚ )
ꢃ1
Comp. code
0d
Co-crystal ligand (FAD)
Gide score (kcal mol
)
1
SER-14 (2.26)
LYS-60 (2.24)
SER-14 (2.26)
GLY-15 (2.14)
ASP-327 (2.78)
TYR-198 (5.45)
ꢃ6.74
ꢃ16.24
ASP-35 (1.86, 2.04)
THR-51 (1.82)
LYS-60 (2.11)
GLY-127 (2.09, 2.13)
ASP-327 (1.85, 2.36)
THR-335 (2.26)
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Fig. 8 Superimposed view of the FAD molecule in the active site of the target PDB-2JK6, and its redocked pose in the same target (RMSD – 0.20 A˚ ).
2.7 In silico molecular docking studies
are involved in the similar kind of hydrogen bond interactions
with both co-crystal ligand and compound 10d.
To nd the putative binding mode of the titled compounds,
a docking study was performed, and the results were analyzed
(
Table 3). The validation of the docking protocol was done by
2
8
.8 Single crystal X-ray crystallographic structure of compound
f
checking the root mean square deviation of the X-ray native
pose of the ligand with its docked pose of ligand (Fig. 8) and
˚
The suitable crystals of compound 8f for single-crystal X-ray
diffraction (SCXRD) study were grown from the mixture of
found to be 0.20 A. This RMSD could be reliable to proceed for
the docking study of the designed scaffolds.
From the docked pose view of extracted co-crystal ligand methanol and dichloromethane (1 : 3). The SCXRD measure-
(
Fig. 9), eight hydrogen bond interactions with the amino acid ments were performed on the Rigaku XtaLAB P200 diffractom-
residues SER14, GLY15, ASP35, THR51, LYS60, GLY127, ASP327 eter using graphite monochromated Mo-Ka radiation (l ¼
˚
and THR335 of the active site of the target protein and one P–P 0.71073 A). The data was collected and reduced using CrysA-
interaction with the amino acid residue TYR198 with a docking lisPro (Rigaku Oxford Diffraction) soware. The data collection
ꢃ1
score value of ꢃ16.24 kcal mol was observed. The docking was carried out at 100 K, and the structures were solved using
score exhibited by the signicantly active compound 10d is Olex2 with the ShelX structure solution program using Direct
ꢃ1
ꢃ6.74 kcal mol . Like co-crystal ligand, compound 10d also Methods and rened with the ShelXL renement package using
made two hydrogen bond interactions with the amino acid Least Squares minimization. The basic crystallographic data is
residues SER14, LYS60 and one P–P interaction with the amino given in a table in ESI.†
acid residue ASP327 of the active site of the target protein
Fig. 10). Upon critical examination of the interactions formed linker per asymmetric unit and one molecule of DCM which is
by the co-crystal ligand to the target protein and the compound disordered over two positions (Fig. 11). The ORTEP diagram of
0d to the active site amino acid residues of the target protein, it the structure shows that the ellipsoids of all the atoms are well
The compound 8f crystallizes in Pbca space group with one
(
1
was found that the same amino acid residues (SER14, LYS60) behaved. Crystallographic Data Center and corresponding
deposition number is CCDC 1991585.†
Fig. 9 Exposed amino-acid residue interactions of the FAD molecule in the actives site of the target PDB-2JK6 (black lines – hydrogen bonds,
blue – pi interaction in 3D, magenta – hydrogen bond, green – pi interaction in 2D).
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Fig. 10 Exposed amino-acid residue interactions of the significantly active compound 10d in the actives site of the target PDB-2JK6 (yellow lines
hydrogen bonds, blue – pi interaction in 3D, magenta – hydrogen bond in 2D).
–
Fig. 11 ORTEP diagram of compound 8f.
Upon closer look at the structure, it was found that the benzene units of one ligand and the imidazole pyridine units of
ligand packs in an interesting manner where the individual the other ligand (Fig. 12). The pi–pi stacking distance is in the
units stack antiparallel to each other to minimize the electronic range of 3.6–3.9 A˚ .
repulsions. The structure show pi–pi stacking between the
Fig. 12 Packing diagram of 8f showing pi–pi stacking arrangement as observed along a (left) and c (right) axis.
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(
2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-nitrophenyl)-
3
. Conclusion
1
H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone (7b). Pale
ꢁ
1
In conclusion, we have designed and synthesized thirty-ve yellow solid; (68%); mp 236–238 C; H NMR (400 MHz, DMSO-d6)
novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3- d 8.96 (s, 1H), 8.45 (d, J ¼ 8.8 Hz, 2H), 8.40 (s, 1H), 8.24 (d, J ¼
carboxamides using substituted pyridine, propargyl bromide, 8.8 Hz, 2H), 7.37 (s, 1H), 6.82 (d, J ¼ 6.8 Hz, 1H), 3.74 (s, 2H), 3.56
13
2
-azidoethyl-4-methyl benzenesulfonate and substituted acety- (s, 4H), 2.61 (d, 4H), 2.35 (s, 6H). C NMR (101 MHz, DMSO-d6)
lenes. The synthesized compounds were well characterized d 161.59, 158.42, 151.16, 147.06, 145.51, 141.40, 137.28, 126.78,
1
13
using H NMR, C NMR, LCMS and elemental analyses. These 126.02, 123.11, 120.92, 115.48, 112.96, 52.91, 52.61, 44.88, 21.25,
compounds were further screened in vitro for antileishmanial 15.50. ESI-MS: (m/z) calcd for C H N O : 460.49, found 461.00 (M
2
3 24 8 3
+
and antitrypanosomal activity against L. major and T. brucei + H) ; anal. calcd for C H N O : (%) C, 59.99; H, 5.25; N, 24.33; O,
2
3 24 8 3
parasites, respectively. Few compounds exhibited signicant to 10.42. Found: C, 59.98; H, 5.65; N, 29.61; O, 5.57.
moderate antileishmanial and antitrypanosomal activity in the
(2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-(triuoro
tested assay system. Five compounds exhibited signicant methyl)-phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
ꢁ
1
antileishmanial activity (8d, 8f, 8j, 10b and 10d), while three methanone (7c). Pale yellow solid; (71%); mp 200–202 C; H NMR
compounds (10b, 11a and 11b) showed signicant activity (400 MHz, DMSO-d6) d 8.94 (s, 1H), 8.78 (s, 1H), 8.29 (m, 2H), 7.86
against the T. brucei parasite. In silico ADME prediction studies (m, 2H), 7.59 (m, 1H), 6.83 (s, 1H), 3.77 (s, 2H), 3.51 (m, 4H), 2.61
13
also depicted that the titled compounds do not violate Lip- (m, 4H), 2.35 (s, 6H). C NMR (101 MHz, DMSO-d6) d 161.46,
inski's rule of ve parameters in comparison with the marketed 159.01, 151.43, 148.18, 146.55, 141.43, 137.64, 126.97, 125.73,
approved drugs. The predicted toxicity prole also conrmed 126.07, 122.23, 120.66, 115.93, 113.13, 52.95, 52.63, 44.76, 21.33,
that the compounds are non-toxic. Finally, molecular docking 15.41. ESI-MS: (m/z) calcd for C H F N O: 483.20, found 484.14
2
4 24 3 7
+
studies was also performed for signicantly active compound (M + H) ; anal. calcd for C H F N O: (%) C, 59.62; H, 5.00; F,
2
4 24 3 7
(10d) in order to study its putative binding pattern at the active 11.79; N, 20.28; O, 3.31. Found: C, 59.65; H, 5.03; F, 11.86; N, 20.25;
site of the selected leishmanial trypanothione reducatse target. O, 3.26.
The crystal structure developed for one of the signicantly active
(2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-ethyl-
antileishmanial compound 8f was found to occupy Pbca space phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
1
group. Further, the crystal structure revealed pi–pi stacking methanone (7d). Sticky liquid; (74%); H NMR (400 MHz,
between the benzene units of one ligand and the imidazole pyri- DMSO-d6) d 8.73 (s, 1H), 8.41 (s, 1H), 7.81 (d, 2H), 7.43 (d, 2H),
dine units of the other. We also observed that all the nal synthe- 6.88 (d, 1H), 3.91 (s, 2H), 3.61 (s, 4H), 2.69 (m, 6H), 2.37 (s, 6H),
1
3
sized compounds were non-toxic to HeLa cell line at 100 mM.
1.22 (t, 3H). C NMR (101 MHz, DMSO-d6) d 161.82, 144.64,
1
5
37.01, 135.43, 130.22, 124.95, 122.43, 122.83, 120.37, 115.91,
2.63, 50.3, 45.06, 27.86, 21.21, 15.47, 14.80. ESI-MS: (m/z) calcd
4
. Experimental section
+
for C H N O: 443.24, found 444.00 (M + H) ; anal. calcd for
2
5
29 7
4.1 Chemistry
25 29 7
C H N O: (%) C, 67.70; H, 6.59; N, 22.11; O, 3.61. Found: C,
6
7.74; H, 6.62; N, 22.07; O, 3.64.
(4-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piper-
The intermediates 2a, 2b, 3a, and 3b were prepared as per the
46
earlier reported literature protocol. The procedures and the
analytical data of the remaining intermediates and nal
compounds (7a–j, 8a–p, 10a–d, and 11a–e) are given in ESI.† The
detailed procedures used for cytotoxicity, in vitro activity studies,
in silico toxicity parameters, molecular docking studies, ligand
and protein preparation methods, receptor grid generation,
docking validation, and docking analysis are also given in ESI.†
azin-1-yl)(2,7-dimethylimidazo-[1,2-a]-pyridin-3-yl)-methanone
ꢁ
1
(7e). Brown solid; (66%); mp 100–102 C; H NMR (400 MHz,
DMSO-d6) d 8.77 (s, 1H), 8.34 (d, 1H), 7.90 (d, 2H), 7.80 (d, 2H),
7
2
.34 (s, 1H), 6.82 (d, 1H), 3.71 (s, 2H), 3.55 (m, 4H), 2.52 (m, 4H),
1
3
.36 (s, 3H), 2.34 (s, 3H). C NMR (101 MHz, DMSO-d6)
d 162.17, 145.09, 137.43, 136.35, 133.21, 126.65, 122.65, 122.33,
21.72, 115.01, 52.79, 52.63–51.9, 45.06, 21.20, 15.59. ESI-MS:
1
+
(m/z) calcd for C23
H24BrN
7
O: 493.12, found 494.06 (M + H) ;
4.2 Analytical data of nal compounds (7a–j, 8a–p, 10a–d,
anal. calcd for C23
H
24BrN O: (%) C, 55.88; H, 4.89; Br, 16.16; N,
7
and 11a–e)
1
9.83; O, 3.24. Found: C, 55.85; H, 4.83; Br, 16.19; N, 19.80; O,
3.20.
(2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-nitrophenyl)-
(7f).
(2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-phenyl-1H-
1
,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone (7a). Sticky
ꢁ
1
liquid; (75%); mp 238–240 C; H NMR (400 MHz, DMSO-d6) 1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone
ꢁ
1
d 8.74 (s, 1H), 8.35 (d, J ¼ 5.6 Hz, 1H), 7.96–7.87 (m, 2H), 7.60 (dd, Yellow solid; (73%); mp 218–220 C; H NMR (400 MHz, DMSO-d6)
J ¼ 10.7, 5.0 Hz, 2H), 7.48 (t, J ¼ 7.4 Hz, 1H), 7.34 (s, 1H), 6.82 (d, J d 8.75 (s, 1H), 8.30 (d, 1H), 7.85 (d, 1H), 7.75 (dd, 1H), 7.65 (s, 1H),
¼
7.1 Hz, 1H), 3.73 (s, 2H), 3.56 (s, 4H), 2.53 (d, J ¼ 6.3 Hz, 4H), 7.50 (d, 1H), 7.30 (s, 1H), 6.79 (d, 1H), 3.69 (s, 2H), 3.53 (m, 4H),
13
13
2
1
1
.36 (s, 6H). C NMR (101 MHz, DMSO) d 162.19, 156.46, 144.67, 2.50 (m, 4H), 2.30 (s, 3H), 2.26 (s, 3H). C NMR (101 MHz, DMSO-
37.43, 137.15, 130.33, 129.01, 126.49, 122.65, 120.40, 115.27, d6) d 161.61, 157.91, 151.47, 147.28, 145.51, 141.44, 137.84, 126.98,
15.01, 55.35, 52.89, 45.04, 29.45, 20.83. ESI-MS: (m/z) calcd for 125.91, 123.10, 120.94, 115.461, 112.34, 110.28, 109.47, 52.92,
C H N O: 415.21, found 416.26 (M + H) ; anal. calcd for 52.60, 44.76, 21.24, 15.48. ESI-MS: (m/z) calcd for C H N O :
+
2
3
25
7
23 24 8 3
+
C H N
23 25 7
O: (%) C, 66.49; H, 6.06; N, 23.60; O, 3.85. Found: C, 460.20, found 461.24 (M + H) ; anal. calcd for C H N O : (%) C,
23 24 8 3
66.45; H, 6.10; N, 23.56; O, 3.81.
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+
59.99; H, 5.25; N, 24.33; O, 10.42. Found: C, 60.04; H, 5.21; N, 24.27; for C22
H22ClN
7
O: 435.16, found 436.19 (M + H) ; anal. calcd for
O, 10.46.
C H ClN O: (%) C, 60.62; H, 5.09; Cl, 8.13; N, 22.49; O, 3.67.
22 22 7
(2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-methoxy
Found: C, 60.57; H, 5.04; Cl, 8.18; N, 22.43; O, 3.71.
phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-nitro-
ꢁ
1
(7g). Brown solid; (67%); mp 95–97 C; H NMR (400 MHz, DMSO) phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone
ꢁ
1
d 8.81 (s, 1H), 8.39 (s, 1H), 7.49 (m, 4H), 7.05 (d, 1H), 6.88 (d, 1H), (8b). Pale yellow solid; (79%); mp 220–221 C; H NMR (400 MHz,
13
3
.86 (m, 6H), 3.62 (s, 4H), 2.74 (s, 3H), 2.38 (s, 6H). C NMR (101 DMSO-d6) d 8.97 (s, 1H), 8.58 (s, 1H), 8.49–8.43 (m, 2H), 8.29–8.22
MHz, DMSO-d6) d 162.93, 161.79, 145.12, 137.64, 136.35, 127.22, (m, 2H), 7.62 (s, 1H), 7.43 (s, 1H), 3.76 (s, 2H), 3.58 (s, 4H), 2.57 (s,
1
3
1
26.61, 126.64, 125.14, 124.32, 122.15, 122.32, 121.77, 115.11, 4H), 2.42–2.33 (m, 3H). C NMR (101 MHz, DMSO) d 170.44,
1
10.17, 57.63, 52.79, 52.14, 45.06, 21.20, 15.59. ESI-MS: (m/z) calcd 166.88, 161.56, 148.66, 147.07, 141.38, 127.41, 126.03, 125.25,
+
for C H N O : 445.22, found 446.16 (M + H) ; anal. calcd for 123.14, 120.96, 119.91, 117.51, 52.69, 45.01, 43.39, 18.59. ESI-MS:
C H N O : (%) C, 64.70; H, 6.11; N, 22.01; O, 7.18. Found: C, (m/z) calcd for C H ClN O : 480.14, found 481.16 (M + H) ;
2
4 27 7 2
+
24
27
7
2
22 21
8 3
6
4.76; H, 6.05; N, 22.09; O, 7.13.
4-((1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-
-yl)(2,7-dimethylimidazo-[1,2-a]-pyridin-3-yl)-methanone (7h).
8 3
anal. calcd for C22H21ClN O : (%) C, 54.95; H, 4.40; Cl, 7.37; N,
23.30; O, 9.98. Found: C, 54.90; H, 4.35; Cl, 7.40; N, 23.34; O, 9.93.
(
1
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-(tri-
ꢁ
1
Off-white solid; (61%); mp 104–105 C; H NMR (400 MHz, DMSO- uoromethyl)-phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-
d6) d 8.60 (d, 1H), 8.44 (d, 1H), 7.79 (dd, 1H), 7.73–7.59 (m, 4H), 1-yl)-methanone (8c). Off-white solid; (85%); mp 95–97 C; H
ꢁ
1
7
2
1
1
.44 (d, 1H), 6.96 (d, 1H), 4.14 (s, 2H), 3.65 (m, 4H), 2.89 (m, 4H), NMR (400 MHz, DMSO) d 8.92 (s, 1H), 8.55 (d, 1H), 8.31–8.26 (m,
13
.41 (s, 6H). C NMR (101 MHz, DMSO) d 161.46, 143.07, 142.32, 2H), 7.80–7.89 (m, 2H), 7.60 (d, 1H), 7.41 (dd, 1H), 3.74 (s, 2H),
1
3
40.65, 139.53, 134.82, 132.25, 131.04, 128.97, 128.82, 127.89, 3.58 (s, 4H), 2.55 (s, 4H), 2.37 (s, 3H). C NMR (101 MHz,
26.89, 126.07, 116.46, 114.13, 52.07, 51.43, 43.83, 21.28, 14.65. DMSO-d6) d 161.34, 145.10, 144.56, 143.97, 137.62, 131.76,
ESI-MS: (m/z) calcd for C23
H
24ClN
24ClN O: (%) C, 61.40; H, 5.38; Cl, 7.88; N, 52.77, 52.71, 45.11, 15.28. ESI-MS: (m/z) calcd for C23
1.79; O, 3.56. Found: C, 61.40; H, 5.42; Cl, 7.92; N, 21.74; O, 3.60.
4-((1-(3-Chloro-4-uorophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-
piperazin-1-yl)(2,7-dimethylimidazo-[1,2-a]-pyridin-3-yl)-metha
7
O: 449.17, found 450.10 (M + 127.29, 125.50, 124.28, 122.96, 119.77, 117.37, 117.03, 109.28,
+
H) ; anal. calcd for C23
H
7
H
21ClF
3
-
-
+
2
N
7
O: 503.14, found 504.17 (M + H) ; anal. calcd for C23
ClF
3.17. Found: C, 54.79; H, 4.25; Cl, 7.07; F, 11.34; N, 19.40; O,
H
21
(
3 7
N O: (%) C, 54.82; H, 4.20; Cl, 7.03; F, 11.31; N, 19.46; O,
ꢁ
1
none (7i). Off-white solid; (83%); mp 128–131 C; H NMR (400 3.12.
MHz, DMSO-d6) d 8.78 (s, 1H), 8.34 (d, 1H), 8.23 (dd, 1H), 7.98 (m,
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-eth-
1
4
H), 7.67 (t, 1H), 7.33 (s, 1H), 6.82 (m, 1H), 3.71 (s, 2H), 3.56 (m, ylphenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
H), 2.52 (m, 4H), 2.36 (s, 3H), 2.34 (s, 3H). C NMR (101 MHz, methanone (8d). Sticky liquid; (74%); H NMR (400 MHz,
1
3
1
DMSO-d6) d 162.05, 158.50, 155.99, 145.03, 137.31, 134.17, DMSO-d6) d 8.70 (s, 1H), 8.56 (s, 1H), 7.81 (d, 2H), 7.60 (d, 1H),
1
1
26.44, 122.98, 122.66, 122.34, 121.21, 121.13, 118.69, 118.46, 7.42 (d, 3H), 3.76 (s, 2H), 3.58 (m, 4H), 2.74–2.64 (m, 4H), 2.37 (s,
1
3
15.45, 114.98, 52.91, 52.71, 45.10, 21.18, 15.48. ESI-MS: (m/z) 3H), 1.22 (t, 3H). C NMR (101 MHz, DMSO-d6) d 161.50,
+
calcd for C H ClFN O: 467.16, found 468.10 (M + H) ; anal. 144.87, 144.77, 135.11, 129.53, 127.31, 125.17, 122.83, 122.78,
2
3
23
7
calcd for C H ClFN O: (%) C, 59.04; H, 4.95; Cl, 7.58; F, 4.06; N, 120.46, 119.78, 117.48, 110.47, 52.61, 52.42, 44.76, 28.13, 15.92,
2
3
23
7
2
0.95; O, 3.42. Found: C, 59.08; H, 4.90; Cl, 7.62; F, 4.09; N, 20.91; 15.46. ESI-MS: (m/z) calcd for C H ClN O: 463.19, found
2
4
26
7
+
O, 3.47.
464.13 (M + H) ; anal. calcd for C24
H26ClN
7
O: (%) C, 62.13; H,
(
2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-methoxy-
5.65; Cl, 7.64; N, 21.13; O, 3.45. Found: C, 62.10; H, 5.69; Cl,
7.60; N, 21.16; O, 3.41.
2
-nitrophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
methanone (7j). Pale yellow solid; (69%); mp 98–100 C;
ꢁ
1
H
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-uo-
NMR (400 MHz, DMSO-d6) d 8.55 (s, 1H), 8.42 (s, 1H), 7.78 (dd, rophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
ꢁ
1
2
4
1
1
5
H), 7.50 (dd, 2H), 6.88 (d, 1H), 3.95 (s, 2H), 3.61 (m, 4H), 2.66 (t, methanone (8e). Brown solid; (62%); mp 109–111 C; H NMR
1
3
H), 2.44–2.31 (m, 6H). C NMR (101 MHz, DMSO-d6) d 165.24, (400 MHz, DMSO-d6) d 8.74 (s, 1H), 8.56 (d, 1H), 7.99–7.93 (m,
60.74, 146.50, 145.52, 138.21, 129.42, 128.06, 126.81, 126.74, 2H), 7.61 (d, 1H), 7.50–7.38 (m, 3H), 3.79 (s, 2H), 3.59 (s, 4H),
1
3
22.52, 119.94, 115.90, 114.81, 111.05, 106.71, 99.39, 57.09, 2.77–2.54 (m, 4H), 2.38 (s, 3H). C NMR (101 MHz, DMSO)
6.08, 52.41, 44.67, 21.24, 15.29. ESI-MS: (m/z) calcd for d 163.26, 161.39, 160.82, 144.68, 143.97, 133.61, 125.05, 123.18,
+
C
C
24
24
H
H
26
N
N
8
O
O
4
4
: 490.21, found 491.17 (M + H) ; anal. calcd for 122.83, 122.75, 119.88, 117.27, 117.04, 52.53, 52.34, 44.65,
26
8
: (%) C, 58.77; H, 5.34; N, 22.84; O, 13.05. Found: C, 15.49, 15.22. ESI-MS: (m/z) calcd for C22
H
21ClFN
21ClFN
6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-phenyl- 58.22; H, 4.66; Cl, 7.81; F, 4.19; N, 21.60; O, 3.52. Found: C,
H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone (8a). 58.20; H, 4.63; Cl, 7.79; F, 4.14; N, 21.63; O, 3.56.
7
O: 453.15,
+
58.72; H, 5.31; N, 22.80; O, 13.08.
found 454.19 (M + H) ; anal. calcd for C22
H
7
O: (%) C,
(
1
ꢁ
1
Brown solid; (82%); mp 99–101 C; H NMR (400 MHz, DMSO-
(4-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-
d6) d 8.74 (s, 1H), 8.55 (d, 1H), 7.91 (d, 2H), 7.62–7.57 (m, 3H), 1-yl)(6-chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)-methanone
ꢁ
1
7
2
1
1
.48 (t, 1H), 7.41 (dd, 1H), 3.72 (s, 2H), 3.57 (s, 4H), 2.55 (s, 4H), (8f). Off-white solid; (74%); mp 93–95 C; H NMR (400 MHz,
1
3
.37 (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.33, 144.75, DMSO-d6) d 8.78 (s, 1H), 8.55 (s, 1H), 7.90 (d, J ¼ 8.9 Hz, 2H), 7.80
44.26, 143.50, 137.14, 130.33, 129.01, 127.33, 125.01, 122.56, (d, 2H), 7.61 (d, 1H), 7.41 (dd, 2H), 3.72 (s, 2H), 3.57 (s, 4H), 2.53 (s,
13
20.39, 117.34, 116.50, 52.75, 45.14, 15.27. ESI-MS: (m/z) calcd 4H), 2.34 (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.48, 145.05,
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1
1
38.51, 136.36, 133.21, 127.31, 125.17, 122.80, 122.32, 121.60, NMR (400 MHz DMSO-d6) d 8.54 (d, 2H), 7.85 (t, 1H), 7.58 (dd,
19.82, 117.56, 55.34, 52.74, 45.06, 15.42. ESI-MS: (m/z) calcd for 4H), 7.44 (dd, 2H), 3.79 (s, 2H), 3.59 (s, 4H), 2.60 (s, 4H), 2.38 (s,
+
13
C H BrClN O: 513.07, found 514.02 (M + H) ; anal. calcd for 3H). C NMR (101 MHz, DMSO-d6) d 161.38, 155.44, 152.95,
22
21
7
C H BrClN O: (%) C, 51.33; H, 4.11; Br, 15.52; Cl, 6.89; N, 19.05; 144.66, 143.83, 131.66, 131.58, 127.32, 126.29, 126.02, 125.23,
22
21
7
O, 3.11. Found: C, 51.37; H, 4.08; Br, 15.55; Cl, 6.83; N, 19.01; O, 125.03, 119.79, 117.70, 117.50, 117.37, 52.69, 52.36, 45.23,
.14. 15.28. ESI-MS: (m/z) calcd for C22 21ClFN O: 453.15, found
6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-nitro- 21ClFN O: (%) C, 58.22; H,
phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone 4.66; Cl, 7.81; F, 4.19; N, 21.60; O, 3.52. Found: C, 58.26; H, 4.68;
8g). Pale yellow solid; (86%); mp 222–223 C; H NMR (400 MHz, Cl, 7.79; F, 4.16; N, 21.63; O, 3.56.
DMSO-d6) d 8.99 (s, 1H), 8.75 (t, 1H), 8.56 (s, 1H), 8.42 (dd, 1H), (6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(2-chlor-
.32 (dd, 1H), 7.89 (dd, 1H), 7.61 (d, 1H), 7.41 (d, 1H), 3.75 (s, 2H), ophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
3
H
H
7
+
(
454.10 (M + H) ; anal. calcd for C22
7
ꢁ
1
(
8
3
1
3
ꢁ
1
.58 (s, 4H), 2.57 (s, 4H), 2.38 (s, 3H). C NMR (101 MHz, DMSO- methanone (8l). Off-white solid; (85%); mp 94–96 C; H NMR
d6) d 161.49, 148.99, 145.24, 137.73, 131.9, 127.29, 126.40, (400 MHz, DMSO) d 8.55 (s, 1H), 8.49 (s, 1H), 7.77 (d, 1H), 7.70 (d,
1
1
C
C
26.06–125.38, 125.01, 123.42, 123.13, 120.13, 119.80, 117.47, 1H), 7.62 (m, 3H), 7.42 (d, 1H), 3.82 (s, 2H), 3.59 (s, 4H), 2.62 (s,
1
3
15.05, 52.74, 45.28, 45.07, 15.48. ESI-MS: (m/z) calcd for 4H), 2.37 (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.05, 154.72,
+
22
H
21ClN
21ClN
8
O
O
3
: 480.14, found 481.19 (M + H) ; anal. calcd for 152.15, 144.62, 142.88, 131.76, 131.91, 127.73, 126.67, 126.73,
: (%) C, 54.95; H, 4.40; Cl, 7.37; N, 23.30; O, 9.98. 124.89, 125.00, 119.21, 117.33, 117.51, 117.46, 52.64, 52.33, 45.24,
22
H
8
3
Found: C, 54.90; H, 4.43; Cl, 7.33; N, 23.33; O, 9.94.
15.22. ESI-MS: (m/z) calcd for C H Cl N O: 469.12, found 470.16
22 21 2 7
+
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-(triuoro (M + H) ; anal. calcd for C H Cl N O: (%) C, 56.18; H, 4.50; Cl,
2
2
21
2 7
methyl)-phenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
15.07; N, 20.85; O, 3.40. Found: C, 56.21; H, 4.55; Cl, 15.04; N,
ꢁ
1
methanone (8h). Brown solid; (60%); mp 123–125 C; H NMR (400 20.88; O, 3.36.
MHz, DMSO-d6) d 8.95 (s, 1H), 8.73 (t, 1H), 8.52 (s, 1H), 8.40 (dd, (6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-chloro-
H), 8.36 (dd, 1H), 7.84 (dd, 1H), 7.75 (d, 1H), 7.36 (d, 1H), 3.70 (s, 4-uorophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
1
13
ꢁ
1
2
H), 3.52 (s, 4H), 2.52 (s, 4H), 2.32 (s, 3H). C NMR (101 MHz, methanone (8m). Pale yellow solid; (55%); mp 213–215 C; H
DMSO-d6) d 161.35, 145.11, 144.76, 143.82, 137.61, 131.74, 127.22, NMR (400 MHz, DMSO-d6) d 8.79 (s, 1H), 8.56 (s, 1H), 8.23 (dd,
25.66, 124.46, 122.71, 119.73, 117.47, 117.01, 109.232, 52.75, 52.12, 1H), 7.98 (m, 1H), 7.68 (t, 1H), 7.61 (d, 1H), 7.42 (d, 1H), 3.72 (s,
1
13
4
5.54, 15.22. ESI-MS: (m/z) calcd for C H ClF N O: 503.14, found 2H), 3.57 (s, 4H), 2.54 (d, 4H), 2.38 (s, 3H). C NMR (101 MHz,
23 21 3 7
+
504.10 (M + H) ; anal. calcd for C H ClF N O: (%) C, 54.82; H, DMSO-d6) d 161.41 (s), 158.45 (s), 156.13 (s), 145.20 (s), 134.25 (s),
23 21 3 7
4
.20; Cl, 7.03; F, 11.31; N, 19.46; O, 3.17. Found: C, 54.85; H, 4.23; Cl, 127.27 (s), 125.23 (d, J ¼ 17.2 Hz), 122.99 (s), 122.66 (s), 121.85–
7.00; F, 11.36; N, 19.50; O, 3.21.
120.93 (m), 119.79 (s), 118.69 (s), 118.47 (s), 52.75 (s), 45.53 (s),
6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-methox- 45.26 (s), 15.44 (s). ESI-MS: (m/z) calcd for C22 FN O: 487.11,
O: (%) C, 54.11;
(
H
20Cl
2
7
+
yphenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-methanone
2 7
found 488.19 (M + H) ; anal. calcd for C22H20Cl FN
ꢁ
1
(8i). Brown solid; (58%); mp 97–98 C; H NMR (400 MHz, H, 4.13; Cl, 14.52; F, 3.89; N, 20.08; O, 3.28. Found: C, 54.15; H,
DMSO-d6) d 8.77 (s, 1H), 8.55 (s, 1H), 7.60 (d, 1H), 7.49 (d, 3H), 4.10; Cl, 14.56; F, 3.72; N, 20.02; O, 3.32.
7
2
.41 (d, 1H), 7.04 (s, 1H), 3.86 (s, 3H), 3.72 (s, 2H), 3.57 (s, 4H),
.54 (d, 4H), 2.37 (s, 3H). C NMR (101 MHz, DMSO-d6) dimethylphenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3,5-
1
3
ꢁ
1
d 161.34, 160.64, 144.62, 143.99, 138.19, 131.25, 127.29, methanone (8n). Off-white solid; (58%); mp 100–102 C;
H
1
5
C
C
25.02, 122.69, 119.77, 117.36, 116.51, 114.72, 112.35, 105.96, NMR (400 MHz, DMSO-d6) d 8.79 (s, 1H), 8.65 (s, 1H), 8.56 (s,
6.06, 52.79, 45.00, 15.29. ESI-MS: (m/z) calcd for 1H), 7.89 (dd, 1H), 7.78 (d, 1H), 7.68 (s, 2H), 7.50 (s, 1H), 3.75 (s,
+
13
23
23
H
H
24ClN
24ClN
7
7
O
O
2
2
: 465.17, found 466.14 (M + H) ; anal. calcd for 2H), 3.60 (s, 4H), 2.57 (d, 4H), 2.35 (s, 3H). C NMR (101 MHz,
: (%) C, 59.29; H, 5.19; Cl, 7.61; N, 21.04; O, 6.87. DMSO-d6) d 161.36, 144.18, 138.81, 137.44, 135.11, 130.82,
Found: C, 59.26; H, 5.22; Cl, 7.65; N, 21.01; O, 6.83.
6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3-chlor-
127.57, 125.08, 122.75, 121.24, 119.27, 117.67, 117.38, 116.54,
(
52.51, 45.27, 44.88, 19.91, 15.41 ESI-MS: (m/z) calcd for
+
ophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
C H ClN O: 463.19, found 464.25 (M + H) ; anal. calcd for
2
4
26
7
ꢁ
1
methanone (8j). Pale brown solid; (81%); mp 89–91 C; H NMR
C
24
H26ClN
7
O: (%) C, 62.13; H, 5.65; Cl, 7.64; N, 21.13; O, 3.45.
(
(
2
1
1
400 MHz, DMSO-d6) d 8.84 (s, 1H), 8.56 (s, 1H), 8.06 (s, 1H), 7.94 Found: C, 62.10; H, 5.69; Cl, 7.60; N, 21.17; O, 3.40.
d, 1H), 7.67–7.53 (m, 3H), 7.42 (d, 1H), 3.78 (s, 2H), 3.59 (s, 4H), (6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(3,4-dime-
.60 (s, 4H), 2.38 (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.15, thylphenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
45.11, 144.49, 143.42, 137.58, 131.79, 127.21, 125.46, 124.67, methanone (8o). Dark brown solid; (56%); mp 101–103 C; H
22.61, 119.41, 117.44, 117.02, 109.78, 52.74, 52.15, 45.54, 15.21. NMR (400 MHz, DMSO-d6) d 8.65 (s, 1H), 8.55 (s, 1H), 7.71 (s, 1H),
1
3
ꢁ
1
ESI-MS: (m/z) calcd for C H Cl N O: 469.12, found 470.17 (M + 7.61 (d, 2H), 7.41 (dd, 1H), 7.33 (d, 1H), 3.71 (s, 2H), 3.57 (s, 4H),
2
2
21
2 7
+
13
H) ; anal. calcd for C H Cl N O: (%) C, 56.18; H, 4.50; Cl, 2.54 (s, 4H), 2.38 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H). C NMR (101
2
2
21
2 7
1
2
5.07; N, 20.85; O, 3.40. Found: C, 56.22; H, 4.56; Cl, 15.10; N, MHz, DMSO-d6) d 161.33, 144.57, 143.98, 138.52, 137.30, 135.10,
0.89; O, 3.44.
6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(2-uo-
rophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)-
methanone (8k). Off-white solid; (63%); mp 105–107 C;
130.97, 129.63, 127.29, 125.02, 122.36, 121.25, 119.77, 117.63,
(
117.37, 116.53, 52.80, 45.06, 44.87, 19.87, 19.41, 15.29. ESI-MS: (m/
+
z) calcd for C24
H
26ClN
7
O: 463.19, found 464.15 (M + H) ; anal.
ꢁ
1
H
38340 | RSC Adv., 2020, 10, 38328–38343
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calcd for C24
H
26ClN
7
O: (%) C, 62.13; H, 5.65; Cl, 7.64; N, 21.13; O, 15.01. ESI-MS: (m/z) calcd for C28
H
35
N
7
O: 485.29, found 486.19
+
3
.45. Found: C, 62.16; H, 5.65; Cl, 7.62; N, 21.16; O, 3.41.
6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-((1-(4-methoxy- 20.19; O, 3.29. Found: C, 69.29; H, 7.32; N, 20.22; O, 3.22.
-nitrophenyl)-1H-1,2,3-triazol-4-yl)-methyl)-piperazin-1-yl)- (6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-(2-(4-propyl-
methanone (8p). Pale yellow solid; (58%); mp 104–105 C; H NMR 1H-1,2,3-triazol-1-yl)-ethyl)-piperazin-1-yl)-methanone (11a).
400 MHz, DMSO-d6) d 8.54 (d, 2H), 7.78 (m, 2H), 7.61 (d, 1H), 7.50 Sticky liquid; (70%); H NMR (400 MHz, DMSO-d6) d 8.56 (s, 1H),
dd, 1H), 7.42 (d, 1H), 3.95 (s, 3H), 3.81 (s, 2H), 3.59 (s, 4H), 2.55 (s, 7.87 (s, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 4.44 (s, 2H), 3.52 (s, 4H),
(M + H) ; anal. calcd for C H N O: (%) C, 69.25; H, 7.26; N,
28 35 7
(
2
ꢁ
1
1
(
(
13
4H), 2.38 (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.42 (s), 160.69 2.79 (s, 2H), 2.55 (d, 4H), 2.42 (s, 2H), 2.36 (s, 3H), 1.60 (d, 2H),
1
3
(
1
1
2
s), 145.54 (s), 144.66 (s), 129.36 (s), 128.06 (s), 127.33 (s), 126.28 (s), 0.90 (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.28, 161.11,
25.02 (s), 122.55 (s), 119.86 (d, J ¼ 9.2 Hz), 117.84–117.78 (m), 147.28, 146.81, 144.38, 127.24, 124.61, 122.92, 119.34, 115.31,
17.57 (d, J ¼ 34.6 Hz), 116.49 (s), 110.99 (s), 57.08 (s), 52.39 (d, J ¼ 57.22, 52.36, 47.33, 45.44, 31.61, 22.09, 15.10, 14.73. ESI-MS: (m/z)
+
0.4 Hz), 52.17–51.19 (m), 44.77 (s), 15.27 (s). ESI-MS: (m/z) calcd for calcd for C H ClN O: 415.19, found 416.26 (M + H) ; anal. calcd
20 26 7
+
C
23
H
23ClN
8
O
4
: 510.15, found 511.10 (M + H) ; anal. calcd for for C20
: (%) C, 54.07; H, 4.54; Cl, 6.94; N, 21.93; O, 12.53. Found: C, 57.72; H, 6.26; Cl, 8.57; N, 23.60; O, 3.82.
(6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-(2-(4-nonyl-
1H-1,2,3-triazol-1-yl)-ethyl)-piperazin-1-yl)-methanone (11b).
,2,3-triazol-1-yl)-ethyl)-piperazin-1-yl)-methanone (10a). Sticky White solid; (64%); mp 90–92 C; H NMR (400 MHz, DMSO-d6)
7
H26ClN O: (%) C, 57.76; H, 6.30; Cl, 8.52; N, 23.57; O, 3.85.
C
23
H23ClN
8 4
O
Found: C, 54.11; H, 4.51; Cl, 6.90; N, 21.96; O, 12.50.
2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-(2-(4-propyl-1H-
1
(
ꢁ
1
1
liquid; (76%); H NMR (400 MHz, DMSO) d 8.42 (s, 1H), 7.86 (d, d 8.55 (d, 1H), 7.86 (s, 1H), 7.61 (d, 1H), 7.42 (d, 1H), 4.44 (t, 2H),
1
1
1
H), 7.47 (d, 1H), 6.84 (d, 1H), 4.59 (s, 1H), 4.44 (s, 1H), 4.38 (s, 3.51 (s, 4H), 2.79 (t, 2H), 2.59 (t, 2H), 2.37 (s, 4H), 1.66–1.50 (m,
1
3
H), 2.78 (t, 2H), 2.62–2.54 (m, 3H), 2.36 (s, 6H), 1.60 (dd, 2H), 2H), 1.39–1.12 (m, 14H), 0.84 (t, 3H). C NMR (101 MHz, DMSO)
1
3
.36–1.20 (m, 2H), 0.89 (t, 3H). C NMR (101 MHz, DMSO-d6) d 161.33, 147.12, 144.69, 127.34, 124.97, 122.66, 119.85, 117.41,
d 161.52, 161.86, 147.77, 146.81, 144.25, 127.28, 124.69, 122.26, 57.21, 52.84, 47.04, 44.91, 31.71, 29.41, 29.24, 28.95, 25.42, 22.53,
1
1
3
7
19.73, 117.57, 57.21, 52.35, 47.16, 45.84, 31.71, 22.94, 21.09, 15.24, 14.39. ESI-MS: (m/z) calcd for C26
H
38ClN
38ClN O: (%) C, 62.45; H,
O: (%) C, 63.77; H, 7.66; Cl, 7.09; N, 19.61; O, 3.20. Found: C, 62.47; H, 7.61; Cl,
.39; N, 24.79; O, 4.05. Found: C, 63.74; H, 7.32; N, 24.75; O, 4.09. 7.11; N, 19.57; O, 3.24.
2,7-Dimethylimidazo-[1,2-a]-pyridin-3-yl)(4-(2-(4-nonyl-1H- (6-Chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)(4-(2-(4-cyclo-
,2,3-triazol-1-yl)-ethyl)-piperazin-1-yl)-methanone (10b). Sticky propyl-1H-1,2,3-triazol-1-yl)-ethyl)-piperazin-1-yl)-methanone
7
O: 499.28, found
+
5.18, 14.85. ESI-MS: (m/z) calcd for C21
96.16 (M + H) ; anal. calcd for C21H N
29 7
H
29
N
7
O: 395.24, found 500.19 (M + H) ; anal. calcd for C26
H
7
+
(
1
1
ꢁ
1
liquid; (72%); H NMR (400 MHz, DMSO-d6) d 8.38 (d, 1H), 7.75 (11c). Pale yellow solid; (81%); mp 105–107 C; H NMR (400
s, 1H), 7.43 (s, 1H), 6.88 (d, 1H), 4.36 (t, 2H), 3.45 (s, 4H), 2.72 (t, MHz, DMSO-d6) d 8.53 (s, 1H), 7.83 (s, 1H), 7.59 (d, 1H), 7.40 (d,
(
2
1
H), 2.47 (s, 4H), 2.40 (t, 2H), 2.35 (s, 6H), 1.72 (m, 2H), 1.32– 1H), 4.40 (t, 2H), 3.52 (s, 4H), 2.77 (t, 2H), 2.52 (s, 4H), 2.35 (s,
.25 (m, 12H) 0.88 (t, 3H). C NMR (101 MHz, DMSO-d6) 3H), 2.00–1.87 (m, 1H), 0.88 (s, 2H), 0.69 (s, 2H). C NMR (101
1
3
13
d 161.53, 161.82, 147.73, 146.73, 144.19, 127.38, 124.73, 122.28, MHz, DMSO-d6) d 161.30, 149.13, 144.62, 144.00, 127.27,
19.69, 117.42, 57.24, 52.45, 47.08, 45.77, 31.68, 29.74–28.62 125.00, 121.49, 119.79, 1187.40, 116.59, 57.22, 52.88, 47.04,
m), 25.41, 22.47, 21.08, 15.24, 14.32. ESI-MS: (m/z) calcd for 45.24, 15.28, 8.08, 7.02. ESI-MS: (m/z) calcd for C H ClN O:
1
(
2
0
24
7
+
+
C H N O: 479.34, found 480.20 (M + H) ; anal. calcd for 413.17, found 414.10 (M + H) ; anal. calcd for C H ClN O: (%)
2
7
41
7
20 24
7
C
27
H
41
N
7
O: (%) C, 67.61; H, 8.62; N, 20.44; O, 3.34. Found: C, C, 58.04; H, 5.84; Cl, 8.56; N, 23.69; O, 3.87. Found: C, 58.07; H,
67.66; H, 8.56; N, 20.84; O, 3.39.
5.81; Cl, 8.51; N, 23.73; O, 3.82.
(
4-(2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-ethyl)-piperazin-1-
(4-(2-(4-(4-(tert-Butyl)-phenyl)-1H-1,2,3-triazol-1-yl)-ethyl)-piper-
yl)(2,7-dimethylimidazo-[1,2-a]-pyridin-3-yl)-methanone (10c). azin-1-yl)(6-chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)-
Sticky liquid; (59%); H NMR (400 MHz, DMSO-d6) d 8.42 (s, methanone (11d). Off-white solid; (72%); mp 187–189 C; H NMR
1
ꢁ
1
1
4
0
1
5
H), 7.84 (s, 1H), 7.41 (s, 1H), 6.85 (d, 1H), 4.40 (t, 2H), 3.51 (s, (400 MHz, DMSO-d6) d 8.57 (s, 2H), 7.85 (m, 2H), 7.61 (dd, 1H),
H), 2.77 (t, 2H), 2.52 (s, 4H), 2.36 (s, 6H), 1.96–1.89 (m, 1H), 7.40 (m, 4H), 4.56 (t, 2H), 3.54 (s, 4H), 2.88 (t, 2H), 2.55 (s, 4H), 2.37
1
3
13
.89 (d, 2H), 0.70 (d, 2H). C NMR (101 MHz, DMSO) d 161.91, (s, 3H). C NMR (101 MHz, DMSO-d6) d 161.30 (s), 146.61 (s),
49.25, 137.18, 127.86, 126.66, 121.85, 121.65, 115.90, 115.71, 144.54 (s), 144.09 (s), 134.61 (s), 131.26 (s), 129.38 (s), 128.30 (s),
7.19, 52.97, 47.02, 45.03, 21.36, 8.09, 7.01. ESI-MS: (m/z) calcd 127.41 (s), 125.59 (s), 124.97 (s), 122.20 (s), 119.88 (s), 117.34 (s),
+
for C21
H
27
N
7
O: 393.23, found 394.35 (M + H) ; anal. calcd for 57.08 (s), 52.84 (s), 47.31 (s), 45.05 (s), 15.18 (s). ESI-MS: (m/z) calcd
+
C
6
21
H
27
N
7
O: (%) C, 64.10; H, 6.92; N, 24.92; O, 4.07. Found: C, for C23
4.13; H, 6.96; N, 24.86; O, 4.01. 24ClN
4-(2-(4-(4-(tert-Butyl)phenyl)-1H-1,2,3-triazol-1-yl)ethyl)-piper- Found: C, 61.46; H, 5.36; Cl, 7.92; N, 21.74; O, 3.52.
azin-1-yl)(2,7-dimethylimidazo-[1,2-a]-pyridin-3-yl)-methanone (4-(2-(4-(4-(tert-Butyl)-phenyl)-1H-1,2,3-triazol-1-yl)-ethyl)-piper-
7
H24ClN O: 449.17, found 450.25 (M + H) ; anal. calcd for
23
C H
7
O: (%) C, 61.40; H, 5.38; Cl, 7.88; N, 21.79; O, 3.56.
(
ꢁ
1
(10d). Pale yellow solid; (63%); mp 148–150 C; H NMR (400 azin-1-yl)(6-chloro-2-methylimidazo-[1,2-a]-pyridin-3-yl)-
ꢁ
1
MHz, DMSO-d6) d 8.52 (s, 2H), 7.76 (d, 2H), 7.46 (d, 3H), 6.83 (s, methanone (11e). Off-white solid; (64%); mp 224–226 C; H NMR
1
6
1
1
H), 4.53 (s, 2H), 3.47 (d, 4H), 2.85 (s, 2H), 2.52 (s, 4H), 2.33 (s, (400 MHz, DMSO-d6) d 8.54 (s, 1H), 7.82 (s, 1H), 7.60 (d, 1H), 7.50
1
3
H), 1.30 (s, 9H). C NMR (101 MHz, DMSO-d6) d 160.98, 154.76, (d, 2H), 7.44 (d, 1H), 7.33 (d, 2H), 4.50 (s, 2H), 3.42 (d, 4H), 2.88 (s,
13
50.71, 146.58, 136.77, 136.68, 128.60, 126.25, 126.07, 125.39, 2H), 2.55 (s, 4H), 2.30 (s, 3H), 1.25 (s, 9H). C NMR (101 MHz,
21.89, 115.61, 57.15, 52.99, 47.30, 45.06, 34.79, 31.53, 21.44, DMSO-d6) d 161.15, 154.78, 150.72, 146.29, 136.73, 136.19, 128.73,
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1
4
5
6
26.79, 126.13, 125.46, 123.87, 121.79, 115.28, 57.15, 52.17, 47.36, 16 W. A. Simon, M. Herrmann, T. Klein, J. M. Shin, R. Huber,
5.73, 34.82, 31.54, 15.02. ESI-MS: (m/z) calcd for C H ClN O:
J. Senn-Bilnger and S. Postius, J. Pharmacol. Exp. Ther.,
2007, 321, 866–874.
27
32
7
+
05.24, found 506.15 (M + H) ; anal. calcd for C H ClN O: (%) C,
27
32
7
4.08; H, 6.37; Cl, 7.01; N, 19.38; O, 3.16. Found: C, 64.11; H, 6.33; 17 S. Boggs, V. I. Elitzin, K. Gudmundsson, M. T. Martin and
Cl, 7.04; N, 19.43; O, 3.13.
M. J. Sharp, Org. Process Res. Dev., 2009, 13, 781–785.
18 O. Kim, Y. Jeong, H. Lee, S. Hong and S. Hong, J. Med. Chem.,
2011, 54, 2455–2466.
Conflicts of interest
19 A. A. Trabanco, G. Tresadern, G. J. MacDonald, J. A. Vega,
A. I. De Lucas, E. Matesanz, A. Garc ´ı a, M. L. Linares,
S. A. Alonso De Diego, J. M. Alonso, D. Oehlrich,
A. Ahnaou, W. Drinkenburg, C. MacKie, J. I. Andr ´e s,
H. Lavreysen and J. M. Cid, J. Med. Chem., 2012, 55, 2688–
Authors declare that there is no conict of interest.
Acknowledgements
2701.
2
0 J. Rether, G. Erkel, T. Anke, J. Bajtner and O. Sterner, Bioorg.
Med. Chem., 2008, 16, 1236–1241.
KVGCS and SM thank DBT, New Delhi [BT/IN/Spain/39/
SMl2017-18] for providing nancial support. The nancial
assistance provided by DIST FIST grant (SR/FST/CSI-240/2012),
New Delhi is gratefully acknowledged. SS thanks CSIR for
providing SRF fellowship. Central analytical lab facilities of
BITS Pilani Hyderabad Campus are gratefully acknowledged.
2
1 C. Castera-Ducros, L. Paloque, P. Verhaeghe, M. Casanova,
C. Cantelli, S. Hutter, F. Tanguy, M. Laget, V. Remusat,
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P. Vanelle, Bioorg. Med. Chem., 2013, 21, 7155–7164.
2 C. Fersing, L. Basmaciyan, C. Boudot, J. Pedron, S. Hutter,
A. Cohen, C. Castera-Ducros, N. Primas, M. Laget,
M. Casanova, S. Bourgeade-Delmas, M. Piednoel,
2
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