Design, synthesis and biological evaluation of imidazo[1,2-a]pyridine analogues or derivatives as anti-helmintic drug

Article abstract of DOI:10.1111/cbdd.13441

The Albendazole was used as the lead compound, which was modified by structural transformation and with alkyl groups. A total of 18 compounds (4a–4r) were designed and synthesized. The in vitro experiment results showed that compounds 4e, 4f, 4k, 4l, 4q and 4r had good inhibitory effect on egg and imago of roundworm. IC₅₀ of compound 4l to anti-egg of roundworm was 0.65?±?0.01?μmol/L and to anti-imago of roundworm was 1.04?±?0.01?μmol/L. At the same time, it showed that compound 4l had the best effect in vivo, and the rate of anti-helmintic could reach more than 99%. The results of acute toxicity tests indicated that these compounds were with LD₅₀ > 2100 mg/kg by oral administration, so they were low toxicity compounds. In a word, compound 4l was most likely to be a new anti-helmintic drug through screening in vitro and in vivo.

Full text of DOI:10.1111/cbdd.13441

DR GANGLIANG HUANG (Orcid ID : 0000-0001-8768-9979)
Article type
: Research Article
Running head: Design, synthesis and activities of imidazo[1,2-a]pyridine analogues or derivatives
Design, synthesis and biological evaluation of imidazo[1,2-a]pyridine analogues or
derivatives as anti-helmintic drug
Shiyang Zhou1,2, Guangying Chen1,2, Gangliang Huang3*
1. College of Chemistry and Chemical Engineerin, Hainan Normal University, Hainan 571158,
China;
2. Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal
University, Hainan 571158, China;
3. Active Carbohydrate Research Institute, Chongqing Key Laboratory of Green Synthesis and
Application, Chongqing Normal University, Chongqing, 401331, China
E-mail: huangdoctor226@163.com
Abstract: The Albendazole was used as the lead compound, which was modified by structural
transformation and with alkyl groups. A total of 18 compounds(4a-4r) were designed and
synthesized.The in vitro experiment results showed thatcompounds 4e, 4f, 4k, 4l, 4q and 4r had good
inhibitory effect on egg and imago of roundworm. IC50 of compound 4l to anti-egg of roundworm was
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lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cbdd.13441
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0.65±0.01 μmol/L and to anti-imago of roundworm was 1.04±0.01 μmol/L. At the same time, it
showed thatcompound 4l had the best effect in vivo, and the rate of anti-helmintic could reach more
than 99%. The acute toxicity test results showed that the LD50＞2100 mg·kg-1 was for these
compounds by oral administration, and they were belong to low toxicity compounds. In a word,
compound 4l was most likely to be a new anti-helmintic drug through screening in vitro and in vivo.
Keyword: imidazo [1, 2-a] pyridine, design, synthesis, biological activities, anti-helmintic
1. Introduction
Helminths are parasites that live in the intestines of humans or other animals, and are primarily
affected by contaminated food or drinking water. There were many kinds of helminths, such as
roundworm, pinworm, hookworm, tapeworm and whipworm1-4. The roundworm is the most widely
distributed parasite in the world and it is the most common parasite in humans. According to the
World Health Organization (WHO) survey, about 25 percent of the world's population was infected
with roundworms, and with an infection rate of more than 70 percent in individual regions5-8.
Helminths are prevalent in countries or regions where are tropical, economically undeveloped, warm
and humid, and in poor sanitation. Anti-helminth drugs can kill or remove the intestinal parasite
(roundworm, pinworm, hookworm, whipworm and tapeworm) for human or other animals9-13. They
include the anti-roundworm drugs, anti-hookworm drugs, anti-pinworm drugs, anti-whipworm drugs
and anti-tapeworm drugs. Some drugs can kill or drove for a variety of helminth infection, also be
known as broad-spectrum anti-helminth. At present, the clinical used main anti-helminth drugs have
imidazoles (Albendazole, Ciclobendazole, Obibendazole, Parbendazole, Mebendazole and
Tiabendazole, Fig. 1), piperazines (Phosphate and Citrate), piperidines (Pyrantel and Oxantel), and
other drugs (Toosendanin and Agrimophol)14-18. These anti-helminth drugs mainly act on the
intestinal, their chemical structure was different, and they differ in the mechanism of action19-21
.
However, the basic mechanism is generally in the neuromuscular system of paralytic body, causing
spasm or paralysis of the worm muscle, also causing the insect body to lose the adsorption capacity of
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the intestinal wall and expel the polypide22. In addition, the action mechanism of some drugs is to
affect the biological activity of the enzyme in the insect, which causes the loss of energy in the
polypide due to the failure of glucose metabolism. The other drugs can directly digest the
polypide23,24
.
In clinical the imidazoles drugs are the most widely used for anti-helmintic25,26, because they can
exorcise roundworm, hookworm, pinworm and whipworm. They are belong to broad-spectrum of
anti-helminth drugs. The pharmacological action of imidazole drugs selectively and irreversibly
inhibit the uptake of glucose by the helminths, which leads to endogenous glycogen depletion of the
helminthes. The inhibition of the fumarate reductase27 hinders the production of adenosine
triphosphate, leading to the gradual death of the helminthes due to energy depletion. There are four
binding sites between fumarate reductase and imidazoles of drug27, which have strong ability of
combination. For imidazole drugs of anti-helmintic, Albendazole is good in the clinical treatment
effect, it has a broad-spectrum of anti-helmintic, such as roundworm, hookworm, whipworm and
pinworm, and it has good to kill or diver effect for imago and egg. Albendazole is an oral absorption
drug, it has side effects on human gastrointestinal,teratogenic and embryo toxic effects on pregnant
women.
Using structural transformation and by modification with alkyl groups, this research used
Albendazole as the lead compound to design a novel ofseriesimidazo [1,2-a] pyridine analogues or
derivatives (Fig. 2). From the perspective of structure-activity relationship (SAR), the newly designed
compounds (4a-4r) and Albendazole are similar to the imidazole ring structure, and mayalso have the
effect of anti-helmintic. The modification with alkyl might reachto design the anti-helmintic drugs
with broad-spectrum, less body to absorb, low toxicity, and low on the gastrointestinal mucosa
irritation.This novel of series imidazo [1, 2-a] pyridine analogues or derivatives were synthesized
using 2-hydrimidazo [1, 2-a] pyridin-2-amine (1a) as the starting material,and the target compounds
were obtained by three steps ofchlorination, amidation, and alkylation, respectively (Scheme 1). The
synthetic route was characterized by simple operation, high total yield, and mild reaction conditions.
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2. Materials and methods
2.1. Chemistry section
2.1.1.Synthesis of 6-chloroimidazo[1,2-a]pyridin-2-amine (2a)
The 2-hydrimidazo[1,2-a]pyridin-2-amine (1a, 14.92 g,0.10mol) was put into 500mL round
bottom flask, then 200mL CHCl3 as solvent and 10 drops of N,N’-dimethyl formamide (DMF) used as
catalyst for the reaction were added. The flask was placed in the ice water bath (≤5℃), and a
magnetic mixer was used to stir until the reaction liquid became clarified. The Ph3P (0.20mol) was
constantly dropped into the flask under stirring, and the drop speed rate and reaction temperature were
controlled (≤5℃ and ≥20min). After the reactants were added, the reaction was lasted for 10 h under
refluxing. The CHCl3 was removed under vacuum. The mixture was dried to give a crude product of
6-chloroimidazo[1,2-a]pyridin-2-amine (2a). The crude product was recrystallised with hexane,
filtered, and dried in vacuum to give pure product 6-chloroimidazo[1,2-a]pyridin-2-amine (2a) as a
white crystal.
2.1.2. A general method for synthesis of compounds 3a-3b
The 6-chloroimidazo[1,2-a]pyridin-2-amine (2a, 16.76 g, 0.10 mol), anhydrous sodium
carbonate (5.30 g, 0.05 mol), and methyl carbonochloridate (7.73 mL, 0.10 mol) were placed in a 500
mL round bottom flask, and 200 mL of toluene was added as a solvent. Under magnetic stirring,the
reaction was heated and refluxed for 12 h. After completion of the reflux, the filtrate was collected by
filtration. The filtrate was cooled and allowed to stand 24 h. The precipitate was completely filtered
and dried to give a crude product of methyl (6-chloroimidazo [1,2-a] pyridin-2-yl) carbamate (3a).
The crude product was recrystallised with acetone, filtered, and dried in vacuum to give pure product
methyl (6-chloroimidazo [1,2-a] pyridin-2-yl) carbamate (3a) as a white crystal. General experimental
method was used for the synthesis of compound 3b.
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2.1.3.A general method for all titled analogues or derivatives 4a-4r
The methyl (6-chloroimidazo [1,2-a] pyridin-2-yl) carbamate (3a, 22.56 g, 0.10 mol), and methyl
carbonochloridate (5.56 mL, 0.10 mol) were placed in a 500 mL round bottom flask, and 200 mL of
ethanol was added as a solvent. Under magnetic stirring, the reaction was heated and refluxed for 6 h.
After completion of the reflux, the filtrate was collected by filtration. The filtrate was cooled and
allowed to stand 12 h. The precipitate was completely filtered and dried to give a crude product of
methyl (6-(ethylamino) imidazo [1,2-a] pyridin-2-yl) carbamate (4a). The crude product was
recrystallised with toluene, filtered, and dried in vacuum to give pure product methyl (6-(ethylamino)
imidazo [1,2-a] pyridin-2-yl) carbamate (4a) as a white powder. General experimental method was
used for the synthesis of compounds 4b-4r.
2.2. Biological section
2.2.1. Screening of biological activity for compounds in vitro
To drive the pig gut roundworm from fresh ripe female roundworms, we chose20 female
roundworms to be partitioned in uterine mouth parts before the 1/3 of eggs, added the saline solution
containing 2% formalin and 0.8 cm high, put in 4 ℃ refrigerator and set aside. The 10 mL of normal
saline containing 2% formalin was taken and placed in 20 clean petri dishes, divided into two portions
on average. One of them was added with 1 drop of roundworm egg concentrate (about 500 eggs), and
then 0.2mL drugs of different concentrations were added to each dish for in vitro sterilization
roundworm eggs experiment. In addition, the 10 mature roundworms were added to each dish for in
vitro sterilization imago experiment. Abendazole was used as positive control. We handled all the
dish, and then put in 5% CO2 with 30 ℃ constant temperature incubator to culture for 24 days. At
the same time, we observed the petri dish solution evaporation conditions for every day, and with
normal saline containing 2% formalin added at any time. After incubation, the eggs were centrifuged
at 3500 r/min for 10 min, the number of hatching eggs was observed by microscope. After the
completion of imago, the death of adult was observed directly. On the basis of screening compounds
with relatively good activity in vitro, further experiments on inhibition of roundworm from different
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sources were carried out. In the experiment, the 100 imago roundworm from human, rabbit, cow, pig
and dog were cultured, respectively.At the same time, we screened compounds (10 μmol/L, 0.2 mL
and n=8). After 24 days of culture under the same conditions, the death of imago roundworm was
directly observed. At the same time, the 100 pinworms, hookworms, roundworms and whipworms
from rats were selected, and the screened compounds (10 μmol/L, 0.2 mL and n=8) was added to
culture under the same conditions. The death of various heminth was observed in 24 days later.
2.2.2. Biological activity of anti-helminticfor compounds in vivo
Female rats with the same degree of roundworm infection were given oral doses of 15mg·kg-1
and 30mg·kg-1 for consecutive 10 days. During continuous feeding of the drug, the egg roundworms
were detected by taking rat feces every day with Kato-Katz modified thick smear method. After
discontinuing the feeding, fecal test was taken for every 3 days, and continuous test was carried out
for 3 times to detect the changes of eggs. After the test was completed, all the rats were killed directly,
and all the rats were dissected to observe the death of imago and the presence of eggs in the uterus. In
vivo, DMSO was used as the blank control experiment, and Albendazole was used as the positive
control experiment. At the same time, we selected the imago of hookworm, whipworm, roundworm,
pinworm infection forrat, rabbit and dogin vivo experiments (n=8). The oral dose was 15mg·kg-1.
3. Results and discussion
3.1. Synthesis
The novel of series imidazo [1, 2-a] pyridine analogues or derivativeswere designed for
anti-helmintic drugs, and Albendazole was used as the lead compound. Their chemical structures were
modified by the structural transformation and with alkyl groups (Fig. 2). Albendazole was an
anti-helmintic drug, andhad imidazole ring structure. We designed the new compounds to have the
imidazole ring structure, which mightalso have the effect on anti-helmintic. In the chemical structural
modification of Albendazole (the lead compound), the basic framework (benzomidazole structure) of
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the compound was retained, the benzomidazole structure became imidazo [1, 2-a] pyridine structure.
We modified the chemical structure of pyridine ring and ester, and chose different substituent groups.
During the modification of pyridine ring, we chose C, N and S atoms to connect alkyl chain R1. We
chose R1as C2H5-, n-C3H7-, and n-C4H9- in designing the target compounds. CH3- and C2H5- were
used as R2 substituents for the imidazo ring ester. We chose different substituents R1-2 and the link
atoms to change the logP and pKaof target compounds for bindingthe compounds to the receptors.
The logP and pKa could the efficacy for pharmacodynamicsto screen out the best target compound.
For the synthesis of imidazo [1, 2-a] pyridine analogues or derivatives, the synthetic route wassimple
operation, high total yield and mild reaction conditions (Scheme 1). A total of 18 compounds were be
synthesized and they were analyzed by 1H NMR, 13C NMR, MS, and elemental analysis, respectively.
Forthe synthesis of target compounds, we used three steps ofchlorination, amidation, and alkylation,
respectively. For the synthesis of 6-chloroimidazo [1, 2-a] pyridin-2-amine (2a), we chose CHCl3 as
solvent, N,N’-dimethyl formamide (DFM) as catalyst, and Ph3P/CHCl3 as chloride reagentin the
refluxing for 10 h to complete the chlorination. The synthesis of compounds 3a-3b, it was general
method, we chosetoluene as solvent, anhydrous sodium carbonate as acid-binding agentin the
refluxing for 12 h to complete the second step reaction. For the synthesis of compounds 4a-4r, it was
the same general method, we choseethanol as solventin the refluxing for6 h to complete the three step
reaction. The synthetic route had high total yield, a simple operation, and mild reaction conditions.
The yield of the target compounds 4a-4r was 78.8%-91.3%.
3.2. The biological activities
3.2.1. The inhibitory activity to anti-helmintic in vitro
In vitro experiment was one of the basic contents to evaluate drug activity, and it was a necessary
approach to researchdrugs.Drug efficacy was often affected by some physical and chemical properties
of compounds, such as lipid-water partition coefficient (logP) and dissociation degree (pKa). In this
part, the physical and chemical properties were studied of imidazo [1, 2-a] pyridine analogues or
derivatives, which was very necessary to study the pharmacodynamics (Table 1). In the Tabel 1, we
could find that target compounds had a certain fat solubility. The compounds with a certain fat
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solubility were favorable for drug absorption. So, they were easy to enter the cells. This logPof
compounds was from 0.95 to 3.15. The pKa would affect the absorption and deliveryof the drugs. The
different environmental (acid and alkalinity) medicine way might be different, sometimes it exists in
the form of ions, sometimes it exists in the form of molecules.Usually drug has no effect in the form
of ion. Therefore, it was necessary to study the dissociation degree (pKa) of drug for studying the
pharmacodynamics. In the Tabel 1, we could find that the pKa of target compounds was from 8.01 to
8.73, and these compounds could be absorbed in intestinal tract. After the physical and chemical
properties were studied, the biological activity would be studied. Inhibition activity of
anti-helminthinvitro, the anti-eggand anti-imago of roundwormwere used as the test indicators (Tabel
1). Half of the inhibition concentration (IC50) was used to evaluate biological activity in vitro. Based
on the data in Table 1, it could be find that these compounds had a certain inhibitory effect
onroundworm. Especially compounds 4e, 4f, 4k, 4l, 4q and 4r had better anti-roudworm. IC50 of
compound 4l to anti-egg of roundworm was 0.65±0.01 μmol/L, and to anti-imago of roundworm was
1.04±0.01 μmol/L. Fig. 3 showed the in vitro inhibition experiments of aphids from different sources
with a concentration of 10 μmol/L and a volume of 0.2 mL. The experimental results showed that 4k
and 4l had better inhibitory effects on aphids from different sources. Based on the data in Fig. 328, the
rate of anti-roudwormfor all the compounds could reach more than 90%. Fig. 4 showed the in vitro
inhibition experiments of these compounds on pinworms, hookworms, roundworms and whipworms
(derived from rat) in the same manner as in vitro screening. The concentration of 10 μmol/L was used
in a volume of 0.2 mL. After 24 days of culture, the intestinal worm survival was observed. In Fig.
428, for all the compounds the rate of anti-helmintic could reach more than 91%, especially compound
4l had the best effect, and the rate of anti-helmintic could be reach more than 99%. It showed from all
the data forin vitro experiment results that their compounds had good anti-helmintic activity,
especially for roundworm, and their compounds were belong to broad-spectrumanti-helmintic
substances.
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3.2.2. The biological activity of anti-helmintic in vivo
The compounds 4e, 4f, 4k, 4l, 4q and 4r were selected from the in vitro activity test. In vivo
experiments, the anti-egg of roundworm, anti-imago helminths (hookworm, whipworm, roundworm,
pinworm), and acute toxicity were used as the test indicators (Table 2, Table 3 and Fig. 5). In Table
2, we chose different dose (15 mg·kg-1·d-1 and 30mg·kg-1·d-1), and used oral administration.
Albendazole was used as the positive reference substance, DMSO was used as the blank control, and
the anti-roundworm was observed (a total of 20 days). The experimental results showed that the
compounds 4e, 4f, 4k, 4l, 4q and 4r had good anti-roundworm activity, especially the compound 4l.
Fig. 5 showed the in vivo anti-enteric test of different animals. The oral dose was 15 mg·kg-1. After
feeding for a certain period of time, the survival of the intestinal mites was observed directly. In Fig.
5, rats, rabbits and dogs were selected as the research objects. The results showed that compound 4l
had good anti-helmintic (hookworm, whipworm, roundworm, pinworm), especially inhibitory of
whipworm and roundworm, and it was a broad-spectrum drug. In Table 3, the acute toxicity test
results showed that they were belong to low toxicity compounds with LD50＞2100 mg·kg-1.
4. Conclusion
Using Albendazole as the lead compound, a total of 18 compounds were designed and synthesized
as imidazo [1, 2-a] pyridine analogues or derivatives. We used the structural transformation and
modification with alkyl for the lead compound. The synthetic route had high total yield, a simple
operation and mild reaction conditions. The novelseries of compounds were studied for their
biological activity in vitro and in vivo. The in vitro experiment results showed that the compounds 4e,
4f, 4k, 4l, 4q and 4r had good inhibitory effect on egg and imago of roundworm. IC50 of compound 4l
to anti-egg of roundworm was0.65±0.01 μmol/L, and was 1.04±0.01 μmol/L to anti-imago of
roundworm. At the same time, in vivo effect on anti-roundworm experiment results showed that the
compound 4l had the best effect, and the rate of anti-helmintic could reach more than 99%. The acute
toxicity test results showed that they were belong to low toxicity compounds with LD50＞2100
mg·kg-1 by oral administration.
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Acknowledgements
The Project is sponsored by the Scientific Research Foundation for the Returned Overseas
Chinese Scholars, State Education Ministry (No. 2015-1098). The work was also supported
by Chongqing Key Research Project of Basic Science & Frontier Technology (No.
cstc2017jcyjBX0012), Foundation Project of Chongqing Normal University (No.
14XYY020), Chongqing General Research Program of Basic Research and Frontier
Technology (No. cstc2015jcyjA10054), and Chongqing Normal University Postgraduate's
Research and Innovation Project (No. YKC17004), China.
Conflict of Interest statement
The authors confirm that this article content has no conflict of interest.
A list of the figure legends
Fig. 1. The structures of imidazoles drugs with anti-helminth.
Fig. 2. Design of imidazo [1, 2-a] pyridine analogues or derivatives.
Scheme 1. The synthetic route of imidazo [1, 2-a] pyridine analogues or derivatives.
Fig. 3. Inhibition rate of roundworms from different sources in vitro.
Fig. 4. Inhibition rate to helminth in vitro.
Fig. 5. Inhibition rate of anti-helminth in vivo.
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Tables
Table 1. The inhibitory activity of anti-roundworm in vitro.
IC50±SD（μmol/L）
Compounds
R1
R2
X
log P
pKa
Egg
Imago
4a
C2H5-
C2H5-
C2H5-
C2H5-
C2H5-
C2H5-
CH3-
C2H5-
CH3-
C2H5-
CH3-
C2H5-
NH
NH
O
0.95
1.28
1.33
1.67
1.89
2.23
1.42
1.77
1.82
2.14
2.38
2.71
1.85
2.19
2.23
2.56
2.78
3.15
——
8.32
8.28
8.01
8.00
8.14
8.09
8.45
8.40
8.25
8.20
8.38
8.30
8.73
8.70
8.55
8.50
8.65
8.58
——
20.33±1.23
20.01±1.06
16.78±1.40
15.22±1.09
1.96±0.05
1.21±0.02
15.77±1.19
14.67±1.09
8.09±0.87
7.56±0.67
0.78±0.01
0.65±0.01
15.08±1.11
14.80±1.08
7.90±0.85
7.00±0.66
1.66±0.03
1.45±0.02
1.05±0.02
40.90±3.02
39.80±3.00
34.09±2.98
30.89±2.78
2.30±0.08
1.80±0.04
30.08±3.11
28.90±2.94
12.09±2.11
11.98±2.01
1.22±0.02
1.04±0.01
30.12±3.00
28.03±2.89
13.23±2.33
12.97±2.01
2.01±0.05
1.95±0.04
1.67±0.18
4b
4c
4d
O
4e
S
4f
S
4g
n-C3H7- CH3-
n-C3H7- C2H5-
n-C3H7- CH3-
n-C3H7- C2H5-
n-C3H7- CH3-
n-C3H7- C2H5-
n-C4H9- CH3-
n-C4H9- C2H5-
n-C4H9- CH3-
n-C4H9- C2H5-
n-C4H9- CH3-
n-C4H9- C2H5-
NH
NH
O
4h
4i
4j
O
4k
S
4l
S
4m
NH
NH
O
4n
4o
4p
O
4q
S
4r
S
Albendazole
——
——
——
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Table 2. The inhibition activity of anti-roundworm in vivo.
Dosage
of drugs
Roundworm egg (U·g-1)
1d 2d 3d 4d
5d
6d
7d
8d
9d
10d
13d 16d 19d
Compounds
(mg·kg-1· 20d
d-1)
15
30
15
30
15
30
15
30
20
30
15
30
-
21 18
0
17 12
0
20 15
0
16 11
0
17 13
0
14 10
0
15 10
0
17
15
12
8
1
4
0
0
0
0
0
3
0
0
0
3
0
1
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
23
0
0
0
0
0
0
0
0
0
0
0
0
22
0
0
0
0
0
0
0
0
0
0
0
0
22
10
13
8
6
2
7
2
2
0
0
0
6
0
3
0
22
10
5
4e
4f
10
6
6
2
4k
4l
4
1
15
30
12
0
7
2
0
4q
4r
18 15
0
17 10
0
18 13
0
16 12
0
22 22
22
12
7
10
3
Blank control
（DMSO）
Albendazole
10
7
6
3
21
21
23
21
21
22
22
0
22 20
0
17
15
10
2
6
0
3
0
0
0
0
0
0
0
0
17
0
11
8
4
0
0
0
0
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Table 3. The median lethal dose (LD50).
LD50±SD（mg·kg-1）
Compound
Structures
s
Rat
Rabbit
Dog
4e
2561.7±2.2
2704.6±2.3
2610.5±2.0
2470.9±3.1
2691.5±2.6
2600.1±2.3
3340.7±3.5
3300.7±3.3
2360.1±2.8
2205.8±1.9
4f
3218.4±3.2
3459.6±3.6
4k
4l
3133.8±3.4
3401.4±3.4
2305.6±2.6
2405.3±2.9
4q
4r
2104.3±2.1
2359.3±2.0
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figure legends for Supporting Information
Fig. 1. The structures of imidazoles drugs with anti-helminth.
Fig. 2. Design of imidazo [1, 2-a] pyridine analogues or derivatives.
Scheme 1. The synthetic route of imidazo [1, 2-a] pyridine analogues or derivatives.
Fig. 3. Inhibition rate of roundworms from different sources in vitro.
Fig. 4. Inhibition rate to helminth in vitro.
Fig. 5. Inhibition rate of anti-helminth in vivo.
Fig. 1. The structures of imidazoles drugs with anti-helminth.
Fig. 2. Design of imidazo [1, 2-a] pyridine analogues or derivatives.
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100
98
96
94
92
90
88
86
84
82
80
Human
Rabbit
Cow
Pig
Dog
4e
4f
4k
4l
4q
4r
Fig. 3. Inhibition rate of roundworms from different sources in vitro.
100
98
96
94
Hookworm
Whipworm
Roundworm
Pinworm
92
90
88
86
84
82
80
4e
4f
4k
4l
4q
4r
Fig. 4. Inhibition rate to helminth in vitro.
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100
99
98
97
96
95
Rat
Rabbit
Dog
Hookworm Whipworm Roundworm Pinworm
Fig. 5. Inhibition rate of anti-helminth in vivo.
Scheme 1. The synthetic route of imidazo [1, 2-a] pyridine analogues or derivatives.
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