Indian Journal of Chemistry
Vol. 56B, January 2017, pp. 112-119
Synthesis and antischistosomal activity of new furoxan derivatives of praziquantel
Singam Naveen Kumara, Partha Sarathi Sadhua, Kirti Kumari Sharmaa,b, Livia Pica-Mattocciac, Annalisa Bassoc,
Donato Ciolic & Vaidya Jayathirtha Rao*a,b
a
Crop Protection Chemicals Division
and
b
Academy of Scientific & Innovative Research (AcSIR)
CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, India
c
Institute of Cell Biology and Neurobiology, National Research Council, 00015 Monterotondo, Rome, Italy
E-mail: vaidya.opv@gmail.com; dcioli@ibc.cnr.it
Received 8 August 2016; accepted (revised) 19 December 2016
A series of new furoxan derivatives of praziquantel have been synthesized and evaluated for antischistosomal activity.
The newly synthesized hybrid compounds have structural modifications at amide and aromatic rings and thus offer broad
structure-activity variations. All the compounds have been tested against adult as well as immature Schistosoma mansoni.
Compounds 15 and 18 show moderate activity against adult schistosomes. On immature worms, only compound 15 shows
substantial activity whereas the standard drug PZQ is practically inactive at this stage.
Keywords: Schistosomiasis, Praziquantel, furoxan, hybrid drug, Schistosoma mansoni, antischistosomal
Schistosomiasis is a chronic infectious disease caused
by trematode flatworms of the genus Schistosoma. It
is the second most prevalent parasitic disease in the
world after malaria1. WHO reports suggest that
240 million people are infected worldwide and
280,000 deaths/year were estimated in sub-Saharan
Africa alone2. In this scenario, Praziquantel (PZQ) is
the sole drug available for the treatment of
schistosomiasis. It is highly effective against all
schistosome species that cause human schistosomiasis
(mainly S. mansoni, S. japonicum and S. haematobium)3,4.
PZQ is administered to millions of people annually in
mass chemotherapy programs. This may lead to the
emergence of drug-resistant parasites. Although no
conclusive report of clinically relevant drug resistance
or tolerance has appeared5, various isolates of
S. mansoni and S. haematobium have shown different
levels of PZQ sensitivity6,7. The main limitation of
PZQ is that it is inactive against juvenile schistosomes8,
a fact that would require the administration of a second
delayed dose to achieve complete cure.
In search of new antischistosomal agents, synthesis
of PZQ analogs has attracted the attention of various
research groups worldwide. A number of structural
modifications were introduced in the PZQ molecule to
improve its antischistosomal activity9-13. Previously,
our group also reported new PZQ analogs having
some antischistosomal activity13. However, PZQ still
remains the most potent drug among all reported
analogs. Recently, novel oxadiazole-2-oxide analogs
(furoxans) were reported as most promising
antischistosomal agents other than PZQ14. Furoxans
are well known to release nitric oxide (NO) in the
presence of TGR (Thioredoxin Glutathione
Reductase) and NADPH and have shown activity
even against the juvenile stage of schistosomes,
unlike PZQ which is fully active only against adult
schistosomes14.
Hybrid molecules are defined as chemical entities
with two or more different pharmacophores. If
pharmacophores have different biological mechanisms
of action, the emergence of drug resistance is much
less likely to occur. The hybrid drug concept has been
introduced for diseases like cancer, heart conditions,
malaria and HIV-AIDS15-18. Recently, a few hybrid
molecules were reported to have moderate
antischistosomal activity19-22.
As a continuation of our work to unearth new
antischistosomal agents13, in this paper we report the
synthesis and antischistosomal activity of twenty new
hybrid entities combining the NO donor furoxan
moiety with PZQ. As both moieties have excellent
activity against schistosome species, we thought that
the hybrid entities might be worth a trial.
KUMAR et al.: FUROXAN DERIVATIVES OF PRAZIQUANTEL
Results and Discussion
Chemistry
The synthetic scheme was designed to prepare
novel hybrid compounds with possible structural
variations for a better understanding of structure–
activity relationships. A total of twenty new
furoxan derivatives of PZQ were prepared with
structural variations at amide and aromatic
moieties. Synthesis of vital intermediate furoxan
compounds
5a-f,
6a-f
is
depicted
in
Scheme I (Ref 23). Synthesis starts with C2-Wittig
homologation of commercially available substituted
benzaldehydes 1a-f to give ethyl cinnamates 2a-f.
Reduction of ester functionality of 2a-f with
DIBAL-H yielded cinnamyl alcohols 3a-f. Further
reaction of 3a-f with sodium nitrite in presence of
glacial acetic acid afforded furoxan methanol
derivatives 4a-f (Ref 23).
Finally, furoxan intermediates i.e., furoxan acid
derivatives 5a-f were synthesized from 4a-f using
Jones oxidation protocol23, whereas synthesis of
bromo derivatives 6a-f was accomplished by
reaction of 4a-f with NBS in the presence of
triphenylphosphine.
Synthesis of hybrid compounds 8-15, 16-27 is
depicted in Scheme II. Hexahydro-4H-pyrazinoisoquinoline derivatives 7a,b were synthesized
according to the literature procedures24. The first
series of hybrid compounds 8-15 were synthesized
by reaction between furoxan acid compouds 5a-f
113
and amine compounds 7a,b under EDCI and HOBT
conditions in 48-65% yields. The second series of
hybrid compounds 16-27 were synthesized by the
reaction of furoxan bromo compounds 6a-f with
7a,b in the presence of K 2CO3 as base.
Biology
In vitro anti-schistosomal test of Furoxan
Derivatives of Praziquantel
In a preliminary activity screening, we tested all
compounds in vitro against adult schistosomes8,
using a high concentration of each substance
(100 µM) that was left continuously in the cultures
for 3 days. Only two compounds showed lethal
effects, while all the rest did not exert any adverse
activity on the schistosomes. Compounds 15 and 18
rendered worms immobile and contracted. The two
positive compounds were then tested at lower
concentration with the standard protocol we use for
PZQ8, namely leaving the substance in contact with
the worms for 20 hr, washing and continuing
culture for 7 days in drug-free medium. Results are
shown in Table I.
To put things in perspective, one should consider
that PZQ under these conditions causes total
contraction and death of adult schistosomes at
concentrations between 1 µM and 3 µM. We also
tested all compounds against immature schistosomes
(4-week-old) that are known to be refractory to PZQ
activity. Following the same procedure we had
Scheme I — Reagents and conditions: (a) (OEt)2P(O)CH2COOEt, NaH, 0°C-RT, 1 h. (b) DIBAL-H, CH2Cl2, 0°C, 4 h. (c) Glacial acetic
acid, NaNO2, RT, 4-6 h, 30-75%. (d) CrO3, H2SO4, Acetone. (e) PPh3, NBS, DCM, 2-3 h.
INDIAN J. CHEM., SEC B, JANUARY 2017
114
Scheme II — Reagents and conditions: (a) 5a-f, EDC, HCl, HOBT, CH2Cl2, −20°C, 1 h., (b) 6a-f, K2CO3, Acetone, 4 h.
Table I — In vitro activity after 20 h exposure followed by culture
in drug-free medium. Observations on day 7 after drug wash.
Each dish contained either 10 adults or ~20 four-week-old worms
Table II — Effect of compounds 15 and 18 on adult worms upon
in vivo treatment
Compd
Immature worms
50 µM
Compd
75% immobile,
contracted
6% immobile,
contracted
Slightly lower
mobility,
otherwise normal
Untreated
control
15
15
18
PZQ
Adult worms
25 µM
50 µM
Slow, slightly Immobile, slightly
contracted
contracted
Slow,
Immobile,
contracted
contracted
Immobile,
Immobile,
contracted
contracted
adopted for the adults, all compounds were left for
3 days in the cultures at the concentration of 100 µM.
As with adults, only compounds 15 and 18 showed
activity. When tested at lower concentration and
following the pulse-and-wash procedure, only
compound 15 showed a substantial activity, while
PZQ, as expected8, was essentially ineffective
(Table I). Since compounds 15 and 18 appear to
possess some antischistosomal activity, we also
carried out preliminary in vitro tests of toxicity using
HepG2 cells. Compound 15 did not show toxic effects
at the highest concentration tested (25 µM), while
cells treated with compound 18 were free of toxic
effects at 5 µM, but gave signs of toxicity at 25 µM.
The two compounds showing some in vitro activity
against adult worms, were also tested in vivo25.
Results are shown in Table II. As a term of
comparison, PZQ at 500 mg/kg causes >80% worm
18
Dose (mg/kg) No. of Worms recovered
(mg/kg)
mice
(mean ± S.D.)
P
(t-test)
–
6
16.0±11.3
–
400
800
400
800
6
6
5
6
16.8±8.6
14.0±2.6
10.4±2.7
17.2±5.4
0,8888 n.s.
0,6820 n.s.
0,3114 n.s.
0,8242 n.s.
reduction. None of the animals showed overt signs of
toxicity after treatment.
Experimental Section
All reagents (highest grade) were commercially
available and were used without further purification
unless otherwise noted. All dry reactions were carried
out under an inert atmosphere unless mentioned
otherwise, and standard syringe-septa techniques were
followed. Solvents were freshly dried and purified by
conventional methods prior to use. The progress of all
reactions was monitored by TLC, using TLC
aluminium-backed sheets precoated with silica
gel 60 F254 to a thickness of 0.25 mm (Merck).
Column chromatography was performed on silica gel
(60–120 mesh and 100-200 mesh), and EtOAc,
hexane were used as eluents. Melting points were
determined using the Barnstead Electrothermal digital
KUMAR et al.: FUROXAN DERIVATIVES OF PRAZIQUANTEL
melting point apparatus and are uncorrected. IR
spectra were recorded with a Perkin-Elmer FT-IR
spectro-photometer. 1H and 13C NMR spectra were
recorded with Varian Gemini 200 MHz, Bruker
Avance 300 MHz, Varian Unity 400 MHz or Varian
Inova 500 MHz spectrometers. TMS was used as an
internal standard in CDCl3. Mass spectra were
recorded with a VG Micromass 7070H (EI), QSTAR
XL high resolution mass spectrometer, and a
Thermo Finnigan ESI ion trap mass spectrometer.
General procedure for the synthesis of final
compounds 8-15
To a solution of acid compound 5a-f (0.10 mmol)
in DCM (25 mL) at −20°C, EDCI (0.2 mmol), HOBT
(0.2 mmol) were added simultaneously. After 15 min of
stirring at the same temperature, the amine compound
7a/7b (0.15 mmol) and triethylamine (0.30 mmol) were
added and the reaction mixture was stirred for one
additional hour. After completion of the reaction, the
mixture was quenched by addition of water and
extracted twice with chloroform (2×10 mL). The
combined organic layer was washed with dil. HCl
and sat. NaHCO3, then dried (Na2SO4) and
concentrated under reduced pressure to give the
crude product. The crude residue was purified by
silica gel column chromatography to yield pure
compound 8-15.
3-(4-Oxo-2,3,4,6,7,11b-hexahydro-1H-pyrazino
[2,1-a]isoquinoline-2-carbonyl)-4-phenyl-1,2,5oxadiazole 2-oxide, 8: Yield 55%. Light brown solid.
m.p.160-63°C; IR (neat): 3012, 2928, 2855, 1656,
1597, 1019, 755 cm−1; 1H NMR (300 MHz, CDCl3):
7.79-7.72 (m, 2H), 7.57-7.43 (m, 3H), 7.33-7.09 (m,
4H), 5.10-5.00 (m, 1H), 4.98-4.72 (m, 2H), 4.16-4.12
(m, 1H), 4.09-3.96 (m, 1H), 3.41-3.20 (m, 1H),
3.05-2.74 (m, 3H); 13C NMR (75 MHz, CDCl3):
163.4, 162.9, 155.1, 135.1, 134.8, 131.8, 131.7, 131.1,
129.5, 129.2, 127.8, 127.7, 127.6, 127.1, 125.6, 125.3,
55.6, 54.5, 50.3, 48.5, 46.7, 45.9, 39.3, 38.8, 28.8,
28.5; ESI-MS: m/z 391 [M+H]+; ESI-HRMS: m/z
Calcd for C21H19N4O4: 391.1406 [M+H]+. Found:
391.1400.
3-(9,10-Dimethoxy-4-oxo-2,3,4,6,7,11b-hexahydro
-1H-pyrazino[2,1-a]isoquinoline-2-carbonyl)-4-phenyl
-1,2,5-oxadiazole 2-oxide, 9: Yield 48%. Brown
solid. m.p.198-200°C; IR (neat): 2930, 1656, 1598,
1253, 1016, 783 cm−1; 1H NMR (300 MHz, CDCl3):
7.78-7.70 (m, 2H), 7.57-7.45 (m, 3H), 6.75-6.61
(m, 2H), 5.03-4.76 (m, 3H), 4.17-4.08 (m, 2H), 3.88
115
(s, 3H), 3.85 (s, 3H), 3.35-3.27 (m, 1H), 2.97-2.79
(m, 2H), 2.74-2.66 (m, 1H). 13C NMR (75 MHz,
CDCl3): 163.4, 162.8, 155.1, 154.8, 154.3, 148.6,
148.2, 131.8, 131.7, 129.2, 127.7, 127.5, 127.2, 125.3,
125.2, 123.4, 122.6, 111.9, 108.0, 56.2, 55.9, 55.4,
54.5, 50.9, 48.6, 46.8, 45.9, 39.5, 38.8, 28.1, 28.4;
ESI-MS: m/z 451 [M+H]+; ESI-HRMS: m/z Calcd for
C23H23N4O6: 451.1617 [M+H]+. Found: 451.1609.
4-(2-Methoxyphenyl)-3-(4-oxo-2,3,4,6,7,11bhexahydro-1H-pyrazino[2,1-a]isoquinoline-2-carbonyl)
-1,2,5-oxadiazole 2-oxide, 10: Yield 48%. White solid.
m.p.115-17°C; IR (neat): 3010, 2925, 2854, 1654,
1596, 1218, 771 cm−1; 1H NMR (300 MHz, CDCl3):
7.77-7.71 (m, 1H), 7.54-7.49 (m, 1H), 7.31-7.25 (m,
3H), 7.23-7.20 (m, 1H), 7.13 (dt, 1H, J = 7.6, 0.7 Hz),
6.95 (dd, 1H, J = 10.5, 8.3 Hz), 5.24-4.91 (m, 2H),
4.89-4.74 (m, 1H), 4.35-4.24 (m, 1H), 4.20-3.97 (m,
1H), 3.72-3.68 (m, 3H), 3.33-3.09 (m, 1H), 3.84-2.87
(m, 2H), 2.85-2.80 (m, 1H); 13C NMR (75 MHz,
CDCl3): 163.6, 163.6, 156.4, 156.2, 155.9, 155.1,
154.5, 135.0, 134.7, 133.2, 133.1, 131.8, 131.3, 130.0,
129.9, 129.4, 129.4, 127.7, 127.7, 127.1, 125.8, 125.3,
121.7, 114.6, 114.4, 112.1, 111.9, 111.2, 55.6, 55.4,
55.3, 54.4, 50.4, 48.3, 46.5, 45.9, 39.0, 38.6, 28.8,
28.6; ESI-MS: m/z 421 [M+H]+; ESI-HRMS: m/z
Calcd for C22H21N4O5: 421.1511 [M+Na]+. Found:
421.1498.
3-(9,10-Dimethoxy-4-oxo-2,3,4,6,7,11b-hexahydro 1H-pyrazino[2,1-a]isoquinoline-2-carbonyl)-4-(2methoxyphenyl)-1,2,5-oxadiazole 2-oxide, 11: Yield
47%. Brown solid. m.p.188-90°C; IR (neat): 3013,
2924, 2853, 1654, 1596, 1218, 771 cm−1; 1H NMR
(300 MHz, CDCl3): 7.76-7.68 (m, 1H), 7.53-7.49
(m, 1H), 7.14-7.10 (m, 1H), 6.95 (dd, 1H, J = 13.7,
8.2 Hz), 6.78-6.65 (m, 2H), 5.14-4.70 (m, 3H),
4.35-4.23 (m, 1H), 4.13-3.99 (m, 1H), 3.89-3.70
(m, 6H), 3.71 (s, 1.5H), 3.65 (s, 1.5H), 3.23-3.13
(m, 1H), 2.98-2.82 (m, 2H), 2.75-2.69 (m, 1H);
13
C NMR (75 MHz, CDCl3): 163.6, 163.4, 156.3,
156.2, 155.7, 154.8, 154.5, 153.8, 148.5, 148.4, 148.1,
148.1, 133.1, 133.0, 129.8, 129.7, 127.3, 126.9, 123.5,
122.8, 121.5, 114.5, 114.3, 112.2, 111.8, 111.6, 111.1,
108.8, 107.9, 56.1, 56.0, 55.8, 55.4, 55.2, 55.2, 54.1,
50.7, 48.2, 46.5, 45.8, 39.0, 38.5, 28.3, 28.0; ESI-MS:
m/z 481 [M+H]+; ESI-HRMS: m/z Calcd for
C24H25N4O7: 481.1723 [M+H]+. Found: 481.1731.
4-(4-Methoxyphenyl)-3-(4-oxo-2,3,4,6,7,11b-hexahydro
-1H-pyrazino[2,1-a]isoquinoline-2-carbonyl)-1,2,5oxadiazole 2-oxide, 12: Yield 52%. Whitish solid.
m.p.184-86°C; IR (neat): 3002, 2925, 2854, 1632,
116
INDIAN J. CHEM., SEC B, JANUARY 2017
1575, 1021, 763 cm−1; 1H NMR (300 MHz, CDCl3):
7.73-7.68 (m, 2H), 7.33-7.10 (m, 4H), 7.01-6.95
(m, 2H), 5.11-5.00 (m, 1H), 4.96-4.73 (m, 2H),
4.15-4.13 (m, 1H), 4.11-3.98 (m, 1H), 3.85 (s, 3H),
3.39-3.19 (m, 1H), 3.00-2.75 (m, 3H); 13C NMR
(75 MHz, CDCl3):
163.4, 162.9, 162.2, 162.1,
155.3, 155.2, 154.6, 154.4, 135.0, 134.8, 131.7, 131.0,
129.4, 129.2, 129.1, 127.8, 127.7, 127.0, 125.5, 125.2,
117.5, 117.3, 114.6, 114.6, 110.4, 110.1, 55.5, 55.4,
55.4, 54.5, 50.7, 50.3, 48.5, 46.6, 45.8, 39.2, 38.7,
28.7, 28.5; ESI-MS: m/z 421 [M+H]+; ESI-HRMS:
m/z Calcd for C22H21N4O5: 421.1511 [M+H]+. Found:
421.1500.
3-(9,10-Dimethoxy-4-oxo-2,3,4,6,7,11b-hexahydro -1Hpyrazino[2,1-a]isoquinoline-2-carbonyl)-4-(4methoxyphenyl)-1,2,5-oxadiazole 2-oxide, 13: Yield
46%. Yellow solid. m.p.96-98°C; IR (neat): 3012,
2924, 2853, 1653, 1575, 1255, 771 cm−1; 1H NMR
(300 MHz, CDCl3): 7.70 (d, 1H, J = 9.0 Hz), 7.65
(d, 1H, J = 9.0 Hz), 6.97 (dd, 2H, J = 12.8, 9.0 Hz),
6.76-6.60 (m, 2H), 5.04-4.77 (m, 3H), 4.19-4.09
(m, 2H), 3.90-3.83 (m, 9H), 3.36-3.26 (m, 1H), 2.96-2.80
(m, 2H), 2.72-2.66 (m, 1H); 13C NMR (75 MHz,
CDCl3): 163.5, 162.8, 162.1, 155.3, 154.5, 154.4,
148.6, 148.5, 148.1, 148.1, 129.2, 129.0, 128.8, 127.5,
127.1, 123.4, 122.5, 117.4, 117.3, 114.6, 114.4, 114.2,
111.8, 111.7, 110.6, 110.0, 108.5, 107.9, 56.1, 56.1,
55.8, 55.4, 54.4, 50.8, 48.5, 46.7, 45.7, 39.5, 38.8,
28.3, 28.0; ESI-MS: m/z 503 [M+Na]+; ESI-HRMS:
m/z Calcd for C24H24N4O7Na: 503.15372 [M+Na]+.
Found: 503.15582.
4-(3-Fluorophenyl)-3-(4-oxo-2,3,4,6,7,11bhexahydro-1H-pyrazino[2,1-a]isoquinoline-2carbonyl)-1,2,5-oxadiazole 2-oxide, 14: Yield 29%.
Yellow solid. m.p.150-52°C; IR (neat): 3018, 2923,
2853, 1655, 1589, 1218, 770 cm−1; 1H NMR (300 MHz,
CDCl3):
7.66-7.41 (m, 3H), 7.36-7.11 (m, 5H),
5.19-4.69 (m, 3H), 4.20-4.13 (m, 1H), 4.20-3.98 (m,
1H), 3.41-3.20 (m, 1H), 3.05-2.77 (m, 3H); ESI-MS:
m/z 409 [M+H]+; ESI-HRMS: m/z Calcd for
C21H18FN4O4: 409.1306 [M+H]+. Found: 409.1303.
4-(2-Fluorophenyl)-3-(4-oxo-2,3,4,6,7,11bhexahydro-1H-pyrazino[2,1-a]isoquinoline2-carbonyl)-1,2,5-oxadiazole 2-oxide, 15: Yield
31%. White solid. m.p.148-50°C; IR (neat): 3011,
2926, 2857, 1726, 1657, 1602, 1459, 1294, 771 cm−1;
1
H NMR (300 MHz, CDCl3): 7.88-7.69 (m, 1H),
7.59-7.51 (m, 1H), 7.38-7.27 (m, 3H), 7.23-7.10 (m,
3H), 5.20-4.75 (m, 3H), 4.26-4.00 (m, 2H), 3.43-3.12
(m, 1H), 3.02-2.88 (m, 2H), 2.85-2.78 (m, 1H);
ESI-MS: m/z 409 [M+H]+; ESI-HRMS: m/z Calcd for
C21H18FN4O4: 409.1304 [M+H]+. Found: 409.1303.
General procedure for the synthesis of final compounds
16-27
To a solution of bromo compound 6a-f (0.10 mmol)
and amine 7a/7b (0.12 mmol) in CH2Cl2, was added
K2CO3 (0.5 mmol) and the reaction mixture was
stirred for 4 h. After completion of reaction, the
reaction mixture was diluted with water, the organic
layer was separated and the aqueous layer was
extracted using chloroform. The combined organic
layer was dried (Na2SO4), concentrated under reduced
pressure and purified using silica gel column
chromatography to yield pure compound.
3-((4-Oxo-3,4,6,7-tetrahydro-1H-pyrazino[2,1a]isoquinolin-2(11bH)-yl)methyl)-4- phenyl-1,2,5oxadiazole 2-oxide, 16: Yield 92%. White solid.
m.p.98-101°C; IR (neat): 3017, 2932, 1645, 1599,
1457, 1027, 757 cm−1; 1H NMR (300 MHz, CDCl3):
7.92 (d, 1H, J = 1.51 Hz), 7.89 (d, 1H, J = 1.5 Hz),
7.58-7.52 (m, 3H), 7.24-7.15 (m, 3H), 7.08-7.04
(m, 1H), 4.86-4.73 (m, 2H), 3.69 (dd, 2H, J = 18.4,
13.5 Hz), 3.58 (dd, 1H, J = 16.0, 1.3 Hz), 3.48 (ddd,
1H, J = 12.0, 4.7, 1.8 Hz), 3.19 (d, 1H, J = 16.05 Hz),
3.04-2.88 (m, 2H), 2.81-2.74 (m, 1H), 2.64-2.57
(m, 1H); 13C NMR (75 MHz, CDCl3): 165.2, 157.4,
134.8, 133.5, 131.3, 129.3, 129.27, 127.8, 127.2,
126.7, 126.4, 124.5, 112.0, 56.7, 55.5, 55.1, 48.6,
38.9, 28.5; ESI-MS: m/z 377 [M+H]+; ESI-HRMS:
m/z Calcd for C21H21O3N4: 377.1608 [M+H]+. Found:
377.1607.
3-((9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)4-phenyl-1,2,5-oxadiazole 2-oxide, 17: Yield 93%.
White solid. m.p.120-22°C; IR (neat): 3014, 2933,
1645, 1598, 1454, 1027, 748 cm−1; 1H NMR
(300 MHz, CDCl3): 7.90 (d, 1H, J = 1.8 Hz), 7.88
(d, 1H, J = 1.8 Hz), 7.58-7.51 (m, 3H), 6.62 (s, 1H),
6.49 (s, 1H), 4.86-4.77 (m, 2H), 3.86 (s, 3H), 3.84
(s, 3H), 3.69 (dd, 2H, J = 17.56, 13.59 Hz), 3.56 (dd,
1H, J = 16.0, 1.3 Hz), 3.44 (ddd, 1H, J = 11.8, 4.3,
1.8 Hz), 3.19 (d, 1H, J = 16.05 Hz), 2.94-2.81
(m, 2H), 2.71-2.63 (m, 1H), 2.58 (dd, 1H, J = 11.89,
10.19 Hz); 13C NMR (75 MHz, CDCl3):
165.0,
157.4, 148.1, 147.8, 131.3, 129.2, 127.8, 127.1, 126.3,
125.2, 112.0, 111.7, 107.5, 56.7, 56.1, 55.8, 55.8,
54.8, 48.5, 38.9, 28.1; ESI-MS: m/z 437 [M+H]+;
ESI-HRMS: m/z Calcd for C23H25O5N4: 437.18195
[M+H]+. Found: 437.18097.
KUMAR et al.: FUROXAN DERIVATIVES OF PRAZIQUANTEL
4-(2-Methoxyphenyl)-3-((4-oxo-3,4,6,7-tetrahydro
-1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)
-1,2,5-oxadiazole 2-oxide, 18: Yield 91%. Light
brown solid. m.p.140-42°C; IR (neat): 3015, 2929,
2843, 1642, 1598, 1217, 749 cm−1; 1H NMR (300 MHz,
CDCl3):
7.56-7.49 (m, 2H), 7.19-7.16 (m, 2H),
7.12-7.09 (m, 3H), 6.88-6.85 (m, 1H), 4.70-4.64 (m,
1H), 4.44 (dd, 1H, J = 9.82, 4.5 Hz), 3.86 (s, 3H),
3.75 (dd, 2H, J = 27.1, 14.3 Hz), 3.32 (dd, 1H,
J = 15.8, 1.5 Hz), 3.23 (ddd, 1H, J = 12.0, 4.5, 2.2
Hz), 2.92 (d, 1H, J = 15.8 Hz), 2.82-2.65 (m, 3H),
2.30 (dd, 1H, J = 12.0, 10.5 Hz); 13C NMR (75 MHz,
CDCl3): 165.2, 157.1, 155.8, 134.7, 133.5, 132.8,
130.6, 129.2, 127.1, 126.5, 124.5, 121.2, 115.6, 113.3,
111.2, 56.4, 55.6, 55.6, 55.0, 48.9, 38.6, 28.5;
ESI-MS: m/z 407 [M+H]+; ESI-HRMS: m/z Calcd for
C22H23N4O4: 407.17193 [M+H]+. Found: 407.17077.
3-((9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)4-(2-methoxyphenyl)-1,2,5-oxadiazole 2-oxide, 19:
Yield 92%. Brownish solid. m.p.148-50°C; IR (neat):
3014, 2929, 2843, 1644, 1598, 1217, 768 cm−1; 1H NMR
(300 MHz, CDCl3): 7.57-7.49 (m, 2H), 7.11-7.01
(m, 2H), 6.58 (s, 1H), 6.38 (s, 1H), 4.78-4.71 (m, 1H),
4.45 (dd, 1H, J = 10.5, 5.2 Hz), 3.86 (s, 3H), 3.85
(drs, 6H), 3.74 (dd, 1H, J = 18.8, 14.3 Hz), 3.31 (dd,
1H, J = 15.8, 1.5 Hz), 3.24 (ddd, 1H, J = 12.0, 4.5, 1.5
Hz), 2.92 (d, 1H, J =15.8 Hz), 2.82-2.55 (m, 3H), 2.31
(dd, 1H, J = 12.0 10.57 Hz); 13C NMR (75 MHz,
CDCl3): 165.1, 156.9, 155.8, 147.9, 147.6, 132.7,
130.4, 127.0, 125.1, 121.1, 115.4, 113.2, 111.5, 111.1,
107.6, 56.2, 56.0, 55.8, 55.7, 55.5, 54.8, 48.7, 38.5,
28.0; ESI-MS: m/z 467 [M+H]+; ESI-HRMS: m/z
Calcd for C24H27N4O6: 467.1924 [M+H]+. Found:
467.19214.
4-(4-Methoxyphenyl)-3-((4-oxo-3,4,6,7-tetrahydro 1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)1,2,5-oxadiazole 2-oxide, 20: Yield 92%. Light
yellow solid. m.p.150-52°C; IR (neat): 3004, 2928,
2837, 1646, 1594, 1016, 762 cm−1; 1H NMR (300 MHz,
CDCl3): 7.83 (d, 1H, J = 8.35 Hz), 7.22-7.20 (m,
2H), 7.16-7.14 (m,1H), 7.07-7.04 (m, 1H), 7.02 (d,
1H, J = 8.35 Hz), 4.83 (dd, 1H, J = 9.4, 4.1 Hz),
4.77-4.74 (m, 1H), 3.86 (s, 3H), 3.66 (dd, 2H,
J = 22.9, 13.5 Hz), 3.56 (dd, 1H, J = 15.6, 1.0 Hz),
3.46 (ddd, 1H, J = 12.5, 5.2, 2.0 Hz), 3.17 (d, 1H,
J = 15.6 Hz), 3.89-3.00 (m, 2H), 2.77-2.73 (m, 1H),
2.60 (m, 1H); 13C NMR (75 MHz, CDCl3): 165.1,
161.8, 157.1, 134.7, 133.5, 129.3, 129.2, 127.1, 126.6,
124.5, 118.6, 114.7, 111.9, 56.7, 55.4, 55.3, 55.0,
117
48.6, 38.8, 28.5; ESI-MS: m/z 407 [M+H]+; ESI-HRMS:
m/z Calcd for C22H23N4O4: 407.1719 [M+H]+. Found:
407.1707.
3-((9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro-1H
-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)-4(4-methoxyphenyl)-1,2,5-oxadiazole 2-oxide, 21:
Yield 91%. Light brown solid. m.p.170-72°C; IR
(neat): 3010, 2928, 2838, 1645, 1594, 1014, 749 cm−1;
1
H NMR (300 MHz, CDCl3): 7.82 (d, 1H, J = 9.4
Hz), 7.02 (d, 1H, J = 9.4 Hz), 6.61 (s, 1H), 6.49 (s,
1H), 4.83-4.76 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.82
(s, 3H), 3.66 (dd, 2H, J = 22.9, 13.5 Hz), 3.55 (dd, 1H,
J = 16.7, 1.0 Hz), 3.42 (ddd, 1H, J = 11.4, 4.1, 2.0
Hz), 3.18 (d, 1H, J = 16.7 Hz), 2.94-2.82 (m, 2H),
2.67-2.63 (m, 1H), 2.59 (d, 1H, J = 12.5, 10.4 Hz);
13
C NMR (75 MHz, CDCl3): 165.0, 161.7, 157.0,
147.9, 147.6, 129.2, 126.9, 125.2, 118.4, 114.5, 111.9,
111.5, 107.4, 56.5, 55.9, 55.6, 55.6, 55.2, 54.7, 48.4,
38.8, 28.0; ESI-MS: m/z 467 [M+H]+; ESI-HRMS:
m/z Calcd for C24H27N4O6: 467.1930 [M+H]+. Found:
467.1921.
4-(3-Bromophenyl)-3-((4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)1,2,5-oxadiazole 2-oxide, 22: Yield 94%. White color
solid. m.p.151-53°C; IR (neat): 3016, 2934, 2844,
1643, 1599, 1217, 750 cm−1; 1H NMR (300 MHz,
CDCl3): 8.24-8.23 (m, 1H), 7.88 (dd, 1H, J = 6.7,
1.5 Hz), 7.22-7.68 (m, 1H), 7.42 (t, 1H, J = 8.3 Hz),
7.25-7.16 (m, 3H), 7.13-7.09 (m, 1H), 4.95 (dd, 1H,
J = 10.5, 4.5 Hz), 4.84-4.78 (m, 1H), 3.69 (s, 2H),
3.57 (dd, 1H, J = 15.8, 1.5 Hz), 3.51 (ddd, 1H,
J = 12.0, 4.5, 2.2 Hz), 3.21 (d, 1H, J = 15.8 Hz),
3.05-2.88 (m, 2H), 2.81-2.75 (m, 1H), 2.66 (dd, 1H,
J = 12.0, 9.8 Hz); 13C NMR (75 MHz, CDCl3):
164.8, 155.9, 134.7, 134.0, 133.3, 131.0, 130.7, 129.2,
128.2, 127.1, 126.6, 126.1, 124.5, 123.0, 111.5, 56.2,
55.7, 55.1, 48.7, 38.7, 28.5; ESI-MS: m/z 455
[M+H]+; ESI-HRMS: m/z Calcd for C21H20O3N4Br:
455.07133 [M+H]+. Found: 455.07050.
4-(3-Bromophenyl)-3-((9,10-dimethoxy-4-oxo3,4,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin2(11bH)-yl)methyl)-1,2,5-oxadiazole 2-oxide, 23:
Yield 92%. Light brown solid. m.p.161-63°C;
IR (neat): 3017, 2937, 2837, 1643, 1601, 1217, 743 cm−1;
1
H NMR (300 MHz, CDCl3):
8.23 (brs, 1H),
7.87 (d, 1H, J = 8.3 Hz), 7.70 (d, 1H, J = 8.3 Hz),
7.42 (t, 1H, J = 8.3 Hz), 6.64 (s, 1H), 6.56 (s, 1H),
6.56 (s, 1H), 4.93-4.83 (m, 2H), 3.86 (s, 3H), 3.85 (s,
3H), 3.69 (s, 2H), 3.56 (d, 1H, J = 15.8 Hz), 3.48 (dd,
1H, J = 12.0, 3.0 Hz), 3.22 (d, 1H, J = 15.8 Hz),
118
INDIAN J. CHEM., SEC B, JANUARY 2017
2.93-2.80 (m, 2H), 2.68-2.60 (m, 2H); 13C NMR
(75 MHz, CDCl3):
164.7, 155.9, 147.9, 147.6,
134.0, 131.0, 130.7, 128.2, 127.0, 126.1, 124.9, 123.0,
111.6, 107.4, 56.2, 56.1, 55.9, 55.7, 54.9, 48.7, 38.7,
28.1; ESI-MS: m/z 515 [M+H]+; ESI-HRMS: m/z
Calcd. for C23H24O5N4Br: 515.09246 [M+H]+. Found:
515.09094.
4-(3-Fluorophenyl)-3-((4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)1,2,5-oxadiazole 2-oxide, 24: Yield 91%. White
solid. m.p.145-47°C; IR (neat): 3010, 2931, 2845,
1643, 1599, 1217, 749 cm−1; 1H NMR (300 MHz,
CDCl3):
7.74-7.70 (m, 2H), 7.56-7.48 (m, 1H),
7.31-7.17 (m, 4H), 7.10-7.05 (m, 1H), 4.48 (dd, 1H,
J = 10.0, 4.5 Hz), 4.81-4.74 (m, 1H), 3.69 (dd, 2H,
J = 16.8, 13.7 Hz), 3.58 (dd, 1H, J = 16.0, 1.5 Hz),
3.48 (ddd, 1H, J = 11.8, 6.4, 1.8 Hz), 3.20 (d, 1H,
J = 16.2 Hz), 3.04-2.89 (m, 2H), 2.82-2.74 (m, 1H),
2.64 (dd, 1H, J = 11.8, 10.1 Hz); 13C NMR (75 MHz,
CDCl3): 164.9, 163.8, 161.9, 156.3, 134.8, 133.4,
131.1, 131.1, 129.3, 128.3, 128.3, 127.2, 126.7, 124.5,
123.6, 123.5, 118.5, 118.3, 115.1, 114.9, 111.7, 56.6,
55.6, 55.1, 48.7, 38.9, 28.6; ESI-MS: m/z 395
[M+H]+; ESI-HRMS: m/z Calcd for C21H20O3N4F:
395.15140 [M+H]+. Found: 395.15057.
3-((9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)4-(3-fluorophenyl)-1,2,5-oxadiazole 2-oxide, 25:
Yield 89%. Light brown solid. m.p.154-56°C;
IR (neat): 3019, 1644, 1601, 1474, 1215, 742 cm−1;
1
H NMR (300 MHz, CDCl3): 7.73-7.69 (m, 2H),
7.56-7.49 (m, 1H), 7.31-7.28 (m, 1H), 6.63 (s, 1H),
6.5 (s, 1H), 4.87-4.79 (m, 2H), 3.86 (s, 3H), 3.84 (s,
3H), 3.69 (dd, 2H, J = 15.8, 13.5 Hz), 3.56 (dd, 1H,
J = 15.8, 1.5 Hz), 3.45 (ddd, 1H, J = 12.0, 4.5, 2.2
Hz), 3.20 (d, 1H, J = 15.8 Hz), 2.90-2.81 (m, 2H),
2.71-2.66 (m, 1H), 2.61 (dd, 1H, J = 12.0, 10.5 Hz);
13
C NMR (75 MHz, CDCl3): 165.0, 164.5, 161.2,
156.4, 148.2, 147.8, 131.2, 131.1, 128.4, 128.2, 127.2,
125.1, 123.6, 123.6, 118.6, 118.3, 115.2, 114.9, 111.8,
111.8, 107.5, 56.5, 56.0, 55.9, 54.9, 48.7, 39.0, 28.2,
25.3; ESI-MS: m/z 455 [M+H]+; ESI-HRMS: m/z
Calcd for C23H24O5N4F: 455.1726 [M+H]+. Found:
455.17087.
4-(4-Fluorophenyl)-3-((4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)1,2,5-oxadiazole 2-oxide, 26: Yield 91%. White
solid. m.p.145-47°C; IR (neat): 3007, 2931, 2847,
1644, 1597, 1297, 771 cm−1; 1H NMR (300 MHz,
CDCl3):
7.75-7.71 (m, 2H), 7.56-7.49 (m, 1H),
7.30-7.15 (m, 5H), 7.11-7.06 (m, 1H), 4.88 (dd, 1H,
J = 9.8, 3.7 Hz), 4.81-4.76 (m, 1H), 3.69 (dd, 2H,
J = 16.6, 13.5 Hz), 3.58 (dd, 1H, J = 15.8 Hz, 1.51
Hz), 3.48 (ddd, 1H, J = 12.0, 4.5, 2.2 Hz), 3.21 (d,
1H, J = 15.8 Hz), 3.04-2.89 (m, 2H), 2.82-2.74 (m,
1H), 2.64 (dd, 1H, J = 11.3, 9.8 Hz); 13C NMR (75
MHz, CDCl3): 164.9, 163.8, 161.9, 156.3, 156.3,
134.8, 133.4, 131.1, 131.1, 129.3, 128.3, 128.3, 127.2,
126.7, 124.5, 123.6, 123.5, 118.5, 118.3, 115.1, 114.9,
111.7, 56.6, 55.6, 55.1, 48.7, 38.8, 28.6; ESI-MS: m/z
395 [M+H]+; ESI-HRMS: m/z Calcd for
C21H20O3N4F: 395.15140 [M+H]+. Found: 395.15063.
3-((9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro1H-pyrazino[2,1-a]isoquinolin-2(11bH)-yl)methyl)4-(4-fluorophenyl)-1,2,5-oxadiazole 2-oxide, 27:
Yield 90%. Light brown solid. m.p.161-63°C; IR
(neat): 3009, 2934, 2836, 1645, 1598, 1221, 771 cm−1;
1
H NMR (300 MHz, CDCl3): 7.74-7.69 (m, 2H),
7.57-7.49 (m, 1H), 7.32-7.28 (m, 1H), 6.63 (s, 1H),
6.51 (s, 1H), 4.87-4.80 (m, 2H), 3.86 (s, 3H), 3.85 (s,
3H), 3.69 (dd, 2H, J = 15.8, 13.5 Hz), 3.56 (dd, 1H,
J = 16.6, 1.5 Hz), 3.45 (ddd, 1H, J = 12.0, 4.5, 2.2
Hz), 3.20 (d, 1H, J = 16.6 Hz), 2.94-2.82 (m, 2H),
2.71-2.65 (m, 1H), 2.62 (dd, 1H, J = 8.3, 6.79 Hz);
13
C NMR (75 MHz, CDCl3): 164.8, 163.8, 161.8,
156.3, 148.1, 147.8, 131.1, 131.0, 128.3, 128.2, 127.1,
125.1, 123.5, 123.5, 118.4, 118.2, 115.1, 114.9, 111.7,
107.5, 56.5, 56.0, 55.9, 55.8, 54.8, 48.6, 38.8, 28.1;
ESI-MS: m/z 455 [M+H]+; ESI-HRMS: m/z Calcd for
C23H24O5N4F: 455.17252 [M+H]+. Found: 455.17087.
Conclusions
The widespread use of a single drug (PZQ) for
treatment of schistosomiasis may lead to the
emergence of resistant parasites. Therefore,
identify-cation of antischistosomal drugs other then
PZQ, or to be used in combination with PZQ, are in
high demand. In this work we successfully
synthesized the furoxan derivatives of praziquantel
and evaluated their antischistosomal activity
against adult S. mansoni. Among all the synthesized
compounds, compounds 15 and 18 showed
unequivocal signs of worm damage in vitro, but not
in vivo. This discrepancy can be most likely
explained in terms of host metabolism. Also,
compound 15 showed substantial activity against
immature worms, while PZQ is inactive at this
stage. As the preliminary study on these hybrid
molecules has provided some hints at possible PZQ
modifications leading to activity against immature
parasites, an attempt is being made to synthesize
KUMAR et al.: FUROXAN DERIVATIVES OF PRAZIQUANTEL
additional hybrid molecules that
enhanced antischistosomal activity.
can
show
Supplementary Information
Supplementary information is available in the
website http://nopr.niscair.res.in/handle/123456789/60.
Acknowledgements
The IICT authors thank the Director IICT for
support. SNK and PSS thank CSIR, New Delhi for the
fellowships. VJR acknowledges ORIGIN-CSC-0108
for financial assistance. The authors from ICBN thank
Giuliana Papoff of the Rome lab, for performing
toxicity tests and Giovina Ruberti for logistic support.
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120 cercariae of S. mansoni. On week 6 after infection, mice
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