Synthesis and anticonvulsant activity of certain substituted furochromone, benzofuran and flavone derivatives

Article abstract of DOI:10.1248/cpb.58.1148

Synthesis of furochromone, 2-phenylchromone (flavone) and benzofuran derivatives substituted with thiosemicarbazide or thiazolidin-4-one moieties were accomplished. All the newly synthesized compounds were tested for their anticonvulsant activity in both subcutaneous pentylenetetrazole induced seizures (scPTZ) and maximal electric shock induced seizures (MES) tests using valproic acid and phenytoin respectively as reference standards. The most active compounds in scPTZ model were 1c, 2b, 5a and 7e showing 100% protection at 300 mg/kg upon intraperitoneal administration. Also, the effect of pre-treatment of three of the most active compounds (1c, 2b, 5a) on 4-amino pyridine-induced lethality in mice was investigated. Pre-treatment with these compounds significantly increased the latency for clonic and tonic seizures and prevented 4-amino pyridine induced death. Hence, this provides evidence for anticonvulsant activity of these compounds, and a neuroprotective activity for them. The structure - activity relationship was studied based on the obtained data.

Full text of DOI:10.1248/cpb.58.1148

1148
Regular Article
Chem. Pharm. Bull. 58(9) 1148—1156 (2010)
Vol. 58, No. 9
Synthesis and Anticonvulsant Activity of Certain Substituted
Furochromone, Benzofuran and Flavone Derivatives
Fatma Abdel-Fattah RAGAB, Nehad Aboul Magd EL-SAYED,
Amal Abdel Haleem Mohamed EISSA,* and Ahmed Mahmoud EL KERDAWY
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University; Kasr El-Aini Street, Cairo 11562,
Egypt. Received March 22, 2010; accepted May 13, 2010; published online June 23, 2010
Synthesis of furochromone, 2-phenylchromone (flavone) and benzofuran derivatives substituted with
thiosemicarbazide or thiazolidin-4-one moieties were accomplished. All the newly synthesized compounds were
tested for their anticonvulsant activity in both subcutaneous pentylenetetrazole induced seizures (scPTZ) and
maximal electric shock induced seizures (MES) tests using valproic acid and phenytoin respectively as reference
standards. The most active compounds in scPTZ model were 1c, 2b, 5a and 7e showing 100% protection at
300 mg/kg upon intraperitoneal administration. Also, the effect of pre-treatment of three of the most active com-
pounds (1c, 2b, 5a) on 4-amino pyridine-induced lethality in mice was investigated. Pre-treatment with these
compounds significantly increased the latency for clonic and tonic seizures and prevented 4-amino pyridine in-
duced death. Hence, this provides evidence for anticonvulsant activity of these compounds, and a neuroprotective
activity for them. The structure–activity relationship was studied based on the obtained data.
Key words chromone; flavone; benzofuran; anticonvulsant; neuroprotective activity
Despite the optimal use of the currently available anti-
epileptic drugs, 30 to 40% of the epileptic population fails to
experience seizure control, and others do so only at the ex-
pense of significant toxic effects that range in severity from
minimal brain impairment to death from aplastic anemia or
hepatic failure.1—3) These facts provoked the need for new
anticonvulsant drugs with higher potency and fewer side ef-
fects. Several studies reported that chromone derivatives are
promising anticonvulsant candidates that perform their activ-
ity through a g-aminobutyric acid (GABA)-mediated mecha-
nism.4—17) Likewise, flavones (2-phenylbenzopyrons) are
with a well known positive GABA-modulating ability; their
central activity was attributed to their potential to penetrate
the blood–brain barrier which is strongly correlated to their of the reported phenyl congener 4 synthesized by Dimmock
lipophilicity.18) Semicarbazones and their bioisosteres thio- et al. which showed marked anticonvulsant activity.20) Re-
semicarbazones, have a documented essential role in the placement of the phenyl ring in 4 by the bicyclic benzofuran
design of novel anticonvulsant agents that performing their structure is thought to increase the hydrophobic aryl area
anticonvulsant activity also through a GABA-mediated me- which binds to the binding site and thus may enhance the
chanism.19—41) Extensive structure–activity relationship stud- binding. Moreover, the effect of the hydrophobic group on
ies proposed certain pharmacophoric requirements for (thio)- the terminal amino group of the thiosemicarbazono moiety
semicarbazones interaction at the binding site which are a was studied in the synthesized compounds of series 1, 2 and
hydrophobic binding area represented by aryl or heteroaryl 3.
group and a hydrogen bonding domain represented by the
Due to certain limitations associated with the (thio)semi-
NH–CO(S)–NH system.24—26,33,38) It was suggested that carbazone functionality, mainly the poor solubility and liabil-
(thio)semicarbazones anticonvulsant activity is mediated ity to metabolism45); improvement of the molecule, pharma-
through GABA-mediated mechanism.19,22,29,32,37,41)
cologically and pharmaceutically, was carried out by replace-
In the present investigation the two anticonvulsant candi- ment of the thiosemicarbazono group with thiazolidin-4-one
dates, chromones or flavones and thiosemicarbazones, were ring to give the more constrained cyclic derivatives 5, 6, 7.
amalgamated to obtain more potent anticonvulsants com- Such particular ring (thiazolidin-4-one) was selected, in part,
pounds of series 1 and 2. In the synthesized hybrid com- because of its involvement in molecules that have been re-
pounds the chromone or the furochromone ring acts as the ported previously as anticonvulsant agents46—56); additionally,
hydrophobic aryl ring required for binding which itself pos- being of a similar size and containing atoms that might par-
sesses anticonvulsant tendency. On the other hand, various ticipate in hydrogen bonding like the parent thiosemicar-
bicyclic heterocycles containing thiosemicarbazono group bazone.45) Different substituents at position 3 and position 5
showed significant anticonvulsant activity.33,34,42—44) Herein in the thiazolidine-4-one nucleus were introduced to study
the tricyclic furochromone moiety was simplified to the bi- their effect on the anticonvulsant activity.
cyclic benzofuran system, which was reported to possess an-
ticonvulsant activity42—44) to give compounds of series 3. Ob- Results and Discussion
viously, the compounds of this series are the bicyclic analogs
Chemistry According to Chart 1, synthesis of the start-
∗ To whom correspondence should be addressed. e-mail: phd_amalabdelhaleem@hotmail.com
© 2010 Pharmaceutical Society of Japan

September 2010
1149
Chart 1
ing two benzofuran ketones 9a and 9b the furobenzopyran
aldehyde 10 and the flavone aldehyde 13 was accomplished
from the naturally occurring furochromones Khellin 8a and
Visnagin 8b. Ring opening of the g-pyrone ring with KOH
gave the ketones 9a and 9b according to the reported proce-
dures.57,58) Conversion of 9a to 4,9-dimethoxy-5-oxo-5H-
furo[3,2-g]chromene-6-carbaldehyde 10 was carried out via
Vilsmeier–Haack reaction.59) Subjecting 9b to Claisen
Schmidt condensation with benzaldehyde produced 1-(6-hy-
droxy-4-methoxy-1-benzofuran-5-yl)-3-phenylprop-2-en-1-
one 1160) which by oxidative cyclization with selenium diox-
ide in butanol gave the furoflavone derivative 12.61) Cleavage
of the furan ring of 12 by chromic acid oxidation gave 7-hy-
droxy-5-methoxy-4-oxo-2-phenyl-4H-chromene-6-carbalde-
hyde 13.61) Following Chart 2, reaction of the chosen alkyl or
phenyl thiosemicarbazides with the aldehyde 10 in ethanol at
room temperature gave the thioureas 1a—e and the aldehyde
13 in ethanol with reflux gave the thioureas 2a—e whereas,
reaction of 9a and 9b with the chosen thiosemicarbazides
was carried out in ethanol containing catalytic amount of
acetic acid with refluxing for 72 h yielded 3a—h, these later
drastic conditions could be attributed to the sterically hin-
dered ketones 9a and 9b. Construction of the thiazolidine-4-
one derivatives 5, 6, 7 was carried out by reaction of the
corresponding thiourea derivatives 1, 2, 3 with mono-
chloroacetic acid or maleic anhydride according to Charts 3
and 4.
Chart 2
Pharmacological Activity All the newly synthesized
compounds in addition to five of the starting or intermediate
compounds (methyl thiosemicarbazide, ethyl thiosemicar-
bazide, 9a, 10, 13) were tested for their potential anticonvul-
sant activity using subcutaneous pentylenetetrazole induced
seizures (scPTZ). Maximal electric shock induced seizures
(MES) method was also applied for all the newly prepared
compounds. Furthermore, the neuroprotective activity using
the 4-amino pyridine (4-AP) method was performed on 3 of
the most active compounds after determining their ED50.
Anticonvulsant Activity All the newly synthesized
compounds in addition to methyl and ethyl thiosemicar-
Chart 3

1150
Vol. 58, No. 9
showed 100% protection at a dose of 150 mg/kg body
weight; while all the others (2a and 2c) were inactive. In this
series cyclization of the thiosemicarbazono group (2) to thia-
zolidin-4-one nucleus (6) markedly decreased the activity of
compound 2b to the half (6b showed 50% protection); while
the activity was completely abolished in all the others. Intro-
duction of acetic acid moiety in 5-position of thiazolidin-4-
one nucleus giving 6e abolished the 50% activity that re-
mained for compound 6b.
Benzofuran ring containing derivatives 3a—d showed a
different pattern of activity. The derivative bearing a free
amino group 3a showed 50% protection, the methyl and allyl
ones 3b and 3d also showed the same percent, while the ethyl
3c showed a little bit higher percent of 67; all at 300 mg/kg
body weight only. When the benzofuran was obtained from
khellin (8a); the activity profile switched again; the one with
a free amino group 3e and the ethyl derivative 3g were com-
pletely inactive at any of the doses administered in spite of
the starting compound 9a exhibiting 100% protection at
Chart 4
bazides and compounds 9a, 10, 13-used to furnish the de- 300 mg/kg in scPTZ test. The methyl derivative 3f together
signed hybridized final compounds—were tested for their an- with the allyl 3h, showed 67% protection at 300 mg/kg body
ticonvulsant activity using the scPTZ method. With regard to weight only.
the furochromone derivatives 1a—e in which the thio-
The cyclization of the thiosemicarbazono group to the thi-
semicarbazono group was attached to the 6-position, com- azolidin-4-one 7a—d in the benzofurans originating from
pound 1c showed 100% protection at 300 mg/kg, which is far visnagin (8b) completely abolished the activity except that
more than either of its counterparts. Also, 1e showed 100% carrying the allyl chain which lent some activity to it; 67% at
protection at a dose of 300 mg/kg. In a dose of 150 mg/kg the 300 mg/kg and 17% at 150 mg/kg body weight. On the other
protection percent decreased for both 1c and 1e to 67 and hand, those from khellin (8a) acted very differently; where
83%, which further decreased to 17% and 0% at 75 mg/kg the activity was greatly potentiated, except the allyl congener
body weight respectively (see Table 1). Compound 1b showed 7h, which completely lost the activity it had. Derivative hav-
50% protection at 300 mg/kg which is lower than both ing the unsubstituted thiazolidinone ring 7e, showed the
its separate entities. 1d with an allyl substitution, showed highest activity; 100%, 67% and 17% protection at 300, 150
50% protection at a dose of 300 mg/kg. Compound 1a which and 75 mg/kg body weight respectively. When the thiazolidi-
has a free terminal amino group showed no activity. This none ring was methyl substituted 7f; the activity increased to
means that the presence of a terminal substituted amino 83 and 50% at 300 and 150 mg/kg body weight only; com-
group is essential for activity. From the above results, pres- pared to its open chain congener (3f). The ethyl congener 7g,
ence of the ethyl or phenyl substitution is preferred to methyl acquired mild activity with a 50% protection at 300 mg/kg
or allyl.
body weight; compared to 3g. Introduction of acetic acid
Cyclization of the thiosemicarbazono group (1) to the con- moiety in 5-position of the thiazolidin-4-one nucleus 7i and
strained (thiazolidin-4-one) derivatives (5) retained activity. 7j abolished the activity.
Activity of compounds 5a and 5c; substituted with methyl
The ED50 for compounds 1c, 2b and 5a was obtained and
and allyl increased than the uncyclized giving 100 and 67% they were tested for their neuroprotective activity. They were
protection respectively at 300 mg/kg body weight. The found to significantly increase the latency for clonic and
methyl one 5a even lent 83% at 150 mg/kg and 17% at tonic seizures and prevented neurotoxicity associated with 4-
75 mg/kg body weight, while the allyl was completely devoid amino-pyridine (4-AP) as exemplified in inducing death in
of activity at these doses. On the other hand, the ethyl con- mice.
gener activity was completely abolished as a result of this cy-
clisation. When an acetic acid moiety was introduced in the Conclusion
5-position of the thiazolidine-4-one nucleus 5d; its protection
Generally, in the newly synthesized compounds; the bi-
percentage was decreased from 100 to 67. This may be at- cyclic benzofuran derivatives were less potent than the tri-
tributed to a corruption in the lipophilicity/hydrophilicity cyclic furochromone derivatives indicating the importance of
balance.
the tricyclic structure for activity; despite the results that
7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromene-6- showed that bicyclic 9a from which series 3 and 7 were pre-
carbaldehyde (13) was tested using scPTZ method and pared was the most active (showed 100% protection at
showed 60% protection at 300 mg/kg body weight. Three 300 mg/kg). Following, was 13 leading to series 2 and 6 then
compounds 2b, 2d and 2e of the thiosemicarbazono series 2 finally 10 which gave series 1 and 5 simultaneously.
showed anticonvulsant activity of 100, 83 and 50% protec-
Sodium valproate group showed 100% protection at the
tion, respectively, at a dose of 300 mg/kg body weight. Those used dose, while the phenytoin group showed prolonged
compounds were the methyl (2b), whose percentage protec- clonic phase and abolished tonic phase so animals’ death oc-
tion surpassed both its parts (60 and 20%); the allyl (2d) and curred without showing tonic phase.
phenyl (2e) substituted ones. The methyl derivative 2b still
In the MES test; all the tested compounds were inactive

September 2010
1151
11.17.
showing no protection against the seizures induced even up
to a dose of 300 mg/kg body weight.
N-Allyl-2-((4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methyl-
ene)hydrazinecarbothioamide 1d 76% yield. mp 184—185 °C. 1H-NMR
(CDCl3) d: 2.19 (1H, s, exch. D2O), 4.11 (3H, s), 4.22 (3H, s), 4.3—5.2 (4H,
br m), 5.95—6.20 (1H, m), 7.05 (1H, d, Jϭ2 Hz), 7.67 (1H, d, Jϭ2 Hz), 8.13
(1H, s), 8.43 (1H, s), 9.75 (1H, s, exch. D2O). IR (KBr) cmϪ1: 3470—3300,
1640, 1610, 1580, 1540, 1210. Anal. Calcd for C18H17N3O5S: C, 52.74; H,
4.79; N, 10.25. Found: C, 52.45; H, 4.26; N, 10.60.
2-((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)-N-
phenylhydrazinecarbothioamide 1e 75% yield. mp 169—170 °C. 1H-
NMR (DMSO-d6) d: 4.01 (3H, s), 4.13 (3H, s), 7.29—7.44 (5H, m), 7.63
(1H, d, Jϭ2 Hz), 8.16 (1H, d, Jϭ2 Hz), 8.30 (1H, s), 9.27 (1H, s), 10.09 (1H,
s, exch. D2O), 11.97 (1H, s, exch. D2O). IR (KBr) cmϪ1: 3300—3100, 1655,
1600, 1580, 1560, 1210. MS m/z: 421 (MϩϪ2) (Calcd for C21H17N3O5S:
423.44). Anal. Calcd for C21H17N3O5S: C, 59.57; H, 4.05; N, 9.92. Found: C,
As a conclusion; five compounds belonging to the differ-
ent synthesized series 1c, 1e, 2b, 5a and 7e showed 100%
protection at a dose of 300 mg/kg in scPTZ test.
Compounds 1c, 2b, 5a were found to counteract the harm-
ful effect of 4-AP. This provides evidence for the anticonvul-
sant activity of these compounds and indicates a neuropro-
tective activity for them.
Experimental
Chemistry All melting points are uncorrected and determined by open
capillary method using ‘Electrothermal capillary melting point apparatus
9100.’ Infrared spectra (IR) were recorded as KBr discs using ‘Schimadzu 59.79; H, 4.00; N, 9.91.
435 IR spectrophotometer.’ Proton magnetic resonance (1H-NMR) spectra
were carried out using ‘Varian Mercury VX-300 NMR spectrophotometer
300 MHz,’ ‘Varian Gemini 200 MHz’ and ‘Jeol FX 90 Q 90 MHz FT spec-
2-((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
ene)hydrazinecarbothioamide 2a. 2-((7-Hydroxy-5-methoxy-4-oxo-2-
phenyl-4H-chromen-6-yl)methylene)-N-substituted Hydrazinecarbo-
trophotometer’ using tetramethylsilane (TMS) as internal standard. Chemi- thioamides 2b—e 7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromene-
cal shift values were recorded in ppm on d scale. Mass spectra were carried 6-carbaldehyde 13 (1 g, 3.4 mmol) and the appropriate thiosemicarbazide
out on ‘Finnigan Mat SSQ-7000 mass spectrophotometer 70 eV.’ Elemental
(3.5 mmol) were refluxed in absolute ethanol (20 ml) for 16 h. The yellow
analyses were carried out at the Micro Analytical Center, Faculty of Science, product 2a—e was filtered while hot, washed with hot ethanol, left to dry
Cairo University; the found values were within the theoretical ones range, and recrystallized from the suitable solvent.
unless otherwise indicated. Thin layer chromatography (TLC) was carried
out using ‘Silica gel/TLC-card DC-Alufolien-Kieselgel F254 (Fluka
60778),’ the developing solvent systems used were CCl4 : CH3OH (9 : 1) or
CCl4 : CH3OH (7 : 3), visualization was performed by illumination with UV
light source (254 nm).
2-((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
ene)hydrazinecarbothioamide 2a 85% yield. mp Ͼ350 °C. Crystalliza-
tion solvent: DMSO/H2O. 1H-NMR: (DMSO-d6) d: 3.39 (1H, s, exch. D2O),
3.84 (3H, s), 6.81 (1H, s), 7.01 (1H, s), 7.58 (3H, m), 7.95—8.30 (4H, m,
exch. D2O), 8.61 (1H, s), 11.50 (1H, br s, exch. D2O). IR (KBr) cmϪ1: 3450,
Compounds throughout this work were chemically named according to 3375, 3250, 3175, 1640, 1620, 1580, 1530, 1215. MS m/z: 369.40 (Mϩ)
the IUPAC system using ‘Chemdraw ultra software V.10 Cambridgesoft®.’
1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethanone 9a. 1-(6-Hy- H, 4.09; N, 11.38. Found: C, 58.78; H, 4.20; N, 11.37.
(Calcd for C18H15N3O4S: 369.39). Anal. Calcd for C18H15N3O4S: C, 58.53;
droxy-4-methoxy-1-benzofuran-5-yl)ethanone 9b Previously report-
2-((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
ene)-N-methylhydrazinecarbothioamide 2b 80% yield. mp 205—
ed.57,58)
4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde 10 206 °C. Crystallization solvent: DMF/H2O. 1H-NMR (DMSO-d6) d: 3.00
Previously reported.59)
1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)-3-phenylprop-2-en-1-one 8.42 (1H, s, exch. D2O), 8.62 (1H, br s), 10.85 (1H, s, exch. D2O), 11.53
11 Previously reported.60)
(1H, s, exch. D2O). IR (KBr) cmϪ1: 3450 (br), 3250, 1630, 1600, 1560,
4-Methoxy-7-phenyl-5H-furo[3,2-g]chromen-5-one 12 Previously re- 1500, 1230. MS m/z: 383 (Mϩ), 384.15 (Mϩϩ1) (Calcd for C19H17N3O4S:
ported.61)
383.42). Anal. Calcd for C19H17N3O4S: C, 59.52; H, 4.47; N, 10.96. Found:
7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromene-6-carbaldehyde C, 59.35; H, 4.64; N, 10.88.
13 Previously reported.61)
N-Ethyl-2-((7-hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-
(3H, s), 3.84 (3H, s), 6.81 (1H, s), 7.03 (1H, s), 7.58 (3H, m), 8.05 (2H, m),
2-((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)hy- yl)methylene)hydrazinecarbothioamide 2c 75% yield. mp 316—317 °C.
drazinecarbothioamide 1a. 2-((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]- Crystallization solvent: DMF/H2O. 1H-NMR (DMSO-d6) d: 1.16 (3H, t),
chromen-6-yl)methylene)-N-substituted Hydrazinecarbothioamides 1b—
4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde 10 (1 g,
3.58 (2H, m), 3.85 (3H, s), 6.78 (1H, s), 6.99 (1H, s), 7.57 (3H, m), 8.03
(2H, m), 8.41 (1H, s, exch. D2O), 8.60 (1H, br s), 11.00 (1H, s, exch. D2O),
11.44 (1H, s, exch. D2O). IR (KBr) cmϪ1: 3450, 3250, 1630, 1600, 1550,
e
3.65 mmol) and the appropriate thiosemicarbazide (3.65 mmol) in absolute
ethanol (25 ml) were stirred at room temperature for 24 h and the obtained 1500, 1220. MS m/z: 397 (Mϩ), 398 (Mϩϩ1) (Calcd for C20H19N3O4S:
yellow precipitate (1a—e) was filtered, washed well with hot water, dried 397.45). Anal. Calcd for C20H19N3O4S: C, 60.44; H, 4.82; N, 10.57. Found:
and recrystallized from N,N-dimethylformamide (DMF)/H2O.
C, 60.22; H, 5.14; N, 10.26.
2-((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)hy-
N-Allyl-2-((7-hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-
drazinecarbothioamide 1a 68% yield. mp 203—204 °C. 1H-NMR yl)methylene)hydrazinecarbothioamide 2d 80% yield. mp Ͼ350 °C.
(DMSO-d6) d: 3.96 (3H, s), 4.10 (3H, s), 7.24 (1H, d, Jϭ2 Hz), 8.01, 8.20 Crystallization solvent: DMF/H2O. IR (KBr) cmϪ1: 3450 (br), 3250, 1630,
(2H, 2s, exch. D2O), 8.10 (1H, d, Jϭ2 Hz), 8.16 (1H, s), 9.01 (1H, s), 11.52 1600, 1560, 1540, 1500, 1220. MS m/z: 409 (Mϩ), 410 (Mϩϩ1) (Calcd for
(1H, s, exch. D2O). IR (KBr) cmϪ1: 3550, 3350, 3150, 1640, 1600, 1580,
1560, 1240. MS m/z: 347(Mϩ) (Calcd for C15H13N3O5S: 347.34). Anal.
Calcd for C15H13N3O5S: C, 51.87; H, 3.77; N, 12.10. Found: C, 51.65; H,
4.01; N, 11.80.
C21H19N3O4S: 409.47). Anal. Calcd for C21H19N3O4S: C, 61.60; H, 4.68; N,
10.26. Found: C, 61.63; H, 5.00; N, 9.96.
2-((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
ene)-N-phenylhydrazinecarbothioamide 2e 80% yield. mp Ͼ350 °C.
2-((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)-N- Crystallization solvent: DMSO/H2O. IR (KBr) cmϪ1: 3450 (br), 3150, 1650,
methylhydrazinecarbothioamide 1b 70% yield. mp 201—202 °C. 1H- 1620, 1580, 1560—1540, 1210. MS m/z: 445.15 (Mϩ) (Calcd for
NMR (DMSO-d6) d: 3.03 (3H, d), 3.99 (3H, s), 4.13 (3H, s), 7.27 (1H, d, C24H19N3O4S: 445.49). Anal. Calcd for C24H19N3O4S: C, 64.71; H, 4.30; N,
Jϭ1 Hz), 8.13 (1H, d, Jϭ1 Hz), 8.15 (1H, s), 8.52 (1H, s, exch. D2O), 9.02 9.43. Found: C, 64.53; H, 4.15; N, 9.44.
(1H, s), 11.61 (1H, s, exch. D2O). IR (KBr) cmϪ1: 3375—3200, 1640, 1620,
2-(1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hy-
1590, 1580, 1210. MS m/z: 360.90 (Mϩ), 361.90 (Mϩϩ1) (Calcd for drazinecarbothioamide 3a. 2-(1-(6-Hydroxy-4-methoxy-1-benzofuran-5-
C16H15N3O5S: 361.37). Anal. Calcd for C16H15N3O5S: C, 53.18; H, 4.18; N, yl)ethylidene)-N-substituted Hydrazinecarbothioamides 3b—d. 2-(1-(6-
11.63. Found: C, 53.30; H, 4.30; N, 11.55.
Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)hydrazinecar-
2-((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)-N- bothioamide 3e. 2-(1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)eth-
ethylhydrazinecarbothioamide 1c 77% yield. mp 189—190 °C. 1H-NMR ylidene)-N-substituted Hydrazinecarbothioamides 3f—h A mixture of
(CDCl3) d: 1.32 (3H, t, Jϭ7.2 Hz), 3.75—3.97 (2H, m, Jϭ7.2 Hz), 4.10
9a or 9b (3 mmol) and the appropriate thiosemicarbazide (9 mmol) in ab-
(3H, s), 4.23 (3H, s), 7.06 (1H, d, Jϭ2 Hz), 7.27 (1H, s, exch. D2O), 7.68 solute ethanol (20 ml) and glacial acetic acid (2 ml) was refluxed for 72 h.
(1H, d, Jϭ2 Hz), 8.03 (1H, s), 8.43 (1H, s), 8.99 (1H, s, exch. D2O). IR The reaction solution was concentrated and poured onto ice-water (20 ml).
(KBr) cmϪ1: 3350—3250, 1650, 1620, 1580, 1560, 1210. MS m/z: 375 The precipitate 3a—h was collected, washed with hot water, dried, and then
(Mϩ), 376 (Mϩϩ1) (Calcd for C17H17N3O5S: 375.400). Anal. Calcd for it was washed with carbon tetrachloride, dried and recrystallized from
C17H17N3O5S: C, 54.39; H, 4.56; N, 11.19. Found: C, 54.58; H, 4.60; N, methanol.

1152
2-(1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hy-
Vol. 58, No. 9
2-(((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)hy-
drazinecarbothioamide 3a 60% yield. mp 196—198 °C. 1H-NMR: drazono)-3-methyl-1,3-thiazolidin-4-one 5a 62% yield. mp 289—
(CDCl3) d: 2.25 (3H, s), 4.12 (3H, s), 6.21 (2H, s, exch. D2O), 6.75 (1H, s),
290 °C. 1H-NMR (DMSO-d6) d: 3.23 (3H, s), 4.01 (2H, s), 4.06 (s, 3H),
6.87 (1H, d, Jϭ1.8 Hz), 7.48 (1H, d, Jϭ1.8 Hz), 8.44, 8.78 (2H, 2s, exch. 4.19 (s, 3H), 7.33 (1H, d, Jϭ2 Hz), 8.18 (1H, d, Jϭ2 Hz), 8.52 (1H, s), 8.75
D2O). IR (KBr) cmϪ1: 3400, 3300, 3150, 1620, 1580, 1540—1500, 1205. (1H, s). IR (KBr) cmϪ1: 1720, 1655, 1610, 1540. MS m/z: 400.90 (Mϩ),
MS m/z: 279(Mϩ), 280 (Mϩϩ1) (Calcd for C12H13N3O3S: 279.31). Anal.
401.9 (Mϩϩ1) (Calcd for C18H15N3O6S: 401.4). Anal. Calcd for
Calcd for C12H13N3O3S: C, 51.60; H, 4.69; N, 15.04. Found: C, 51.43; H, C18H15N3O6S: C, 53.86; H, 3.77; N, 10.47. Found: C, 54.00; H, 3.90; N,
5.07; N, 14.75.
10.35.
2-(((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)hy-
2-(1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)-N-methyl-
hydrazinecarbothioamide 3b 64% yield. mp 185—187 °C. 1H-NMR drazono)-3-ethyl-1,3-thiazolidin-4-one 5b 75% yield. mp 244—245 °C.
(CDCl3) d: 2.21 (3H, s), 3.19 (3H, d), 4.08 (3H, s), 6.72 (1H, s), 6.82 (1H, d, 1H-NMR (CDCl3) d: 1.31 (3H, t, Jϭ7 Hz), 3.80 (2H, s), 3.92 (2H, q,
Jϭ1.8 Hz), 7.64 (1H, d, Jϭ1.8 Hz), 8.18, 8.43, 8.75 (3s, 3H, exch. D2O); IR Jϭ7 Hz), 4.11 (s, 3H), 4.26 (s, 3H), 7.08 (1H, d, Jϭ2 Hz), 7.70 (1H, d,
(KBr) cmϪ1: 3350, 3200, 1620, 1600, 1540, 1250. MS m/z: 293 (Mϩ), 294 Jϭ2 Hz), 8.66 (1H, s), 8.73 (1H, s). IR (KBr) cmϪ1: 1710, 1655, 1610, 1560.
(Mϩϩ1) (Calcd for C13H15N3O3S: 293.34). Anal. Calcd for C13H15N3O3S: C,
53.23; H, 5.15; N, 14.32. Found: C, 53.22; H, 5.22; N, 14.09.
MS m/z: 414.90 (Mϩ), 415.9 (Mϩϩ1) (Calcd for C19H17N3O6S: 415.4).
Anal. Calcd for C19H17N3O6S: C, 54.94; H, 4.12; N, 10.12. Found: C, 54.70;
N-Ethyl-2-(1-(6-hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hy- H, 4.30; N, 9.95.
drazinecarbothioamide 3c 58% yield. mp 178—179 °C. 1H-NMR:
3-Allyl-2-(((4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methyl-
(CDCl3) d: 1.26 (3H, t, Jϭ7.4 Hz), 2.21 (3H, s), 3.63—3.76 (2H, m, ene)hydrazono)-1,3-thiazolidin-4-one 5c 70% yield. mp 247—248 °C.
Jϭ7.4 Hz), 4.06 (3H, s), 6.72 (1H, s), 6.82 (1H, d, Jϭ1.8 Hz), 7.38 (1H, d,
1H-NMR (DMSO-d6) d: 4.04 (2H, s), 4.00 (s, 3H), 4.15 (s, 3H), 4.34 (2H, d,
Jϭ1.8 Hz), 7.61, 8.40, 8.90 (3H, 3s, exch. D2O); IR (KBr) cmϪ1: 3350, Jϭ5 Hz), 5.23 (2H, d, Jϭ5 Hz), 5.80—6.00 (1H, m), 7.30 (1H, d, Jϭ2 Hz),
3300, 3100, 1620, 1590, 1550, 1210. MS m/z: 307 (Mϩ), 308 (Mϩϩ1) 8.16 (1H, d, Jϭ2 Hz), 8.45 (1H, s), 8.72 (1H, s). IR (KBr) cmϪ1: 1720,
(Calcd for C14H17N3O3S: 307.38). Anal. Calcd for C14H17N3O3S: C, 54.71; 1655, 1610, 1560. MS m/z: 427.15 (Mϩ), 428.15 (Mϩϩ1) (Calcd for
H, 5.57; N, 13.67. Found: C, 55.60; H, 5.16; N, 13.85. C20H17N3O6S: 427.44). Anal. Calcd for C20H17N3O6S: C, 56.20; H, 4.01; N,
N-Allyl-2-(1-(6-hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hy- 9.83. Found: C, 55.96; H, 4.12; N, 9.60.
drazinecarbothioamide 3d 65% yield. mp 161—163 °C. 1H-NMR
2-(2-(((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)-
(CDCl3) d: 2.22 (3H, s), 4.08 (3H, s), 4.27 (1H, s, exch. D2O), 4.33—5.37 hydrazono)-3-methyl-4-oxo-1,3-thiazolidin-5-yl)acetic acid 5d To a
(4H, m (br), 5.90—6.20 (1H, m), 6.69 (1H, s), 6.83 (1H, d, Jϭ2.2 Hz), 7.40
stirred solution of compound 1b (0.5 g, 1 mmol) in glacial acetic acid
(1H, d, Jϭ2.2 Hz), 7.60 (1H, br s, exch. D2O), 8.49 (1H, s, exch. D2O). IR (10 ml), maleic anhydride (0.1 g, 1.1 mmol) was added. The reaction mixture
(KBr) cmϪ1: 3300, 3150, 1620, 1600, 1540, 1210. MS m/z: 319 (Mϩ), 320 was heated under reflux with stirring for 12 h. After cooling, the formed pre-
(Mϩϩ1) (Calcd for C15H17N3O3S: 319.39). Anal. Calcd for C15H17N3O3S: C,
56.41; H, 5.37; N, 13.16. Found: C, 56.37; H, 5.17; N, 13.41.
2-(1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)hy-
cipitate was filtered and dried to yield 5d (0.32 g, 50%) which was recrystal-
lized from DMF/H2O.
50% yield. mp 268—269 °C. H-NMR (DMSO-d6) d: 2.95 (2H, d,), 3.31
1
drazinecarbothioamide 3e 70% yield. mp 192—194 °C. 1H-NMR (3H, s), 3.99 (s, 3H), 4.12 (s, 3H), 4.41 (1H, t), 7.29 (1H, d, Jϭ2 Hz), 7.68
(CDCl3) d: 2.27 (3H, s), 4.01 (3H, s), 4.14 (3H, s), 6.28 (2H, br s, exch. (1H, d, Jϭ2 Hz), 8.47 (1H, s), 8.72 (1H, s), 12.50 (1H, br s, exch. D2O);
D2O), 6.90 (1H, d, Jϭ2.4 Hz), 7.30 (1H, br s, exch. D2O), 7.54 (1H, d, IR (KBr) cmϪ1: 3300—2800, 1725 br, 1650, 1620, 1570. MS m/z: 459
Jϭ2.4 Hz), 8.5 (1H, br s, exch. D2O). IR (KBr) cmϪ1: 3400, 3250, 3150,
(Mϩ), 460 (Mϩϩ1) (Calcd for C20H17N3O8S: 459.43). Anal. Calcd for
1620, 1600, 1560, 1200. MS m/z: 309 (Mϩ), 310 (Mϩϩ1) (Calcd for C20H17N3O8S: C, 52.29; H, 3.73; N, 9.15. Found: C, 52.54; H, 3.87; N, 9.08.
C13H15N3O4S: 309.34). Anal. Calcd for C13H15N3O4S: C, 50.48; H, 4.89; N,
13.58. Found: C, 50.30; H, 5.00; N, 13.63.
2-(((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
ene)hydrazono)-1,3-thiazolidin-4-one 6a Compound 2a (1 g, 2.5 mmol)
2-(1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)-N- was dissolved in the least amount of dimethyl sulphoxide (12 ml). Anhy-
methylhydrazinecarbothioamide 3f 73% yield. mp 213—215 °C. 1H-
drous sodium acetate (0.21 g, 2.6 mmol) and monochloroacetic acid (0.25 g,
NMR (CDCl3) d: 2.24 (3H, s), 3.20 (3H, d), 3.98 (s, 3H), 4.10 (s, 3H), 6.16 2.6 mmol) were added and the reaction mixture was heated with stirring for
(1H, br s, exch. D2O), 6.86 (1H, d, Jϭ2.2 Hz), 7.91 (1H, d, Jϭ2.2 Hz), 7.81
8 h in boiling water bath. The produced yellow precipitate 6a was filtered,
(1H, s, exch. D2O), 8.47 (1H, br s, exch. D2O). IR (cmϪ1): 3350, 3250 (NHs, dried and recrystallized from dimethyl sulfoxide (DMSO)/H2O.
1
OH), 1610, 1560, 1510—1480 (CϭN, NH, CϭC), 1230 (CϭS). MS m/z:
70% yield. mp 321—323 °C. H-NMR (DMSO-d6) d: 3.89 (3H, s), 4.02
323 (Mϩ), 324.15 (Mϩϩ1) (Calcd for C14H17N3O4S: 323.37). Anal. Calcd
(2H, s), 6.82 (1H, s), 7.03 (1H, s), 7.55 (3H, m), 8.03 (2H, m), 8.74 (1H, s),
for C13H15N3O4S: C, 52.00; H, 5.30; N, 12.99. Found: C, 51.67; H, 5.04; N, 12.32 (2H, br s, exch. D2O). IR (KBr) cmϪ1: 3450—3350 (br), 1720, 1640,
12.83.
1610, 1560, 1540. MS m/z: 409 (Mϩ), 410 (Mϩϩ1) (Calcd for
N-Ethyl-2-(1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethyl- C20H15N3O5S: 409.41). Anal. Calcd for C20H15N3O5S: C, 58.67; H, 3.69; N,
idene)hydrazinecarbothioamide 3g 60% yield. mp 218—220 °C. 1H-
NMR (CDCl3) d: 1.12 (3H, t, Jϭ7.5 Hz), 2.17 (3H, s), 5.51—3.56 (2H, m,
10.26. Found: C, 58.41; H, 4.02; N, 9.95.
2-(((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
Jϭ7.5 Hz), 3.92 (s, 3H), 3.95 (s, 3H), 7.16 (1H, d, Jϭ2.4 Hz), 7.89 (1H, d, ene)hydrazono)-3-substituted-1,3-thiazolidin-4-ones 6b—d To a solu-
Jϭ2.4 Hz), 8.32 (1H, br s, exch. D2O), 8.43 (1H, s, exch. D2O), 9.51 (1H,
tion of the chosen thiourea derivative 2b—d (2.5 mmol) in glacial acetic
acid (15 ml), anhydrous sodium acetate (0.21 g, 2.6 mmol) and mono-
br s, exch. D2O). IR (KBr) cmϪ1: 3350, 3250, 1610, 1540, 1510—1480,
1210. MS m/z: 337 (Mϩ), 338 (Mϩϩ1) (Calcd for C15H19N3O4S: 337.39). chloroacetic acid (0.25 g, 2.6 mmol) were added. The reaction mixture was
Anal. Calcd for C15H19N3O4S: C, 53.40; H, 5.68; N, 12.45. Found: C, 53.78; heated under reflux with stirring for 8 h; the obtained yellow precipitate
H, 5.84; N, 11.98.
6b—d was collected, dried and recrystallized from DMF/H2O.
N-Allyl-2-(1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethyl-
2-(((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)methyl-
ene)hydrazono)3-methyl-1,3-thiazolidin-4-one 6b 75% yield. mp 340—
idene)hydrazinecarbothioamide 3h 75% yield. mp 162—163 °C. 1H-
NMR (CDCl3) d: 2.25 (3H, s), 3.99 (s, 3H), 4.04 (s, 3H), 4.27 (1H, s, exch. 341 °C. IR (KBr) cmϪ1: 3425, 1730, 1650, 1610, 1560. MS m/z: 423 (Mϩ),
D2O), 4.32—5.37 (4H, br m), 5.90—6.20 (1H, m), 6.49 (1H, br s, exch. 424 (Mϩϩ1) (Calcd for C21H17N3O5S: 423.45). Anal. Calcd for
D2O), 6.87 (1H, d, Jϭ2.24 Hz), 7.46 (1H, d, Jϭ2.24 Hz), 8.61 (1H, br s,
exch. D2O). IR (KBr) cmϪ1: 3300, 3250, 1610, 1580, 1560, 1210. MS m/z:
C21H17N3O5S: C, 59.57; H, 4.05; N, 9.92. Found: C, 59.86; H, 4.05; N, 9.60.
3-Ethyl-2-(((7-hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-
349 (Mϩ), 350 (Mϩϩ1) (Calcd for C16H19N3O4S: 349.42). Anal. Calcd for yl)methylene)hydrazono)-1,3-thiazolidin-4-one 6c 78% yield. mp 315—
C16H19N3O4S: C, 55.00; H, 5.48; N, 12.03. Found: C, 54.91; H, 5.33; N, 316 °C. 1H-NMR (DMSO-d6) d: 1.21 (3H, t), 3.79 (2H, m), 3.92 (3H, s),
12.22.
2-(((4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)hy- (1H, s), 12.32 (1H, br s, exch. D2O). IR (KBr) cmϪ1: 3450 (br), 1720, 1650,
drazono)-3-substituted-1,3-thiazolidin-4-ones 5a—c A mixture of the
1610, 1550—1490. MS m/z: 437.15 (Mϩ), 438.15 (Mϩϩ1) (Calcd for
appropriate thiourea derivative 1b—d (2.5 mmol), anhydrous sodium acetate C22H19N3O5S: 437.47). Anal. Calcd for C22H19N3O5S: C, 60.40; H, 4.38; N,
4.06 (2H, s), 6.81 (1H, s), 7.02 (1H, s), 7.57 (3H, m), 8.03 (2H, m), 8.84
(0.21 g, 2.6 mmol) and monochloroacetic acid (0.25 g, 2.6 mmol) in glacial
acetic acid (15 ml) was refluxed for 16 h with stirring; the reaction mixture
9.61. Found: C, 60.68; H, 4.43; N, 9.40.
3-Allyl-2-(((7-hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-
was then cooled and poured on ice. The obtained precipitate 5a—c was col- yl)methylene)hydrazono)-1,3-thiazolidin-4-one 6d 75% yield. mp 277—
lected by filtration, washed with water, dried and recrystallized from 278 °C. 1H-NMR (DMSO-d6) d: 3.93 (3H, s), 4.16 (2H, s), 4.37 (d, 2H,
DMF/H2O.
Jϭ5 Hz), 5.23 (2H, d, Jϭ5 Hz), 5.85—5.94 (1H, m), 6.84 (1H, s), 7.06 (1H,

September 2010
1153
1H-NMR (CDCl3) d: 1.33 (3H, t, Jϭ7 Hz), 2.66 (3H, s), 3.85 (2H, s), 3.94—
3.99 (2H, m, Jϭ7 Hz), 4.00 (s, 3H), 4.10 (s, 3H), 6.85 (1H, d, Jϭ2.2 Hz),
7.50 (1H, d, Jϭ2.2 Hz), 12.00 (1H, br s, exch. D2O). IR (KBr) cmϪ1: 3350,
1700, 1600, 1540, 1510, 1480. MS m/z: 377 (Mϩ), 378 (Mϩϩ1) (Calcd for
C17H19N3O5S: 377.41). Anal. Calcd for C17H19N3O5S: C, 52.84; H, 5.22; N,
10.87. Found: C, 52.30; H, 4.99; N, 10.88.
s), 7.59 (3H, m), 8.06 (2H, m), 8.82 (1H, s), 12.29 (1H, br s, exch. D2O); IR
(KBr) cmϪ1: 3475, 1720, 1650, 1610, 1560. MS m/z: 449.15 (Mϩ) (Calcd
for C23H19N3O5S: 449.48). Anal. Calcd for C23H19N3O5S: C, 61.46; H, 4.26;
N, 9.35. Found: C, 61.80; H, 4.64; N, 8.78.
2-(2-(((7-Hydroxy-5-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)meth-
ylene)hydrazono)-3-methyl-4-oxo-1,3-thiazolidin-5-yl)acetic Acid 6e
A
mixture of 2b (0.77 g, 2 mmol) and maleic anhydride (0.2 g, 2.2 mmol) in
glacial acetic acid (10 ml) was refluxed with stirring for 12 h. The reaction
mixture was cooled and the resulted precipitate was filtered, left to dry to
give 0.6 g of 6e which was recrystallized from DMF/H2O.
3-Allyl-2-((1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethyl-
idene)hydrazono)-1,3-thiazolidin-4-one 7h 68% yield. mp 132—134 °C.
1H-NMR (CDCl3) d: 2.62 (3H, s), 3.85 (2H, s), 3.98 (s, 3H), 4.08 (s, 3H),
4.43—5.40 (4H, br m), 5.90—6.20 (1H, m), 6.84 (1H, s), 7.49 (1H, s), 11.90
(1H, br s, exch. D2O). IR (KBr) cmϪ1: 3450 (br), 1720, 1580, 1520, 1480.
MS m/z: 389 (Mϩ), 390 (Mϩϩ1) (Calcd for C18H19N3O5S: 389.42). Anal.
Calcd for C18H19N3O5S: C, 55.52; H, 4.92; N, 10.79. Found: C, 55.51; H,
4.88; N, 10.56.
2-(2-((1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-3-methyl-4-oxo-1,3-thiazolidin-5-yl)acetic Acid 7i. 2-(2-((1-(6-Hy-
droxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)hydrazono)-3-
methyl-4-oxo-1,3-thiazolidin-5-yl)acetic Acid 7j To a solution of the ap-
propriate thiourea derivative 3b or 3f (1.7 mmol) in glacial acetic acid
(10 ml), maleic anhydride (0.16 g, 1.8 mmol) was added and the mixture was
refluxed with stirring for 16 h. The reaction solution was concentrated,
poured onto ice-water; the produced precipitate 7i, 7j was collected, left to
dry and then recrystallized from methanol.
2-(2-((1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-3-methyl-4-oxo-1,3-thiazolidin-5-yl)acetic Acid 7i 50% yield. mp
179—180 °C. 1H-NMR (CDCl3) d: 2.63 (3H, s), 2.88—3.01 (2H, d), 3.36
(3H, s), 4.09 (3H, s), 4.36 (1H, t), 6.83 (2H, d), 7.44 (1H, d), 7.60—8.40
(2H, br s, exch. D2O). IR (KBr) cmϪ1: 3450 (br), 1730, 1690, 1630, 1600,
1550. MS m/z: 391 (Mϩ), 392 (Mϩϩ1) (Calcd for C17H17N3O6S: 391.40).
Anal. Calcd for C17H17N3O6S: C, 52.17; H, 4.38; N, 10.74. Found: C, 52.23;
H, 4.12; N, 10.63.
2-(2-((1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)hy-
drazono)-3-methyl-4-oxo-1,3-thiazolidin-5-yl)acetic Acid 7j 55% yield.
mp 144—146 °C. 1H-NMR (CDCl3) d: 2.64 (3H, s), 2.87—3.01 (2H, d),
3.36 (3H, s), 3.98 (s, 3H), 4.08 (s, 3H), 4.38 (1H, t), 4.99—5.17 (2H, br s,
exch. D2O), 6.84 (1H, d), 7.49 (1H, d). IR (KBr) cmϪ1: 3550, 3450, 1700 br,
1600, 1560. MS m/z: 421 (Mϩ), 422 (Mϩϩ1) (Calcd for C18H19N3O7S:
421.42). Anal. Calcd for C17H17N3O6S. H2O: C, 49.20; H, 4.82; N, 9.56.
Found: C, 49.17; H, 5.11; N, 9.70.
1
60% yield. mp 294—295 °C. H-NMR (DMSO-d6) d: 3.00 (2H, d), 3.18
(3H, s), 3.39 (1H, br s, exch. D2O), 3.91 (3H, s), 4.53 (1H, t), 6.82 (1H, s),
7.00 (1H, s), 7.48—7.57 (3H, m), 8.03 (2H, br m), 8.81 (1H, s), 12.27 (1H,
br s, exch. D2O). IR (KBr) cmϪ1: 3425, 3300—2800, 1725 br, 1640, 1610,
1555. MS m/z: 481 (Mϩ) 482 (Mϩϩ1) (Calcd for C23H19N3O7S: 481.47).
Anal. Calcd for C23H19N3O7S: C, 57.37; H, 3.98; N, 8.73. Found: C, 57.52;
H, 4.07; N, 8.38.
2-((1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-1,3-thiazolidin-4-one 7a. 2-((1-(6-Hydroxy-4-methoxy-1-benzofu-
ran-5-yl)ethylidene)hydrazono)-3-substituted-1,3-thiazolidin-4-ones
7b—d. 2-((1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)-
hydrazono)-1,3-thiazolidin-4-one 7e. 2-((1-(6-Hydroxy-4,7-dimethoxy-1-
benzofuran-5-yl)ethylidene)hydrazono)-3-substituted-1,3-thiazolidin-4-
ones 7f—h A mixture comprised of the appropriate thiourea derivative
3a—h (2.5 mmol), anhydrous sodium acetate (0.21 g, 2.6 mmol) and mono-
chloroacetic acid (0.25 g, 2.6 mmol) in absolute ethanol (20 ml) and glacial
acetic acid (2 ml) was refluxed for 16 h with stirring. Then it was concen-
trated and poured onto crushed ice. The formed precipitate 7a—h was fil-
tered, washed with water, dried and recrystallized from methanol.
2-((1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-1,3-thiazolidin-4-one 7a 65% yield. mp 223—225 °C. 1H-NMR
(DMSO-d6) d: 2.31 (3H, s), 3.87 (2H, s), 3.99 (3H, s), 6.77 (1H, s), 7.06
(1H, d, Jϭ2.2 Hz), 7.77 (1H, d, Jϭ2.2 Hz), 10.47 (1H, s, exch. D2O), 11.91
(1H, s, exch. D2O). IR (KBr) cmϪ1: 3500 (br), 1720, 1620, 1560, 1550. MS
m/z: 319 (Mϩ), 320 (Mϩϩ1) (Calcd for C14H13N3O4S: 319.34). Anal. Calcd
for C14H13N3O4S: C, 52.66; H, 4.10; N, 13.16. Found: C, 53.00; H, 4.40; N,
12.84.
2-((1-(6-Hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-3-methyl-1,3-thiazolidin-4-one 7b 60% yield. mp 174—175 °C.
1H-NMR (CDCl3) d: 2.62 (3H, s), 3.33 (3H, s), 3.83 (2H, s), 4.07 (3H, s),
6.83 (3H, br s, exch. D2O), 7.43 (1H, d, Jϭ2.0 Hz). IR (KBr) cmϪ1: 3450,
1720, 1590, 1560. MS m/z: 333 (Mϩ), 334 (Mϩϩ1) (Calcd for
C15H15N3O4S: 333.37). Anal. Calcd for C14H13N3O4S: C, 54.04; H, 4.54; N,
12.60. Found: C, 54.34; H, 4.88; N, 12.26.
3-Ethyl-2-((1-(6-hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hy-
drazono)-1,3-thiazolidin-4-one 7c 55% yield. mp 113—115 °C. IR (KBr)
cmϪ1: 3450, 1710, 1590, 1550. MS m/z: 347.05 (Mϩ), 348.05 (Mϩϩ1)
(Calcd for C16H17N3O4S: 347.39). Anal. Calcd for C16H17N3O4S: C, 55.32;
H, 4.93; N, 12.10. Found: C, 55.53; H, 5.22; N, 11.76.
3-Allyl-2-((1-(6-hydroxy-4-methoxy-1-benzofuran-5-yl)ethylidene)hy-
drazono)-1,3-thiazolidin-4-one 7d 68% yield. mp 129—130 °C. 1H-
NMR (CDCl3) d: 2.60 (3H, s), 3.84 (2H, s), 4.06 (3H, s), 4.43—5.42 (4H,
br m), 5.95—6.20 (1H, m), 6.83 (2H, s), 7.42 (1H, s), 11.95 (1H, br s, exch.
D2O). IR (KBr) cmϪ1: 3450, 1710, 1620, 1580. MS m/z: 359 (Mϩ), 360
(Mϩϩ1) (Calcd for C17H17N3O4S: 359.40). Anal. Calcd for C17H17N3O4S: C,
56.81; H, 4.77; N, 11.69. Found: C, 56.48; H, 5.10; N, 11.44.
2-((1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-1,3-thiazolidin-4-one 7e 65% yield. mp 200—202 °C. 1H-NMR
(CDCl3) d: 1.63 (1H, br s, exch. D2O), 2.59 (3H, s), 3.88 (2H, s), 3.99 (s,
3H), 4.10 (s, 3H), 6.84 (1H, d, Jϭ2.4 Hz), 7.49 (1H, d, Jϭ 2.4 Hz), 11.60
(1H, br s, exch. D2O). IR (KBr) cmϪ1: 3450 (br), 3200, 1710, 1600, 1540,
1520. MS m/z: 349 (Mϩ), 350 (Mϩϩ1) (Calcd for C15H15N3O5S: 349.36).
Anal. Calcd for C15H15N3O5S: C, 51.57; H, 4.33; N, 12.03. Found: C, 51.94;
H, 4.70; N, 11.79.
Anticonvulsant Activity All the newly synthesized compounds were
tested for their anticonvulsant activity using the scPTZ62,63) and MES64)
methods in mice. Also, representatives of the starting and intermediate com-
pounds were tested for their anticonvulsant efficacy using the scPTZ
method. In addition the ED50 was determined to the most active compounds.
Also, the neurotoxicity for the active compounds was performed using the 4-
Amino Pyridine (4-AP) method.
Method I: Protection against Pentylenetetrazole Induced Seizures
(scPTZ) Albino mice of either sex, weighing 20—30 g, obtained from the
animal house of Faculty of Pharmacy, Mansoura University (Mansoura,
Egypt) were used in the experiments. Animals were randomly divided into
groups, which are test groups, one control group and one reference group;
each group consisted of six animals. The tested compounds were suspended
in 0.5% methyl cellulose-water mixture as a vehicle, whereas PTZ and
sodium valproate were dissolved in saline. The compounds were adminis-
tered at doses of 75, 150 and 300 mg/kg intraperitoneally (i.p.) to the test
groups. In the reference group sodium valproate was administered as a stan-
dard pharmacological drug against clonic phase of PTZ-induced seizures at
a dose of 650 mg/kg. The control group was treated with the vehicle only.
PTZ was applied S.C. at a dose of 85 mg/kg 30 min after injection of the
tested compounds, standards or vehicle in the different groups. Each animal
was placed into an individual glass cage and observed for 60 min for the ap-
pearance of seizures. One clonic seizure for a minimum period of 5 s was
considered a threshold of convulsion. Transient intermittent jerks or tremu-
lousness were not taken into account.63)
2-((1-(6-Hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethylidene)hydra-
zono)-3-methyl-1,3-thiazolidin-4-one 7f 75% yield. mp 158—160 °C.
1H-NMR (CDCl3) d: 2.64 (3H, s), 3.34 (3H, s), 3.84 (2H, s), 3.98 (3H, s),
4.09 (3H, s), 6.29 (1H, d, Jϭ2 Hz), 7.82 (1H, d, Jϭ2 Hz), 11.87 (1H, s, exch.
D2O). IR (KBr) cmϪ1: 3400, 1720, 1600, 1540, 1520. MS m/z: 363 (Mϩ),
364 (Mϩϩ1) (Calcd for C16H17N3O5S: 363.39). Anal. Calcd for
C15H15N3O5S: C, 52.88; H, 4.72; N, 11.56. Found: C, 53.14; H, 4.92; N,
11.30.
Animals showing no threshold convulsion during the period of 60 min
were considered protected. The number of protected animals in each group
was recorded and the percentage of protected animals in each group was de-
termined.
Method II: Protection against Electrical Shock Induced Seizures
(MES) Albino mice of either sex, weighing 20—30 g, obtained from the
animal house of Faculty of Pharmacy, Cairo University (Cairo, Egypt) were
used in the experiments. Animals were randomly divided into groups, which
are test groups, one control group and one reference group; each group con-
sisted of six animals. The tested compounds and the standard reference
3-Ethyl-2-((1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethyl-
idene)hydrazono)-1,3-thiazolidin-4-one 7g 60% yield. mp 141—143 °C.

1154
Vol. 58, No. 9
phenytoin were suspended in water using few drops of Tween 80. The tested mals that presented seizures (clonic and tonic) in relation to animals treated
compounds and phenytoin were administered at doses of 75, 150 and
300 mg/kg intraperitoneally (i.p.) to the test groups. The control group was
with 4-AP only.
Materials and Methods A) The tested compound or the reference drug
treated with saline only. The animals were stimulated through Auricular (valproic acid) is injected intraperitoneally (i.p.) to groups of 10 mice (18—
electrodes with 18 mA current, shock duration 1 s, frequency of 100 pulse/s
and pulse width of 0.5 ms at 0.5 and 4 h from the time of the tested or stan-
dard compounds injection using ‘CD-S104-Cudos stimulator, (SC-electron-
ics) Brookwood, Surrey, England.’ The abolition of hind limb tonic extensor
spasm was recorded as a measure of anticonvulsant activity.64) The number
of protected animals in each group was recorded and the percentage of pro-
tected animals in each group was determined.
Table 1. Number of Animals Protected in Each Group, Its Percentage at
Each Dose in scPTZ Method and the Calculated Log P Values of the New
Compounds
Compound
300 mg/kg
150 mg/kg
75 mg/kg
Log P
Method III: Protection against 4-Amino Pyridine (4-AP) Induced
Seizures Animals (8 groups each of 10 mice) were pretreated with a single
injection of valproic acid (300 mg/kg, in distilled water), 1c, 2b and 5a (5,
10, and 10 mg/kg body weight, intraperitoneally (i.p.) suspended with few
drops of Tween 80 in distilled water, or distilled water alone (vehicle or con-
trol). After 30 min of administration, animals were treated with a single in-
jection of 4-AP (12 mg/kg body weight, intraperitoneally (i.p.), dissolved in
water), and were divided as follows:
Group 1, control [distilled water]; group 2, [distilled waterϩ4-AP]; group
3, [valproic acidϩwater]; group 4, [valproic acid 300 mg/kgϩ4-AP]; group
5, [1c 5 mg/kgϩwater]; group 6, [1c 5 mg/kgϩ4-AP]; group 7, [2b
10 mg/kgϩwater]; group 8, [2b 10 mg/kgϩ4-AP]; group 9, [5a 10 mg/kgϩ
water]; group 10, [5a 10 mg/kgϩ4-AP].
Pre-treated mice with the newly synthesized compounds or vehicle were
placed in individual Plexiglas chambers (20ϫ20ϫ19 cm), and their behavior
was observed for 30 min for the appearance of seizures (clonic, tonic) or
death. Thereafter the animals were treated with 4-AP and the behavior was
observed for additional 60 min for the appearance of seizures (clonic, tonic)
or death.65)
The ED50 for the compounds were determined through a pilot study and
the therapeutic doses were selected accordingly.66,67) The dose for valproic
acid was based on experimental evidence that doses from 0.1 to 0.4 g/kg are
effective in animal models.68,69) In addition, the convulsive dose of 4-AP was
selected in accordance with Wong et al. (2002).70)
Results 1) In the scPTZ test, the anticonvulsant activity results of the
newly synthesized compounds and their calculated Log P are listed in Table
1.
2) In the MES test, all the tested compounds were considered inactive
(doses up to 300 mg/kg showed no protection whereas, phenytoin showed
100% protection in all the used doses).
3) Table 2 show that a single administration of 4-AP (12 mg/kg) caused
clonic and tonic seizures in all mice, followed by death of all mice. In con-
trast, pre-treatment of animals with valproic acid (300 mg/kg) caused a sig-
nificant latency of clonic seizures and completely prevented the incidence of
tonic seizures as well as death. Compound 1c (5 mg/kg) also caused latency
of clonic seizures and completely prevented the incidence of tonic seizures
as well as death. The same applies with compounds 2b and 5a. Pre-treat-
ment with 2b (10 mg/kg) or 5a (10 mg/kg), significantly increased latency
for seizures (clonic and tonic) and completely abolished death. On the other
hand, pre-treatment with valproic acid, 1c, 2b, 5a reduced the number of ani-
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
3g
3h
5a
5b
5c
5d
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
(0/6) 0%
(3/6) 50%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
Ϫ0.19
0.33
0.66
1.16
1.99
2.22
2.74
3.08
3.57
4.41
0.85
1.37
1.71
2.20
0.72
1.24
1.58
2.08
0.70
1.04
1.40
0.42
2.88
3.12
3.46
3.81
2.83
1.51
1.75
2.09
2.44
1.39
1.62
1.96
2.26
1.16
1.34
(6/6) 100% (4/6) 66.6% (1/6) 16.6%
(3/6) 50% (0/6) 0% (0/6) 0%
(6/6) 100% (5/6) 83.3% (0/6) 0%
(0/6) 0% (0/6) 0% (0/6) 0%
(6/6) 100% (6/6) 100% (0/6) 0%
(0/6) 0%
(5/6) 83.3% (0/6) 0%
(3/6) 50%
(3/6) 50%
(3/6) 50%
(4/6) 66.6% (0/6) 0%
(3/6) 50%
(0/6) 0%
(4/6) 66.6% (0/6) 0%
(0/6) 0% (0/6) 0%
(4/6) 66.6% (0/6) 0%
(6/6) 100% (5/6) 83.3% (1/6) 16.6%
(0/6) 0%
(4/6) 66.6% (0/6) 0%
(4/6) 66.6% (0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(3/6) 50%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(4/6) 66.6% (1/6) 16.6% (0/6) 0%
(6/6) 100% (4/6) 66.6% (1/6) 16.6%
(5/6) 83.3% (3/6) 50%
(3/6) 50%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
7g
7h
7i
7j
(0/6) 0%
(0/6) 0%
(0/6) 0%
(0/6) 0%
Sodium
valproate
Vehicle
(6/6) 100% (6/6) 100% (6/6) 100%
(0/6) 0% (0/6) 0% (0/6) 0%
2.58
Table 2. Influence of Pre-treatment with Compounds 1c, 2b, 5a and Valproic Acid on Latency for Seizures (Clonic and Tonic) and Death Using 4-AP-
Induced Method
Latency for clonic seizures
(min)
Latency for tonic seizures
(min)
Groups
Clonic seizures
Tonic seizures
Survival
1
2
3
4
5
6
7
8
9
0/8
8/8c)
0/6
1/6
0/5
6/6
0/5
2/7
0/6
1/8d)
60.00Ϯ0.00
9.13Ϯ1.19a)
60.00Ϯ0.00
48.26Ϯ3.57b)
60.00Ϯ0.00
20.17Ϯ1.76b)
60.00Ϯ0.00
43.67Ϯ10.45b)
60.00Ϯ0.00
46.50Ϯ8.88b)
0/8
60.00Ϯ0.00
18.13Ϯ3.68a)
60.00Ϯ0.00
60.00Ϯ0.00b)
60.00Ϯ0.00
60.00Ϯ0.00b)
60.00Ϯ0.00
60.00Ϯ0.00b)
60.00Ϯ0.00
60.00Ϯ0.00b)
8/8
8/8c)
0/6
0/8c)
6/6
0/6d)
0/5
6/6d)
5/5
0/6d)
0/5
6/6d)
5/5
0/7d)
0/6
7/7d)
6/6
10
0/8d)
8/8d)
* Group 1, control [distilled water]; group 2, [distilled waterϩ4-AP]; group 3, [300 mg/kg valproic acidϩwater]; group 4, [300 mg/kg valproic acidϩ4-AP]; group 5, [5 mg/kg
1cϩwater]; group 6, [5 mg/kg 1cϩ4-AP]; group 7, [10 mg/kg 2bϩwater]; group 8, [10 mg/kg 2bϩ4-AP]; group 9, [10 mg/kg 5aϩwater]; group 10, [10 mg/kg 5aϩ4-AP]. a)
Significantly different from distilled water, pϽ0.05 by Mann–Whitney U-test. b) Significantly different from distilled waterϩ4-AP, pϽ0.05 by Mann–Whitney U-test. c) Signifi-
cantly different from distilled water, pϽ0.05 by Fisher exact test. d) Significantly different from distilled waterϩ4-AP, pϽ0.05 by Fisher exact test. ** Last animal died at
32.13Ϯ6.42 min.

September 2010
1155
22 g). Another group of 10 mice served as control. Fifteen minutes after in-
588 (1990).
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R. S., Quail J. W., Pugazhenthi U., Ong A., Bikker J. A., Weaver D. F.,
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287—301 (1995).
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M., Kao G. Y., Balzarini J., DeClercq E., Eur. J. Med. Chem., 30,
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25) Dimmock J. R., Puthucode R. N., Smith J. M., Hetherington M., Quail
J. W., Pugazhenthi U., Lechler T., Stables J. P., J. Med. Chem., 39,
3984—3997 (1996).
B) Male mice (groups of 10 mice) for neuroprotective method (20—25 g),
were maintained at 12 h light/dark cycle (07:00—19:00 h lights on) and at a
room temperature of 22Ϯ2 °C. All animals had free access to food and
water. The animals were used according to the guidelines of the Committee
on Care and Use of Experimental Animal Resources of the German univer-
sity in Cairo, Cairo, Egypt.
Evaluation The number of protected animals in the treated groups is
calculated as percentage of affected animals in the control group. ED50 value
was then calculated.69,70)
Acknowledgement The authors are grateful to Dr. Hamdy Ghoneim
(Lecturer of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura 26) Puthucode R. N., Pugazhenthi U., Quail J. W., Stables J. P., Dimmock
Univ.) for his effort in performing the pharmacological screening (scPTZ) of J. R., Eur. J. Med. Chem., 33, 595—607 (1998).
the newly investigated compounds. Dr. Hala Fahmy (Associate Prof. Faculty 27) Pandeya S. N., Yogeeswari P., Stables J. P., Eur. J. Med. Chem., 35,
of Pharmacy, Cairo Univ.) for performing the scPTZ test for the starting and 879—886 (2000).
intermediate compounds. Prof. Hekmat Abdel Tawab (Professor of Pharma- 28) Yogeeswari P., Thirumurugan R., Kavya R., Samuel J. S., Stables J.,
cology & Toxicology, Faculty of pharmacy, Cairo Univ.) for her effort in per- Sriram D., Eur. J. Med. Chem., 39, 729—734 (2004).
forming the pharmacological screening (MES test) of the newly investigated 29) Thirumurugan R., Sriram D., Saxena A., Stables J., Yogeeswari P.,
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for her effort in performing the neuroprotective activity of the active com-
pounds.
565—571 (2003).
31) Yogeeswari P., Sriram D., Pandeya S. N., Stables J. P., Il Farmaco., 59,
609—613 (2004).
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