Synthesis, nematicidal and antimicrobial activity of 3-(5-3-methyl-5-[(3- methyl-7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b] furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(aryl)-1, 3-thiazolan-4-one

Article abstract of DOI:10.1248/cpb.58.805

A new series of 3-(5-3-methyl-5-[(3-methyl-7-5-[2-(aryl)-4-oxo-1,3- thiazolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo-[b]furan-5-yl)methyl]benzo[b] furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(aryl)-1,3-thiazolan-4-one 5a-j has been synthesized by the reaction of N2-[(E)-1-(4-methylphenyl)methylidene]-5-(3- methyl-5-[3-methyl-7-(5-[(E)-1-(4-methylphenyl)methylidene]amino-1,3, 4-thiadiazol-2-yl)benzo[b]furan-5-yl]methylbenzo[b]furan-7-yl)-1,3, 4-thiadiazol-2-amine 4a - j with thioglycolic acid. Chemical structures of all the new compounds were established by their IR, ¹H-NMR, ¹³C-NMR, MS and elemental data. The 5a - j have been assayed for their nematicidal activity against Ditylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. The screened data reveal that, the 5e is most effective against D. myceliophagus and C. elegans with 50% lethal dose (LD₅₀) of 170 and 190 ppm, respectively and is almost equal to the activity of standard levamisole. The 5h and 5j are also most active against C. elegans with LD₅₀ of 200 ppm and D. myceliophagus with LD ₅₀ of 190 ppm, respectively. Further, the 5a - j were screened for their antibacterial activity against three representative, Gram-positive bacteria viz. Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538p and Micrococcus luteus IFC 12708, and three Gram-negative bacteria viz. Proteus vulgaris ATCC 3851, Salmonella typhimurium ATCC 14028 and Escherichia coli ATCC 25922, and also screened for their antifungal activity against four fungal organisms viz. Candida albicans ATCC 10231, Aspergillus fumigatus HIC 6094, Trichophyton rubrum IFO 9185 and Trichophyton mentagrophytes IFO 40996. Most of these new compounds showed appreciable activity against the test bacteria and fungi, and emerged as potential molecules for further development.

Full text of DOI:10.1248/cpb.58.805

June 2010
Regular Article
Chem. Pharm. Bull. 58(6) 805—810 (2010)
805
Synthesis, Nematicidal and Antimicrobial Activity of 3-(5-3-Methyl-5-
[(3-methyl-7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-
ylbenzo[b]furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-
2-(aryl)-1,3-thiazolan-4-one
b
Cherkupally SANJEEVA REDDY, ,a Dasari CHANDRASHEKAR RAO,a Vookanti YAKUB,a and Adki NAGARAJ
*
a Department of Chemistry, Kakatiya University; Warangal–506 009, India: and b Department of Pharmaceutical
Chemistry, Telangana University; Nizamabad–503 175, India.
Received December 9, 2009; accepted February 26, 2010; published online March 8, 2010
A new series of 3-(5-3-methyl-5-[(3-methyl-7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo-
[b]furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(aryl)-1,3-thiazolan-4-one 5a—j has been syn-
thesized by the reaction of N2-[(E)-1-(4-methylphenyl)methylidene]-5-(3-methyl-5-[3-methyl-7-(5-[(E)-1-(4-
methylphenyl)methylidene]amino-1,3,4-thiadiazol-2-yl)benzo[b]furan-5-yl]methylbenzo[b]furan-7-yl)-1,3,4-thia-
diazol-2-amine 4a—j with thioglycolic acid. Chemical structures of all the new compounds were established by
their IR, 1H-NMR, 13C-NMR, MS and elemental data. The 5a—j have been assayed for their nematicidal activity
against Ditylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. The
screened data reveal that, the 5e is most effective against D. myceliophagus and C. elegans with 50% lethal dose
(LD50) of 170 and 190 ppm, respectively and is almost equal to the activity of standard levamisole. The 5h and 5j
are also most active against C. elegans with LD50 of 200 ppm and D. myceliophagus with LD50 of 190 ppm, respec-
tively. Further, the 5a—j were screened for their antibacterial activity against three representative, Gram-posi-
tive bacteria viz. Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538p and Micrococcus luteus IFC
12708, and three Gram-negative bacteria viz. Proteus vulgaris ATCC 3851, Salmonella typhimurium ATCC 14028
and Escherichia coli ATCC 25922, and also screened for their antifungal activity against four fungal organisms
viz. Candida albicans ATCC 10231, Aspergillus fumigatus HIC 6094, Trichophyton rubrum IFO 9185 and Tri-
chophyton mentagrophytes IFO 40996. Most of these new compounds showed appreciable activity against the test
bacteria and fungi, and emerged as potential molecules for further development.
Key words thiadiazolo-thiazolidine-4-one; nematicidal activity; antimicrobial activity
Several naturally occurring and synthetic benzofuran de- mochloropropane (DBCP) and ethylenedibromide (EDB)
rivatives are known to be associated with biological and have been withdrawn from the market due to their deleterious
pharmacological activities.1—6) Among the heterocyclics, effects on humans and the environment. Methyl bromide, the
thiadiazoles exhibited a broad spectrum of biological effec- most effective and widely used fumigant for soil borne pests
tiveness such as anti-parkinsonism,7) hypoglycaemic,8) anti- including nematodes, has already been banned. The use of
cancer,9) anti-inflammatory,10) anti-asthmatic11) and anti-hy- nonfumigant nematicides, based on organophosphates and
pertensive12) activities. Further, there has been considerable carbamates, is expected to increase the withdrawal of methyl
interest in the chemistry of thiazolidine-4-one ring system, bromide, which will bring about new environmental con-
which is a core structure in various synthetic pharmaceuticals cerns. In fact, the highly toxic aldicarb used to control insects
displaying a broad spectrum of biological activities.13—15) and nematodes has been detected in ground water.36) There-
Thiazolidine-4-one ring also occurs in nature; thus actithiazic fore, alternative nematode control methods or less toxic
acid isolated from Streptomyces strains exhibits highly spe- nematicides need to be developed.37) One way of searching
cific in vitro activity against Mycobacterium tuberculosis.16) for such nematicidal compounds is to screen naturally oc-
Thiazolidine-4-one derivatives are known to exhibit diverse curring compounds in plants. Several such compounds,
bioactivities such as anti-convulsant,17) antidiarrheal,18) anti- e.g. alkaloids, phenols, sesquiterpenes, diterpenes, poly-
platelet activating factor,19—21) anti-histaminic,22,23) anti- acetylenes and thienyl derivatives have nematicidal activ-
microbial,24,25) anti-diabetic,26) cyclooxygenase (COX) in- ity.38) For example, a-terthienyl is a highly effective nemati-
hibitory,27) Ca2ꢀ-channel blocker,28) platelet activating factor cidal compound.39) Other compounds with nematicidal activ-
(PAF) antagonist,29) cardioprotective,30) anti-ischemic,31) anti- ity have been isolated from plants, mainly from the family
cancer,32) tumour necrosis factor-a antagonist33) and nemati- Asteraceae.38) However, compounds of plant origin and their
cidal activities.34)
Nematodes are tiny worms, some of them are plant para- cides, hence there is a need to develop commercial synthesis.
sites and can play an important role in the predisposition of In recent years, attention has been increasingly paid to the
analogs have not been developed into commercial nemati-
the host plant to the invasion by secondary pathogens.35) synthesis of bis-heterocyclic compounds which exhibit vari-
Plants attacked by nematodes show retarded growth and ous biological activities40—43) including antibacterial, fungi-
development, as well as loss in the quality and quantity of cidal, tuberculostatic and plant growth regulative properties.
the harvest. The nematicide use is slated for reduction due to Furthermore, it was indicated that bis-heterocyclic com-
environmental problems, and human and animal health pounds displayed much better antibacterial activity than the
concerns. For example, effective nematicides such as dibro- mono heterocyclic compounds.44—47)
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: chsrkuc@yahoo.co.in

806
Vol. 58, No. 6
Inspired by the biological profile of benzofuran, thiadia-
Compound 3 on reaction with the corresponding arylalde-
zole, thiazolidine-4-one and their increasing importance in hyde in the presence of acetic acid at reflux for 3 h furnished
pharmaceutical and biological field, and in continuation of the corresponding N2-[(E)-1-(aryl))methylidene]-5-(3-
our research on biologically active heterocycles,48—51) and in methyl-5-[3-methyl-7-(5-[(E)-1-(aryl)methylidene]amino-
order to enhance the biological activity, it was thought of in- 1,3,4-thiadiazol-2-yl)benzo[b]furan-5-yl]methylbenzo[b]-
terest to accommodate thiadiazole and thiazolidine-4-one furan-7-yl)-1,3,4-thiadiazol-2-amine 4a—j in 74—79%
moieties in a single molecular frame work and to synthesize yield. The 4a—j when reacted with thioglycolic acid in the
the bis-heterocyclics for enhancing biological activity. The presence of ZnCl2 in N,N-dimethylformamide (DMF) at re-
present investigation deals with the use of bis-salicylic acid flux temperature for 6 h afforded 3-(5-3-methyl-5-[(3-methyl-
in the synthesis of some interesting bis-thiadiazolo-thiazo- 7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-yl-
lidin-4-ones of expected pharmacological action and to study benzo[b]furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadia-
their effect on nematodes, bacteria and fungi.
zol-2-yl)-2-(aryl)-1,3-thiazolan-4-one 5a—j in 71—82%
yield (Chart 2). The versatility of the reaction is well demon-
strated by the fact that a variety of arylaldehydes, with elec-
Results and Discussion
Synthesis Compound 1 was prepared according to the tron-releasing and electron-withdrawing groups, afforded
procedure described in the literature.52) Condensation of 1 their corresponding 5a—j in good yields. The structures of
with chloroacetone in the presence of K2CO3 and catalytic newly described compounds were confirmed by elemental
amount of KI at reflux for 12 h followed by cyclization in alc. analysis, IR, 1H-NMR, 13C-NMR and MS spectral data.
KOH at reflux for 18 h gave 5-[(7-carboxy-3-methylbenzo-
In the IR spectra of 5a—j appearance of amide carbonyl
[b]furan-5-yl)methyl]-3-methylbenzo[b]furan-7-carboxylic (CꢁO) absorption band at about 1698 cmꢂ1, and the band
acid 2 in 72% yield. Further, condensation of 2 with 712 cmꢂ1 corresponding to the C–S–C stretching vibration
thiosemicarbazide in ethanol at reflux for 10 h, followed by provided the evidence for ring closure. Further support was
cyclization in conc. H2SO4 at room temperature afforded 5- obtained from the 1H-NMR spectra, the N–CH–S proton and
(5-{[7-(5-amino-1,3,4-thiadiazol-2-yl)-3-methylbenzo[b]- CH2–S protons of thiazolidine-4-one ring appeared at 5.94
furan-5-yl]methyl}-3-methylbenzo[b]furan-7-yl)-1,3,4-thia- and 3.67 ppm, respectively as singlets. These signals demon-
diazol-2-amine 3 in 78% yield (Chart 1).
strate that the cyclization has occurred. In the 13C-NMR
Reagents and conditions: (i) Acetone, K2CO3, KI, reflux 12 h, alc. KOH, reflux 18 h, 72%; (ii) EtOH, reflux 10 h, Conc. H2SO4, rt, 78%.
Chart 1
4/5
R
4/5
R
4/5
R
4/5
R
4/5
R
a
c
e
g
i
b
d
f
h
j
Reagents and conditions: (iii) AcOH, reflux 3 h, 74—79%; (iv) DMF, ZnCl2, reflux 6 h, 71—82%.
Chart 2

June 2010
807
spectra, the prominent signals corresponding to the carbons mg/ml), was determined for all the compounds and compared
of thiadiazole and thiazolidine-4-one ring in all the com- with the control. The MIC values of the compounds assayed
pounds observed nearly at 173.2 and 154.9 ppm and at 170.5, are presented in Table 2. All assays included the solvent and
72.0 and 33.9 ppm, respectively, are proof of further evidence reference controls, Ampicillin was used as standard drug.
of their structures. In summary all the synthesized com-
pounds exhibited satisfactory spectral data consistent with that all the tested compounds exhibited interesting biological
their molecular structures. activity, however, with a degree of variation. Compound 5c is
The investigation of antibacterial screening data revealed
Biological Properties. Nematicidal Activity All the highly active against all the microorganisms employed, ex-
newly synthesized compounds 5a—j in this study were as- cept Escherichia coli, at 1.56 mg/ml concentration; it is al-
sayed for their nematicidal activity against Ditylenchus myce- most equal to the standard. Compound 5j is also highly ac-
liophagus and Caenorhabditis elegans by aqueous in vitro tive but only against M. luteus and P. vulgaris at the same
screening technique53) at various concentrations. The nemati- concentration as 5c. Compound 5e also showed good anti-
cidal activity of each test compound was compared with the bacterial activity against B. subtilis, S. aureus, M. Luteus and
standard drug levamisole. The results have been expressed in S. typhimurium. Compound 5a is almost inactive towards M.
terms of 50% lethal dose (LD50) i.e. median lethal dose at luteus, P. vulgaris and E. coli. The remaining compounds
which 50% nematodes became immobile (dead). The showed moderate good activity.
screened data reveal that, 5e is the most effective against
Antifungal Activity Compounds 5a—j were also
D. myceliophagus and C. elegans with LD50 of 170 and screened for their antifungal activity against four fungal or-
190 ppm, respectively. The compounds 5h and 5j are also ganisms viz. Candida albicans ATCC 10231, Aspergillus fu-
most active against C. elegans with LD50 of 200 ppm and D. migatus HIC 6094, Trichophyton rubrum IFO 9185, and Tri-
myceliophagus with LD50 of 190 ppm, respectively. The ac- chophyton mentagrophytes IFO 40996 in dimethyl sulfoxide
tivity of 5e is almost equal to the activity of standard lev- (DMSO) by broth dilution method.55) Amphotericin B was
amisole, the other test compounds showed moderate activity. used as a standard drug and the minimum inhibitory concen-
The LD50 values of the compounds screened are presented in tration (MIC, mg/ml) were measured and compared with con-
Table 1.
trols, the MIC values of the compounds screened are given in
Antibacterial Activity Compounds 5a—j were assayed Table 3.
for their antibacterial activity against three representative
The antifungal screening data showed good activity of the
Gram-positive bacteria viz. Bacillus subtilis ATCC 6633, test compounds. Among the screened compounds, 5c is
Staphylococcus aureus ATCC 6538p and Micrococcus luteus highly active against T. rubrum, T. mentagrophytes, 5e is also
IFC 12708, and three Gram-negative bacteria viz. Proteus active against only C. albicans and 5i is highly active against
vulgaris ATCC 3851, Salmonella typhimurium ATCC 14028 C. albicans, T. mentagrophytes, the activity of these com-
and Escherichia coli ATCC 25922 by the broth dilution pounds are almost equal to the standard. It is interesting to
method, recommended by National Committee for Clinical note that 5e and 5i showed good antifungal activity towards
Laboratory Stadards (NCCLS).54) The lowest concentration C. albicans at the concentration of 3.12 mg/ml, which is less
(highest dilution) required to arrest the growth of bacteria than the concentration of the standard.
was regarded as minimum inhibitory concentration (MIC,
Table 1. Median Lethal Dose LD50 (ppm) of Compounds 5a—j against Tested Nematodes
Compound
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
Levamisole
D. myceliophagus
C. elegans
790
760
850
770
560
360
600
550
170
190
270
220
950
870
430
200
570
610
190
780
170
180
LD50, median lethal dose (the concentration at which 50% nematodes became immobile).
Table 2. Antibacterial Activity of Compounds 5a—j
Minimum inhibitory concentration (MIC) in mg/ml
Compound
B. subtilis
S. aureus
M. luteus
P. vulgaris
S. typhimurium
E. coli
5a
5b
5c
5d
5e
5f
5g
5h
25.0
12.5
1.56
12.5
6.25
25.0
25.0
6.25
3.12
12.5
1.56
25.0
12.5
1.56
12.5
6.25
12.5
25.0
12.5
6.25
12.5
1.56
ꢃ50.0
12.5
1.56
6.25
1.56
3.12
50.0
12.5
12.5
1.56
1.56
ꢃ50.0
12.5
1.56
ꢃ50.0
1.56
12.5
12.5
25.0
6.25
1.56
3.12
25.0
12.5
1.56
12.5
3.12
6.25
50.0
12.5
12.5
12.5
3.12
ꢃ50.0
25.0
12.5
25.0
1.56
25.0
ꢃ50.0
25.0
12.5
25.0
12.5
5i
5j
Ampicillin
MIC, minimum inhibitory concentration (the lowest concentration that inhibited the bacterial growth). Standard deviation 0.05.

808
Vol. 58, No. 6
Table 3. Antifungal Activity of Compounds 5a—j
methylbenzo[b]furan-5-yl]methyl}-3-methylbenzo[b]furan-7-yl)-1,3,4-
thiadiazol-2-amine (3) A mixture of 2 (5 mmol) and thiosemicarbazide
(10 mmol) in acetone (20 ml) was refluxed for 10 h. The reaction mixture
was allowed to cool, and the solid separated was collected by filtration. The
crude product was dissolved in conc. H2SO4 (5 ml) and stirred at room tem-
perature for few minutes and left overnight. It was then poured on crussed
ice, the resulting suspension was kept in ammonical water (25 ml) for 4 h,
filtered the solid and recrystallized from ethanol to give pure 3 as yellow
solid. Yield 78%, mp 192—194 °C. IR (KBr) cmꢂ1: 3350, 3050, 2985, 1605,
Minimum inhibitory concentration (MIC) in mg/ml
Compound
C. albicans
A. fumigatus
T. rubrum T. mentagropytes
5a
5b
5c
5d
5e
5f
5g
5h
25.0
25.0
12.5
25.0
3.12
50.0
25.0
6.25
3.12
50.0
6.25
12.5
25.0
6.25
12.5
12.5
25.0
25.0
12.5
6.25
50.0
3.12
ꢃ50.0
25.0
25.0
25.0
3.12
6.25
12.5
3.12
1
12.5
25.0
12.5
25.0
12.5
1030, 712. H-NMR (DMSO-d6) d: 7.65—7.60 (m, 4H, Ar-H), 7.47 (s, 2H,
Ar-H), 4.92 (s, 4H, NH2), 4.10 (s, 2H, CH2). 13C-NMR (DMSO-d6) d: 168.2,
163.4, 153.4, 141.7, 136.1, 130.6, 128.2, 127.1, 123.4, 119.1, 42.6, 9.1. MS
m/z: 475 (Mꢀꢀ1, 18%), 106 (100%). Anal. Calcd for C23H18N6O2S2: C,
58.21; H, 3.82; N, 17.71. Found: C, 58.16; H, 3.80; N, 17.69.
12.5
12.5
25.0
5i
5j
6.25
50.0
3.12
3.12
25.0
3.12
Typical Procedure N2-[(E)-1-(4-methylphenyl)methylidene]-5-(3-
methyl-5-[3-methyl-7-(5-[(E)-1-(4-methylphenyl)methylidene]amino-
1,3,4-thiadiazol-2-yl)benzo[b]furan-5-yl]methylbenzo[b]furan-7-yl)-
1,3,4-thiadiazol-2-amine (4a) A mixture of 3 (5 mmol), p-methylben-
zaldehyde (10 mmol) and acetic acid (0.5 ml) was refluxed in toluene for 3 h
using a Dean-stark apparatus and the water formed was removed azeiotropi-
cally. The progress of the reaction was checked by TLC using toluene : ethyl
acetate (4 : 1) as an eluent. After completion of the reaction, solvent was re-
moved by distillation to give solid, which was filtered, and recrystallized
from ethyl alcohol to give pure 4a as yellow solid. Yield 74%, mp 186—
188 °C. IR (KBr) cmꢂ1: 3052, 2988, 1625, 1610, 1070, 714. 1H-NMR
(DMSO-d6) d: 8.76 (s, 2H, CH), 7.70 (d, Jꢁ7.6 Hz, 4H, Ar-H), 7.59 (s, 2H,
Ar-H), 7.55—7.50 (m, 4H, Ar-H), 7.00 (d, Jꢁ7.6 Hz, 4H, Ar-H), 4.12 (s,
2H, CH2), 2.44 (s, 6H, CH3), 2.21 (s, 6H, CH3). 13C-NMR (DMSO-d6) d:
Amphotericin B
MIC, minimum inhibitory concentration (the lowest concentration that inhibited the
fungal growth). Standard deviation 0.05.
Conclusion
In conclusion, a new series of 3-(5-3-methyl-5-[(3-methyl-
7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-yl-
benzo[b]furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadia-
zol-2-yl)-2-(aryl)-1,3-thiazolane-4-one 5a—j has been syn-
thesized and evaluated for their nematicidal activity, most of 165.3, 162.7, 161.4, 150.6, 143.4, 135.6, 135.0, 133.9, 131.7, 129.6, 128.7,
the compounds showed appreciable nematicidal activity. The
126.4, 122.8, 118.5, 42.0, 20.7, 9.7. MS m/z: 678 (Mꢀ). Anal. Calcd for
C39H30N6O2S2: C, 69.01; H, 4.45; N, 12.38. Found: C, 68.95; H, 4.40; N,
12.33. The other compounds (4b—j) were prepared using the same proce-
dure.
antibacterial (MIC) activity and antifungal (MIC) activity of
these compounds were also evaluated against various bacte-
ria and fungi. Many of the synthesized compounds showed
good activity against the test bacteria and fungi and emerged
as potential molecules for further development.
Typical Procedure 3-(5-3-Methyl-5-[(3-methyl-7-5-[2-(aryl)-4-oxo-1,3-
thiazolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b]furan-5-yl)methyl]benzo-
[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(aryl)-1,3-thiazolan-4-one (5a—j)
A mixture of 4 (5 mmol), thioglycolic acid (12 mmol) in N,N-dimethylfor-
mamide (40 ml) with a pinch of anhydrous ZnCl2, was refluxed for 6 h, the
Experimental
General Reagents were of commercial grade and were used as supplied progress of the reaction was checked by TLC using toluene : ether (3 : 1) as
or were prepared according to procedures described in literature. Solvents an eluent. The reaction mixture was cooled to room temperature and then
except analytical reagent grade were dried and purified according to litera- poured into crussed ice. It was set-aside at room temperature overnight. The
ture when necessary. Reactions were monitored by thin-layer chromatogra- solid thus separated was filtered, washed several times with water and puri-
phy (TLC) on pre-coated silica gel F254 plates from Merck and compounds
fied by column chromatography on silica-gel with hexane–ethyl acetate as
visualized either by exposure to UV light or dipping in 1% aqueous potas- eluent to afford pure compounds.
sium permanganate solution. Chromatographic columns 70—230 mesh sil-
3-(5-3-Methyl-5-[(3-methyl-7-5-[2-(4-methylphenyl)-4-oxo-1,3-thia-
ica gel for separations were used. Melting points were determined through a zolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b]furan-5-yl)methyl]benzo[b]-
Fisher–Johns apparatus and are uncorrected. IR spectra were recorded using furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(4-methylphenyl)-1,3-thiazolan-4-one
KBr disk on a Perkin–Elmer FT-IR spectrometer. The 1H- and 13C-NMR (5a) This was obtained by reacting 4a (3.38 g) and thioglycolic acid
1
spectra were recorded on a Varian Gemini spectrometer (300 MHz for H-
and 75 MHz for 13C-NMR). Chemical shifts are reported in d ppm units
with respect to tetramethylsilane (TMS) as internal standard and coupling
constants (J) are reported in Hz units. Mass spectra were recorded on a VG
(1.12 g) as described in the typical procedure and isolated as brown solid.
Yield 71%, mp 210—212 °C. IR (KBr) cmꢂ1: 3062, 1698, 1612, 1604,
1
1475, 1066, 712. H-NMR (DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s, 2H,
Ar-H), 7.25—7.19 (m, 6H, Ar-H), 7.10 (d, Jꢁ7.9 Hz, 4H, Ar-H), 5.94 (s,
micro mass 7070H spectrometer. Elemental analyses (C, H, N) determined 2H, CH), 4.20 (s, 2H, CH2), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3), 2.24 (s,
by means of a Perkin-Elmer 240 CHN elemental analyzer, were within 6H, CH3). 13C-NMR (DMSO-d6) d: 173.2, 170.6, 154.9, 150.8, 142.9,
ꢄ0.4% of theory.
137.9, 135.2, 135.0, 132.0, 127.4, 126.9, 125.8, 124.6, 123.7, 118.9, 72.0,
Typical Procedure 5-[(7-Carboxy-3-methylbenzo[b]furan-5-yl)- 42.0, 33.9, 22.1, 9.20. MS m/z: 828 (Mꢀ). Anal. Calcd for C43H34N4O4S4: C,
methyl]-3-methylbenzo[b]furan-7-carboxylic Acid (2) To a stirred solu-
tion of 1 (5 mmol), anhydrous potassium carbonate (3 mmol) and a catalytic
amount of potassium iodide in dry acetone (30 ml), was added drop wise a
solution of chloroacetone (10 mmol) in dry acetone (20 ml) at reflux temper-
62.45; H, 4.14; N, 10.16. Found: C, 62.90; H, 4.10; N, 10.11.
2-(4-Chlorophenyl)-3-(5-5-[(7-5-[2-(4-chlorophenyl)-4-oxo-1,3-thia-
zolan-3-yl]-1,3,4-thiadiazol-2-yl-3-methylbenzo[b]furan-5-yl)methyl]-3-
methylbenzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-1,3-thiazolan-4-one (5b)
ature. Reflux was continued for 12 h. The reaction mixture was concentrated This was obtained by reacting 4b (3.6 g) and thioglycolic acid (1.12 g) as de-
to dryness and then transferred to ice water, and the solid separated was col- scribed in the typical procedure and isolated as brown solid. Yield 73%, mp
lected by filtration. The crude product was dissolved in ethanolic potassium 201—203 °C. IR (KBr) cmꢂ1: 3062, 1696, 1612, 1604, 1475, 1065, 712,
hydroxide (10%, 100 ml) and further refluxed for 18 h. The excess ethanol 685. 1H-NMR (DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-H), 7.30 (d,
was then removed by distillation in vacuo, the reaction mixture was poured Jꢁ8.2 Hz, 4H, Ar-H), 7.25—7.19 (m, 6H, Ar-H), 5.94 (s, 2H, CH), 4.20 (s,
into ice-cold aq. HCl and the solid collected by filtration, purified by column
2H, CH2), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3). 13C-NMR (DMSO-d6) d:
chromatography using pet-ether (60—80 °C) as eluent to give pure 2 as yel- 173.2, 170.5, 154.9, 150.8, 142.7, 138.9, 135.2, 133.1, 132.0, 129.7, 128.6,
low solid. Yield 72%, mp 182—184 °C. IR (KBr) cmꢂ1: 3300—3200, 3037, 127.4, 126.8, 125.8, 123.7, 118.9, 72.0, 42.0, 33.9, 9.20. MS m/z: 868 (Mꢀ).
1
1695, 1030. H-NMR (DMSO-d6) d: 9.90 (s, 2H, OH), 7.79 (s, 2H, Ar-H), Anal. Calcd for C41H28Cl2N6O4S4: C, 56.74; H, 3.25; N, 9.68. Found: C,
7.65—7.60 (m, 4H, Ar-H), 4.11 (s, 2H, CH2), 2.39 (s, 6H, CH3). 13C-NMR 56.70; H, 3.21; N, 9.70.
(DMSO-d6) d: 172.6, 152.7, 143.9, 135.2, 132.9, 132.0, 124.6, 121.2, 119.1,
42.7, 9.2. MS m/z: 365 (Mꢀꢀ1, 10%), 106 (100%). Anal. Calcd for zolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b]furan-5-yl)methyl]benzo[b]-
C21H16O8: C, 69.23; H, 4.43. Found: C, 69.18; H, 4.40.
furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(4-nitrophenyl)-1,3-thiazolan-4-one
Typical Procedure 5-(5-{[7-(5-Amino-1,3,4-thiadiazol-2-yl)-3- (5c) This was obtained by reacting 4c (3.7 g) and thioglycolic acid (1.12 g)
3-(5-3-Methyl-5-[(3-methyl-7-5-[2-(4-nitrophenyl)-4-oxo-1,3-thia-

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809
as described in the typical procedure and isolated as yellow solid. Yield 132.1, 127.3, 126.7, 125.8, 123.6, 119.3, 118.8, 109.6, 56.0, 42.0, 34.0,
74%, mp 198—200 °C. IR (KBr) cmꢂ1:3065, 1698, 1612, 1604, 1520, 1475, 9.31. MS m/z: 892 (Mꢀ). Anal. Calcd for C43H34N6O8S4: C, 57.96; H, 3.85;
1370, 1066, 712. 1H-NMR (DMSO-d6) d: 7.69 (d, Jꢁ8.2 Hz, 4H, Ar-H), N, 9.43. Found: C, 57.90; H, 3.81; N, 9.38.
7.60 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-H), 7.41 (d, Jꢁ8.2 Hz, 4H, Ar-H), 7.24
2-(2-Furyl)-3-(5-5-[(7-5-[2-(2-furyl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-
(s, 2H, Ar-H), 5.94 (s, 2H, CH), 4.20 (s, 2H, CH2), 3.67 (s, 4H, CH2), 2.36 thiadiazol-2-yl-3-methylbennzo[b]furan-5-yl)methyl]-3-methylbenzo-
(s, 6H, CH3). 13C-NMR (DMSO-d6) d: 173.3, 170.5, 154.8, 150.7, 142.8, [b]furan-7-yl-1,3,4-thiadiazol-2-yl)-1,3-thiazolan-4-one (5i) This was
146.2, 146.0, 135.2, 132.0, 128.1, 127.4, 126.8, 125.8, 123.8, 123.0, 118.8,
72.0, 42.0, 34.0, 9.20. MS m/z: 888 (Mꢀ). Anal. Calcd for C41H28N8O8S4: C,
55.40; H, 3.17; N, 12.61. Found: C, 55.36; H,3.10; N,12.55.
obtained by reacting 4i (3.15 g) and thioglycolic acid (1.12 g) as described in
the typical procedure and isolated as black solid. Yield 82%, mp 177—
179 °C. IR (KBr) cmꢂ1: 3070, 1698, 1610, 1604, 1475, 1062, 714. 1H-NMR
3-(5-3-Methyl-5-[(3-methyl-7-5-[2-(3-nitrophenyl)-4-oxo-1,3-thia- (DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-H), 7.56 (d, Jꢁ8.0 Hz,
zolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b]furan-5-yl)methyl]benzo[b]- 2H, Ar-H), 7.24 (s, 2H, Ar-H), 6.50—6.40 (m, 4H, Ar-H), 6.22 (s, 2H, CH),
furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(3-nitrophenyl)-1,3-thiazolan-4-one
4.20 (s, 2H, CH2), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3). 13C-NMR (DMSO-
(5d) This was obtained by reacting 4d (3.7 g) and thioglycolic acid (1.12 g) d6) d: 173.0, 170.1, 154.7, 150.8, 142.9, 147.6, 145.8, 144.3, 135.2, 132.1,
as described in the typical procedure and isolated as brown solid. Yield 76%, 127.2, 126.8, 125.9, 123.6, 121.7, 118.9, 106.1, 58.7, 42.0, 34.2, 9.21. MS
mp 209—211 °C. IR (KBr) cmꢂ1: 3070, 1696, 1612, 1604, 1520, 1475,
m/z: 778 (Mꢀ). Anal. Calcd for C37H26N6O6S4: C, 57.06; H, 3.36; N, 10.79.
1370, 1066, 712. 1H-NMR (DMSO-d6) d: 8.20 (s, 2H, CH), 8.11 (d, Found: C, 57.00; H, 3.30; N, 10.72.
Jꢁ8.4 Hz, 2H, Ar-H), 7.64 (s, 2H, Ar-H), 7.56 (d, Jꢁ7.8 Hz, 4H, Ar-H),
2-(1,3-Benzodioxol-5-yl)-3-(5-5-[(7-5-[2-(1,3-benzodioxol-5-yl)-4-oxo-
7.49 (s, 2H, Ar-H), 7.41 (d, Jꢁ7.8 Hz, 4H, Ar-H), 7.24 (s, 2H, Ar-H), 6.11 1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-yl-3-methylbenzo[b]furan-5-
(s, 2H, CH), 4.20 (s, 2H, CH2), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3). 13C- yl)methyl]-3-methylbenzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-1,3-thia-
NMR (DMSO-d6) d: 173.5, 170.6, 154.7, 150.6, 142.7, 141.4, 147.6, 135.2, zolan-4-one (5j) This was obtained by reacting 4j (3.69 g) and thioglycolic
132.8, 132.0, 130.1, 127.3, 126.7, 125.8, 124.5, 123.7, 120.5, 118.6, 72.58, acid (1.12 g) as described in the typical procedure and isolated as black
42.0, 34.0, 9.20. MS m/z: 888 (Mꢀ). Anal. Calcd for C41H28N8O8S4: C, solid. Yield 77%, mp 211—213 °C. IR (KBr) cmꢂ1: 3072, 1698, 1612, 1604,
55.40; H, 3.17; N,12.61. Found: C, 55.37; H, 3.14; N, 12.65.
1475, 1066, 1027, 713. 1H-NMR (DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s,
2-(4-Hydroxyphenyl)-3-(5-5-[(7-5-[2-(4-hydroxyphenyl)-4-oxo-1,3-thi- 2H, Ar-H), 7.24 (s, 2H, Ar-H), 7.14 (d, Jꢁ7.9 Hz, 2H, Ar-H), 6.98—6.90
azolan-3-yl]-1,3,4-thiadiazol-2-yl-3-methylbenzo[b]furan-5-yl)methyl]-3- (m, 4H, Ar-H), 5.94 (s, 2H, CH), 5.92 (s, 4H, CH2), 4.20 (s, 2H, CH2), 3.67
methylbenzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-1,3-thiazolan-4-one (5e) (s, 4H, CH2), 2.36 (s, 6H, CH3). 13C-NMR (DMSO-d6) d: 173.2, 170.6,
This was obtained by reacting 4e (3.41 g) and thioglycolic acid (1.12 g) as 154.6, 150.8, 148.1, 147.9, 142.7, 135.9, 135.2, 132.0, 127.1, 126.9, 125.8,
described in the typical procedure and isolated as brown solid. Yield 77%,
123.6, 119.7, 118.7, 109.2, 105.3, 72.8, 42.0, 34.0, 9.20. MS m/z: 886 (Mꢀ).
Anal. Calcd for C43H30N6O8S4: C, 58.23; H, 3.41; N, 9.47. Found: C, 58.20;
mp 188—190 °C. IR (KBr) cmꢂ1: 3372, 3047, 1699, 1612, 1604, 1475,
1
1064, 712. H-NMR (DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-H), H, 3.36; N, 9.42.
7.25—7.19 (m, 6H, Ar-H), 6.99 (d, Jꢁ8.2 Hz, 4H, Ar-H), 5.94 (s, 2H, CH),
Nematicidal Assay For the nematicidal assay the D. myceliophagus was
extracted from the cultivated mushrooms (Agaricus bisporus) infected with
5.00 (s, 2H, OH), 4.20 (s, 2H, CH2), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3).
13C-NMR (DMSO-d6) d: 173.2, 170.5, 157.9, 154.6, 150.6, 142.8, 134.9, the nematode, and C. elegans was grown on 10 cm 8P plates55) on a E. coli
135.2, 132.0, 127.3, 126.8, 126.0, 125.8, 123.6, 118.5, 114.7, 72.0, 42.0,
34.0, 9.20. MS m/z: 830 (Mꢀ). Anal. Calcd for C41H30N6O6S4: C, 59.26; H, dant food source for large quantities on nematode. The nematode water sus-
3.64; N,10.11. Found: C, 59.29; H, 3.60; N, 10.07. pension was collected in Petri dishes. Suspension of adult worms from 5 d
NA22 bacteria diet, which grow in a very thick layer and constitute an abun-
2-(2-Hydroxyphenyl)-3-(5-5-[(7-5-[2-(2-hydroxyphenyl)-4-oxo-1,3-thi- old culture was diluted with approximately 100 to 250 nematodes/ml of
azolan-3-yl]-1,3,4-thiadiazol-2-yl-3-methylbenzo[b]furan-5-yl)methyl]-3- water, 100 ml of the nematode suspension was introduced into a solution of
methylbenzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-1,3-thiazolan-4-one (5f) each test compound at various concentrations in a well of 24-well plates and
This was obtained by reacting 4f (3.41 g) and thioglycolic acid (1.12 g) as incubated at 25 °C. The percentage of immobile nematodes was recorded
described in the typical procedure and isolated as brown solid. Yield 75%,
after 2 d. The LD50 values of the compounds screened are presented in Table
1.
Antibacterial Activity For the antibacterial assay the bacteria were
grown over night in Luria Bertani (LB) broth at 37 °C, harvested by centrifu-
mp 190—192 °C. IR (KBr) cmꢂ1: 3272, 3049, 1698, 1612, 1604, 1475,
1
1062, 710. H-NMR (DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-H),
7.25—7.19 (m, 6H, Ar-H), 6.88—6.78 (m, 4H, Ar-H), 6.61 (s, 2H, OH),
6.11 (s, 2H, CH), 4.20 (s, 2H, CH2), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3). gation, and then washed twice with sterile distilled water. Stock solutions of
13C-NMR (DMSO-d6) d: 173.2, 170.4, 154.8, 152.7, 150.8, 142.7, 135.2, the series of compounds were prepared in DMSO. Each stock solution was
132.0, 128.4, 127.3, 127.0, 126.7, 125.8, 123.5, 122.6, 120.6, 118.6, 115.7,
66.7, 42.0, 34.1, 9.30. MS m/z: 830 (Mꢀ). Anal. Calcd for C41H30N6O6S4: C,
59.26; H, 3.64; N, 10.11. Found: C, 59.20; H, 3.59; N, 10.09.
diluted with standard method broth (Difco) to prepare serial two-fold dilu-
tions in the range of 50—0.8 mg/ml. Ten microliters of the broth containing
about 105 colony forming units (cfu)/ml of test bacteria wasere added to
2-[4-(Dimethylamino)phenyl]-3-[5-(5-[7-(5-2-[4-(dimethylamino)- each well of 96-well microtiter plate. Culture plates were incubated for 24 h
phenyl]-4-oxo-1,3-thiazolan-3-yl-1,3,4-thiadiazol-2-yl)-3-methylbenzo- at 37 °C, and the growth was monitored visually and spectrophotometrically.
[b]furan-5-yl]methyl-3-methylbenzo[b]furan-7-yl)-1,3,4-thiadiazol-2-yl]-
1,3-thiazolan-4-one (5g) This was obtained by reacting 4g (3.68 g) and
Antifungal Activity For the antifungal assay the C. albicans was grown
for 48 h at 28 °C in YPD broth (1% yeast extract, 2% peptone, and 2% dex-
thioglycolic acid (1.12 g) as described in the typical procedure and isolated trose), harvested by centrifugation and then washed twice with sterile dis-
as black solid. Yield 74%, mp 222—224 °C. IR (KBr) cmꢂ1: 3062, 1698, tilled water. A. fumigatus, T. rubrum and T. mentagrophytes were plated in
1
1612, 1605, 1475, 1065, 711. H-NMR (DMSO-d6) d: 7.64 (s, 2H, Ar-H), potato dextrose agar (PDA) (Difco) and incubated at 28 °C for two weeks.
7.49 (s, 2H, Ar-H), 7.24 (s, 2H, Ar-H), 7.14 (d, Jꢁ7.8 Hz, 4H, Ar-H), 6.38 Spores were washed three times with sterile distilled water and resuspended
(d, Jꢁ7.8 Hz, 4H, Ar-H), 5.94 (s, 2H, CH), 4.20 (s, 2H, CH2), 3.67 (s, 4H, in distilled water to obtain an initial inoculum size of 105 spores/ml. Each
CH2), 3.00 (s, 12H, CH3), 2.36 (s, 6H, CH3). 13C-NMR (DMSO-d6) d: test compound was dissolved in DMSO and diluted with potato dextrose
173.1, 170.3, 154.7, 150.6, 142.9, 142.6, 135.2, 134.6, 132.0, 127.9, 127.0, broth (Difco) to prepare serial two-fold dilutions in the range of 100 to
126.8, 125.7, 123.6, 118.7, 112.4, 72.0, 44.5, 42.0, 34.0, 9.20. MS m/z: 886 0.8 mg/ml. Ten microliters of the broth containing about 103 (for yeast) and
(Mꢀ). Anal. Calcd for C45H40N8O4S4: C, 61.07; H, 4.55; N, 12.66. Found: C, 104 (for filamentous fungi) cells/ml of test fungi was added to each well of a
61.00; H, 4.50; N, 12.60.
96-well microtiter plate. Culture plates were incubated for 48—72 h at
2-(4-Hydroxy-3-methoxyphenyl)-3-(5-5-[(7-5-[2-(4-hydroxy-3- 28 °C.
methoxyphenyl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-yl-3-
methylbenzo[b]furan-5-yl)methyl]-3-methylbenzo[b]furan-7-yl-1,3,4-
Acknowledgements The authors are grateful to the Director, Indian In-
thiadiazol-2-yl)-1,3-thiazolan-4-one (5h) This was obtained by reacting stitute of Chemical Technology, Hyderabad, India, for providing NMR and
4h (3.71 g) and thioglycolic acid (1.12 g) as described in the typical proce- Mass spectral data. Financial assistance from the UGC SAP (Phase-I)-DRS
dure and isolated as black solid. Yield 79%, mp 237—239 °C. IR (KBr)
Programme, New Delhi, India, is greatly acknowledged.
cmꢂ1: 3290, 3061, 1697, 1612, 1604, 1475, 1066, 1030, 712. 1H-NMR
(DMSO-d6) d: 7.64 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-H), 7.24 (s, 2H, Ar-H), References and Notes
7.14—6.90 (m, 6H, Ar-H), 5.94 (s, 2H, CH), 4.87 (s, 2H, OH), 4.20 (s, 2H,
CH2), 3.77 (s, 6H, CH3), 3.67 (s, 4H, CH2), 2.36 (s, 6H, CH3). 13C-NMR
(DMSO-d6) d: 173.2, 170.4, 154.8, 150.8, 148.7, 147.8, 142.9, 135.9, 135.1,
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