Synthesis and evaluation of some new spiro indoline-based heterocycles as potentially active antimicrobial agents

Article abstract of DOI:10.1016/j.bmc.2003.10.063

Several new spiro indoline-based heterocycles were synthesized by prior preparation of the 4-(2^′-oxo-indol-3^′-ylidene) -oxazol-5-one derivatives and subsequent reaction of the produced indol-3-ylidene based heterocycles with activated nitrile reagents. The obtained products were allowed to react with hydrazine hydrate in alcoholic basic to give the target compounds. Structure of these products was confirmed on the bases of elemental as well as spectral data. Representative compounds of the hitherto synthesized products were tested and evaluated as antimicrobial agents.

Full text of DOI:10.1016/j.bmc.2003.10.063

Bioorganic & Medicinal Chemistry 12 (2004) 2483–2488
Synthesis and evaluation of some new spiro indoline-based
heterocycles as potentially active antimicrobial agents
A. H. Abdel-Rahman,a,* E. M. Keshk,a M. A. Hannab and Sh. M. El-Badyb,
aChemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
bChemistry Department, Faculty of Science at Damietta, Mansoura Uni., Damietta, Egypt
Received 12 June 2003; accepted 3 October 2003
Abstract—Several new spiro indoline-based heterocycles were synthesized by prior preparation of the 4-(20-oxo-indol-30-ylidene)-
oxazol-5-one derivatives and subsequent reaction of the produced indol-3-ylidene based heterocycles with activated nitrile reagents.
The obtained products were allowed to react with hydrazine hydrate in alcoholic basic to give the target compounds. Structure of
these products was confirmed on the bases of elemental as well as spectral data. Representative compounds of the hitherto syn-
thesized products were tested and evaluated as antimicrobial agents.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and Discussion
Long time ago, several patents and reports that, deal
with pharmacological studies on various heterocyclic
systems, have been published. Of these various hetero-
cycles, the indole nucleus has been reported to possess
great importance in the field of medicine and biochem-
istry.1–5
The hitherto synthesized compounds were prepared
according to the sequence of reactions that are illus-
trated in Charts 1–3. Thus, refluxing an ethanolic solu-
tion of the previously unreported 1,2-oxazolone
derivatives with ethyl cyanoacetate in presence of few
drops of piperidine afforded pure colored products in an
average good yield. The latter products might be for-
mulated as the intermediate adducts 5a,b or their spiro
(30H) indol-30,4-(4H)-pyrano(3,2-d)-1,2-oxazole end
products 6a,b.
On the other hand, pyran nucleus has been found to be
associated with a group of biological activities.6;7 Fur-
thermore, it has been reported that sharing of the indole
3-carbon atom in the formation of spiro indoline
derivatives highly enhances biological activity.8
Analytical data of the synthesized compounds indicated
a molecular formulae of C17H15N3O5 and C22H17N3O5,
respectively, which are in accordance with the latter
structure 6. 1H NMR spectrum of compound 6b
revealed no singlet signals in the region of 4.40–
4.00 ppm. If the obtained products are the acyclic oxa-
zole derivatives 5, at least two singlet signals in this
range, which corresponds to the activated methine
protons, should have been expected to appear for each
product in its 1H NMR spectrum. The latter observation
confirms the conversion of the intermediate Michael
adducts 5a,b into the corresponding spiro end products
6a and 6b, respectively.
Prompted by these findings and the reported9 impor-
tance of reactions of arylidene azolones with activated
nitriles to form polycyclic products, we report herein in
this thesis about the behavior of 4-(30-indol-30-ylidene)-
3-substituted 1,2-oxazoline-5-one derivatives 4 toward
the same reagents.
Keywords: Spiro indoline-based heterocycles; Synthesis; Antimicrobial
evaluations.
Reaction of 4a,b with malononitrile in alcoholic
basic medium yielded pure yellow-colored products 6c,d.
IR spectra of these products exhibited five characteris-
tic absorption bands at 3480–3210, 2220–2200, 1675,
* Corresponding author. Fax: +20-50-22-46-781; e-mail: mahanna69@
hotmail.com
Taken in part from M.Sc. Thesis of the fourth author.
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.10.063

2484
A. H. Abdel-Rahman et al. / Bioorg. Med. Chem. 12 (2004) 2483–2488
O
O
CN
H2C
O
O
O
+
O
X
X
CH2 COOH
NHCO Ar
Ac2O
NaOAc
N
N
Ar
R
N
H
H2C
+
3 a, b
CN
2 a, b
N
H
O
a: X = COOEt
b: X = CN
1
a: R = CH3
b: R = Ph
8 a, b
1
a: Ar = C6H5
b: Ar = C6 H4 NO2
9 a, b
P
O
1
+
3 a, b
N
H
O
O
O
N
CN
X
3 a, b
O
X
C
R
O
N
H
CN
N
O
O
N
H
4 a, b
N
H
O
Ar
X
10 a-d
7 a, b
CN
3 a, b
O
N
H
8 a, b
CN
X
7 a, b
O
N
C
11 a-d
H
O
O
X
N
H
N
O
R
2 a, b
O
Ar
R
10, 11
a
b
c
5 a-d
COOEt
COOEt
CN
C
H
Ar
6
6
5
4
5
O
N
N
C
C
C
H
H
H
-NO -p
2
6
H
-NO -p
4 2
d
CN
6
6 a-d
C
O
N
X
OH
X
NH2
X
5, 6
a
b
c
d
R
NH
O
O
CH
COOEt
N
H
N
3
R
O
C
H
COOEt
CN
CN
5
6
O
X
CH
3
5
O
C H
6
Ar
Ar
N
N
O
N
H
O
N
NH2
H
HN
11 a-d
O
O
O
X
X
O
N
Chart 2.
N
O
N
H
O
N
R
R
H
which then cyclize under the reaction conditions to the
isolable end products (Chart 1).
6 a-d
Chart 1.
Further confirmation for the suggested structures was
obtained from an independent synthesis via prior prep-
aration of the arylidene derivatives 7a,b and subsequent
reaction of the latter products with the oxazolone
derivatives 2a,b to give the end products 6 in good yield.
No depression in melting points was observed on
admixing a sample of any of the latter end products with
authentic samples that were prepared via the previously
mentioned first pathway (Chart 1).
1625–1620, and 1180 cmꢀ1 that correspond to NH2 and
NH, cyano, cyclic secondary amidic, C@N and cyclic
ether linkage, respectively. 1H NMR spectra also
revealed the absence of any singlet signals that might
correspond to the previously mentioned methine pro-
tons.
Besides the normal signals that correspond to the dif-
ferent protons of aromatic and alkyl moieties in 1H
NMR spectrum of compound 6c, there were appeared
two other broad signals at 11.30 and 7.55 ppm that dis-
appeared on adding deuterium oxide. The latter signal
might be ascribed to the two exchangeable protons of the
amino function. The presence of the latter amino protons
signal and the absence of any methine signal in 1H NMR
spectrum of compound 6c highly substantiate the sug-
gested enamino nitrile structure 6 for this product.
Similarly, 4-(20-oxo-indol-30-ylidene)-1,3-oxazol-5-one
derivatives 9a,b showed the same behavior, when sub-
jected to react, under similar reaction conditions, with
the same reagents. Thus, prior preparation of com-
pounds 9, by reaction of 2,3-dioxoindole with hippuric
acid derivatives 8 and subsequent treatment of the pre-
pared compounds with active nitrile reagents afforded
the intermediate Michael adducts 10 that cyclize simul-
taneously to the spiro (30H)-indol-30,4-(4H) pyrano(3,2-
d)-1,3-oxazole end products 11a–d (Chart 2).
The formation of products 6 from the reaction of 4 with
malononitrile or ethyl cyanoacetate is assumed to pro-
ceed via addition of the active methylene reagents (Mi-
chael donors) to the activated double bond in 4 (Michael
acceptors) to yield the intermediate Michael adducts 5,
Besides correct elemental analysis, structure of the
hitherto synthesized spiro compounds 11 was confirmed
on the basis of spectral data and whenever possible, by

A. H. Abdel-Rahman et al. / Bioorg. Med. Chem. 12 (2004) 2483–2488
2485
NH
Thus, reaction of each of products 6 and 11 with
hydrazine hydrate in absolute ethanol in presence of few
drops of piperidine or triethyl amine yielded a group of
spiro indoline-based fused tricyclic products that were
formulated as the spiro (30H)-indol-30,4-(4H)pyrazolo-
(3,4-b)pyrano(3,2-d)-1,2-oxazole derivatives 12 and 13
and spiro (30H)-indol-30,4-(4H)pyrazolo-(3,4-b)pyr-
ano(3,2-d)-1,3-oxazole derivatives 14 and 15, respec-
tively (Chart 3). Structure of the latter pyrazolo
derivatives was established on the basis of correct ele-
mental and spectral data (see Experimental). Besides,
the characteristic absorption bands for the cyclic amidic
functions in the hitherto prepared indolene-based spiro
pyrazolo(3,4-b)pyrano(3,2-d)oxazole derivatives 12–15,
IR spectra of compounds 12 revealed their NH
HN
O
O
+ 6 a, b
O
N
O
N
R
H
12 a, b
NH
N
O
H2N
+ 6 c, d
O
N
O
N
H
R
12, 13,
14 & 15
R
13 a, b
12a, 13a
CH
H2N NH2.H2O
3
5
5
C
C
H
H
H
12b, 13b
14a, 15a
14b, 15b
6
6
6
stretching vibrations in the region of 3240–3200 cmꢀ1
.
C
-NO p
2-
4
NH
HN
O
O
The synthesized spiro tricyclic compounds might exhibit
enhanced and/or altered biological activities as a result
of the presence of an extended fused pyrazole moiety in
their structure.
O
+ 11 a, b
N
O
N
R
H
14 a, b
NH
N
O
H2N
+ 11 c, d
3. Antimicrobial screening
O
N
O
N
R
The antibacterial as well as antifungal activities of a
solution of the hitherto synthesized compounds in
dimethyl formamide (DMF) were tested and evaluated
against some gram positive (Bacillus subtilis and Bacillus
megatherium, gram negative (Escherichia coli) and fungi
(Aspergillus niger and Aspergillus oryzae) and compared
with respect to some reference antibiotics that were
purchased from Egyptian market. The obtained results
(Table 4) revealed that while most of the prepared spiro
3H-indole-3,40-pyrano(30,20-d)oxazole derivatives (6a–d
and 11a–d) showed comparable activity, the spiro
3H-indole-3,40-pyrazolo(30,40-b)pyrano(30,20-d)oxazole
derivatives (12a,b, 13a,b, 14a,b, and 15a,b) revealed very
high activity with respect to the used references. On the
other hand, nearly all of the prepared compounds
exhibited an interesting high antifungal activity against
the reference chemotherapeutics.
H
15 a, b
Chart 3.
an independent synthetic pathways. Thus, compounds
11a,b were independently synthesized by refluxing the
arylidene derivatives 7a,b with hippuric acid derivatives
in acetic anhydride in the presence of a catalytic amount
of fused sodium acetate. IR spectrum of compound 11c
showed absorption bands at 3460–3240, 2220, 1675,
1625, and 1180 cmꢀ1 that might be ascribed to the amino
and NH, cyano, cyclic secondary amidic C@N and
pyran ether moieties, respectively.
Besides, the multiplet aromatic signals that appeared in
1
the range of 7.15–6.65 ppm in H NMR of the cyano
derivative 11d, there were appeared, as for compound
6c, two other exchangeable broad signals that were
centered near 10.25 and 7.35 ppm and might be attrib-
uted to the cyclic amidic and primary amino protons,
respectively.
4. Experimental
In this aspect, it is also interesting to mention that the
amino signal of structure 6b is deshielded by 0.50–
0.70 ppm as compared to that in compounds 6c and 11d.
This low field shift is due to the anisotropic effect of the
ethoxycarbonyl function in 6b.
The homogeneity and purity of the prepared com-
pounds were checked by TLC. Melting points are
uncorrected and measured on a Fisher–Johns apparatus.
Recorded yields correspond to the pure products. IR
(KBr) spectra were recorded on a Perkin Elmer SP-880
spectrophotometer and 1H NMR spectra were measured
on a Varian 270 MHz spectrometer using CDCl3 solvent
and tetramethylsilane (TMS) as in internal standard
(chemical shifts are given as in ppm). Microanalyses
were carried out in the Microanalytical data unit in
Cairo and at University of Mansoura. Nomenclature of
the hitherto prepared compounds is given in accordance
with IUPAC rules for nomenclature of organic com-
pounds.
In view of literature reports11;12 about the reaction of
acyclic and cyclic b-enamino esters and b-enamino
nitriles with hydrazines and amines to yield Michael
adducts, which then undergo further reactions depend-
ing on the nature of the reacting enamino ester or nitrile,
It seems worthy to investigate and rationalize this
behavior on the hitherto prepared enamino nitriles and
esters 6 and 11, respectively.

2486
A. H. Abdel-Rahman et al. / Bioorg. Med. Chem. 12 (2004) 2483–2488
Table 1. Physical and spectral data of the newly synthesized compounds (4a,b) and (6a–d)
Compd
no.
Mp (°C)
yield (%)
Molecular
formula
(M. wt.)
% Analysis Calcd/(Found)
IR (m, cmꢀ1) and 1H NMR (CDCl3, ppm)
C
H
N
4a
4b
6a
205 (70)
245 (75)
230 (70)
C12H8N2O3
(228.22)
63.15 (63.26)
70.33 (70.23)
59.81 (59.73)
3.54 (3.32)
3.48 (3.37)
4.44 (4.67)
12.2 (12.39)
9.65 (9.56)
12.31 (12.51)
IR: 3210 (NH), 1695 (C@O), 1680 (sec-amidic
C@O), 1630 (C@N)
IR: 3200 (NH), 1695 (C@O), 1680 (sec-amidic
C@O), 1625 (C@N)
IR: 3460 (NH2), 3240 (NH), 1725 (COOC2H5),
1680 (sec-amidic C@O), 1625 (C@N), 1175
(ether linkage of pyran moiety)
C17H10N2O3
(290.29)
C17H15N3O5
(341.35)
6b
6c
6d
265 (80)
250 (80)
281 (75)
C22H17N3O5
(403.42)
65.50 (65.33)
61.22 (61.09)
67.40 (67.33)
4.26 (4.16)
3.43 (3.55)
3.40 (3.28)
10.42 (10.33)
19.04 (18.86)
15.73 (15.64)
IR: 3480 (NH2), 3220 (NH), 1725 (COOC2H5),
1680 (sec-amidic C@O), 1620 (C@N), 1175
(ether linkage of pyran moiety). H NMR: 11.35
(br, 1H, amidic NH, ex.), 8.05 (br, 2H, NH2,
ex.), 7.45-6.90 (m, 9H, Ar–H) 4.15 (q, 2H,
CH2–CH3), 1.10 (t, 3H, CH2–CH3)
C15H10N4O3
(294.29)
IR: 3460 (NH2), 3210 (NH),2200 (CBN), 1675
(sec-amidic C@O), 1625 (C@N) 1180 (ether
linkage of pyran moiety) H NMR: 11.30 (br,
1H, amidic NH), 7.55 (br, 2H, NH2, ex.) 7.35-
6.95 (m, 4H, Ar–H), 0.95 (s, 3H, oxazolyl CH3
protons)
C20H12N4O3
(356.36)
IR: 3480 (NH2), 3240 (NH), 2220 (CBN), 1675
(sec-amidic C@O), 1620 (C@N),1180 (ether
linkage of pyran moiety)
4.1. Synthesis of 4-(20-oxo-indol-30-ylidene)-1,2-oxazol-5-
one derivatives (4a,b)
containing 3 drops of piperidine, was refluxed for 6 h,
then left to cool. Following up the reaction as in 4.1 gave
pure, pale to deep red products 6a–d (cf. Table 1).
A mixture of isatin (10 mmol) and 3-substituted iso-
xazolone derivatives 2a,b (10 mmol in each case) in
absolute ethanol (20 mL) containing 3 drops of piperi-
dine was refluxed for 6 h. The solid that separated was
filtered off and recrystallized from ethanol to give pure
orange to red products 4a,b (cf. Table 1).
4.5. Synthesis of 4-(20-oxo-indol-30-ylidene)-1,3-oxazol-5-
one derivatives (9a,b)
A mixture of isatin (10 mmol) and hippuric acid deriv-
atives 8a,b (10 mmol in each case) in acetic acid anhy-
dride (15 mL) containing fused sodium acetate (1 g) was
refluxed in water bath for 3 h, then left to cool. Ethanol
(15 mL) was added to the mixture and left it overnight.
Following up the reaction as in 4.1 yielded pure gray to
black products 9a,b (cf. Table 2).
4.2. Synthesis of 6-amino spiro [30H-indol-30,4-(4H)-
pyrano (3,2-d)-1,2-oxazol] (10H)-20-one derivatives (6a–d)
To a solution of 4a,b (10 mmol in each case) in absolute
ethanol (20 mL) containing 3 drops of piperidine, ethyl
cyanoacetate 3a or malono nitrile 3b (10 mmol in each
case) was added and the whole reaction mixture was
refluxed for 6 h, Following up the reaction as in 4.1 gave
pure pale to deep red products 6a–d (cf. Table 1).
4.6. Synthesis of 6-amino spiro [30H-indol-30,4-(4H)-
pyrano(3,2-d)-1,3-oxazol] (10H)-20-one derivatives (11a–d)
To a suspension of 9a,b (10 mmol in each case) in
absolute ethanol (20 mL) containing 3 drops of piperi-
dine, 3a,b (10 mmol in each case) was added. After
refluxing for 4 h, the reaction mixture was poured onto
ice water and the resulting precipitate filtered off.
Recrystallization of the latter crude product, from
methanol, afforded pure orange to brown products
(cf. Table 2).
4.3. Synthesis of 2-oxo-(3H)-indol-3-ylidene malononitrile
and 2-oxo-(3H)-indol-3-ylidene ethyl cyanoacetate (7a,b)
To a solution of isatin (10 mmol) in absolute ethanol
(20 mL) containing 3 drops of piperidine, ethyl cyano-
acetate 3a or malononitrile 3b (10 mmol in each case)
was added. The reaction mixture was heated for 5 min,
then left to cool. Following up the reaction as in 4.1 gave
pure pale to deep red products 7a,b.
4.7. Alternative synthetic route for preparation
of compounds 11a–d
4.4. Alternative synthetic route for preparation
of compounds 6a–d
A mixture of 8a,b (5 mmol in each case) and fused so-
dium acetate (0.3 g) in acetic anhydride (10 mL) was
refluxed in water bath for 40 min. Then 7a,b (5 mmol in
each case) was added to the reaction mixture and ref-
A mixture of 2a,b (10 mmol in each case) and 7a,b10
(10 mmol in each case) in absolute ethanol (20 mL)

A. H. Abdel-Rahman et al. / Bioorg. Med. Chem. 12 (2004) 2483–2488
2487
Table 2. Physical and spectral data of the newly synthesized compounds (9a,b) and (11a–d)
Compd
no.
Mp (°C),
yield (%)
Molecular
formula
(M. wt.)
% Analysis calcd/(found)
IR (m, cmꢀ1) and 1H NMR (CDCl3, d/ppm)
C
H
N
9a
160 (90)
80 (220)
195 (70)
C17H10N2O3
(290.29)
70.33 (70.45)
60.89 (60.73)
65.50 (65.35)
3.48 (3.52)
2.71 (2.89)
4.26 (4.33)
9.65 (9.69)
IR: 3210 (NH), 1695 (C@O), 1680 (sec-amidic
C@O), 1620 (C@N)
IR: 3200 (NH), 1695 (C@O), 1680 (sec-amidic
C@O), 1625 (C@N)
IR: 3450 (NH2), 3220 (NH), 1720 (COOC2H5),
1680 (sec-amidic C@O) 1620 (C@N), 1170 (ether
linkage of pyran moiety)
9b
C17H9N3O5
(335.29)
12.54 (12.62)
10.42 (10.53)
11a
C22H17N3O5
(403.42)
11b
11c
11d
220 (80)
230 (85)
258 (80)
C22H16N4O7
(448.42)
58.92 (58.80)
67.40 (67.64)
59.85 (59.71)
3.60 (3.71)
3.40 (3.21)
2.77 (2.68)
12.50 (12.55)
15.73 (15.84)
17.45 (17.52)
IR: 3470 (NH2), 3210 (NH), 1725 (COOC2H5),
1680 (sec-amidic C@O), 1625 C@N), 1170 (ether
linkage of pyran moiety)
C20H12N4O3
(356.36)
IR: 3460 (NH2), 3240 (NH), 2220 (CBN), 1675
(sec-amidic C@O), 1625 (C@N), 1180 (ether
linkage of pyran moiety)
C20H11N5O5
(401.36)
IR: 3480 (NH2), 3200 (NH), 2220 (CBN), 1675
(sec-amidic C@O), 1620 (C@N), 1180 (ether
linkage of pyran moiety) H NMR: 10.25 (br, 1H,
amidic NH, ex.), 7.35 (br, 2H, NH2, ex.), 7.15-
6.65 (m, 8H, Ar–H)
luxed for 6 h, then left to cool. Ethanol (15 mL) was
added to the mixture and poured onto ice water. The
resulting precipitate filtered off and recrystallized from
ethanol to give pure orange to brown products 11a–d
(cf. Table 2).
the reaction conditions as in 4.1, pure yellow to
brown products 12a,b and 13a,b were obtained (cf.
Table 3).
4.9. Synthesis of spiro [(3H)-indol-3,40-(40H)-pyrazolo-
(3,4-b)pyrano(3,2-d)-10,30-oxazol]2-(1H)-one derivatives
(14 and 15)
4.8. Synthesis of spiro [(3H)-indol-3,40-(40H)-pyrazolo-
(3,4-b)pyrano(3,2-d)-10,20-oxazol] 2-(1H)-one derivatives
(12, 13)
The reactants, 11a–d (10 mmol in each case) and
hydrazine hydrate (10 mmol), were mixed as described
above. Following up the reaction yielded pure gray to
black products 14a,b and 15a,b (cf. Table 3).
Using a solution of 6a–d (10 mmol in each case)
and hydrazine hydrate (10 mmol) and following up
Table 3. Physical and spectral data of the newly synthesized compounds (12a,b), (13a,b), (14a,b) and (15a,b)
Compd
no.
Mp (°C),
yield (%)
Molecular
formula
(M. wt.)
% Analysis calcd/(found)
IR (m, cmꢀ1) and 1H NMR (CDCl3, d/ppm)
C
H
N
12a
12b
13a
>300 (65)
>300 (70)
>300 (75)
C15H10N4O4
(310.29)
58.06 (58.31)
64.51 (64.40)
58.24 (58.41)
3.26 (3.42)
3.26 (3.41)
3.59 (3.72)
18.06 (18.07)
15.05 (14.98)
22.65 (22.66)
IR: 3220 (NH), 1675 (sec-amidic C@O), 1620
(C@N), 1180 (ether linkage of pyran moiety)
IR: 3200 (NH), 1680 (sec-amidic C@O), 1625
(C@N), 1170 (ether linkage of pyran moiety)
IR: 3460 (NH2), 3210 (NH),1675 (sec-amidic
C@O), 1625 (C@N), 1175 (ether linkage of
pyran moiety)
C20H12N4O4
(372.36)
C15H11N5O3
(309.31)
13b
>300 (80)
C20H13N5O3
(371.38)
64.68 (64.51)
3.54 (3.62)
18.86 (18.95)
IR: 3480 (NH2), 3220 (NH),1680 (sec-amidic
C@O), 1620 (C@N), 1185 (ether linkage of
pyran moiety)
14a
14b
>300 (65)
>300 (75)
C
20H12N4O4
(372.36)
20H11N5O6
64.51 (64.63)
57.55 (57.46)
3.26 (3.58)
2.66 (2.80)
15.05 (14.93)
16.78 (16.85)
IR: 3220 (NH), 1675 (sec-amidic C@O), 1625
(C@N), 1180 (ether linkage of pyran moiety)
IR: 3240(NH),1680 (sec-amidic C@O),
1620(C@N), 1180 (ether linkage of pyran
moiety)
C
(417.36)
15a
15b
>300 (70)
>300 (75)
C20H13N5O3
(371.38)
64.68 (64.63)
57.69 (57.81)
3.54 (3.36)
2.91 (2.83)
18.86 (18.90)
20.19 (20.28)
IR: 3465 (NH2), 3220 (NH),1680 (sec-amidic
C@O), 1625 (C@N), 1185 (ether linkage of
pyran moiety)
C20H12N6O5
(416.38)
IR: 3480 (NH2), 3200 (NH),1675 (sec-amidic
C@O), 1625 (C@N), 1180 (ether linkage of
pyran moiety)

2488
A. H. Abdel-Rahman et al. / Bioorg. Med. Chem. 12 (2004) 2483–2488
Table 4. Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial and antifungal activities of the newly synthesized spiro
indoline-based heterocycles
Compound number
Inhibition zone in mm
Bacteria
Gram positive bacteria
Fungi
Gram negative bacteria
S. subtilis
B. megatherium
E. coli
A. niger
A. oryzae
6a
6b
66
42
35
34
42
––
56
––
65
75
85
81
87
84
76
85
18
55
43
40
34
35
60
63
––
69
65
76
72
86
85
75
70
––
––
––
30
25
––
40
––
––
54
59
60
58
45
40
49
35
15
63
58
66
75
69
72
77
81
85
70
77
84
80
79
90
79
11
71
69
78
74
73
75
79
84
88
80
79
89
86
82
92
86
––
6c
6d
11a
11b
11c
11d
12a
12b
13a
13b
14a
14b
15a
15b
DMF
Reference drugs
Ampicillin
41
28
––
29
55
––
26
48
––
33
35
22
––
––
16
Chloramphenicol
Fluconazle
7. Otsuka, Pharmaceutical Co. Ltd., Jpn. Pat. 8,651,085,
1980; Chem. Abstr., 1980, 93, 186924.
References and notes
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10. Yokoyama, M. J. Chem. Soc. Jpn. 1936, 57, 251.
11. Elnagdi, M. H.; Wamhoff, H. J. Heterocycl. Chem. 1981,
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