Synthesis and biological activity of functionalized indole-2-carboxylates, triazino- and pyridazino-indoles

Article abstract of DOI:10.1002/ardp.200700161

Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4-6; Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7-9. The Mannich reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholinomethyl)-substituted-1H-indole-2- carboxylates 10-12. The 5,7-dichloro-1H-indole-2-carbohydrazide 13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol- 1(2H)-one 14. Vilsmeier-Haack formylation of 7-9 gave ethyl 3-formyl- substituted-1H-indole-2-carboxylates 15-17 whose 2,2′-((5-chloro-2- (ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfanediyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by conventional and microwave methods gave ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2- carboxylates 19-29. In a cyclocondensation reaction of 19-25 with thiolactic acid or thioglycolic acid substituted indolylthiazolidinones 30-33 were prepared. Reaction of hydrazine hydrate with 15-17 did not give the respective hydrazones but directly led to the cyclized products substituted-3H- pyridazino[4,5-b]indol-4(5H)-ones 34-36, while a reaction with 2,4-dichlorophenylhydrazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl₃ gave pyridazino[ 4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34 with formaldehyde and N-ethylpiperazine gave 8-chloro-3-((4- ethylpiperazin-1-yl)methyl)-3H-pyridazino[ 4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound effect on the reaction speed. The structures of the new compounds were confirmed by both analytical and spectral data. Some compounds were subjected to investigations concerning their antimicrobial, tranquilizing, and anticonvulsant activities.

Full text of DOI:10.1002/ardp.200700161

294
Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
Full Paper
Synthesis and Biological Activity of Functionalized Indole-2-
carboxylates, Triazino- and Pyridazino-indoles
Adel A. El-Gendy1, Mohamed M. Said2, Nagat Ghareb2, Yasser M. Mostafa3,
and El Sayed H. El-Ashry4
1 Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
2 Organic Chemistry Department, Faculty of Pharmacy, Suez-Canal University, Ismailia, Egypt
3 Pharmacology Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
4 International Center for Chemical and Biological Sciences (HEJ Research Institute for Chemistry), Karachi
University, Karachi, Pakistan
Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4–6;
Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7–9. The Mannich
reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholino-
methyl)-substituted-1H-indole-2-carboxylates 10-12. The 5,7-dichloro-1H-indole-2-carbohydrazide
13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol-
1(2H)-one 14. Vilsmeier–Haack formylation of 7–9 gave ethyl 3-formyl-substituted-1H-indole-2-
carboxylates 15–17 whose 2,29-((5-chloro-2-(ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfane-
diyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by con-
ventional and microwave methods gave ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2-carboxy-
lates 19–29. In a cyclocondensation reaction of 19–25 with thiolactic acid or thioglycolic acid
substituted indolylthiazolidinones 30–33 were prepared. Reaction of hydrazine hydrate with
15–17 did not give the respective hydrazones but directly led to the cyclized products substi-
tuted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34–36, while a reaction with 2,4-dichlorophenylhy-
drazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl3 gave pyri-
dazino[4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine
gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34
with formaldehyde and N-ethylpiperazine gave 8-chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-pyri-
dazino[4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound
effect on the reaction speed. The structures of the new compounds were confirmed by both ana-
lytical and spectral data. Some compounds were subjected to investigations concerning their
antimicrobial, tranquilizing, and anticonvulsant activities.
Keywords: Fischer Indolization / Substituted phenylhydrazone / Schiff's base / Vilsmeier–Haack Formylation / Thiolac-
tic acid /
Received: July 31, 2007; accepted: November 30, 2007
DOI 10.1002/ardp.200700161
Supporting Information for this article is available from the author or on the WWW under http://www.wiley-vch.de/con-
tents/jc_2019/2007_00161_s.pdf
none moieties were found to possess antibacterial [4–5],
fungicidal [6], antifertility [7], and anticonvulsant [8–9]
Introduction
activities. Likewise, the pyridazino[4,5-b]indole-ring sys-
The incorporation of a nitrogen heterocycle on an ali-
phatic side chain at position-3 of the indole-2-carboxylate
led to diverse biological effects as anti-inflammatory [1],
selective D4 ligands [2], and 5-HT3 antagonists [3]. Indole
compounds containing either linked or fused thiazolidi-
Correspondence: E. S. H. El Ashry, Chemistry Department, Faculty of
Science, Alexandria University, Alexandria, Egypt.
E-mail: Eelashry60@hotmail.com
Fax: +20 342 71360
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
Functionalized Indoles
295
tem has been known for several decades, and, so far, a
variety of biological activities has been reported for its
derivatives, such as antihypertensive [10–14], antiplate-
let aggregation [15–17], and HIV-1 reverse transcriptase
inhibitory [18] activities. In view of these findings, the
present work includes the synthesis of some halogenated
indole-2-carboxylates linked or fused to heterocycles
such as morpholine, pyrazine, pyrazoline, 5H-pyrida-
zino[4,5-b]indoles, and thiazolidin-4-ones and we tested
them for their antimicrobial, tranquilizing, and anticon-
vulsant activities.
Results and discussion
Chemistry
In the present investigation, the synthesis of 4-chloro-, 4-
fluoro-, and 2,4-dichloro-phenylhydrazines 1–3 was car-
ried out by reduction of the diazonium salt of the respec-
tive substituted aniline with stannous chloride in acid
medium [19]. Fischer indolization [20] of the correspond-
ing ethyl pyruvate derivatives 4–6 [21] gave the substi-
tuted-1H-indole-2-carboxylic acid ethyl esters 7–9. Reac-
tion of 5,7-dichloro-1H-indole-2-carboxylic acid ethyl
ester 9 with hydrazine hydrate gave 5,7-dichloro-1H-
indole-2-carbohydrazide 13 [23], and refluxing with the
one-carbon inserting reagent methyl orthoformate in
DMF gave 6,8-dichloro-1,2,4-triazino[4,5-a]indole-1(2H)-
one 14 (Scheme 1, [24]). The assignment of structure 14
for that product where the carbons were inserted
between the hydrazine moeity and the indole NH rather
than the indole carbon was based on the absence of the
indole NH in its 1H-NMR spectrum, and the presence of
the proton on the indole C-10 (d 9.22 ppm).
Scheme 1. Synthesis of indolyl heterocycles.
lylthiazolidinone derivatives, ethyl 5-chloro-3-(5-methyl-
4-oxo-3-arylthiazolidin-2-yl)-1H-indole-2-carboxylates 30–
33 were prepared by cyclocondensation of Schiff's bases
20, 21, 24 and 25 with thioglycolic acid [28–29] and thio-
lactic acid [30] (Scheme 2).
The Mannich reaction [22] of 7–9 with formaldehyde
and morpholine in the presence of glacial acetic acid
gave ethyl-substituted-3-(morpholinyl-methyl)-1H-indole-
2-carboxylates 10–12.
Substituted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34–
36 were prepared by boiling 15–17 with hydrazine
hydrate for six hours with 80% yield; under microwave
irradiation, only 3 min were required to reach better
yields. On the other hand, reaction of 3-formyl-substi-
tuted-1H-indole-2-carboxylic acid ethyl esters 16 and 17
with 2,4-dichlorophenylhydrazine did not give the pyri-
dazino derivatives, but the corresponding hydrazones 37
and 38, respectivly, were formed. 4-Chloro-substituted-
5H-pyridazino[4,5-b]indoles 39 and 40 were prepared by
boiling 35 and 36 with POCl3 for 10 h; their reaction with
morpholine in DMF [31] led to the formation of 4-mor-
pholino-substituted-5H-pyridazino[4,5-b]indoles 41 and
42. Mannich condensation [32] of 5-chloro-3H-pyrida-
zino[4,5-b]indol-4(5H)-one 34 with 4-ethylpiperazine and
The Vilsmeier–Haack formylation [25–26] of 7–9
using POCl3/DMF gave 3-formyl-substituted-1H-indole-2-
carboxylic acid ethyl esters 15–17. Refluxing a mixture
of 15, aniline and thioglycolic acid [7] gave 2,29-((5-chloro-
2-(ethoxycarbonyl)-1H-indole-3-yl)methylene)-bis(sulfane-
diyl)diacetic acid 18, instead of the expected thiazolidi-
none which may be attributed to a faster reaction of the
aldehyde with thioglycolic acid rather than with the
amine. Thus, ethyl 3-(N-aryliminomethyl)5-halo-1H-
indole-2-carboxylates 19–29 were prepared [27] by boil-
ing the respective aldehyde with the substituted aniline
in methanol in the presence of glacial acetic acid for six
hours; microwave irradiation of a mixture of the two
components for 5 min gave the same products. The indo-
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

296
A. A. El-Gendy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
Scheme 2. Synthesis and reactions of formyl indoles.
Table 1. Anticonvulsant activity.
Groups
Time of death Significant (a) Significant (b) Significant (c)
after injection vs. Strychnine- vs. pheno-
vs. diazepam
(min)
injected group barbital
treated with
Scheme 3. Synthesis of pyridazino indoles.
vehicle
were induced by strychnine (2 mg/kg body weight)
injected intraperitoneally, the end point was calculated
by occurence of death (time in minutes) after strychnine
injection. On the other hand, compound 32 showed no
anticonvulsant activity. Meanwhile, the anticonvulsant
activities of compounds 30, 31, and 33 were less than the
activity of phenobarbital sodium (PB) (200 mg/kg body
weight) and diazepam (DZP) (1 mg/kg body weight) which
were used as standards (Table 1).
Vehicle
PB
DZP
30
31
32
4.83 l 0.0042
9.61 l 0.020
7.13 l 0.036
5.83 l 0.048
4.43 l 0.028
3.63 l 0.028
6.95 l 0.035
-
-
-
-
-
-
-
a (p a 0.05)
a (p a 0.05)
a (p a 0.05)
a (p a 0.05)
-
b (p a 0.05)
b (p a 0.05)
-
c (p a 0.05)
c (p a 0.05)
-
33
a (p a 0.05)
b (p a 0.05)
c (p a 0.05)
formaldehyde in ethanol gave 8-chloro-3-((4-ethylpipera-
zin-1-yl)methyl)-3H-pyridazino[4,5-b]indol-4(5H)-one
43
(Scheme 3).
Tranquilizing activity
The tranquilizing activity of the tested compounds 30–
33 was studied by observing their effect on the behavior
of mice while monitoring their activity in the catalepsy
test [34]; chlorpromazine (CPZ) (4 mg/kg body weight)
was used as reference standard. The number of animals
that failed to remain on the rod for 3 min at intervals of
30, 60, 80, and 120 minutes after administration of the
tested compounds were recorded and calculated as per-
centage. Failure of the mice to remain on the rod for
Biological studies
Compounds 30–33 (10 mg/kg body weight) were eval-
uated for their anticonvulsant and tranquilizing activ-
ities following the methods of Kerley et al. [33] and Jans-
sen et al. [34], respectively.
Anticonvulsant activity
The results showed that compounds 30, 31, and 33 have
significant (p a 0.05) anticonvulsant activity. Convulsions
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
Table 2. Effect on motility using rotating rod.
Functionalized Indoles
297
Table 4. Antimicrobial activity of tested compounds*.
Groups
Intervals (min)
90
Compound Gram-nega- Gram-positive bacteria Fungi
tive bacteria
30
60
120
E. coli
S. aureus
B. subtilis C. albicans
Vehicle
188 l 3.742
194 l 5.99
212 l 8.602
222 l11.58
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
–
+
+
+
+
+
+
+
+
+
+
+
–
–
–
–
+++
–
–
–
–
–
–
–
–
–
–
–
+
+
+
+
+++
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
+
+
+
+
+
+
+
+
+
+
+
++
++
++
++
Table 3. Failure (%) before 180 seconds.
Compound
Failure (%)
CPZ *
30
31
32
33
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
* CPZ, chlorpromazine
Solvent: DMF, [c] = 20 lL mL– 1. Rating: + = moderately active
(inhibition zone 1–5 mm); ++ = more active (inhibition zone 5-
10 mm); +++ = highly active (inhibition zone 10–15 mm); refer-
ence substance for bacteria: chloramphenicol; reference sub-
stance for fungi: nystatine.
3 min indicated motor incoordination (Table 2). The
results in Table 3 indicate that compounds 30–33 had
incoordination behavior (tranquilizing activity).
Antimicrobial activity
The activities of compound 18, Schiff's bases 19–29, and
the substituted indolylthiazolidinones 30–33 against
Demonstrator of Microbiology, Faculty of Pharmacy, Suez
representative Gram-positive and Gram-negative bacteria Canal University, for carrying out the antimicrobial screening.
as well as fungi were tested by the disk-diffusion method
[35]. The results showed that compound 18 had high
activity against Gram-positive bacteria, while compounds
19–29 had moderate activity against Gram-negative bac-
teria and fungi; compounds 30–33 possess high activity
against fungi and moderate activity against Gram posi-
tive strains (Table 4).
The authors have declared no conflict of interest.
Experimental
Chemistry
Melting points were measured in open capillary tubes using
Stuart melting point apparatus SMP10 (Stuart Scientific. Stone,
Staffordshire, UK) and are uncorrected. Infrared (IR) spectra
were measured on a Vector 22 Infrared spectrophotometer
(mmax in cm– 1; Bruker, Bioscience, Billerica, MA, USA). Proton
magnetic resonance (1H-NMR) spectra were recorded on Bruker
AM 300 spectrometer (300 MHz). Chemical shifts are reported in
d values (parts per million, ppm) relative to tetramethylsilane
(TMS) as internal standard and the coupling constant values are
given in Hz. Abbreviation used in NMR analysis are as follows: d
= doublet, dd = doublet of doublets, m = multiplet, q = quartet, s
= singlet, t = triplet. Electron impact mass spectra (EI-MS) were
recorded on a Finnigan MAT 312 mass spectrometer connected
with a MASPEC Data System (Thermo Electron Corporation, Ger-
many). High-resolution electron impact mass measurements
(HREI-MS) were carried out on JEOL JMS HX 110 mass spectrome-
ter (JEOL, Tokyo, Japan). Elemental analyses were performed in
the Microanalytical center, Cairo University, Egypt. Reactions
were monitored by thin layer chromatography (TLC) on Merck
silica gel 60F254 (Merck, Germany) and visualized with UV light.
Microwave irradiation was achieved using a domestic micro-
wave oven MS-3443A (1000-W output power) frequency 2450 Hz,
containing glass tray and rotating ring. Analytical data for the
compounds is shown in Supplemental Material.
Conclusions
Indole 2-cartboxylates were used as precursors for the
respective 3-formyl derivatives and indolyl heterocycles
as well as pyridazino-indoles. A selected series was also
synthesized under microwave irradiation which, as
expected [40], saved much time. The physical data of the
newly synthesized compounds is presented in Table 5.
The anticonvulsant, tranquilizing, and antimicrobial
activities of selected compounds showed promising
results.
The authors are grateful to HEC (Higher Education Commis-
sion), Pakistan, for the partial financial support and Professor
Dr. M. Iqbal Choudhary, H. E. J. Research Institute of Chemistry
(ICCBS), Karachi University, for providing facilities for measur-
ing spectral data. Special thanks to Pharmacist Marwa Azap,
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

298
A. A. El-Gendy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
Table 5. Physical Data of Ethyl 3-(N-aryliminomethyl)-5-halo-indole-2-carboxylates 19–29.
Compound X1
X2
R1^
R2
R3
Mp. (8C)
Yield (%)
Conventional Microwave
19
20
21
22
23
24
25
26
27
28
29
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
OCH3
Cl
H
H
H
H
H
H
H
Cl
OH
OH
H
H
H
H
H
H
H
H
CH3
H
H
H
195
192
187
230
260
170
150
205
216
270
238
70
75
75
80
82
60
60
77
75
70
82
*
*
*
*
*
*
*
85
88
80
90
F
F
F
CH3
NO3
Cl
H
H
Cl
* This experiment was not carried out
Substituted phenylhydrazines 1–3
Ethyl 3-(morpholinyl-methyl)-substituted-1H-indole-2-
Concentrated HCl (100 mL) was added with stirring to a solution
of the substituted aniline (40 mmol) in glacial acetic acid
(20 mL) at room temperature. The reaction mixture was then
cooled to 08C and treated with sodium nitrite solution (2.76 g,
40 mmol in 8 mL water). The cold diazonium salt solution was
rapidly filtered and treated dropwise with a cold solution of
stannous chloride dihydrate (20 g) in conc. HCl (20 mL). The
insoluble salt was collected by filtration and washed with satur-
ated sodium chloride solution (30 mL). The substituted phenyl-
hydrazine was liberated from the salt by treatment with aque-
ous sodium hydroxide (15%, 200 mL). The product was extracted
twice with ether (200 mL). The combined extracts were washed
with water and then dried over anhydrous Na2SO4. The ethereal
solution was evaporated, then dried and recrystallized from
ethanol. 4-Chlorophenyl hydrazine 1: mp. 838C, lit. [19] mp. 85–
878C (yield 60%). 4-Fluorophenyl hydrazine 2: mp. 608C, lit. [36]
mp. 63–658C (yield 50%). 2,4-Dichlorophenyl hydrazine 3: mp.
93–958C, lit. [37] mp. 94–958C (yield 40%).
carboxylates 10–12
A
solution of the substituted-1H-indole-2-carboxylate 7–9
(0.26 mmol) in methanol (20 mL) was added to a well stirred mix-
ture of formaline (0.02 mL), morpholine (0.52 mmol), and glacial
acetic acid (3 mL). The mixture was then refluxed for 12 h. The
resulting solution was evaporated to dryness. The product was
crystallized from methanol.
5,7-Dichloro-1H-indole-2-carbohydrazide 13
A mixture of 5,7-dichloro-1H-indole-2-carboxylate 9 (61 mg,
0.0235 mmol) and hydrazine hydrate (2 mL, 80%) was mixed uni-
formly and irradiated by microwave for 3 min. After cooling, the
product was crystallized from ethanol.
6,8-Dichloro-[1,2,4]triazino[4,5-a]indol-1(2H)-one 14
A mixture of 5,7-dichloro-1H-indole-2-carbohydrazide 13 (133
mg, 0.547 mmol), N,N-dimethylformamide (1 mL), and trimethyl
orthoformate (0.089 mL, 0.84 mmol) was boiled for 6 h. The sol-
vent was removed in vacuo and the residue was recystallized
from a DMF/ethanol mixture.
Ethyl-pyruvate-substituted phenylhydrazones 4–6
Ethyl pyruvate (1.3 g, 11 mmol) was added dropwise with stir-
ring into an alcoholic solution of substituted phenylhydrazine
1–3 (11 mmol) in the presence of glacial acetic acid (0.5 mL). The
resulting precipitate was further stirred for 15 minutes at room
temperature and then left for complete precipitation. The prod-
uct was filtered, dried, and recrystallized from ethanol. Ethyl
pyruvate 4-chlorophenylhydrazone 4, mp. 1368C, lit. [21] mp.
1388C (yield 74%).
Ethyl 3-formyl-substituted-1H-indole-2-carboxylates
15–17
In a 250 mL two-necked round-bottomed flask, dry N,N-dimethyl-
formamide (2 mL, 0.026 mol) was cooled in an ice-bath for
30 min. Phosphorus oxychloride (0.7 mL, 0.004 mol) was
dropped into the reaction flask in about 5min. The cooling bath
was removed and the reaction mixture was then stirred at room
temperature for 30 min. The mixture was newly cooled in an ice-
bath and a solution of substituted-1H-indole-2-carboxylates 7–9
(4 mmol) in DMF (2 mL) was dropped into the reaction flask (tak-
ing about 5 min). The mixture was then stirred for 2 h at 80–
1008C. The colored solution obtained was poured over crushed
ice (20 g). The resulting orange precipitate was left overnight for
complete precipitation. The collected product was filtered and
washed first with warm H2O and then with ethanol/water mix-
ture. The resulting products were crystallized from ethanol.
Ethyl-substituted-1H-indole-2-carboxylates 7–9
A mixture of p-toluenesulfonic acid (3 g, 17.4 mmol) and dry
benzene (50 mL) was heated under reflux using Dean–Stark
apparatus for 1.5 h. A suspension of the hydrazone 4–6
(10 mmol) in dry benzene (30 mL) was added and the whole mix-
ture was refluxed for 5 h. The resulting solution was diluted
with benzene, washed with aqueous NaHCO3, dried over anhy-
drous Na2SO4, and evaporated to dryness. The resulting product
was crystallized from ethanol.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
Functionalized Indoles
299
2,29-((5-Chloro-2-(ethoxycarbonyl)-1H-indol-3-
yl)methylene)bis(sulfanediyl)diacetic acid 18
Ethyl 3-((2-(2,4-dichlorophenyl)hydrazono)methyl)-
substituted-1H-indole-2-carboxylates 37–38
In a 250 mL two-necked round-bottomed flask, a mixture of
ethyl 5-chloro-3-formyl-1H-indole-2-carboxylate 15 (100 mg,
0.4 mmol), thioglycollic acid (0.036 mL, 0.4 mmol), and dry tol-
uene (30 mL) was heated under reflux for 12 h until the theoret-
ical amount of water was collected azeotropically. The reaction
mixture was cooled, washed with water, dried over anhydrous
Na2SO4, and evaporated to dryness. The resulting product was
recrystallized from ethanol.
Conventional method
2,4-Dichlorophenylhydrazine (0.09 mmol) was added to a solu-
tion of ethyl 3-formyl-substituted-1H-indole-2-carboxylate 16, 17
(0.09 mmol) in methanol (10 mL) and the resulting reaction mix-
ture was refluxed for 6 h. The solid that separated on cooling
was recrystallized from ethanol (yield 80%).
Microwave method
A mixture of 3-formyl-substituted-1H-indole-2-carboxylic acid
ethyl esters 16–17 (0.09 mmol), 2,4-dichlorophenylhydrazine
(0.09 mmol), and methanol (2 mL) was mixed uniformly and
irradiated by microwave for 5 min. After cooling, the product
was crystallized from ethanol (yield 88%).
Ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2-
carboxylates 19–29
Conventional method
A mixture of ethyl 3-formyl-5-halo-1H-indole-2-carboxylate 15–
16 (1 mmol) and glacial acetic acid (0.5 mL) was dissolved in
methanol (10 mL) by heating. Then, the appropriate aniline
derivative (1 mmol) was added to this solution and the whole sol-
ution was refluxed for 6 h. The hot solution was left at room tem-
perature. The collected solid was filtered, dried, and recystal-
lized from ethanol.
4-Chloro-substituted-5H-pyridazino[4,5-b]indoles 39–40
A mixture of substituted-3H-pyridazino[4,5-b]indol-4(5H)-ones
34–35 (1.1 mmol) and phosphorus oxychloride (20 mL) was
refluxed at 3008C for 10 h. A dark-yellow-colored solution
formed. It was cooled, then diluted with a large amount of
diethyl ether (100 mL). The collected product was filtered and
washed with cold H2O and then dried. The resulting product was
crystallized from a dichloromethane/methanol mixture.
Microwave method
A mixture of ethyl 3-formyl-5-halo-1H-indole-2-carboxylate 15–
16 (0.5 mmol), glacial acetic acid (1 drop), methanol (1 mL), and
the appropriate aniline derivative (0.5 mmol) was mixed uni-
formly and irradiated by microwave for 5 min. After cooling, the
product was crystallized from ethanol (Table 5).
4-(Substituted-5H-pyridazino[4,5-b]indol-4-yl)-
morpholines 41–42
A
mixture of 4-chloro-substituted-5H-pyridazino[4,5-b]indole
39–40 (0.09 mmol), morpholine (0.1 mmol) and dry N,N-
dimethyl formamide (4 mL) was refluxed for 7 h. The reaction
mixture was cooled, poured into crushed ice and finally left
overnight. The collected solid was filtered, dried, and recrystal-
lized from DMF / ethanol mixture.
Ethyl 3-(3-aryl-5-methyl-4-oxothiazolidin-2-yl)-5-chloro-
1H-indole-2-carboxylates 30–33
In a 250 mL two-necked round-bottomed flask, a mixture of the
appropriate ethyl 3-(N-aryliminomethyl)-5-chloro-1H-indole-2-
carboxylate 20–21, 24–25 (2 mmol), toluene (30 mL), and thio-
lactic acid (2 mmol) was heated under reflux using Dean–Stark
apparatus for 32 h. The reaction mixture was cooled, washed
with water, dried over anhydrous Na2SO4, and evaporated to dry-
ness. The resulting product was crystallized from ethanol.
8-Chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-
pyridazino[4,5-b]indol-4(5H)-one 43
A well-stirred mixture of formaline (0.2 mL), N-ethyl piperazine
(0.3 mmol), and glacial acetic acid (5 drops) was added to a sus-
pension of 8-chloro-3H-pyridazino[4,5-b]indol-4(5H)-one 33
(0.26 mmol) in ethanol (20 mL). The whole mixture was then
refluxed for 24 h. The resulting mixture was filtered, dried, and
recrystallized from a DMF / ethanol mixture.
Substituted-3H-pyridazino-[4,5-b]indol-4(5H)-ones
34–36
Biological studies
Compounds 30–33 were evaluated for their anticonvulsant,
tranquilizing, and antimicrobial activities.The anticonvulsant
activity was determined according to the method of Kerley et al.
[33] using 28 male mice (20–25 g). The mice were divided into
seven groups of four mice each. The first group served as control
and was injected with the vehicle (1% Tween80). The second was
given phenobarbital sodium (PB) (200 mg/kg b.wt.; ip). The third
one was injected with diazepam (DZP) (1 mg/kg b.wt.; ip). The
other groups were injected with the test compounds 30–33
(100 mg/kg b.wt.; ip). After 60 min., each mouse was injected
with strychnine sulfate (2 mg/kg b.wt.; ip; LD99 for mice). The
end point was to measure the ability of these four compounds to
prolong life beyond the time of death observed after strychnine
injection in comparison to the control animals. Compounds
which provided significant anticonvulsant activity were addi-
Conventional method
To a solution of ethyl 3-formyl-substituted-1H-indole-2-carboxy-
late 15–17 (0.18 mmol) in methanol (20 mL), 80% hydrazine
hydrate (0.562 mmol) was added. The mixture was boiled for 6 h.
The white product which formed was crystallized from DMF/
ethanol mixture (yield 80%).
Microwave method
A mixture of ethyl 3-formyl-substituted-1H-indole-2-carboxylate
15–17 (0.09 mmol) and 80% hydrazine hydrate (0.281 mmol)
was mixed uniformly and irradiated by microwave for 3 min.
After cooling, the product was crystallized from DMF/ethanol
(yield 93.44%).
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

300
A. A. El-Gendy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 294–300
tionally compared to the classical standard anticonvulsant
drugs, PB and DZP.
[17] A. Monge, I. Aldana, M. Losa, M. Font, et al., J. Pharm. Sci.
1993, 82, 526–530.
The activities of compound 18, Schiff's bases 19–29, and sub-
stituted indolylthiazolidinones 30–33 against representative
Gram positive and Gram-negative bacteria and fungi were tested
by the disk diffusion method [35]. The results are listed in
Table 4. From the data it is clear that compound 18 shows high
activity against Gram positive bacteria, while compounds 19–29
possess moderate activity against Gram negative bacteria and
fungi, compounds 30–33 possess more activity against fungi
and moderate activity against Gram positive strains.
[18] A. Monge, M. Font, A. Cuartero, A. Elorriaga, et al., Eur. J.
Med. Chem. 1995, 30, 963–971.
[19] Heinrich Wieland, Egon Popper, H. Seefried, Chem. Ber.
1922, 55, 1816–1834.
[20] Y. Murakami, Y. Yokoyama, T. Mitura, H. Hirasawa, et al.,
Heterocycles 1984, 22, 1211–1216.
[21] H. N. Rydon, J. C. Tweddle, J. Chem. Soc. 1955, 3499–3503.
[22] E. Badger, S. Dicataldo, A. D. Kahle, J. Nadelson, M. J. Sha-
piro, J. Heterocycl Chem. 1981, 18, 623–626.
[23] A. Monge, E. Fernandez, An. Quim. 1972, 68, 1153.
[24] A. Monge, P. Parrado, M. Font, E. Fernandez, J. Med. Chem.
1987, 30, 1029–1035.
References
[25] T. Norgady, L. Morris, Can. J. Chem. 1969, 47, 1999–2002.
[1] M. Verma, V. R. Gujrati, M. S. Sharma, K. Anil, et al., Arch.
Pharm. 1982, 358–363.
[26] A. Monge, I. Aldana, I. Lezamiz, E. Fernandez, Synthesis
1984, 2, 160–161.
[2] A. Moll, H. Hꢀbner, P. Gmeiner, R. Troschꢀtz, Bioorg. Med.
Chem. 2002, 10, 1671–1679.
[27] K. C. Joshi, R. Jain, S. Nishith, J. Indian Chem. Soc. 1991, 68,
625–627.
[3] Y. Makato, S. Hiroaki, K. Harunhiko, H. Koichiro, Jpn.
Kokai tokkyo koho 1992 Jp 03, 161, 470 [91, 161, 470] (Cl
CO7D209/42). C. A. 116, 41299m.
[28] S. R. El–Ezbawy, M. A. Alshaikh, J. Indian Chem. Soc. 1990,
67, 398–400.
[4] K. C. Joshi, V. N. Pathak, S. K. Jain, J. Indian Chem. Soc. 1980,
LVII, 1176–1980.
[29] S. P. Lawande, B. R. Arbad, J. Indian Chem. Soc. 2000, 77,
352–354.
[5] A. M. Mahmoud, A. E. Abdel Rahman, G. M. Naggar, H. A.
[30] B. Goel, T. Ram, R. Tyagi, E. Bansal, et al., Eur. J. Med. Chem.
1999, 34, 265–269.
El-Sherief, Indian J. Chem. 1984, 23B, 379–381.
[6] K. M. Hussain, T. Shallendra, B. Kahkashan, Indian J. Chem.
1998, 37B, 1075–1077.
[31] A. Monge, I. Aldana, E. Fernandez, J. Heterocylic Chem. 1981,
18, 1533–1536.
[7] K. C. Joshi, R. Jain, P. Chand, S. Gavg, J. Indian Chem. Soc.
1983, LX, 760–761.
[32] S. Swaminathan, K. Narisimhan, Chem. Ber. 1966, 99, 889–
894.
[8] M. Rajopadhye, F. D. Popp, J. Heterocycl Chem. 1984, 21,
[33] T. L. Kerley, A. C. Richard, R. W. Begley, B. E. Abery, L. C.
289–291.
Weaver, J. Pharmacol. Exp. Ther. 1961, 132, 360–365.
[9] A. A. El-Gendy, N. A. Abdou, E. Z. Sarhan, H. A. El-Banna,
[34] P. Janssen, A. Jageneau, J. Pharmacol. Exp. Ther. 1960, 129,
Alex J. Pharm. Sci. 1993, 7, 99–103.
471–475.
[10] A. Monge, I. Aldana, E. Fernandez, Eur. J. Med. (Chim. Ther.)
1978, 13, 573–575.
[35] A. W. Bauer, W. M. Kirby, J. C. Scherris, Am. J. Clin. Pathol.
1966, 45, 493–496.
[11] A. Monge, J. Palop, C. Gracia, E. Fernandez, An. Real. Acad.
Farm. 1982, 48, 213–228.
[36] F. L. Allen, J. C. Brunton, H. Suschitzky, J. Chem. Soc. 1955,
1283–1286.
[12] A. Monge, I. Aldana, M. Font, P. Parado, et al., An. Quim. Ser.
C. 1983, 79, 242–247.
[37] C. Frederick, P. Charles, J. Chem. Soc. 1915, 107, 32–34.
[38] H. Ishii, Y. Murakami, K. Hosoya, H. Takeda, et al., Chem.
Pharm. Bull. 1973, 21, 1481–1494.
[13] A. Monge, M. Font, P. Parrado, E. Fernandez, Eur. J. Med.
Chem. 1988, 23, 547–552.
[39] A. A. El-Gendy, A. F. Abou-Sier, Egypt J. Pharm. Sci. 1993, 34,
[14] A. Monge, I. Aldana, T. Alvarez, M. Losa, et al., Eur. J. Med.
Chem. 1991, 26, 655–658.
207–218.
[40] E. S. H. El Ashry, E. Ramadan, A. A. Kassem, M. Haggar,
Adv. Heterocycl. Chem. 2005, 88, 1–110; E. S. H. El Ashry, E.
Ramadan, A. A. Kassem, Adv. Heterocycl. Chem. 2006, 90, 1–
127; E. S. H. El Ashry, E. Ramadan, A. A. Kassem, Arkivoc
2006, ix, 1–15.
[15] N. N. Suvorov, Zh. D. Ovchinnikova, Yu. N. Sheinker, Zh.
Obshch. Khim. 1961, 31, 2333–2339.
[16] A. Monge, I. Aldana, M. Losa, M. Font, E. Cenarruzabitia,
Arzneim. Forsch. 1993, 43, 1175–1180.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com