Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives, their 1,2,4-triazole thioglycosides and acyclic analogs

Article abstract of DOI:10.1007/s12272-011-0706-y

New 1-[(tetrazol-5-yl)methyl]indole derivatives, their acyclic nucleoside analogs and the corresponding glycoside derivatives were synthesized. Furthermore, the [)(1,2,4-triazol-3-yl)methyl])-2H-tetrazole derivative as well as the corresponding thioglucos

Full text of DOI:10.1007/s12272-011-0706-y

Arch Pharm Res Vol 34, No 7, 1085-1096, 2011
DOI 10.1007/s12272-011-0706-y
Synthesis and Antimicrobial Activity of New 1-[(tetrazol-5-yl)methyl]
indole Derivatives, their 1,2,4-Triazole Thioglycosides and Acyclic
Analogs
Weal A. El-Sayed, Randa E. Abdel Megeid, and Hebat-Allah S. Abbas
Photochemistry Department, National Research Center, El-Dokki, Cairo 72427, Egypt
(Received July 18, 2010/Revised November 11, 2010/Accepted December 20, 2010)
New 1-[(tetrazol-5-yl)methyl]indole derivatives, their acyclic nucleoside analogs and the corre-
sponding glycoside derivatives were synthesized. Furthermore, the [(1,2,4-triazol-3-yl)methyl]-
2
H
-tetrazole derivative as well as the corresponding thioglucoside were prepared. The synthe-
sized compounds were tested for their antimicrobial activity against Aspergillus Niger Peni-
cillium sp Candida albican Bacillus subtilis, Streptococcus lacti Escherichia coli Pseudomonas
sp., and streptomyces sp. Compounds and 19b exhibited potent antibacterial activity and
and 10 exhibited high activities against the tested fungi compared with
,
,
,
,
,
3, 5
compounds
fusidic acid.
4, 5
Key words: Indole, 1,2,4-Triazole thioglycosides, Tetrazole glycosides, Antibacterial, Antifun-
gal activity
relationships for many indole compounds revealed
that -alkylation (Webber et al., 1996; Velezheva et
INTRODUCTION
N
Indole is an important structural motif present in al., 2004) is effective in causing a marked rise in
many biologically active natural products (Saxton, activity against various bacteria, fungi and viruses.
1983; Hashimoto et al., 1984; Shimizu et al., 1984; On the other hand, tetrazole derivatives have been
Kamijo and Yamamoto, 2003). The chemistry of in- found to have applications as carboxylic surrogates,
doles has been increasingly studied because of their bioisosteres of carboxylic acids (Herr, 2002; Master et
interesting biological activities (Nakashima et al., al., 2005) and lipophilic spacers in pharmaceuticals.
1984; Chen et al., 1998; Hong et al., 2002; Chang et This has led to therapeutic appli- cations resulting in
al., 2005). They have been reported to possess a wide compounds with antihypertensive, antiallergic and
variety of biological properties including anti-inflam- antibiotic activities (Bond et al., 2006). Structural
matory (Andreani et al., 1994; Misra et al., 1996), anti- fragments or formulas with tetrazole derivatives having
bacterial (Pandeya et al., 1999; Samosorn et al., 2006), pronounced antimicrobial activities include the
N-
antiviral (Bal et al., 2005; Pirrung et al., 2005), anti- substituted tetrazole (Fig. 1) which also has antino-
I
TB (Sriram et al., 2005) and antifungal activities (Lundt ciceptive activity (Rajasekaran and Thampi, 2005). It
and Anderson, 1971) as well as analgesic (Dekker et has been reported that the attachment of sugar moi-
al., 1975), and antitumor effects (Blum et al., 2001; eties to the 1,2,4-triazole nucleus through a thiogly-
Zhang et al., 2005). A number of indole derivatives are cosidic linkage enhances its antimicrobial activity.
inhibitors of the Nor A efflux pump in the human The 1,2,4-triazole thioglycosides with formula II (Fig.
pathogenic (bacterium Staphylococcus) (Markham 1) have been shown to possess potential antimicrobial
et al., 1999). Investigation of the structure-activity activity (Khalil, 2006, 2007). The above facts and our
interest (El-Sayed et al., 2008a, 2008b, 2009a, 2009b,
2009c) in novel biologically active leads by means of
attaching of carbohydrate moieties to newly synthesiz-
ed heterocycles promoted us to synthesize new sub-
stituted tetrazole glycosides, their acyclic analogs and
Correspondence to: Weal A. El-Sayed, Photochemistry Depart-
ment, National Research Center, El-Dokki, Cairo 72427, Egypt
Tel: 2-48-299-3760, Fax: 2-2-3337-0931
E-mail: waelshendy@gmail.com
1085

1086
W. A. El-Sayed et al.
141.20, 145,66, 149.25 (Ar-8C), 182.16 (C=O). Anal.
Calcd. for C12H10N2O (198.22): C, 72.71; H, 5.08; N,
14.13. Found: C, 72.43; H, 4.89; N, 13.92.
1-[1-(2
H
-Tetrazol-5-ylmethyl)-1
H
-indol-3-yl]
ethanone (3)
A mixture of compound
2 (3.96 g, 20 mmol), sodium
azide (1.3 g, 20 mmol) and ammonium chloride (1.06
g, 20 mmol) in -dimethylformamide (30 mL) was
N,N
heated for 7 h at 120ºC. The solvent was removed
under reduced pressure and the residue was dissolved
in water (100 mL) and carefully acidified with conc.
hydrochloric acid to pH 2. The solution was cooled to
5ºC in an ice bath to precipitate compound
yellow powder (3.42 g, 71%), m.p. 212-213oC; IR (KBr)
3265 (NH), 1708 cm−1 (C=O); 1H-NMR (DMSO-d6):
2.48 (s, 3H, CH3CO), 5.33 (s, 2H, CH2), 7.31 (m, 1H,
1,2,4-triazoles thioglycosides, and to evaluate their Ar-H), 7.42 (m, 1H, Ar-H), 7.46 (d, 1H, = 8.0 Hz, Ar-
antimicrobial activity. Furthermore, it was of interest H), 7.87 (d, 1H, = 8.2 Hz, Ar-H), 8.72 (s, 1H, Ar-H),
to determine the influence of attachment of sugar moi- 12.15 (s, 1H, NH); 13C-NMR (DMSO-d6):
26.76
CH3CO), 44.52 (CH2), 119.24, 123.55, 134.61, 138.33,
3. Pale
Fig. 1. Antimicrobial substituted tetrazole and trriazole
derivatives
ν
δ
J
J
δ
eties to the synthesized tetrazole and substituted 1,2,
4-triazole derivatives on their antimicrobial activity.
(
140.05, 141.80, 145,69, 149.84 (Ar-8C), 156.81 (C=N),
182.18 (C=O). Anal. Calcd. for C12H11N5O (241.10): C,
59.74; H, 4.60; N, 29.03. Found: C, 59.61; H, 4.49; N,
28.79.
MATERIALS AND METHODS
Melting points were determined using a kofler block
apparatus and are uncorrected. The IR spectra were
recorded on a Perkin-Elmer model 1720 FTIR spectro-
meter using KBr discs. NMR spectra were recorded on
Ethyl{5-[(3-acetyl-1
razol-2-yl}acetate (4)
To a solution of compound
H
-indol-1-yl)methyl]-2
H
-tet-
3 (2.41 g, 10 mmol) and
a Varian Gemini 300 NMR Spectrometer at 300 MHz anhydrous potassium carbonate (1.38 g, 10 mmol) in
1
for H and 75 MHz for 13C or on a Bruker Ac-250 FT
N,N-dimethylformamide (30 mL), ethyl chloroacetate
1
spectrometer at 250 MHz for H and at 62.9 MHz for (1.22 g, 10 mmol) was added dropwise. The mixture
13C with TMS as a standard. Progress of the reactions was stirred at room temperature for 8 h and then
was monitored by TLC (aluminum silica gel plates 60 poured into ice-cold water. The formed solid was fil-
F 245). Elemental analyses were performed at the tered, dried and recrystallized from ethanol to afford
Microanalytical Data Centre at Faculty of Science, compound
Cairo University, Egypt.
139-140oC; IR (KBr)
1H-NMR (CDCl3):
1.44 (t, 3H,
2.42 (s, 3H, CH3CO), 3.92 (q, 2H,
4
. Pale yellow powder (2.42 g, 74%), m.p.
ν
1745 (C=O), 1705 cm−1 (C=O);
δ
J
= 5.8 Hz, CH2CH3),
= 5.8 Hz, CH2CH3),
J
(3-Acetyl-1H-indol-1-yl)acetonitrile (2)
To a solution of 3-acetylindole (3.18 g, 20 mmol) and 4.55 (s, 2H, CH2), 5.41 (s, 2H, CH2), 7.33 (m, 1H, Ar-
sodium hydride (0.24 g, 20 mmol) in -dimethyl- H), 7.40 (m, 1H, Ar-H), 7.47 (d, 1H, = 8.0 Hz, Ar-H),
formamide (30 mL), was added chloroacetonitrile (1.51 7.84 (d, 1H,
= 8.2 Hz, Ar-H), 8.72 (s, 1H, Ar-H); 13C-
g, 20 mmol) dropwise and the reaction mixture was NMR (CDCl3): 20.15, 26.76 (2CH3), 39.20, 42.76,
N,N
J
J
δ
stirred for 12 h at room temperature, then poured into 45.85 (3CH2), 118.89, 123.79, 135.11, 138.54, 140.10,
ice water. The obtained precipitate was filtered, dried, 141.87, 145.62, 149.95 (Ar-8C), 156.81 (C=N), 169.25,
and recrystallized from ethanol to give compound
Pale yellow powder (2.89 g, 73%), m.p. 182-183oC; IR C, 58.71; H, 5.23; N, 21.39. Found: C, 58.52; H, 5.11;
(KBr)
2214 (CN), 1705 cm−1 (C=O); 1H-NMR (DMSO- N, 21.14.
d6): 2.48 (s, 3H, CH3CO), 5.32 (s, 2H, CH2), 7.28 (m,
1H, Ar-H), 7.38 (m, 1H, Ar-H), 7.42 (d, 1H, = 8.0 Hz,
Ar-H), 7.82 (d, 1H, = 8.2 Hz, Ar-H), 8.74 (s, 1H, Ar-
H); 13C-NMR (DMSO-d6):
26.75 (CH3CO), 44.5 (CH2),
116.85 (CN), 118.25, 122.95, 133.67, 137.12, 139.95, hydrazine hydrate (2 mL, 99%) was refluxed in dry
2.
182.21 (2C=O). Anal. Calcd. for C16H17N5O3 (327.34):
ν
δ
J
2-{5-[(3-Acetyl-1
zol-2-yl}acetohydrazide (5)
A mixture of compound (3.27 g, 10 mmol) and
H-indol-1-yl)methyl]-2H-tetra-
J
δ
4

Antimicrobial Activity of New Indole Derivatives
1087
ethanol (20 mL) for 4 h. The solvent was reduced 7.22 (d, 2H,
J
= 8.5 Hz, Ar-H), 7.33 (m, 1H, Ar-H), 7.38
under vacuum and left to stand overnight at 5oC. The (m, 1H, Ar-H), 7.42 (d, 1H,
J
= 8.0 Hz, Ar-H), 7.69 (d,
= 8.5 Hz, Ar-H), 7.87 (d, 1H, = 8.2 Hz, Ar-H),
with cold ethanol, dried and recrystallized from an 8.72 (s, 1H, Ar-H), 12.88 (s, 1H, NH); 13C-NMR (CDCl3):
ethanol-water mixture (1:1) to give compound . Pale 25.89 (CH3), 42.62, 45.25 (2CH2), 119.18-149.62 (Ar-
yellow powder (2.51 g, 80%), m.p. 225-226oC; IR (KBr) 14C), 155.95, 156.24 (2C=N), 170.87 (C=S), 182.21 (C=O).
3342 (NH2), 3315 (NH), 1705 cm−1 (C=O), 1668 (C=O); Anal. Calcd. for C21H17ClN8OS (464.93): C, 54.25; H,
1H-NMR (DMSO-d6):
2.40 (s, 3H, CH3CO), 4.57 (s, 3.69; N, 24.10. Found: C, 54.18; H, 3.80; N, 23.89.
2H, CH2), 5.38 (s, 2H, CH2), 5.58 (s, 2H, NH2), 7.30 (m,
1H, Ar-H), 7.38 (m, 1H, Ar-H), 7.47 (d, 1H, = 8.0 Hz,
Ar-H), 7.82 (d, 1H, = 8.2 Hz, Ar-H), 8.74 (s, 1H, Ar-
H), 9.87 (s, 1H, NH); 13C-NMR (DMSO-d6):
26.50
precipitated solid was filtered, washed several times 2H,
J
J
5
δ
ν
δ
J
3-Acetyl-1-{2-[[4-(4-chlorophenyl)-5-(2,3,4,6-tetra-
-acetyl- -D-glucopyranosylthio)-4 -1,2,4-tria-
zol-3-yl]methyl]-2 -tetrazol-5-yl}methyl-1 -indole
(9)
To a solution of compound
J
O
β
H
δ
H
H
(CH3), 42.45, 45.59 (2CH2), 118.84, 123.72, 134.88,
138.24, 139.79, 141.15, 145.60, 148.68 (Ar-8C), 156.14
7
(2.33 g, 5 mmol) in
(C=N), 167.12, 182.17 (2C=O). Anal. Calcd. for C14H15N7O2 aqueous potassium hydroxide [0.28 g, 5 mmol in
(313.31): C, 53.67; H, 4.83; N, 31.29. Found: C, 53.52; distilled water (3 mL)] was added a solution of 2,3,4,6-
H, 5.10; N, 31.14.
tetra-O-acetyl-α-D-glucopyranosyl bromide (2.06 g, 5
mmol) in acetone (30 mL). The reaction mixture was
stirred at room temperature until the reaction was
complete as assessed by TLC (chloroform/methanol
99.5:0.5). The solvent was evaporated under reduced
1-{2-[5-[(3-Acetyl-1H-indol-1-yl)methyl]-2H-tet-
razol-2-yl]acetyl}-4-(4-chlorophenyl)thiosemi-
carbazide (6)
To a well-stirred solution of compound
mmol) in absolute ethanol (30 mL), -chloropheny- distilled water to remove potassium bromide formed.
lisothiocyanate (1.86 g, 10 mmol) was added and the The product was dried and crystallized from ethanol
5
(3.31 g, 10 pressure at 40oC and the residue was washed with
p
reaction mixture was heated under reflux for 2 h. The to give compound 8. Pale yellow powder (3.18 g, 80%),
mixture was poured into ice water and the precipitate m.p. 149-150oC; IR (KBr)
ν
1745 (C=O), 1705 cm−1
1
was filtered, washed several times with water, dried (C=O); H-NMR (CDCl3):
δ 1.95, 2.05, 2.11, 2.14, 2.41
and recrystallized from dioxan to give compound
Pale yellow powder (3.89 g, 78%), m.p. 219-220oC; IR J6,6 = 11.4 Hz, J5,6 = 2.8 Hz, H-6), 4.17 (m, 1H, H-6),
(KBr)
3322 (NH), 1705 (C=O), 1665 cm−1 (C=O); 1H- 4.85 (s, 2H, CH2), 4.95 (t, 1H, J3,4 = 9.3 Hz, H-4), 5.25
NMR (DMSO-d6): 2.41 (s, 3H, CH3CO), 4.54 (s, 2H, (dd, 1H, J2,3 = 9.6 Hz, J3,4 = 9.3 Hz, H-3), 5.37 (t, 1H,
CH2), 5.40 (s, 2H, CH2), 7.20 (d, 2H, = 8.5 Hz, Ar-H), J2,3 = 9.6 Hz, H-2), 5.39 (s, 2H, CH2), 5.76 (d, 1H, J1,2
7.31 (m, 1H, Ar-H), 7.39 (m, 1H, Ar-H), 7.45 (d, 1H, = 10.2 Hz, H-1), 7.25 (d, 2H, = 8.5 Hz, Ar-H), 7.37
= 8.0 Hz, Ar-H), 7.62 (d, 2H, = 8.5 Hz, Ar-H), 7.80 (d, (m, 1H, Ar-H), 7.41 (m, 1H, Ar-H), 7.50 (m, 3H, Ar-H),
1H, = 8.2 Hz, Ar-H), 8.74 (s, 1H, Ar-H), 9.78 (s, 1H, 7.88 (d, 1H,
= 8.2 Hz, Ar-H), 8.73 (s, 1H, Ar-H); 13C-
NH), 10.12 (bs, 2H, 2NH); 13C-NMR (DMSO-d6):
26.51 NMR (CDCl3): 19.30, 19.55, 20.19, 20.23, 25.41
6.
(5s, 15H, 5 CH3CO), 4.05 (m, 1H, H-5), 4.14 (dd, 1H,
ν
δ
J
J
J
J
J
J
δ
δ
(CH3), 42.64, 45.59 (2CH2), 118.50-149.97 (Ar-14C), (5CH3CO), 49.30, 52.27 (2CH2), 62.71 (C-6), 64.23 (C-
156.23 (C=N), 167.43 (C=O), 173.86 (C=S), 182.27 (C=O). 4), 68.72 (C-3), 71.24 (C-2), 71.92 (C-5), 87.12 (C-1),
Anal. Calcd. for C21H19ClN8O2S (482.95): C, 52.23; H, 119.10-150.05 (Ar-14C), 156.40, 157.05, 159.41 (3C=N),
3.97; N, 23.20. Found: C, 52.11; H, 4.05; N, 23.10.
169.64, 170.30, 171.27, 171.49, 182.18 (5C=O). Anal.
Calcd. for C35H35ClN8O10S (795.22): C, 52.86; H, 4.44;
N, 14.09. Found: C, 52.67; H, 4.25; N, 13.88.
3-Acetyl-1-{2-[[4-(4-chlorophenyl)-5-mercapto-
4
H
-1,2,4-triazol-3-yl]methyl]-2
methyl-1 -indole (7)
Compound (2.50 g, 5 mmol) was heated under
reflux in 30 mL of 2 sodium hydroxide solution for 4
h. The reaction mixture was cooled and acidified with
diluted hydrochloric acid to afford a precipitate which tion of a protected glucoside
was filtered, washed with ice-cold water, dried and methanol (20 mL) at 0oC for 1 h and then stirring was
crystallized from ethanol to give compound . Pale continued at room temperature for 5 h. The solvent
yellow powder (1.76 g, 76%), m.p. 207-208oC; IR (KBr) was evaporated under reduced pressure at 40oC to
3322 (NH), 1705 cm−1 (C=O); 1H-NMR (CDCl3):
2.41 give a solid residue, which was recrystallized from etha-
(s, 3H, CH3CO), 4.56 (s, 2H, CH2), 5.42 (s, 2H, CH2), nol to give compound 10. Pale yellow powder (2.45 g,
H-tetrazol-5-yl}
H
3-Acetyl-1-{2-[[4-(4-chlorophenyl)-5-(
copyranosylthio)-4 -1,2,4-triazol-3-yl]methyl]-
-tetrazol-5-yl}methyl-1 -indole (10)
Dry gaseous ammonia was passed through a solu-
(3.98 g, 5 mmol) in dry
β-D-glu-
6
H
N
2H
H
9
7
ν
δ

1088
W. A. El-Sayed et al.
78%), m.p. 189-190oC; IR (KBr)
ν
3467-3440 (OH), 1710
2.42 (s, 3H, CH3CO),
3.39 (m, 2H, H-6,6), 3.49 (m, 1H, H-5), 3.73 (m, 2H, H- Pale yellow powder (1.46 g, 79%), m.p. 157-158oC; IR
3, H-4), 4.20 (t, 1H, J2,3 = 9.2 Hz, H-2), 4.27 (t, 1H, (KBr)
1742 (C=O), 1710 cm−1 (C=O); 1H-NMR (CDCl3):
6.4 Hz, OH), 4.35 (m, 1H, OH), 4.87 (s, 2H, CH2), 4.95 2.08, 2.44 (2s, 6H, 2CH3CO), 3.87 (t, 2H, = 5.8 Hz,
(m, 1H, OH), 5.12 (t, 1H, = 6.2 Hz, OH), 5.41 (s, 2H, CH2), 4.12 (t, 2H, = 5.6 Hz, CH2), 4.24 (t, 2H, = 5.6
CH2), 5.80 (d, 1H, J1,2 = 9.8 Hz, H-1), 7.25 (d, 2H, Hz, CH2), 5.10 (t, 2H, = 5.8 Hz, CH2), 5.37 (s, 2H,
8.5 Hz, Ar-H), 7.37 (m, 1H, Ar-H), 7.41 (m, 1H, Ar-H), CH2), 7.28 (m, 2H, Ar-H), 7.36 (d, 1H, = 8.0 Hz, Ar-H),
7.48 (m, 3H, Ar-H), 7.84 (d, 1H, = 8.2 Hz, Ar-H), 8.74 7.50 (d, 1H,
= 8.0 Hz, Ar-H), 8.74 (s, 1H, Ar-H); 13C-
(s, 1H, Ar-H); 13C-NMR (DMSO-d6):
25.41 (CH3), NMR (CDCl3): 20.14, 26.76 (2CH3), 48.50, 49.77, 60.90,
2-{3-[5-[(3-Acetyl-1
razol-2-yl]propoxy}ethyl acetate (12)
H-indol-1-yl)methyl]-2H-tet-
cm−1 (C=O); 1H-NMR (DMSO-d6):
δ
J
=
ν
δ
J
J
J
J
J
=
J
J
J
J
δ
δ
49.25, 52.21 (2CH2), 62.83 (C-6), 65.12 (C-4), 69.10 (C- 64.44, 69.58 (5CH2), 119.15, 123.57, 134.60, 137.42,
3), 70.82 (C-2), 72.61 (C-5), 89.66 (C-1), 119.18-149.89 140.23, 142.15, 145.731, 149.91 (Ar-8C), 156.92 (C=N),
(Ar-14C), 156.42, 157.12, 159.42 (3C=N), 182.42 (C=O). 169.89, 182.44 (2C=O). Anal. Calcd. for C18H21N5O4
Anal. Calcd. for C27H27ClN8O6S (627.07): C, 51.71; H, (371.39): C, 58.21; H, 5.70; N, 18.86. Found: C, 58.25;
4.34; N, 17.87. Found: C, 51.40; H, 4.25; N, 17.67.
H, 5.76; N, 18.91.
General procedure of Synthesis of compounds 1-{1-[[2-(2,3-Dihydroxypropyl)-2
H
-tetrazol-5-yl]
-indol-3-yl}ethanone (13)
(1.21 g, 5 Pale yellow powder (1.17 g, 74%), m.p. 214-215oC; IR
3428 (OH), 1708 cm−1 (C=O); 1H-NMR (DMSO-
2.47 (s, 3H, CH3CO), 4.62 (d, 2H, = 6.4 Hz,
2-(2-chloroethoxy)ethanol, 3-chloropropane-1,2-diol, 2- CH2), 4.92 (m, 2H, CH2), 5.05 (m, 1H, CHOH), 5.12 (d,
chloro-1,1-dimethoxyethane or chloroethylmethyl ether 1H, = 5.4 Hz, OH), 5.20 (m, 1H, OH), 5.35 (s, 2H,
(5 mmol) and stirring was continued at 70oC for 6-9 h CH2), 7.28 (m, 1H, Ar-H), 7.37 (m, 1H, Ar-H), 7.51 (d,
(TLC). The solvent was evaporated under reduced 1H, = 8.0 Hz, Ar-H), 7.84 (d, 1H, = 8.2 Hz, Ar-H),
pressure and the residue was recrystallized from 8.73 (s, 1H, Ar-H); 13C-NMR (DMSO-d6):
ethanol to give compounds 11 13 15 and 16 CH3CO), 50.40, 53.34, 64.18 (3CH2), 78.18 (
11, 13, 15 and 16
To a well-stirred solution of compound
methyl]-1H
3
mmol) and anhydrous potassium carbonate (0.69 g, 5 (KBr)
mmol) in -dimethylformamide (15 mL) was added d6):
ν
N,N
δ
J
J
J
J
δ
C
26.76
HOH),
,
,
.
(
118.98, 124.23, 134.65, 137.29, 140.15, 142.12, 145.73,
150.12 (Ar-8C), 156.79 (C=N), 182.42 (C=O). Anal.
General procedure of Synthesis of 12 and 14
To a solution of compound 11 or 13 (5 mmol) in Calcd. for C15H17N5O3 (315.33): C, 57.13; H, 5.43; N,
pyridine (10 mL) was added acetic anhydride (5 mmol 22.21. Found: C, 56.90; H, 5.18; N, 21.92.
or 10 mmol, respectively). The solution was stirred at
room temperature for 6-8 h (TLC). The reaction mix-
tures were poured into ice water with stirring and the
3-{5-[(3-Acetyl-1
H-indol-1-yl)methyl]-2H-tetrazol-
2-yl}propane-1,2-diyl diacetate (14)
solids that precipitated were collected by filtration, Pale yellow powder (1.60 g, 80%), m.p. 151-152oC; IR
washed with water, dried and recrystallized from dio- (KBr)
xane/ethanol to give compounds 12 or 14, respectively. 2.05, 2.11, 2.47 (3s, 9H, 3CH3CO), 4.64 (d, 2H,
6.2 Hz, CH2), 4.93 (d, 2H, = 6.4 Hz, CH2), 5.12 (m,
1H, CHOAc), 5.40 (s, 2H, CH2), 7.30 (m, 1H, Ar-H),
7.39 (m, 1H, Ar-H), 7.52 (d, 1H, = 8.0 Hz, Ar-H),
Pale yellow powder (1.23 g, 75%), m.p. 203-204oC; IR 7.87 (d, 1H, = 8.2 Hz, Ar-H), 8.74 (s, 1H, Ar-H); 13C-
3426 (OH), 1705 cm−1 (C=O); 1H-NMR (DMSO- NMR (CDCl3):
20.12, 20.55, 26.74 (3CH3), 50.55,
= 5.8 Hz, 53.42, 64.78 (3CH2), 78.20 ( HOAc), 119.28, 124.51,
ν
1742 (C=O), 1708 cm−1 (C=O); 1H-NMR (CDCl3):
δ
J =
J
1-{1-[[2-[-(2-Hydroxyethoxy)ethyl]-2H-tetrazol-
J
5-yl]methyl]-1 -indol-3-yl}ethanone (11)
H
J
(KBr)
d6):
ν
δ
δ
2.42 (s, 3H, CH3CO), 3.87 (t, 2H,
J
C
CH2), 4.12 (m, 2H, CH2), 4.24 (t, 2H,
4.88 (m, 1H, OH), 5.10 (t, 2H, = 5.6 Hz, CH2), 5.35 156.88 (C=N), 169.91, 170.92, 182.40 (3C=O). Anal.
(s, 2H, CH2), 7.28 (m, 1H, Ar-H), 7.37 (m, 1H, Ar-H), Calcd. for C19H21N5O5 (399.40): C, 57.14; H, 5.30; N,
7.48 (d, 1H, = 8.0 Hz, Ar-H), 7.84 (d, 1H, = 8.2 Hz, 17.53. Found: C, 56.92; H, 5.17; N, 17.12.
Ar-H), 8.71 (s, 1H, Ar-H); 13C-NMR (DMSO-d6):
J = 5.8 Hz, CH2), 134.71, 138.32, 140.24, 143.08, 146.10, 150.11 (Ar-8C),
J
J
J
δ
26.76 (CH3CO), 48.32, 49.70, 60.74, 64.12, 69.52 (5CH2),
1-{1-[[2-(2,2-Dimethoxyethyl)-2H-tetrazol-5-yl]
119.30, 123.51, 134.62, 137.37, 140.12, 142.10, 145,71,
methyl]-1H-indol-3-yl}ethanone (15)
150.11 (Ar-8C), 156.84 (C=N), 182.44 (C=O). Anal. Pale yellow powder (1.27 g, 77%), m.p. 157-158oC; IR
1
Calcd. for C16H19N5O3 (329.35): C, 58.35; H, 5.81; N, (KBr)
21.26. Found: C, 58.30; H, 5.84; N, 21.31.
ν
1708 cm−1 (C=O); H-NMR (CDCl3):
δ
2.47 (s,
= 6.2
3H, CH3CO), 3.72 (s, 6H, 2OCH3), 4.94 (d, 2H,
J

Antimicrobial Activity of New Indole Derivatives
1089
Hz, CH2), 5.12 (d, 1H,
2H, CH2), 7.32 (m, 1H, Ar-H), 7.38 (m, 1H, Ar-H), 7.52 = 8.2 Hz, Ar-H), 7.90 (d, 1H,
(d, 1H, = 8.0 Hz, Ar-H), 7.88 (d, 1H,
= 8.2 Hz, Ar- 1H, Ar-H); 13C-NMR (CDCl3):
H), 8.78 (s, 1H, Ar-H); 13C-NMR (CDCl3):
35.12 (2CH3), 51.52, 53.40 (2CH2), 78.21 (
J
= 6.2 Hz, CHOCH3), 5.42 (s, 7.29 (m, 1H, Ar-H), 7.41 (m, 1H, Ar-H), 7.49 (d, 1H,
J
J
= 8.4 Hz, Ar-H), 8.75 (s,
J
J
δ
19.27, 19.23, 20.44,
26.74 (CH3), 20.65, 26.76 (5CH3CO), 49.50 (CH2), 118.78, 123.51,
HOCH3), 134.62, 138.38, 141.12, 141.88, 146.10, 149.92 (Ar-8C),
δ
C
119.28, 124.51, 134.71, 138.32, 140.24, 143.08, 146.10, 157.05 (C=N), 169.41, 170.55, 171.28, 171.70, 182.42
150.11 (Ar-8C), 156.89 (C=N), 182.40 (C=O). Anal. (5C=O). Anal. Calcd. for C26H29N5O10 (571.54): C, 54.64;
Calcd. for C16H19N5O3 (329.35): C, 58.35; H, 5.81; N, H, 5.11; N, 12.25. Found: C, 64.49; H, 4.89; N, 12.15.
21.26. Found: C, 58.18; H, 5.69; N, 21.18.
3-Acetyl-1-{2-[(2,3,4-tri-
-tetrazol-5-yl]methyl]- nosyl)-2 -tetrazol-5-yl]methyl}-1
Pale yellow powder (1.92 g, 77%), m.p. 159-160oC; IR
1H-indol-3-yl}ethanone (16)
O
-acetyl-
β
-D-xylopyra-
1-{1-[[2-(2-Methoxyethyl)-2
H
H
H-indole (18b)
Pale yellow powder (1.18 g, 79%), m.p. 152-153oC; IR (KBr)
ν
1748 (C=O), 1708 cm−1 (C=O); 1H-NMR (CDCl3):
1
(KBr)
ν
1705 cm−1 (C=O); H-NMR (CDCl3):
δ
2.43 (s,
= 5.8 1H, H-4), 4.14 (dd, 1H, J5,5 = 11.2 Hz, J4,5 = 2.8 Hz, H-
= 5.8 Hz, CH2), 5.35 (s, 2H, 5), 4.19 (dd, 1H, J5,5 = 11.2 Hz, J4,5 = 3.2 Hz, H-5), 5.10
CH2), 7.29 (m, 1H, Ar-H), 7.38 (m, 1H, Ar-H), 7.52 (d, (t, 1H, J2,3 = 9.4 Hz, H-3), 5.27 (t, 1H, J2,3 = 9.4 Hz, H-
1H, = 8.2 Hz, Ar-H), 7.49 (d, 1H, = 8.4 Hz, Ar-H), 2), 5.36 (s, 2H, CH2), 5.86 (d, 1H, J1,2 = 9.6 Hz, H-1),
8.72 (s, 1H, Ar-H); 13C-NMR (CDCl3):
26.76 (CH3CO), 7.31 (m, 1H, Ar-H), 7.42 (m, 1H, Ar-H), 7.51 (d, 1H,
35.25 (CH3), 49.39, 52.35, 64.22 (3CH2), 119.28, 124.25, = 8.0 Hz, Ar-H), 7.90 (d, 1H, = 8.2 Hz, Ar-H), 8.75 (s,
135.18, 137.44, 140.28, 142.33, 145.81, 149.76 (Ar-8C), 1H, Ar-H); 13C-NMR (CDCl3):
19.27, 19.23, 20.65,
δ 1.91, 1.95, 2.10, 2.45 (4s, 12H, 4CH3CO), 4.08 (m,
3H, CH3CO), 3.72 (s, 3H, OCH3), 4.11 (t, 2H,
Hz, CH2), 4.88 (t, 1H,
J
J
J
J
δ
J
J
δ
156.72 (C=N), 182.43 (C=O). Anal. Calcd. for C15H17N5O2 26.76 (4CH3), 459.56 (CH2), 61.94 (C-5), 68.12 (C-3),
(299.33): C, 60.19; H, 5.72; N, 23.40. Found: C, 59.91; 71.18 (C-2), 71.98 (C-4), 92.87 (C-1), 119.18, 123.48,
H, 5.58; N, 23.18.
134.67, 137.89, 142.08, 142.61, 146.25, 149.95 (Ar-8C),
157.18 (C=N), 169.41, 170.55, 171.18, 182.40 (4C=O).
Anal. Calcd. for C23H25N5O8 (499.47): C, 55.31; H,
5.05; N, 14.02. Found: C, 55.19; H, 4.90; N, 13.89.
3-Acetyl-1-{2-[(
tetrazol-5-yl]methyl}-1
To a solution of compound
dimethylformamide (7 mL) was added Et3N (0.85 mL,
6 mmol) and 2,3,4,6-tetr- -acetyl- -D-gluco or 2,3,4-
tri- -acetyl- -D-xylopyranosyl bromide (6 mmol) and
O
-acetyl-
β
-D-glycopyranosyl)-2
-indole (18a,b)
(1.21 g, 5 mmol) in
H-
H
3
N,N-
3-Acetyl-1-{2-[(
5-yl]methyl}-1
Gaseous ammonia was passed through a solution of
β
-D-glycopyranosyl)-2
H-tetrazol-
O
α
H-indole (19a,b)
O
α
the reaction mixture was stirred at room temperature protected glycosides 18a,b (5 mmol) in dry methanol
until complete as assessed by TLC (chloroform/metha- (20 mL) at 0oC for 1 h and then the mixture was
nol 99.7:0.3). The reaction mixture was concentrated stirred at room temperature for 8 h. The solvent was
under reduced pressure, diluted with CH2Cl2 (40 mL) evaporated under reduced pressure at 40oC to give a
and washed with water (3
was dried (Na2SO4), filtered, evaporated under reduc- give compound 19a,b.
×, 30 mL). The organic layer solid residue, which was recrystallized from ethanol to
ed pressure and the residue was triturated with
petroleum ether (bp 40-60oC: 45 mL) and the solid
product was filtered, dried and recrystallized from
ethanol.
3-Acetyl-1-{2-[(β-D-glucopyranosyl)-2H-tetrazol-
5-yl]methyl}-1H-indole (19a)
Pale yellow powder (1.56 g, 82%), m.p. 197-198oC; IR
1
(KBr)
(DMSO-d6):
4.12 (m, 2H, H-3,4), 4.35 (t, 1H, J2,3 = 9.4 Hz, H-2),
4.75 (t, 1H, = 6.2 Hz, OH), 4.85 (d, 1H, = 6.4 Hz,
ν
3441-3460 (OH), 1708 cm−1 (C=O); H-NMR
δ
3.44 (m, 2H, H-6,6), 3.49 (m, 1H, H-5),
3-Acetyl-1-{2-[(2,3,4,6-tetra-
O
-acetyl- -D-glu-
β
copyranosyl)-2H-tetrazol-5-yl]methyl}-1H-indole
J
J
(18a)
Pale yellow powder (2.23 g, 78%), m.p. 157-158oC; IR OH), 5.21 (m, 1H, OH), 5.28 (m, 1H, OH), 5.38 (s, 2H,
(KBr)
1.90, 1.94, 1.99, 2.04, 2.48 (5s, 15H, 5CH3CO), 4.08 H), 7.43 (d, 1H,
(m, 1H, H-5), 4.14 (dd, 1H, J6,6 = 11.4 Hz, J5,6 = 2.8 Hz, Hz, Ar-H), 8.74 (s, 1H, Ar-H); 13C-NMR (DMSO-d6):
ν
1750 (C=O), 1708 cm−1 (C=O); 1H-NMR (CDCl3): CH2), 5.82 (d, 1H,
J
= 10.2 Hz, H-1), 17.28 (m, 2H, Ar-
δ
J
= 8.2 Hz, Ar-H), 7.51 (d, 1H, = 8.4
J
δ
H-6), 4.19 (dd, 1H, J6,6 = 11.4 Hz, J5,6 = 3.2 Hz, H-6), 26.11 (CH3), 49.92 (CH2), 62.69 (C-6), 64.42 (C-4), 68.67
5.10 (t, 1H, J3,4 = 9.4 Hz, H-4), 5.22 (dd, 1H, J2,3 = 9.6 (C-3), 71.29 (C-2), 72.28 (C-5), 90.14 (C-1), 119.89,
Hz, J3,4 = 9.4 Hz, H-3), 5.27 (t, 1H, J2,3 = 9.6 Hz, H-2), 124.49, 135.12, 13858, 142.32, 141.93, 146.14, 150.24
5.38 (s, 2H, CH2), 5.87 (d, 1H, J1,2 = 10.2 Hz, H-1), (Ar-8C), 157.12 (C=N), 182.44 (C=O). Anal. Calcd. for

1090
W. A. El-Sayed et al.
C18H21N5O6 (403.39): C, 53.59; H, 5.25; N, 17.36. Found: nutrient agar medium. The antifungal activities of the
C, 53.41; H, 5.18; N, 17.27.
compounds were tested against Candida albicans,
Aspergillus Niger and Pencillium sp. in Sabouraud
dextrose agar medium.
3-Acetyl-1-{2-[(
β
-D-xylopyranosyl)-2
H-tetrazol-
5-yl]methyl}-1
H-indol (19b)
Pale yellow powder (1.49 g, 80%), m.p. 195-196oC; IR
Agar diffusion medium
All compounds were screened in vitro for their anti-
1
(KBr)
(DMSO-d6):
4.54 (t, 1H, J2,3 = 9.4 Hz, H-2), 4.79 (d, 1H,
OH), 5.21 (m, 1H, OH), 5.29 (m, 1H, OH), 5.40 (s, 2H, organisms were added to sterile nutrient agar media
CH2), 5.68 (d, 1H,
= 9.9 Hz, H-1), 7.30 (m, 1H, Ar-H), at 45oC, the mixture was transferred to sterile Petri
7.41 (m, 1H, Ar-H), 7.52 (d, 1H, = 8.0 Hz, Ar-H), dishes and allowed to solidify. Holes of 10 mm in
7.90 (d, 1H,
= 8.2 Hz, Ar-H), 8.73 (s, 1H, Ar-1H); 13C- diameter were made using a cork borer. An amount of
NMR (CDCl3): 26.11 (CH3CO), 46.12 (CH2), 62.69 (C- 0.1 mL of the synthesized compounds was added
ν
3450-3472 (OH), 1705 cm−1 (C=O); H-NMR
δ
3.45 (m, 2H, H-5,5), 4.18 (m, 2H, H-3,4), microbial activity using an agar diffusion method
= 6.4 Hz, (Cruickshank et al., 1975). A suspension of the
J
J
J
J
δ
5), 68.69 (C-3), 71.30 (C-2), 72.33 (C-4), 91.46 (C-1), inside the holes. A hole filled with DMSO was also
119.82, 123.49, 135.14, 138.49, 141.32, 144.93, 146.21, used as control. The plates were pre-incubated for 1 h
150.14 (Ar-8C), 156.78 (C=N), 182.45 (C=O). Anal. at room temperature as a period of diffusion to minim-
Calcd. for C17H19N5O5 (373.36): C, 54.69; H, 5.13; N, ize the effects to variation in time between the appli-
18.76. Found: C, 54.42; H, 4.94; N, 18.57.
cations of the different solutions. The plates were then
incubated at 37oC for 24 h and observed for antibac-
terial activity. The diameters of the zone of inhibition
Antimicrobial activity
The antibacterial activities of the synthesized com- were measured and compared with those of the stand-
pounds were tested against Bacillus subtilis, Strepto- ards; ciprofloxacin (Dahiya, 2008; Su et al., 2010) (50
coccus lactis (Gram-positive bacteria), Escherichia
µ
g/mL) and fusidic acid (Poyner and Dass, 1996; Al-
coli Pseudomonas sp. (Gram-negative bacteria) in Omar and Amr, 2010) (50
,
µg/mL) were used as
Table I. Inhibition zone in mm as a criterion for antibacterial and antifungal activities of the newly synthesized com-
pounds
Microorganism zone of inhibition diameter (mm)
Gram-positive bacteria
Gram-negative bacteria
Fungi
Compound
Bacillus
subtilis
Streptococcus Escherichia Pseudomonas
Candida
albicans
Aspergillus
niger
Penicillium
lactis
coli
aeruginosa
sp.
2
3
4
5
6
7
6
21
6
26
18
3
3
20
3
16
15
4
7
13
6
22
10
8
6
15
6
23
11
6
6
6
13
17
11
6
1
2
15
16
11
8
2
6
14
18
10
3
9
10
11
12
22
24
6
15
6
19
21
2
12
6
14
16
4
13
6
14
15
4
12
9
5
16
16
3
13
4
15
16
6
14
6
17
12
16
9
13
14
15
16
18a
18b
12
10
12
17
16
18
24
23
−
9
8
9
13
15
14
14
21
−
6
15
9
11
13
16
17
13
−
12
8
8
14
11
14
16
14
−
8
5
7
5
5
11
9
−
15
11
5
7
6
4
8
6
−
14
8
6
5
8
6
6
5
−
19a
19b
Ciprofloxacin
Fucidic acid
15

Antimicrobial Activity of New Indole Derivatives
1091
Table II. MIC* in mg/mL of the newly synthesized compounds against Gram-positive and Gram-negative bacteria
Gram-positive bacteria
Gram-negative bacteria
Escherichia coli Pseudomonas aeruginosa
Compound
Bacillus subtilis
Streptococcus lactis
3
5
9
10
12
0.14
0.12
0.34
0.24
0.68
0.34
0.12
0.12
0.17
0.21
0.34
0.14
0.34
0.34
0.24
0.15
0.42
0.10
0.18
0.22
0.34
0.12
0.12
0.10
0.20
0.17
0.34
0.24
0.27
0.19
0.18
0.19
19a
19b
Ciprofloxacin
*MIC values were calculated as the concentration at which there was >99% inhibition of the microorganism on the plate.
standards for antibacterial and antifungal activities,
respectively. The observed zone of inhibitions are
presented in Table I.
Table III. MIC in mg/mL of the newly synthesized com-
pounds against fungi
Candida
albicans
Aspergillus
niger
Penicillium
Compound
sp.
Minimum inhibitory concentration
4
5
9
10
12
0.21
0.11
>100
0.11
0.15
0.10
0.11
0.14
0.15
0.16
0.18
0.11
0.14
0.10
0.14
0.10
0.16
0.08
Minimum inhibitory concentration (MIC) of the test
compounds were determined by an agar streak dilu-
tion method. Stock solution (68 mg/mL) of the syn-
thesized compounds were made using DMSO as the
solvent. From this stock solution, the following con-
centrations (0.17; 0.34; 0.68; 0.85 and 1.7 mg/mL) of
the tested compounds solutions were mixed with the
Fucidic acid
known quantities of molten sterile agar media asepti- absorption bands at 3265 cm−1 for the NH and 1708
cally. About 20 mL of the media containing the tested cm−1 for the C=O which appeared in the 13C-NMR
1
compound was dispensed into each sterile Petri dish. spectrum at
Then the media were allowed to solidify. Microorgan- revealed the presence of the acetyl-methyl signal at
δ
182.18 ppm. The H-NMR spectrum
δ
isms were then streaked on the agar plates asepti- 2.48 ppm and the CH2 as singlet at
δ 5.33 ppm which
cally. The plates were then incubated at 37oC for 24 h have been confirmed in the 13C-NMR spectrum at
or 48 h for bacterial and fungal plates, respectively. 26.76 and 44.52, respectively.
δ
Then the plates were observed for the growth of
microorganisms. The lowest concentration of the syn- chloroacetate in DMF at room temperature afforded
thesized compounds inhibiting the growth of the given the corresponding -substituted ethyl ester derivative
bacteria/fungus was considered as the MIC of the test in 69% yield. When the ester was allowed to react
compounds. The MIC values of each compound against with hydrazine hydrate in ethanol, the corresponding
various bacteria and fungus are tabulated in Tables II acid hydrazide derivative was obtained in 80% yield.
and III. MIC values of compounds against bacteria The H-NMR spectrum of the ester
showed the
(Table II) were calculated as the concentration which signals of the ethyl group which are not present in the
resulted in > 99% inhibition of the microorganism on 1H-NMR spectrum of the hydrazide
. Instead, a
signal corresponding to the NH2 group observable. In
Reaction of the tetrazole derivative 3 with ethyl
N
4
3
5
1
4
5
the plate.
addition, the 13C-NMR spectra of
cordance with the assigned structure.
Reaction of the acid hydrazide
4
and
5
are in ac-
RESULTS AND DISCUSSION
5
with p
-chloro-
In this investigation (3-acetyl-1
trile ( ) was synthesized by reaction of 3-acetylindole the corresponding thiosemicarbazide derivative
) with chloroacetonitrile in DMF with the presence IR spectrum showed characteristic absorption bands
of sodium hydride. When compound
was reacted at 1705 and 1664 for the C=O groups and its 13C-NMR
with sodium azide in DMF in the presence of ammo- spectrum showed the signals of the aromatic carbons
H-indol-1-yl)acetoni- phenylisothiocyante at reflux temperature afforded
2
6. The
(1
2
nium chloride at 100oC, the tetrazole derivative
obtained in 71% yield. The IR spectrum of showed at
3
was at
δ
δ
118.50-149.67 ppm in addition to the C=S signal
173.86 ppm. It is well known that thiosemicar-
3

1092
W. A. El-Sayed et al.
bazide derivatives are useful intermediates for the ginosa) and the yeast-like pathogenic fungus (Candida
synthesis of a variety of five-membered heterocyclic albicans, Aspergillus niger and Penicillium sp.). The
compounds. Thus, when compound
6
was heated in 2 results of the preliminary antibacterial and the
N
sodium hydroxide solution at reflux temperature, antifungal activates are shown in Table I. The results
the 1,2,4-triazole derivative
7 was obtained in 78% revealed that compounds showed varying degrees of
yield. The structure of the resulting 1,2,4-triazole deri- inhibition against the tested microorganisms. In
vative
was confirmed by IR, 1H- and 13C-NMR spec- general, the best antibacterial activity was displayed
tra as well as elemental analysis. When the 1,2,4- by compounds 10 and 19b. Compounds 19a
tiazole derivative was reacted with 2,3,4,6-tetra- and 19b showed strong activity against the Gram-
acetyl- -D-glucopyranosyl bromide ( ), the correspond- negative bacteria Escherichia coli and Pseudomonas
ing substituted -glucoside derivative was afforded aeruginosa, while compounds displayed strong
in 80% yield. The 1H-NMR spectrum showed the activity against Escherichia coli. These results proved
anomeric proton of the sugar moiety at 5.76 ppm as that the attachment of substituted tetrazolyls or
a doublet, with a coupling constant equal to 10.2 Hz, [(triazol-3-yl)methyl]-2 -tetrazol-5-yl to the indole
indicating the -orientation of the thioglycosidic bond. derivative resulted in increased inhibitory activity.
7
3, 5, 9,
7
O-
α
8
S
9
5
δ
H
β
2
The absence of a signal corresponding to the C=S in This is clear as the activity increased in the resulting
the 13C-NMR spectrum confirmed the attachment of compounds compared to the relatively low activity of
the sugar moiety at the sulfur atom, rather than the
nitrogen atom, which has also been supported by the against Streptococcus lactis followed by compounds
chemical shift of the anomeric proton. Deacetylation 12 19a and 19b which were moderately active. Com-
afforded the -glucoside derivative 10 whose spectral pounds and 19b showed good activity against
and analytical data were in agreement with the Pseudomonas sp. followed by compounds 10 12
assigned structure (see experimental part). and 19a. The antifungal activities depicted in Table I
Reaction of the tetrazole derivatives with 2-(2- revealed that compounds and 10 exhibited inter-
chloroethoxyehanol), 3-chloropropane-1,2-diol, 2-chloro- estingly high antifungal activities followed by com-
1,1-dimethoxyethane or 1-chloro-2-methoxyethane in pounds , and 12, which also showed strong to
DMF at 70ºC afforded the -substituted acyclic nucleo- moderate activity.
side analogues 11 13 15 and 16, respectively. Acety- The MIC of the most active compounds, the anti-
alation of compounds 11 and 13 using acetic anhydride bacterial antibiotic ciprofloxacin and the antifungal
2. Compounds 3, 5 and 10 showed good activity
9,
,
S
5
3,
9,
,
3
5
4, 9
N
,
,
afforded the corresponding
O-acetyl derivatives 12 drug fusidic acid, which are shown in Tables II and
and 14, respectively. The 1H-NMR spectra of the ace- III, were in accordance with the results obtained in
tylated derivatives 12 and 14 revealed the presence of the primary screening.
the
NMR spectrum at
to the
ppm for compounds 12 and 14, respectively. Reaction through a thioglycosidic linkage resulted in marked
of with acetobromo sugars 17a gave the acetyl- increases in inhibition activity. Furthermore, tetra-
ated -glycoside derivatives 18a , respectively. The zoles with a free NH and the N-substituted hydrazide
1H-NMR spectra showed the anomeric proton of the
displayed the highest activities. This tetrazole
sugar moiety in the range of 5.86-5.89 ppm as a hydrazide showed high activity against Gram-positive
doublet, with coupling constants equal to 10.2 and 9.6 bacteria (Bacillus subtilis), the Gram-negative bac-
Hz indicating the -orientation of the glycosidic bond. teria (Escherichia coli and Pseudomonas aeruginosa),
Deprotection of 18a gave the deacetylated -gly- and the yeast-like pathogenic fungi (Candida albicans,
coside derivatives 19a (Scheme 2) whose spectral Aspergillus niger and Penicillium sp.). Additionally,
and analytical data were in agreement with the assign- the antibacterial activity observed for the -sub-
indicated the
O
-acetyl methyl groups which appeared in the 13C-
The antimicrobial activities and structure-activity
δ
20.14 and 20.55 ppm in addition relationships indicated that the attachment of gly-
-acetyl carbonyl carbons at δ 169.89-182.44 cosyl moieties to the substituted 1,2,4-triazole ring
O
2
, b
, b
N
5
δ
β
,
b
N
,
b
N
ed structure (see experimental part).
stituted tetrazole glycosides 19a, b
importance of the free hydroxyl glycopyranosylthio
moiety as the activity was reduced when this group
Antimicrobial activity
The synthesized compounds were tested for their in was replaced with the corresponding
O-acetylated
vitro antimicrobial activity against a panel of stand- glycosyles in the protected derivatives as well as the
ard strains of the Gram-positive bacteria (Bacillus acyclic analogs. The antibacterial activity observed for
subtilis and Streptococcus lactis), the Gram-negative the xylopyranosyl derivative was also relatively higher
bacteria (Escherichia coli and Pseudomonas aeru- than that of the corresponding glucopyranosyl 19a
.

Antimicrobial Activity of New Indole Derivatives
1093
Scheme 1. Synthesis of [(1,2,4-triazol-3-yl)methyl]-2H-tetrazole glycoside derivatives
The antibacterial activities also indicated that the marked increase in activity as the activity was obvi-
attachment of glycopyranosyl sugar moieties to the ously increased in compounds and 10 when com-
synthesized 1,2,4-triazole derivatives resulted in a pared to compound . On the other hand, the attach-
9
7

1094
W. A. El-Sayed et al.
Scheme 2. Synthesis of N-substituted tetrazole derivatives
ment of the xylopyranosyl sugar moiety to the syn- antibacterial activities against Bacillus subtilis and
thesized tetrazole derivative resulted in an increase in Escherichia coli
.

Antimicrobial Activity of New Indole Derivatives
1095
Synthesis and evaluation of anti-HIV activity of isatin β-
thiosemicarbazone derivatives. Bioorg. Med. Chem. Lett.,
15, 4451-4455 (2005).
Blum, C. A., Xu, M., Orner, G. A., Fong, A. T., Bailey, G. S.,
The antifungal activity test revealed that the N-sub-
stituted hydrazide of the tetrazolyl moiety
5 and the
free hydroxyl glucoside of the substituted 1,2,4-tria-
zole 10 are most potent. Furthermore, the results
indicated that the activities of the glycosides of the
substituted 1,2,4-triazole were higher than that of
those attached to the tetrazolyl moieties. It was also
obvious that the free hydroxyl glycosides were highly
Stoner, G. D., Horio, D. T., and Dashwood, R. H.,
mutation in rat colon tumors initiated by 1,2-dimethyl-
hydrazine and 2-amino-3-methylimidazo[4,5- ]quinoline,
β-Catenin
f
and the effect of post-initiation treatment with chloro-
phyllin and indole-3-carbinol. Carcinogenesis, 22, 315-320
(2001).
Bond, A. D., Fleming, A., Kelleher, F., McGinley, J., and
Prajapati, V., Reactions of 1,4-bis(tetrazole)benzenes: for-
mation of long chain alkyl halides. Tetrahedron, 62, 9577-
9581 (2006).
Chang, X., Tou, J. C., Hong, C., Kim, H. A., Riby, J. E.,
Firestone, G. L., and Bjeldanes, L. F., 3,3'-Diindolylmethane
inhibits angiogenesis and the growth of transplantable
human breast carcinoma in athymic mice. Carcinogenesis,
26, 771-778 (2005).
active then their corresponding
O-acetylated analogs.
In addition, the -substituted tetrazole ethyl ester
N
which displayed weak activity against Gram-positive
bacteria and Gram-negative bacteria showed high
activity against the yeast-like pathogenic fungi (Can-
dida albicans, Aspergillus niger and Penicillium sp.).
The antifungal activities indicated that the attach-
ment of sugar moieties to the synthesized 1,2,4-tria-
zole derivatives led to markedly increased activities as
the activity was increased for glycoside 10 compared
to the triazole
sugar moieties to the tetrazole
ate increase in antifungal activities against Candida
albicans and Aspergillus niger
New 1-[(tetrazol-5-yl)methyl]indoles, the corres-
ponding glycoside derivatives, their acyclic analogous
7
. On the other hand, the attachment of
Chen, I., McDougal, A., Wang, F., and Safe, S., Aryl hydro-
carbon receptor-mediated antiestrogenic and antitumor-
igenic activity of diindolylmethane. Carcinogenesis, 19, 1631-
1639 (1998).
Cruickshank, R., Duguid, J. P., Marmion, B. P., and Swain,
R. H., Medical Microbiology (12th ed). Longman group
Ltd., Edinburgh, London, pp. 180-188, (1975).
Dahiya, R., Synthesis, characterization and antimicrobial
studies on some newer imidazole analogs. Sci. Pharm., 76,
217-239 (2008).
3
resulted in a moder-
.
and the [(1,2,4-triazol-3-yl)methyl]-2H-tetrazole deriva-
tive as well as the corresponding thioglucosides were
synthesized and evaluated for their antimicrobial
activities. Some of the synthesized compounds were
highly active with respect to their antibacterial and
antifungal activities. The attachment of free hydroxyl
glycosyl moieties to tetrazole and 1,2,4-triazole ring
systems increased their antibacterial activity, whereas
only 1,2,4-triazole thioglucosides revealed high anti-
fungal activity.
Dekker, W. H., Selling, H. A., and Overeem, J. C., Structure-
activity relationships to some antifungal indoles. J. Agric.
Food Chem., 23, 785-791 (1975).
El-Sayed, W. A., Ramiz, M. M. M., and Abdel-Rahman, A. A.
H.,
C-Furyl glycosides, I. Synthesis and antimicrobial
evaluation of
C-furyl glycosides and chalcones derived
therefrom. Monatsh. Chem., 139, 1499-1505 (2008a).
El-Sayed, W. A., Fathi, N. M., Gad, W. A., and El-Ashry, E.
S. H., Synthesis, and antiviral evaluation of some 5-N-
arylaminomethyl-2-glycosylsulphanyl-1,3,4-oxadiazoles
and their analogues against hepatitis A and herpes simplex
viruses. J. Carbohydr. Chem., 27, 357-372 (2008b).
El-Sayed, W. A., Ramiz, M. M. M., and Abdel-Rahman, A. A.
H., Anti-hepatitis B virus activity of new N4-β-D-gly-
coside pyrazolo[3,4-d]pyrimidine derivatives. Z. Natur-
forsch., 64, 323-328 (2009a).
ACKNOWLEDGEMENTS
The authors would like to thank Dr. El-Sayed E.
Mostafa, Department of Microbial Chemistry, National
Research Center, Cairo, Egypt for performing the anti-
microbial activity assays of the synthesized com-
pounds.
El-Sayed, W. A., Nassar, I. F., and Abdel-Rahman, A. A. H.,
REFERENCES
C-Furyl glycosides, II: synthesis and antimicrobial eval-
uation of C-furyl glycosides bearing pyrazolines, isoxa-
zolines, and 5,6-dihydropyrimidine-2(1H)-thiones. Monatsh.
Chem., 140, 365-370 (2009b).
El-Sayed, W. A., Rashad, A. E., Awad, S. M., and Ali, M. M.,
Synthesis and in vitro antitumor activity of some new
substituted thiopyrimidine acyclic nucleosides and their
thioglycoside analogs. Nucleosides Nucleotides Nucleic
Acids, 28, 261-274 (2009c).
Al-Omar, M. A. and Amr, A. E. G. E., Synthesis of some new
pyridine-2,6-carboxamide-derived Schiff bases as poten-
tial antimicrobial agents. Molecules, 15, 4711-4721 (2010).
Andreani, A., Rambaldi, M., Locatelli, A., and Pifferi, G.,
Synthesis and antiinflammatory activity of indolylacrylic
and methylacrylic acids. Eur. J. Med. Chem., 29, 903-906
(1994).
Bal, T. R., Anand, B., Yogeeswari, P., and Sriram, D.,
Hashimoto, Y., Shudo, K., and Okamoto, T., Deoxyribonu-

1096
W. A. El-Sayed et al.
cleic acid modification by mutagenic 3-amino-1-methyl-
5H-pyrido[4,3-b]indole: the chemical events. Chem. Pharm.
Bull., 32, 4300-4308 (1984).
Herr, R. J., 5-Substituted-1H-tetrazoles as carboxylic acid
isosteres: medicinal chemistry and synthetic methods.
Bioorg. Med. Chem., 10, 3379-3393 (2002).
Hong, C., Firestone, G. L., and Bjeldanes, L. F., Bcl-2 family-
mediated apoptotic effects of 3,3'-diindolylmethane (DIM)
in human breast cancer cells. Biochem. Pharmacol., 63,
1085-1097 (2002).
thiosemicarbazones as anti-poxvirus agents. J. Med.
Chem., 48, 3045-3050 (2005).
Poyner, T. F. and Dass, B. K., The role of Staphylococcus
aureus in atopic eczema. J. Eur. Acad. Dermatol. Venereol.,
7, S23-S30 (1996).
Rajasekaran, A. and Thampi, P. P., Synthesis and antino-
ciceptive activity of some substituted-{5-[2-(1,2,3,4-tetra-
hydrocarbazol-9-yl)ethyl]tetrazol-1-yl}alkanones. Eur. J.
Med. Chem., 40, 1359-1364 (2005).
Samosorn, S., Bremner, J. B., Ball, A., and Lewis, K., Syn-
thesis of functionalized 2-aryl-5-nitro-1H-indoles and their
activity as bacterial NorA efflux pump inhibitors. Bioorg.
Med. Chem., 14, 857-865 (2006).
Kamijo, S. and Yamamoto, Y., A bimetallic catalyst and dual
role catalyst: synthesis of
N-(alkoxycarbonyl)indoles from
2-(alkynyl)phenylisocyanates. J. Org. Chem., 68, 4764-4771
(2003).
Khalil, N. S. A. M., Efficient synthesis, structure, and
Saxton, J. E., Indoles. Wiely-Interscience, New York, Part 4
(1983).
antimicrobial activity of some novel N- and S-
cosides of 5-pyridin-3-yl-1,2,4-triazoles. Carbohydr. Res.,
341, 2187-2199 (2006).
β
-D-glu-
Shimizu, M., Ishikawa, M., Komoda, Y., Nakajima, T.,
Yamaguchi, K., and Yoneda, N., Stereochemistry of methyl
2-benzyl-3-methoxycarbonyl-9-methyl-1, 2, 3, 4-tetrahydro-
9H-pyrido[3,4-b]indole-1-propionate. Chem. Pharm. Bull.,
32, 463-474 (1984).
Khalil, N. S. A. M.,
N- and S-α-l-arabinopyranosyl[1,2,4]
triazolo[3,4- ][1,3,4]thiadiazoles. First synthesis and bio-
b
logical evaluation. Eur. J. Med. Chem., 42, 1193-1199 (2007). Sriram, D., Yogeeswari, P., and Gopal, G., Synthesis, anti-
Lundt, B. F. and Anderson, W., Analgesic 3-(aminoalkoxy)
Indoles. Ger. Offen. 2,024,966 (1970).
HIV and antitubercular activities of lamivudine prodrugs.
Eur. J. Med. Chem., 40, 1373-1376 (2005).
Markham, P. N., Westhaus, E., Klyachko, K., Johnson, M.
E., and Neyfakh, A. A., Multiple novel inhibitors of the
Su, H. C., Ramkissoon, K., Doolittle, J., Clark, M., Khatun,
J., Secrest, A., Wolfgang, M. C., and Giddings, M. C., The
development of ciprofloxacin resistance in Pseudomonas
aeruginosa involves multiple response stages and multi-
ple proteins. Antimicrob. Agents Chemother., 54, 4626-
4635 (2010).
NorA multidrug transporter of Staphylococcus aureus
.
Antimicrob. Agents Chemother., 43, 2404-2408 (1999).
Master, H. E., Khan, S. I., and Poojari, K. A., Design and
synthesis of low molecular weight compounds with com-
plement inhibition activity. Bioorg. Med. Chem., 13, 4891-
4899 (2005).
Misra, U., Hitkari, A., Saxena, A. K., Gurtu, S., and Shanker,
K., Biologically active indolylmethyl-1,3,4-oxadiazoles,
1,3,4-thiadiazoles, 4H-1,3,4-triazoles and 1,2,4-triazines.
Eur. J. Med. Chem., 31, 629-634 (1996).
Nakashima, Y., Kawashima, Y., Amanuma, F., Sota, K.,
Tanaka, A., and Kameyama, T., Furo[3,2-b]indole deriva-
tives. I. Synthesis and analgesic and anti-inflammatory
activities of 4, 6-disubstituted-furo[3,2-b]indole-2-carbox-
amide derivatives. Chem. Pharm. Bull., 32, 4271-4280
(1984).
Pandeya, S. N., Sriram, D., Nath, G., and DeClercq, E., Syn-
thesis, antibacterial, antifungal and anti HIV activities of
Schiff and Mannich bases derived from isatin derivatives
and N-[4-(4'-chlorophenyl)thiazol-2-yl]thiosemicarbazide.
Eur. J. Pharm. Sci., 9, 25-31 (1999).
Velezheva, V. S., Brennan, P. J., Marshakov, V. Y., Gusev,
D. V., Lisichkina, I. N., Peregudov, A. S., Tchernousova, L.
N., Smirnova, T. G., Andreevskaya, S. N., and Medvedev,
A. E., Novel pyridazino[4,3-b]indoles with dual inhibitory
activity against Mycobacterium tuberculosis and mono-
amine oxidase. J. Med. Chem., 47, 3455-3461 (2004).
Webber, S. E., Tikhe, J., Worland, S. T., Fuhrman, S. A.,
Hendrickson, T. F., Matthews, D. A., Love, R. A., Patick,
A. K., Meador, J. W., Ferre, R. A., Brown, E. L., DeLisle,
D. M., Ford, C. E., and Binford, S. L., Design, synthesis,
and evaluation of nonpeptidic inhibitors of human rhino-
virus 3C protease. J. Med. Chem., 39, 5072-5082 (1996).
Zhang, H. Z., Kasibhatla, S., Kuemmerle, J., Kemnitzer, W.,
Ollis-Mason, K., Qiu, L., Crogan-Grundy, C., Tseng, B.,
Drewe, J., and Cai, S. X., Discovery and structure-activity
relationship of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new
series of apoptosis inducers and potential anticancer
agents. J. Med. Chem., 48, 5215-5223 (2005).
Pirrung, M. C., Pansare, S. V., Das Sarma, K., Keith, K. A.,
and Kern, E. R., Combinatorial optimization of isatin-β-