Amino acid derivatives, VII [1]: Synthesis and antiviral evaluation of α-amino acid esters bearing an indazole side chain

Article abstract of DOI:10.1007/s00706-007-0770-7

A series of peptide and dipeptide derivatives conjugated with an indazole residue were synthesized. The new compounds were evaluated in vitro for cytotoxicity against Hepatitis-A virus (HAV-27), Herpes Simplex virus-1 (HSV-1), and Hepatitis-B virus (HBV) and showed moderate to high activity.

Full text of DOI:10.1007/s00706-007-0770-7

Monatsh Chem 139, 289–297 (2008)
DOI 10.1007/s00706-007-0770-7
Printed in The Netherlands
Amino Acid Derivatives, VII [1]: Synthesis and Antiviral Evaluation
of a-Amino Acid Esters Bearing an Indazole Side Chain
ꢀ
Adel A.-H. Abdel-Rahman
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Received July 13, 2007; accepted July 13, 2007; published online February 12, 2008
# Springer-Verlag 2008
Summary. A series of peptide and dipeptide derivatives con-
jugated with an indazole residue were synthesized. The new
compounds were evaluated in vitro for cytotoxicity against
Hepatitis-A virus (HAV-27), Herpes Simplex virus-1 (HSV-
1), and Hepatitis-B virus (HBV) and showed moderate to high
activity.
pharmacological properties of indazoles and amino
acid derivatives we were prompted to prepare new
N1- and N2-indazole bearing amino acid derivatives
to study, in vitro, their inhibitory activity for HAV-
27, HSV-1, and HBV.
Keywords. Indazole; Regioisomers; Amino acids; Dipep-
tides; Antiviral activity.
Results and Discussion
Chemistry
Introduction
Indazole (1) was treated with ethyl chloroacetate in
dry acetone containing anhydrous K2CO3 at reflux
temperature to afford N1- and N2-regioisomers,
which were separated by means of column chroma-
tography on silica gel. For both compounds 2 and 3,
elemental analysis and mass spectral data [m=z 204
(Mþ), 227 (M þ Naþ)] established their molecular
formula as C11H12N2O2, suggesting that they are
possibly the 1-(ethoxycarbonylmethyl)-1H-indazole
(2) and 2-(ethoxycarbonylmethyl)-2H-indazole (3)
The indazole nucleus is a pharmaceutically im-
portant structure and constitutes the key subunit in
many drugs with a broad range of pharmacological
activities [2] including antitumor [3], antimicrobial
[4], antiplatelet [5], and anti-inflammatory activities
[6]. However, there is still a lack of general and
efficient methodologies for the synthesis of N-substi-
tuted indazoles [7]. On the other hand, a new target
for the development of anti-HIV and antitumor ther-
apies has been reported by the use, in vivo and in
vitro, of amino acid derived heterocycles. Such com-
pounds are the lysyl amide prodrug of 2-(4-amino-
3-methylphenyl)-5-fluorobenzothiazole [8], amino
acid derivatives of paclitaxel [9], cysteine-modifying
agents [10], and isoquinoline carboxylic acid deriva-
tives as building blocks for HIV protease inhibitors
[11]. In connection with our strategy in synthesis of
new ꢀ-amino acid derivatives [12] and due to the
1
regioisomers. Although MS and D NMR spectral
analysis could not distinguish them, their HMBC
spectra were used successfully to confirm their iso-
meric structures. As shown in Fig. 1, the signal of N–
CH2-moiety of compound 2 showed a 3J-correlation
with its 7a-carbon. In contrast, the signal of the N–
CH2-moiety of compound 3 exhibited a 3J-correlation
with its 3-carbon. Based on these data, compound
2 was identified as N1-(ethoxycarbonylmethyl)-1H-
indazole and compound 3 was confirmed as N2-
1
ꢀ
Corresponding author. E-mail: adelnassar63@hotmail.com
(ethoxycarbonylmethyl)-2H-indazole. The H NMR

290
A. A.-H. Abdel-Rahman
signals of four aromatic protons appeared as two
triplets and two doublets at ꢁ ¼ 7.16, 7.33, 7.40,
and 7.74 ppm, while the singlet at ꢁ ¼ 8.05 ppm cor-
responds to H-3. The 13C NMR spectrum showed
signals at ꢁ ¼ 13.9 and 61.5 ppm pertaining to OEt.
The signal at ꢁ ¼ 50.1 ppm for N1-CH2, signals at
ꢁ ¼ 108.6–140.0 ppm for Ar-carbons, and the signal
at ꢁ ¼ 167.8 ppm to the C¼O group were assigned.
1
The H NMR spectrum of 3 showed a triplet at
ꢁ ¼ 1.25 ppm and a quartet at ꢁ ¼ 4.24 ppm cor-
responding to OEt. The singlet at ꢁ ¼ 5.17 ppm cor-
responds to N2-CH2. The signals of four aromatic
protons appeared as two triplets and two doublets at
ꢁ ¼ 7.08, 7.28, 7.65, and 7.69 ppm, while the singlet
at ꢁ ¼ 7.98 ppm corresponds to H-3. The 13C NMR
spectrum showed signals at ꢁ ¼ 13.9 and 62.0 ppm
corresponding to OEt. The signal at ꢁ ¼ 54.4 ppm for
N2-CH2, signals at ꢁ ¼ 117.4–149.1 ppm for Ar-car-
bons, and a signal at ꢁ ¼ 167.0 ppm to the C¼O group
3
Fig. 1. JCH Correlations in 2 and 3
spectrum of 2 showed a triplet at ꢁ ¼ 1.23 ppm and a
quartet at ꢁ ¼ 4.20ppm corresponding to OEt. The sin-
glet at ꢁ ¼ 5.14 ppm corresponds to N1-CH2. The
Scheme 1

Amino Acid Derivatives, VII
291
were assigned. Treatment of 2 or 3 with hydrazine
hydrate in ethanol gave the corresponding hydrazide
derivatives 4 or 5 in 90–93% yield. These hydra-
zides were selected as starting materials for the cou-
pling reaction with the appropriate acylated amino
acides, via the azide-coupling method [13]. Thus,
treatment of 4 or 5 at ꢁ5ꢂC in AcOH and 1 N HC1
with NaNO2 afforded the inseparable azide deriva-
tive. The yellow syrupy azide compound was then
treated, in situ, with the appropriate amino acid
methyl esters in ethyl acetate containing Et3N at
0ꢂC to give, after neutralization, the desired peptides
6–12 in 78–84% or 13–19 in 72–77% yields. The
20 or 21 at ꢁ5ꢂC in AcOH and 1 N HCl with NaNO2
afforded the inseparable azide derivatives. The yel-
low syrupy azide compounds were treated, as men-
tioned above, with the appropriate amino acid methyl
esters in ethyl acetate containing Et3N at 0ꢂC to
afford 22–28 in 75–80% and 29–35 in 70–73%
yields. The structures of the dipeptide derivatives
1
were confirmed by their H, 13C NMR, and mass
spectra (Scheme 2).
Antiviral Activity
The plaque infectivity assay [14] was carried out to
test the prepared compounds for antiviral activity. The
test was performed to include three possibilities for
antiviral activity, virucidal effect, virus adsorption,
and effect on virus replication for both Hepatitis-A
virus (HAV-27) and Herpes Simplex virus-1 (HSV-1).
1
structures of 6–19 were assigned from their H, 13C
NMR, and mass spectra (Scheme 1).
Treating of 6 or 13 with N2H4 ꢃ H2O in ethanol at
reflux temperature afforded the corresponding hy-
drazides 20 or 21 in 96–98% yields. Treatment of
Scheme 2

292
A. A.-H. Abdel-Rahman
General Procedure for the Preparation of 1-(Ethoxy-
For the antiviral activity against HAV-27 it was
noted that, at both concentrations 10 and 20 ꢂg=105
cells, compounds 7, 9–12, 18, and 25–28 revealed
the highest antiviral activity in this series of com-
pounds and compounds 8, 14, 17, 19, 23, and 24
revealed high activity at 10 ꢂg=105 cells using aman-
carbonylmethyl)-1H-indazole (2, C11H12N2O2) and 2-
(Ethoxycarbonylmethyl)-2H-indazole (3, C11H12N2O2)
A mixture of 11.8g 1 (0.1mol), 14.7g ethyl chloroacetate
(0.12 mol), and 13.8g anhydrous K2CO3 (0.1mol) in 36cm3
dry acetone was refluxed for 5 h (TLC). The solvent was re-
moved in vacuo and the residue was diluted with H2O and
extracted with CH2Cl2 (3ꢄ30cm3). The combined organic
layers were dried (Na2SO4) and the solvent was evaporated.
The residue was purified by silica gel column chromatography
using petroleum ether:ethylacetate¼ 7:1 to afford 12.24g 2
(60%) and 6.12 g 3 (30%).
ꢀ
tadine (C ) as a control. Compounds 15, 16, and
33–35, showed moderate activity, while at concen-
trations of 20 ꢂg=105 cells, compounds 6, 13, 22, 29,
and 30–32 revealed little antiviral activity.
For the antiviral activity against HSV-1 the re-
sults revealed that compounds 7–12 and 22–25
showed the highest effect on HSV-1 at concentration
10 ꢂg=105 cells, while compounds 6, 13–19, and
29–35 showed moderate activity.
On testing preliminary a viral screening against
Hepatitis-B virus (HBV) (Hep G2 2.2.15 cell meth-
od) [15] indicated that compounds 10–12, 23 and
25–28 were active against HBV replication with
IC50 85–95 ꢂM and CC50 90–100 ꢂM, while com-
pounds 6–9, 13–19, 22, 24, and 29–35 showed mod-
erate viral replication inhibition and moderate
cytotoxicity. The drug Lamivudine, which is a potent
selective inhibitor of HBV replication [16] was used
as a standard for the comparative studies.
Compound 2: Colorless syrup; 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 1.23 (t, J ¼ 6.1 Hz, CH3CH2O), 4.21 (q, J ¼ 6.1 Hz,
CH3CH2O), 5.14 (s, N1-CH2), 7.16 (t, J ¼ 7.5 Hz, H-5), 7.33
(t, J ¼ 7.6 Hz, H-6), 7.40 (d, J ¼ 8.6 Hz, H-4), 7.74 (d,
J ¼ 8.5Hz, H-7), 8.05 (s, H-3) ppm; 13C NMR (CDC13,
62.5MHz): ꢁ ¼ 13.9 (CH3CH2O), 50.1 (N1-CH2), 61.5
(CH3CH2O), 108.6 (C-7), 120.8 (C-5), 121.1 (C-4), 124.1
(C-3a), 126.6 (C-6), 134.1 (C-3), 140.0 (C-7a), 167.8 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
Compound 3: Colorless syrup; 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 1.25 (t, J ¼ 6.1 Hz, CH3CH2O), 4.24 (q, J ¼ 6.1 Hz,
CH3CH2O), 5.17 (s, N2-CH2), 7.08 (t, J ¼ 7.5 Hz, H-5), 7.28
(t, J ¼ 7.6 Hz, H-6), 7.65 (d, J ¼ 8.6 Hz, H-4), 7.70 (d,
J ¼ 8.5Hz, H-7), 7.98 (s, H-3) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 13.9 (CH3CH2O), 54.4 (N2-CH2), 62.0
(CH3CH2O), 117.4 (C-7), 120.2 (C-5), 121.9 (C-4), 122.1
(C-3a), 124.3 (C-6), 134.1 (C-3), 149.0 (C-7a), 167.0 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
General Procedure for the Preparation of 1-Acetylhydrazine-
1H-indazole (4, C9H10N4O) and 2-Acetylhydrazine-2H-
indazole (5, C9H10N4O)
Conclusions
New ꢀ-amino acid derivatives bearing indazole side
chain were synthesized in order to increase the num-
ber of tested compounds screened for antiviral activ-
ity. Some of them displayed promising activities.
A mixture of 2 or 3 (10 mmol) and 1.25g N2H4 ꢃ H2O
(25 mmol) in 30cm3 ethanol was heated under reflux for
2 h. The excess of ethanol was removed under reduced pres-
sure and the resulting precipitate was filtered off, washed with
ethanol, and recrystallized from ethanol, to give 4 (93%) and 5
(90%).
Compound 4: Mp 120–122ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢁ ¼ 4.90 (br, s, NHNH2), 5.16 (s, N1-CH2), 7.18
(t, J ¼ 7.5 Hz, H-5), 7.40 (t, J ¼ 7.6 Hz, H-6), 7.50
(d, J ¼ 8.6 Hz, H-4), 7.78 (d, J ¼ 8.5 Hz, H-7), 8.11 (s, H-
3), 9.80 (br, s, NHNH2) ppm; 13C NMR (DMSO-d6,
62.5 MHz): ꢁ ¼ 50.15 (N1-CH2), 110.0 (C-7), 120.0 (C-5),
121.4 (C-4), 124.8 (C-3a), 126.9 (C-6), 134.6 (C-3),
140.1 (C-7a), 168.7 (C¼O) ppm; MS (ESI): m=z ¼ 213
[M þ Na]þ.
Experimental
General
Melting points were determined using a Kofler block in-
strument. TLC was performed on plastic plates Silica Gel
60 F254 (E. Merck, layer thickness 0.2 mm). NMR spectra
were recorded on a Bruker AC 250 FT NMR spectrometer
1
at 250 MHz for H NMR and 62.9MHz for 13C NMR with
TMS as an internal standard. ES mass spectra were obtained
from an Esquire 3000plus iontrap mass spectrometer from
Bruker Daltonics. The microanalyses were performed at the
microanalytical unit, Tokyo University, Japan, and were found
to agree favourably with the calculated values. Viral screening
against HAV and HSV was conducted at the Environmental
Virology Lab., Department of Water Pollution Research,
National Research Centre, Cairo, Egypt. Viral screening
against HBV was conducted at the National Liver Institute,
Menoufia University, Egypt.
Compound 5: Mp 167–169ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢁ ¼ 4.88 (br, s, NHNH2), 5.22 (s, N2-CH2),
7.19 (t, J ¼ 7.5 Hz, H-5), 7.31 (t, J ¼ 7.6 Hz, H-6), 7.69
(d, J ¼ 8.6 Hz, H-4), 7.75 (d, J ¼ 8.5 Hz, H-7), 8.00 (s,
H-3), 9.77 (br, s, NHNH2) ppm; 13C NMR (DMSO-d6,
62.5 MHz): ꢁ ¼ 55.04 (N2-CH2), 118.1 (C-7), 120.7 (C-
5), 121.1 (C-4), 122.8 (C-3a), 125.5 (C-6), 134.9 (C-3),
149.6 (C-7a), 168.4 (C¼O) ppm; MS (ESI): m=z ¼ 213
[M þ Na]þ.

Amino Acid Derivatives, VII
293
General Procedure for the Preparation of N1- and N2-
Indazole Bearing Amino Acid Esters 6–19
J ¼ 7.5 Hz, H-5), 7.33 (t, J ¼ 7.6 Hz, H-6), 7.40 (d, J ¼
8.6 Hz, H-4), 7.77 (d, J ¼ 8.5Hz, H-7), 8.09 (s, H-3), 8.40
(br, s, NH) ppm; 13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 16.5
(CH3), 18.6 (CH3), 31.6 (CH), 51.0 (CH), 52.8 (N1-CH2),
54.5 (OCH3), 109.2 (C-7), 120.9 (C-5), 121.4 (C-4), 124.8
(C-3a), 127.2 (C-6), 134.6 (C-3), 141.0 (C-7a), 167.4 (C¼O),
175.1 (C¼O) ppm; MS (ESI): m=z ¼ 312 [M þ Na]þ.
A solution of 1.90g 4 or 5 (4mmol) in 30 cm3 HOAc, 15 cm3
1 N HCl, and 125 cm3 H2O was cooled in an ice-bath (ꢁ5ꢂC).
Sodium nitrite (4.35 g, 63 mmol) in 15 cm3 cold H2O was
added with stirring. After stirring at ꢁ5ꢂC for 15 min, the
yellow syrup was formed. The azide was taken in cold
150 cm3 ethyl acetate, washed with 150 cm3 NaHCO3 (3%),
150 cm3 H2O, and dried (Na2SO4). A solution of the appropri-
ate amino acid methyl ester hydrochloride (4.5mmol) in
100 cm3 ethyl acetate containing 1.0 cm3 Et3N was stirred
at 0ꢂC for 20 min, filtered, and the filtrate was added to the
azide solution. The mixture was kept at ꢁ5ꢂC for 12h, then at
room temperature for another 12 h, followed by washing with
150 cm3 0.5 N HC1, 150 cm3 NaHCO3 (3%), 150 cm3 H2O,
and dried (Na2SO4). The filtrate was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography using petroleum ether:ethylacetate¼ 7:1 to
afford 6–12 in 78–84% and 13–19 in 72–77% yields.
1-Acetyl-1H-indazole L-leucine methyl ester (10, C16H21N3O3)
Colorless syrup (81%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.90
(dd, J ¼ 1.9, 7.2 Hz, 2CH3), 1.40–1.69 (m, CH2, CH), 3.60 (s,
OCH3), 4.22–4.31 (m, CH), 5.53 (s, N1-CH2), 7.15 (t, J ¼
7.5 Hz, H-5), 7.37 (t, J ¼ 7.6 Hz, H-6), 7.45 (d, J ¼ 8.6 Hz,
H-4), 7.81 (d, J ¼ 8.5 Hz, H-7), 8.08 (s, H-3), 8.15 (br, s,
NH) ppm; 13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 21.6 (2CH3),
25.8 (CH), 39.6 (CH2), 51.6 (CH), 53.7 (N1-CH2), 54.3
(OCH3), 108.6 (C-7), 120.5 (C-5), 121.8 (C-4), 124.3 (C-3a),
126.9 (C-6), 134.0 (C-3), 140.5 (C-7a), 167.5 (C¼O), 172.5
(C¼O) ppm; MS (ESI): m=z ¼ 326 [Mþ Na]þ.
1-Acetyl-1H-indazole L-methionine methyl ester
1-Acetyl-1H-indazole L-glycine methyl ester (6, C12H13N3O3)
Colorless syrup (78%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.60
(s, OCH3), 4.18 (s, CH2), 5.54 (s, N1-CH2), 7.15 (t, J ¼ 7.5 Hz,
H-5), 7.20 (br, s, NH) 7.35 (t, J ¼ 7.6 Hz, H-6), 7.41 (d,
J ¼ 8.6 Hz, H-4), 7.76 (d, J ¼ 8.5 Hz, H-7), 8.07 (s, H-3)
ppm; 13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 51.0 (N1-CH2),
52.7 (CH2), 53.8 (OCH3), 108.6 (C-7), 120.4 (C-5), 121.4
(C-4), 124.0 (C-3a), 126.5 (C-6), 134.6 (C-3), 140.2 (C-7a),
167.6 (C¼O), 172.7 (C¼O) ppm; MS (ESI): m=z ¼ 270
[Mþ Na]þ.
(11, C15H19N3O3S)
Pale yellow syrup (78%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 2.34–2.57 (m, 2CH2, SCH3), 3.63 (s, OCH3), 4.40–4.55
(m, CH), 5.52 (s, N1-CH2), 7.14 (t, J ¼ 7.5 Hz, H-5), 7.36 (t,
J ¼ 7.6Hz, H-6), 7.40 (d, J ¼ 8.6 Hz, H-4), 7.80 (d, J ¼ 8.5 Hz,
H-7), 8.09 (br, s, H-3, NH) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 14.5 (SCH3), 30.0 (CH2), 31.5 (CH2), 46.9
(CH), 52.5 (N1-CH2), 53.5 (OCH3), 109.6 (C-7), 121.2 (C-
5), 121.9 (C-4), 124.3 (C-3a), 126.6 (C-6), 134.2 (C-3),
140.4 (C-7a), 167.8 (C¼O), 177.0 (C¼O) ppm; MS (ESI):
m=z ¼ 344 [Mþ Na]þ.
1-Acetyl-1H-indazole L-alanine methyl ester (7, C13H15N3O3)
Colorless syrup (79%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.45
(d, J ¼ 5.0 Hz, CH3), 3.58 (s, OCH3), 4.67 (q, J ¼ 5.0 Hz, CH),
5.57 (s, N1-CH2), 7.15 (t, J ¼ 7.5 Hz, H-5), 7.25 (br, s, NH),
7.38 (t, J ¼ 7.6 Hz, H-6), 7.47 (d, J ¼ 8.6Hz, H-4), 7.79 (d,
J ¼ 8.5 Hz, H-7), 8.08 (s, H-3) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 17.5 (CH3), 47.7 (CH), 52.5 (N1-CH2), 54.3
(OCH3), 108.9 (C-7), 120.4 (C-5), 121.3 (C-4), 124.8 (C-3a),
126.9 (C-6), 134.7 (C-3), 140.5 (C-7a), 168.0 (C¼O), 173.6
(C¼O) ppm; MS (ESI): m=z ¼ 284 [Mþ Na]þ.
1-Acetyl-1H-indazole L-phenylglycine methyl ester
(12, C18H17N3O3)
Colorless syrup (84%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.65
(s, OCH3), 4.70 (s, CH), 5.53 (s, N1-CH2), 7.10 (t, J ¼ 7.5 Hz,
H-5), 7.20–7.27 (m, Ph-H), 7.33–7.44 (m, Ph-H, H-4, H-6),
7.80 (d, J ¼ 8.5 Hz, H-7), 8.08 (s, H-3), 9.08 (br, s, NH) ppm;
13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 52.4 (N1-CH2), 53.9
(OCH3), 56.5 (CH), 108.6 (C-7), 120.8 (C-5), 121.1 (C-4),
124.1 (C-3a), 125.5, 126.9, 132.1, 134.6, 137.9 (Ph-C, C-3,
C-6), 141.0 (C-7a), 167.4 (C¼O), 172.4 (C¼O) ppm; MS
(ESI): m=z ¼ 346 [Mþ Na]þ.
1-Acetyl-1H-indazole L-serine methyl ester (8, C13H15N3O4)
Colorless syrup (78%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼
3.30–3.40 (m, CH2) 3.61 (s, OCH3), 4.50–4.58 (m, CH),
5.53 (s, N1-CH2), 6.60 (br, s, OH), 7.10 (br, s, NH), 7.19 (t,
J ¼ 7.5 Hz, H-5), 7.37 (t, J ¼ 7.6 Hz, H-6), 7.43 (d, J ¼
8.6 Hz, H-4), 7.79 (d, J ¼ 8.5 Hz, H-7), 8.10 (s, H-3) ppm;
13C NMR (CDCl3, 62.5 MHz): ꢁ ¼ 52.3 (N1-CH2), 53.9
(OCH3), 54.9 (CH), 71.8 (OCH2), 109.0 (C-7), 121.1 (C-
5), 121.9 (C-4), 124.0 (C-3a), 126.9 (C-6), 134.7 (C-3),
140.3 (C-7a), 167.6 (C¼O), 173.6 (C¼O) ppm; MS (ESI):
m=z ¼ 300 [M þ Na]þ.
2-Acetyl-2H-indazole L-glycine methyl ester (13, C12H13N3O3)
Colorless syrup (73%); 1H NMR (CDCl3, 250MHz): ꢁ ¼ 3.60
(s, OCH3), 4.17 (s, CH2), 5.17 (s, N2-CH2), 7.11 (t, J ¼ 7.5 Hz,
H-5), 7.22 (br, s, NH), 7.30 (t, J ¼ 7.6Hz, H-6), 7.63 (d, J ¼
8.6 Hz, H-4), 7.73 (d, J ¼ 8.5Hz, H-7), 7.95 (s, H-3) ppm; 13C
NMR (CDCl3, 62.5MHz): ꢁ ¼ 52.5 (N2-CH2), 52.9 (CH2),
53.2 (OCH3), 117.0 (C-7), 120.5 (C-5), 121.9 (C-4), 122.4
(C-3a), 124.8 (C-6), 134.5 (C-3), 149.2 (C-7a), 167.1 (C¼O),
172.6 (C¼O) ppm; MS (ESI): m=z ¼ 270 [M þ Na]þ.
1-Acetyl-1H-indazole L-valine methyl ester (9, C15H19N3O3)
Colorless syrup (79%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.95
(dd, J ¼ 1.9, 7.2 Hz, 2CH3), 2.22–2.29 (m, CH), 3.62 (s,
OCH3), 4.40–4.50 (m, CH), 5.52 (s, N1-CH2), 7.15 (t,
2-Acetyl-2H-indazole L-alanine methyl ester (14, C13H15N3O3)
Colorless syrup (74%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.50
(d, J ¼ 5.0 Hz, CH3), 3.67 (s, OCH3), 4.68 (q, J ¼ 5.0 Hz, CH),

294
A. A.-H. Abdel-Rahman
2-Acetyl-2H-indazole L-phenylglycine methyl ester
5.18 (s, N2-CH2), 7.13 (t, J ¼ 7.5 Hz, H-5), 7.26 (br, s, NH),
7.34 (t, J ¼ 7.6 Hz, H-6), 7.69 (d, J ¼ 8.6Hz, H-4), 7.79 (d,
J ¼ 8.5 Hz, H-7), 7.99 (s, H-3) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 17.8 (CH3), 47.9 (CH), 52.6 (N2-CH2), 54.6
(OCH3), 117.2 (C-7), 120.5 (C-5), 121.9 (C-4), 122.7 (C-3a),
124.0 (C-6), 134.0 (C-3), 149.0 (C-7a), 167.0 (C¼O), 173.5
(C¼O) ppm; MS (ESI): m=z ¼ 284 [Mþ Na]þ.
(19, C18H17N3O3)
Colorless syrup (77%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.65
(s, OCH3), 5.17 (s, N2-CH2), 4.73 (s, CH), 7.03 (t, J ¼ 7.5 Hz,
H-5), 7.20–7.44 (m, Ph-H, H-6), 7.68 (d, J ¼ 8.6 Hz, H-4),
7.79 (d, J ¼ 8.5Hz, H-7), 7.97 (s, H-3), 8.16 (br, s, NH)
ppm; 13C NMR (CDCl3, 62.5 MHz): ꢁ ¼ 52.6 (N2-CH2),
53.5 (OCH3), 56.5 (CH), 117.4 (C-7), 120.2 (C-5), 121.8
(C-4), 122.2 (C-3a), 124.4 (C-6), 125.5, 129.9, 131.1, 134.5,
137.7 (Ph-C, C-3), 149.5 (C-7a), 167.6 (C¼O), 173.3 (C¼O)
ppm; MS (ESI): m=z ¼ 346 [Mþ Na]þ.
2-Acetyl-2H-indazole L-serine methyl ester (15, C13H15N3O4)
Colorless syrup (72%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 3.30–3.40 (m, CH2) 3.61 (s, OCH3), 4.48–4.59 (m, CH),
5.17 (s, N2-CH2), 6.67 (br, s, OH), 7.06 (t, J ¼ 7.5 Hz, H-5),
7.15 (br, s, NH), 7.29 (t, J ¼ 7.6 Hz, H-6), 7.62 (d, J ¼
8.6 Hz, H-4), 7.77 (d, J ¼ 8.5 Hz, H-7), 7.96 (s, H-3) ppm;
13C NMR (CDCl3, 62.5 MHz): ꢁ ¼ 52.5 (N2-CH2), 53.5
(OCH3), 54.5 (CH), 72.1 (OCH2), 117.4 (C-7), 120.6 (C-
5), 122.0 (C-4), 122.7 (C-3a), 124.8 (C-6), 134.3 (C-3),
149.2 (C-7a), 167.0 (C¼O), 173.3 (C¼O) ppm; MS (ESI):
m=z ¼ 300 [M þ Na]þ.
General Procedure for the Preparation of the Hydrazides
20 and 21
A mixture of 1.23g 6 or 13 (5mmol) and 0.63g N2H4 ꢃ H2O
(12.5 mmol) in 15 cm3 EtOH was heated under reflux for 4 h.
The excess of EtOH was removed under reduced pressure and
the resulting precipitate was filtered off and recrystallized
from EtOH to give 20 and 21 in 96–98% yields.
2-Acetyl-2H-indazole L-valine methyl ester (16, C15H19N3O3)
Colorless syrup (76%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.93
(dd, J ¼ 1.9, 7.2 Hz, 2CH3), 2.22–2.33 (m, CH), 3.63 (s,
OCH3), 4.44–4.54 (m, CH), 5.12 (s, N2-CH2), 7.09 (t,
J ¼ 7.5 Hz, H-5), 7.26 (t, J ¼ 7.6 Hz, H-6), 7.60 (d,
J ¼ 8.6 Hz, H-4), 7.74 (d, J ¼ 8.5 Hz, H-7), 7.95 (s, H-3),
8.00 (br, s, NH) ppm; 13C NMR (CDCl3, 62.5MHz):
ꢁ ¼ 16.5 (CH3), 18.5 (CH3), 31.6 (CH), 51.9 (CH), 52.8
(N2-CH2), 57.7 (OCH3), 117.4 (C-7), 120.5 (C-5), 121.6
(C-4), 122.5 (C-3a), 124.9 (C-6), 134.3 (C-3), 149.1 (C-7a),
167.0 (C¼O), 175.7 (C¼O) ppm; MS (ESI): m=z ¼ 312
[Mþ Na]þ.
1-Acetyl-1H-indazole L-glycine hydrazide (20, C11H13N5O2)
1
White powder (98%), mp 177–179ꢂC; H NMR (DMSO-d6,
250 MHz): ꢁ ¼ 3.55 (s, CH2), 4.98 (br, s, NHNH2), 5.14 (s,
N1-CH2), 7.18 (t, J ¼ 7.5 Hz, H-5), 7.38 (t, J ¼ 7.6 Hz, H-6),
7.43 (d, J ¼ 8.6 Hz, H-4), 7.52 (br, s, NH), 7.81 (d, J ¼ 8.5 Hz,
H-7), 8.07 (s, H-3), 9.45 (br, s, NHNH2) ppm; 13C NMR
(DMSO-d6, 62.5MHz): ꢁ ¼ 40.4 (CH2), 51.3 (N1-CH2), 112.4
(C-7a), 151.7 (C-5), 153.2 (C-3a), 154.7 (C-7), 164.1 (C¼O),
169.6 (C¼O) ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
2-Acetyl-2H-indazole L-glycine hydrazide (21, C11H13N5O2)
1
White powder (96%), mp 190–192ꢂC; H NMR (DMSO-d6,
250 MHz): ꢁ ¼ 3.53 (s, CH2), 4.82 (br, s, NHNH2), 5.14 (s, N2-
CH2), 7.08 (t, J ¼ 7.5 Hz, H-5), 7.25 (t, J ¼ 7.6 Hz, H-6), 7.51
(br, s, NH), 7.62 (d, J ¼ 8.6 Hz, H-4), 7.70 (d, J ¼ 8.5 Hz, H-
7), 7.96 (s, H-3), 9.45 (br, s, NHNH2) ppm; 13C NMR (DMSO-
d6, 62.5MHz): ꢁ ¼ 40.5 (CH2), 51.8 (N2-CH2), 112.6 (C-7a),
151.6 (C-5), 153.1 (C-3a), 154.9 (C-7), 164.1 (C¼O), 169.3
(C¼O) ppm; MS (ESI): m=z ¼ 227 [M þ Na]þ.
2-Acetyl-2H-indazole L-leucine methyl ester (17, C16H21N3O3)
Colorless syrup (76%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.91
(dd, J ¼ 1.9, 7.2 Hz, 2CH3), 1.52–1.68 (m, CH2, CH), 3.66 (s,
OCH3), 4.26–4.36 (m, CH), 5.17 (s, N2-CH2), 7.07 (t,
J ¼ 7.5 Hz, H-5), 7.25 (t, J ¼ 7.6 Hz, H-6), 7.62 (d,
J ¼ 8.6 Hz, H-4), 7.70 (d, J ¼ 8.5 Hz, H-7), 7.98 (s, H-3),
8.15 (br, s, NH) ppm; 13C NMR (CDCl3, 62.5MHz):
ꢁ ¼ 21.9 (2CH3), 24.9 (CH), 40.2 (CH2), 51.2 (CH), 53.5
(N2-CH2), 53.9 (OCH3), 117.7 (C-7), 121.2 (C-5), 121.9
(C-4), 122.5 (C-3a), 124.0 (C-6), 134.0 (C-3), 149.4 (C-7a),
167.1 (C¼O), 172.1 (C¼O) ppm; MS (ESI): m=z ¼ 326
[Mþ Na]þ.
General Procedure for the Preparation of Dipeptides 22–35
A solution of 0.19 g 20 or 21 (0.80 mmol) in 6 cm3 HOAc,
3 cm3 1 N HCl, and 25cm3 H2O was cooled in an ice-bath
(ꢁ5ꢂC). Sodium nitrite (0.87 g, 12.60 mmol) in 3 cm3 cold
H2O was added with stirring. After stirring at ꢁ5ꢂC for
15min, the yellow syrup was formed. The azide was taken
in 30cm3 cold ethyl acetate, washed with 30cm3 NaHCO3
(3%), 30cm3 H2O, and dried (Na2SO4). A solution of the ap-
propriate amino acid methyl ester hydrochloride (0.90 mmol)
in 20cm3 ethyl acetate containing 0.2 cm3 Et3N was stirred
at 0ꢂC for 20min, filtered, and the filtrate was added to the
azide solution. The mixture was kept at ꢁ5ꢂC for 12h, then at
room temperature for another 12h, followed by washing with
30cm3 0.5 N HCl, 30cm3 NaHCO3 (3%), 30cm3 H2O, and
dried (Na2SO4). The filtrate was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography using petroleum ether:ethylacetate¼ 5:1 to
afford 22–28 in 75–80% and 29–35 in 70–73% yields.
2-Acetyl-2H-indazole L-methionine methyl ester
(18, C15H19N3O3S)
Pale yellow syrup (73%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 2.20–2.55 (m, 2CH2, SCH3), 3.62 (s, OCH3), 4.45–4.59
(m, CH), 5.13 (s, N2-CH2), 7.12 (t, J ¼ 7.5 Hz, H-5), 7.25 (t,
J ¼ 7.6 Hz, H-6), 7.68 (d, J ¼ 8.6 Hz, H-4), 7.72 (d, J ¼ 8.5 Hz,
H-7), 7.91 (s, H-3), 8.01 (br, s, NH) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 14.5 (SCH3), 29.5 (CH2), 30.9 (CH2), 46.7
(CH), 52.5 (N2-CH2), 53.3 (OCH3), 117.5 (C-7), 120.7
(C-5), 121.9 (C-4), 122.6 (C-3a), 124.0 (C-6), 134.0 (C-3),
149.1 (C-7a), 167.2 (C¼O), 177.0 (C¼O) ppm; MS (ESI):
m=z ¼ 344 [M þ Na]þ.

Amino Acid Derivatives, VII
295
5.19 (s, N1-CH2), 7.17 (t, J ¼ 7.5 Hz, H-5), 7.33 (t, J ¼ 7.6 Hz,
H-6), 7.40 (d, J ¼ 8.6 Hz, H-4), 7.76 (d, J ¼ 8.5 Hz, H-7), 8.03
(s, H-3), 9.02 (br, s, NH) ppm; 13C NMR (CDCl3, 62.5 MHz):
ꢁ ¼ 21.7 (2CH3), 24.2 (CH), 39.5 (CH2), 49.5 (CH2), 51.0
(CH), 51.8 (N1-CH2), 52.3 (OCH3), 108.9 (C-7), 120.8
(C-5), 121.1 (C-4), 124.1 (C-3a), 126.6 (C-6), 134.1 (C-3),
140.0 (C-7a), 167.8 (C¼O), 169.1 (C¼O), 172.5 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
1-Acetyl-1H-indazole L-glycyl-L-glycine methyl ester
(22, C14H16N4O4)
White foam (75%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.53 (s,
OCH3), 3.69 (s, CH2), 3.89 (s, CH2), 5.19 (s, N1-CH2), 7.14 (t,
J ¼ 7.5 Hz, H-5), 7.38 (t, J ¼ 7.6Hz, H-6), 7.47 (d, J ¼ 8.6 Hz,
H-4), 7.76 (d, J ¼ 8.5 Hz, H-7), 8.06 (s, H-3), 8.52 (br, s, NH)
ppm; 13C NMR (CDCl3, 62.5 MHz): ꢁ ¼ 41.5 (CH2), 42.6
(CH2), 51.6 (N1-CH2), 53.6 (OCH3), 108.9 (C-7), 120.8 (C-
5), 121.2 (C-4), 124.7 (C-3a), 127.0 (C-6), 134.6 (C-3), 140.4
(C-7a), 167.5 (C¼O), 171.0 (C¼O), 171.9 (C¼O) ppm; MS
(ESI): m=z ¼ 227 [M þ Na]þ.
1-Acetyl-1H-indazole L-glycyl-L-methionine methyl ester
(27, C17H22N4O4S)
1
Yellow foam (76%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 2.22–
2.52 (m, SCH3, 2CH2), 3.52 (s, OCH3), 3.70 (s, CH2), 4.40–
4.51 (m, CH), 5.16 (s, N1-CH2), 7.18 (t, J ¼ 7.5 Hz, H-5),
7.38 (t, J ¼ 7.6 Hz, H-6), 7.42 (d, J ¼ 8.6 Hz, H-4), 7.74
(d, J ¼ 8.5 Hz, H-7), 8.05 (s, H-3), 8.79 (br, s, NH) ppm;
13C NMR (CDCl3, 62.5 MHz): ꢁ ¼ 14.5 (SCH3), 29.2
(CH2), 30.6 (CH2), 43.4 (CH2), 46.5 (CH), 51.7 (N1-CH2),
53.5 (OCH3), 108.5 (C-7), 120.5 (C-5), 121.5 (C-4), 124.4
(C-3a), 126.5 (C-6), 134.3 (C-3), 140.1 (C-7a), 167.5 (C¼O),
171.5 (C¼O), 175.1 (C¼O) ppm; MS (ESI): m=z ¼ 227
[Mþ Na]þ.
1-Acetyl-1H-indazole L-glycyl-L-alanine methyl ester
(23, C15H18N4O4)
White foam (76%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.33 (d,
J ¼ 5.0 Hz, CH3), 3.61 (s, CH2), 3.70 (s, OCH3), 4.52 (q,
J ¼ 5.0 Hz, CH), 5.18 (s, N1-CH2), 7.16 (t, J ¼ 7.5 Hz, H-5),
7.38 (t, J ¼ 7.6 Hz, H-6), 7.44 (d, J ¼ 8.6 Hz, H-4), 7.75
(d, J ¼ 8.5 Hz, H-7), 8.04 (s, H-3), 9.00 (br, s, NH) ppm;
13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 18.2 (CH3), 45.8 (CH2),
48.3 (CH), 51.5 (N1-CH2), 52.8 (OCH3), 108.6 (C-7), 120.8
(C-5), 121.5 (C-4), 124.5 (C-3a), 126.9 (C-6), 134.1 (C-3),
140.1 (C-7a), 167.8 (C¼O), 168.9 (C¼O), 172.2 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
1-Acetyl-1H-indazole L-glycyl-L-phenylglycine methyl ester
(28, C20H20N4O4)
White foam (80%); 1H NMR (CDCl3, 250MHz): ꢁ ¼ 1.41 (d,
J ¼ 5.0 Hz, CH3), 3.62 (s, OCH3), 3.90 (s, CH2), 4.60 (q,
J ¼ 5.1Hz, CH), 5.13 (s, N1-CH2), 7.15 (t, J ¼ 7.5 Hz, H-5),
7.29–7.45 (m, Ph-H, H-4, H-6), 7.74 (d, J ¼ 8.5 Hz, H-7), 8.03
(s, H-3), 8.66 (br, s, NH) ppm; 13C NMR (CDCl3, 62.5 MHz):
ꢁ ¼ 17.5 (CH3), 41.6 (CH2), 44.6 (CH), 51.5 (N1-CH2), 53.5
(OCH3), 108.6 (C-7), 120.9 (C-5), 121.5 (C-4), 124.9, 126.5,
129.9, 131.1, 137.7 (Ph-C, C-3, C-3a, C-6), 140.0 (C-7a),
167.5 (C¼O), 172.6 (C¼O), 173.2 (C¼O) ppm; MS (ESI):
m=z ¼ 227 [Mþ Na]þ.
1-Acetyl-lH-indazole L-glycyl-L-serine methyl ester
(24, C15H18N4O5)
1
White foam (77%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.40–
3.52 (m, OCH2), 3.63 (s, OCH3), 3.70 (s, CH2), 4.45–4.56 (m,
CH), 5.12 (s, N1-CH2), 6.66 (br, s, OH), 7.16 (t, J ¼ 7.5 Hz,
H-5), 7.30 (t, J ¼ 7.6 Hz, H-6), 7.40 (d, J ¼ 8.6 Hz, H-4), 7.70
(d, J ¼ 8.5 Hz, H-7), 7.91 (br, s, NH), 8.07 (s, H-3) ppm;
13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 41.5 (CH2), 43.6 (CH2),
51.3 (N1-CH2), 53.5 (OCH3), 54.5 (CH), 71.6 (OCH2), 108.9
(C-7), 120.8 (C-5), 121.2 (C-4), 124.1 (C-3a), 126.6 (C-6),
134.4 (C-3), 140.2 (C-7a), 167.5 (C¼O), 167.7 (C¼O),
172.0 (C¼O) ppm; MS (ESI): m=z ¼ 227 [M þ Na]þ.
2-Acetyl-2H-indazole L-glycyl-L-glycine methyl ester
(29, C14H16N4O4)
White foam (70%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.50 (s,
OCH3), 3.70 (s, CH2), 3.97 (s, CH2), 5.14 (s, N2-CH2), 7.02 (t,
J ¼ 7.5Hz, H-5), 7.28 (t, J ¼ 7.6 Hz, H-6), 7.66 (d, J ¼ 8.6 Hz,
H-4), 7.70 (d, J ¼ 8.5 Hz, H-7), 7.94 (s, H-3), 8.55 (br, s, NH)
ppm; 13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 41.5 (CH2), 42.9
(CH2), 51.5 (N2-CH2), 53.5 (OCH3), 117.5 (C-7), 120.5
(C-5), 121.9 (C-4), 122.5 (C-3a), 124.5 (C-6), 134.5 (C-3),
149.0 (C-7a), 167.0 (C¼O), 170.1 (C¼O), 171.3 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
1-Acetyl-1H-indazole L-glycyl-L-valine methyl ester
(25, C17H22N4O4)
1
White foam (79%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.94
(dd, J ¼ 1.9, 7.3 Hz, 2CH3), 2.25–2.32 (m, CH), 3.53 (s,
OCH3), 3.70 (s, CH2), 3.79 (s, CH2), 4.36–4.48 (m, CH),
5.17 (s, N1-CH2), 7.18 (t, J ¼ 7.5Hz, H-5), 7.33 (t, J ¼
7.6 Hz, H-6), 7.45 (d, J ¼ 8.6 Hz, H-4), 7.75 (d, J ¼ 8.5 Hz,
H-7), 8.05 (s, H-3), 8.88 (br, s, NH) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 17.1, 19.1 (2CH3), 32.5 (CH), 43.6 (CH2),
51.5 (N1-CH2), 51.9 (CH), 55.5 (OCH3), 108.8 (C-7), 120.8
(C-5), 121.4 (C-4), 124.0 (C-3a), 126.7 (C-6), 134.0 (C-3),
140.0 (C-7a), 167.5 (C¼O), 168.5 (C¼O), 175.1 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
2-Acetyl-2H-indazole L-glycyl-L-alanine methyl ester
(30, C15H18N4O4)
White foam (72%); 1H NMR (CDCl3, 250MHz): ꢁ ¼ 1.33 (d,
J ¼ 5.0 Hz, CH3), 3.61 (s, CH2), 3.65 (s, OCH3), 4.51 (q,
J ¼ 5.0Hz, CH), 5.18 (s, N2-CH2), 7.06 (t, J ¼ 7.5 Hz, H-5),
7.28 (t, J ¼ 7.6Hz, H-6), 7.66 (d, J ¼ 8.6Hz, H-4), 7.73
(d, J ¼ 8.5Hz, H-7), 7.96 (s, H-3), 9.00 (br, s, NH) ppm;
13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 18.2 (CH3), 45.2 (CH2),
48.1 (CH), 51.7 (N2-CH2), 52.6 (OCH3), 117.4 (C-7), 120.4
(C-5), 121.9 (C-4), 122.7 (C-3a), 124.9 (C-6), 134.1 (C-3),
1-Acetyl-1H-indazole L-glycyl-L-leucine methyl ester
(26, C18H24N4O4)
1
White foam (76%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.91
(dd, J ¼ 1.8, 7.3 Hz, 2CH3), 1.45–1.60 (m, CH2, CH), 3.61
(s, OCH3), 3.70 (s, CH2), 3.72 (s, CH2), 4.16–4.26 (m, CH),

296
A. A.-H. Abdel-Rahman
149.2 (C-7a), 167.0 (C¼O), 168.3 (C¼O), 173.0 (C¼O) ppm;
MS (ESI): m=z ¼ 227 [Mþ Na]þ.
2-Acetyl-2H-indazole L-glycyl-L-phenylglycine methyl ester
(35, C20H20N4O4)
White foam (73%); 1H NMR (CDCl3, 250MHz): ꢁ ¼ 1.34 (d,
J ¼ 5.0 Hz, CH3), 3.62 (s, OCH3), 3.90 (s, CH2), 4.60 (q,
J ¼ 5.1Hz, CH), 5.13 (s, N2-CH2), 7.12 (t, J ¼ 7.5 Hz, H-5),
7.25–7.48 (m, Ph-H, H-6), 7.68 (d, J ¼ 8.6Hz, H-4), 7.83
(d, J ¼ 8.5Hz, H-7), 7.97 (s, H-3), 8.66 (br, s, NH) ppm;
13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 17.5 (CH3), 41.5 (CH2),
44.6 (CH), 51.9 (N2-CH2), 53.5 (OCH3), 117.0 (C-7), 120.5
(C-5), 121.9 (C-4), 122.5 (C-3a), 124.7 (C-6), 125.7, 129.9,
131.5, 134.5, 137.9 (Ph-C, C-3), 149.2 (C-7a), 167.1 (C¼O),
172.1 (C¼O), 173.0 (C¼O) ppm; MS (ESI): m=z ¼ 227
[Mþ Na]þ.
2-Acetyl-2H-indazole L-glycyl-L-serine methyl ester
(31, C15H18N4O5)
1
White foam (71%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.45–
3.53 (m, OCH2), 3.64 (s, OCH3), 3.70 (s, CH2), 4.45–4.57
(m, CH), 5.12 (s, N2-CH2), 6.52 (br, s, OH), 7.08 (t,
J ¼ 7.5 Hz, H-5), 7.29 (t, J ¼ 7.6 Hz, H-6), 7.66 (d, J ¼
8.6 Hz, H-4), 7.70 (d, J ¼ 8.5 Hz, H-7), 7.86 (br, s, NH),
7.99 (s, H-3) ppm; 13C NMR (CDCl3, 62.5 MHz): ꢁ ¼ 41.6
(CH2), 43.5 (CH2), 51.8 (N2-CH2), 53.5 (OCH3), 54.5 (CH),
72.1 (OCH2), 117.2 (C-7), 120.2 (C-5), 121.9 (C-4), 122.3
(C-3a), 124.9 (C-6), 134.1 (C-3), 149.0 (C-7a), 167.1 (C¼O),
167.3 (C¼O), 173.5 (C¼O) ppm; MS (ESI): m=z ¼ 227
[M þ Na]þ.
References
[1] Part VI: Abdel-Rahman AA-H (2007) Monatsh Chem
(in press)
2-Acetyl-2H-indazole L-glycyl-L-valine methyl ester
(32, C17H22N4O4)
[2] a) Cerecetto H, Gerpe A, Gonzalez M, Aran VJ, Ochoa
de Ocariz C (2005) Mini-Reviews in Med Chem 5: 869;
b) Lein JC, Lee FY, Huang LJ, Pan S-L, Guh JH, Teng
CM, Kuo SC (2002) J Med Chem 45: 4947; c) Yeu JP,
Yeh JT, Chen TY, Uang BJ (2001) Synthesis: 1775; d)
Caron S, Vazquez E (1999) Synthesis: 588; e) Sun JH,
Teleha CA, Yan JS, Rodgers JD, Nugiel DA (1997)
J Org Chem 62: 5627; f) Yoshida T, Matsuura N,
Yamamoto K, Doi M, Shimada K, Morie T, Kato S
(1996) Heterocycles 43: 2701; g) Rodgers JD, Johnson
BL, Wang H, Greenberg RA, Erickson-Viitanen S,
Klabe RM, Cordova BC, Rayner MM, Lam GN, Chang
CH (1996) Bioorg Med Chem Lett 6: 2919; h) Norman
MH, Navas F III, Thompson JB, Rigdon GC (1996) J
Med Chem 39: 4692; i) Keppler BK, Hartmann M
(1994) Met Based Drugs 1: 145; j) Robertson DW,
Bloomquist W, Cohen ML, Reid LR, Schenck K, Wong
DT (1990) J Med Chem 33: 3176
[3] Baraldi PG, Balboni G, Pavani MG, Spalluto G, Tabrizi
MA, De Clercq E, Balzarini J, Bando T, Sugiyama H,
Romagnoli R (2001) J Med Chem 44: 2536
[4] Li X, Chu S, Feher VA, Khalili M, Nie Z, Margosiak
S, Nikulin V, Levin J, Sprankle KG, Tedder ME,
Almassy R, Appelt K, Yager KM (2003) J Med Chem
46: 5663
[5] Lee FY, Lien JC, Huang LJ, Huang TM, Tsai SC, Teng
CM, Wu CC, Cheng FC, Kuo SC (2001) J Med Chem 44:
3746
1
White foam (72%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.95
(dd, J ¼ 1.9, 7.3 Hz, 2CH3), 2.22–2.33 (m, CH), 3.54 (s,
OCH3), 3.69 (s, CH2), 3.79 (s, CH2), 4.34–4.47 (m, CH),
5.17 (s, N2-CH2), 7.07 (t, J ¼ 7.5Hz, H-5), 7.28 (t, J ¼
7.6 Hz, H-6), 7.67 (d, J ¼ 8.6 Hz, H-4), 7.76 (d, J ¼ 8.5 Hz,
H-7), 7.91 (s, H-3), 8.88 (br, s, NH) ppm; 13C NMR (CDCl3,
62.5MHz): ꢁ ¼ 17.0, 19.0 (2CH3), 33.1 (CH), 44.2 (CH2),
51.8 (N2-CH2), 52.3 (CH), 54.2 (OCH3), 117.5 (C-7), 120.5
(C-5), 122.5 (C-4), 123.2 (C-3a), 124.3 (C-6), 134.4 (C-3),
149.0 (C-7a), 167.0 (C¼O), 168.5 (C¼O), 175.1 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
2-Acetyl-2H-indazole L-glycyl-L-leucine methyl ester
(33, C18H24N4O4)
1
White foam (70%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.85
(dd, J ¼ 1.8, 7.3 Hz, 2CH3), 1.49–1.68 (m, CH2, CH), 3.62
(s, OCH3), 3.77 (s, CH2), 3.81 (s, CH2), 4.11–4.25 (m, CH),
5.19 (s, N2-CH2), 7.04 (t, J ¼ 7.5 Hz, H-5), 7.32 (t, J ¼ 7.6 Hz,
H-6), 7.66 (d, J ¼ 8.6 Hz, H-4), 7.72 (d, J ¼ 8.5 Hz, H-7), 7.94
(s, H-3), 9.12 (br, s, NH) ppm; 13C NMR (CDCl3, 62.5 MHz):
ꢁ ¼ 21.7 (2CH3), 24.5 (CH), 39.3 (CH2), 49.2 (CH2), 51.1
(CH), 51.9 (N2-CH2), 52.7 (OCH3), 117.4 (C-7), 120.0
(C-5), 121.7 (C-4), 122.0 (C-3a), 124.9 (C-6), 134.0 (C-3),
149.0 (C-7a), 167.1 (C¼O), 169.2 (C¼O), 172.7 (C¼O)
ppm; MS (ESI): m=z ¼ 227 [Mþ Na]þ.
2-Acetyl-2H-indazole L-glycyl-L-methionine methyl ester
(34, C17H22N4O4S)
[6] Wrobleski ST, Chen P, Hynes J Jr, Lin S, Norris DJ,
Pandit CR, Spergel S, Wu H, Tokarski JS, Chen X,
Gillooly KM, Kiener PA, McIntyre KW, Patil-koota V,
Shuster DJ, Turk LA, Yang G, Leftheris K (2003) J Med
Chem 46: 2110
[7] a) Rosati O, Curini M, Marcotullio MC, Macchiarulo A,
Perfumi M, Mattioli L, Rismondo F, Cravotto G (2007)
Bioorg Med Chem 15: 3463; b) Huang LJ, Shih ML,
Chen HS, Pan SL, Teng CM, Lee FY, Kuo SC (2006)
Bioorg Med Chem 14: 528; c) Lebedev AY, Khartulyari
AS, Voskobonynikov AZ (2005) J Org Chem 70: 596;
d) Pabba C, Wang HJ, Mulligan SR, Chen ZJ, Stark TM,
1
Yellow foam (71%); H NMR (CDCl3, 250 MHz): ꢁ ¼ 2.24–
2.55 (m, SCH3, 2CH2), 3.57 (s, OCH3), 3.77 (s, CH2), 4.40–
4.45 (m, CH), 5.11 (s, N2-CH2), 7.11 (t, J ¼ 7.5 Hz, H-5),
7.32 (t, J ¼ 7.6 Hz, H-6), 7.65 (d, J ¼ 8.6 Hz, H-4), 7.73
(d, J ¼ 8.5 Hz, H-7), 7.93 (s, H-3), 8.60 (br, s, NH) ppm;
13C NMR (CDCl3, 62.5MHz): ꢁ ¼ 14.4 (SCH3), 29.0
(CH2), 30.8 (CH2), 43.7 (CH2), 46.5 (CH), 51.9 (N2-CH2),
53.7 (OCH3), 117.4 (C-7), 120.2 (C-5), 121.9 (C-4), 122.1
(C-3a), 124.3 (C-6), 134.1 (C-3), 149.0 (C-7a), 167.0 (C¼O),
171.0 (C¼O), 172.0 (C¼O) ppm; MS (ESI): m=z ¼ 227
[Mþ Na]þ.

Amino Acid Derivatives, VII
297
Gregg BT (2005) Tetrahedron Lett 46: 7553; e) Lee KY,
Gowrisankar S, Kim JN (2005) Tetrahedron Lett 46:
5387; f) Shirtcliff LD, Weakley TJR, Haley MM, Kohler
F, Herges R (2004) J Org Chem 69: 6979; g) Antilla JC,
Baskin JM, Barder TE, Buchwald SL (2004) J Org Chem
69: 5578; h) Cheung M, Boloor A, Stafford JA (2003) J
Org Chem 68: 4093; i) Song JJ, Yee NK (2001) Tetra-
[12] a) Ali IAI, Al-Masoudi IA, Saeed B, Al-Masoudi NA,
La Colla P (2005) Heteroatom Chem 16: 148; b) Al-
Masoudi NA, Al-Masoudi IA, Ali IAI, Al-Soud YA,
Saeed B, La Colla P (2005) Heteroatom Chem 16:
576; c) Al-Masoudi NA, Al-Masoudi IA, Ali IAI,
Al-Soud YA, Saeed B, La Colla P (2006) Acta Pharm
56: 175; d) Ali IAI, Ali OM, Abdel-Rahman AA-H
(2007) Monatsh Chem (in press); e) Ali OM, Abdel-
Rahman AA-H (2007) Monatsh Chem (in press)
[13] Schwyzer R, Kappeler H (1961) Helv Chim Acta 44:
1991
´ ´
hedron Lett 42: 2937; j) Lorand T, Kocsis B, Emody L,
´
^
Sohar P (1999) Eur J Med Chem 34: 1009
[8] Bradshaw TD, Bibby MC, Double JA, Fichtner I, Cooper
PA, Alley MC, Donohue S, Stinson SF, Tomaszewjski
JE, Sausville EA, Stevens MFG (2002) Mol Cancer Ther
1: 239
[14] Farag RS, Shalaby AS, El-Baroty GA, Ibrahim NA
(2004) Phytother Res 18: 30
[9] a) Wittman MD, Kadow JF (1996) US Pat 5,489,589, 6
Feb; b) Chem Abstr (1996) 124: 289947a
[10] Casini A, Scozzafava A, Supuran CT (2002) Environ
Health Perspect 110: 801
[15] a) Sells MA, Zelent AZ, Shvartsman M, Acs G (1988) J
Virol 62: 2836; b) Korba BE, Gerin JL (1992) Antiviral
Res 19: 55; c) Fouad T, Nielsen C, Brunn L, Pederson
EB (1998) J Az Med Fac (GIRLS) 19: 1173
[11] Yu KL, Harte WE, Spinazze P, Martin JC, Mansuri MM
(1993) Bioorg Med Chem Lett 3: 535
[16] Doong SL, Tsai CH, Schinazi RF, Liotta DC, Cheng YC
(1991) Proc Nat Acad Sci USA 88: 4895