Synthesis and anti-HIV activity of new benzimidazole, benzothiazole and carbohyrazide derivatives of the anti-inflammatory drug indomethacin

Article abstract of DOI:10.1515/znb-2011-0914

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains. New derivatives of the non-steroidal anti-inflammatory drug indomethacin bearing benzim

Full text of DOI:10.1515/znb-2011-0914

Synthesis and anti-HIV Activity of New Benzimidazole, Benzothiazole and
Carbohyrazide Derivatives of the anti-Inflammatory Drug Indomethacin
Najim A. Al-Masoudia, Nadhir N. A. Jafarb, Layla J. Abbasc, Sadiq J. Baqirb,
and Christophe Pannecouqued
a Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
b Department of Chemistry, College of Science, University of Babil, Babil, Iraq
c College of Pharmacy, University of Basrah, Basrah, Iraq
d Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
Reprint requests to Prof. N. A. Al-Masoudi. E-mail: najim.al-masoudi@gmx.de
Z. Naturforsch. 2011, 66b, 953 – 960; received June 2, 2011
There is an urgent need for the design and development of new and safer drugs for the treatment of
HIV infection, active against the currently resistant viral strains. New derivatives of the non-steroidal
anti-inflammatory drug indomethacin bearing benzimidazoles, benzothiazole, purine and pyridine
residues 8 – 13 were synthesized with the aim of developing new non-nucleoside reverse transcriptase
inhibitors (NNRTIs). Alternatively, new imine analogs 16 – 20 were synthesized from condensation of
indomethacinyl hydrazide 15, prepared from the ester 14, with various ketone precursors. Treatment
of 15 with phenyl isothiocyanate or triethyl orthoformate afforded the phenylcarbonothioyl and the
oxadiazole derivatives 21 and 22, respectively. The new compounds were assayed against HIV-1 and
HIV-2 in MT-4 cells. Compounds 9 and 10 were the most active in inhibiting HIV-2 and HIV-1,
respectively, with EC50 ≥ 17.60 µg mL−1 and > 1.15 µg mL−1 (therapeutic indexes (SI) of ≥ 3
and < 1, respectively), and are leading candidates for further development.
Key words: Anti-HIV Activity, Benzimidazole, Indomethacin, Non-nucleoside Reverse
Transcriptase Inhibitors
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs)
are important therapeutic agents for the treatment of
pain and inflammation related to a large variety of
pathologies [1]. NSAIDs inhibit the cyclooxgenase
(COX) activity resulting in decreased synthesis of
prostaglandin, leukotriene and thromboxane precur-
sors. Several reports indicate that NSAIDs can pre-
vent the developmentof various human tumors, includ-
ing colon, breast, lung, gastric, and esophageal neo-
plasias [2].
Fig. 1.
Indomethacin is a drug which belongs to the NSAID
drug class, acts by inhibiting isoforms of cyclooxy-
genase 1 and 2, having activity to treat inflammatory
rheumatoid diseases and relieve acute pain. Rogers et
al. [3] reported the strategy of addressing the stimula-
tion of the immune system which has been effective
in reducing Alzheimer’s disease progression in clin-
ical trials related to the cyclooxygenase inhibitor in-
domethacin, which rapidly and efficiently penetrates
the blood-brain barrier. However, indomethacin can
cause severe adverse gastrointestinal effects in humans
and animals, particularly when administered orally [4].
Recently, Kalgutkar et al. [5] have synthesized some
indolyl esters and amides related to indomethacin
as selective COX-2 inhibitors (Fig. 1). Furthermore,
Camaco-Camaco et al. [6] have reported the synthe-
sis and in vitro cytotoxicity of various indomethacin-
derived n-alkyl-tin complexes, while Jones et al. [7]
reported the cytotoxic activity of a new indomethacin
c
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Scheme 1. Synthesis of benzimidazoles 8 – 10, imidazolo-pyridine 11, purine 12, and benzothiazole 13 derivatives from
indomethacin (1) and various arene diamines (2 – 6) and 2-aminobenzenethiol (7).
analog, 7-(4-chlorobenzoyl)-4,6-dimethoxy-2-methyl-
3-phenylindole.
In continuation of our attempts in searching for new
anti-HIV agents [20 – 28] and on the basis of the above
mentioned promising biological results, we consid-
ered benzimidazoles and their analogs particularly in-
teresting to optimize the synthetic approaches to our
antiviral agents. In this study, the anti-inflammatory
drug indomethacin [29] has been selected as a main
backbone for the synthesis of new benzimidazole and
benzothiazole derivatives and their analogs, using the
microwave irradiation method.
The metal complexes of indomethacin exhibited re-
markably potent activity in humans [8]. While as-
pirin [9], ibuprofen [10], and indomethacin [11] are
very weak free radical scavengers for in vitro systems,
their copper complexes are very efficient free radical
scavengers [12]. These drugs are thus expected to cir-
cumvent the toxicity of reactive oxygen species gener-
ated in the activated microglia. Yi and coworkers [13]
reported that the copper complex exhibited higher an-
tibacterial activity than the parent drug whose IC50
value was 1.5 and 2.3 times lower than that of in-
domethacin to S. aureus and E. coli, respectively. It
was indicated that when the copper ion is coupled with
indomethacin, the drug is more potent as a bacterio-
static.
On the other hand, benzimidazoles were reported
to be potent biological molecules as anti-ulcer, anti-
hypertensive, antiviral, antifungal, anticancer, and an-
tihistaminic agents [14]. Some benzimidazoles have
been reported as HIV-1 reverse transcriptase in-
hibitors, and/or potent DNA gyrase inhibitors, for ex-
Results and Discussion
Synthesis
Treatment of indomethacin 1 with the appropri-
ate 1,2-arenediamines 2 – 6 or 2-amino-thiophenol
(7) in the presence of p-toluenesulfonic acid (p-
TsOH) and Al2O3 under MW irradiation (20– 30 min,
100– 150 W) afforded the benzimidazole-bearing in-
domethacin 8 and the related analogs 9 – 13, iso-
lated by conventional work-up, in 55 – 71 % yield
(Scheme 1).
The structures of 8 – 13 were assigned on the ba-
ample thiazolo[3,4-a]benzimidazoles (TBZs) and their sis of their 1H, 13C NMR and mass spectra. They
analogs [15 – 17] and 1-(2,6-difluorophenyl)-thiazolo- showed similar NMR patterns of aliphatic and aro-
[3,4-a]benzimidazole (NSC625487), since they inhib- matic H atoms. Compounds 8 – 13 showed two dou-
ited the replication of various strains of HIV-1 includ- blets at higher fields (δ = 7.72– 7.65 and 7.51–
ing a zidovudine-resistant strain (G910-6) [18]. Mon- 7.43 ppm), attributed to 2-Harom-Cl, 6-Harom-Cl and
forte and coworkers [19] have reported the synthesis of 3-Harom-Cl, 5-Harom-Cl (J = 6.7 – 7.0 Hz), respectively.
new thiazolo[3,4-a]benzimidazoles and 2-aryl-1-benz- The doublet at δ = 7.66 ppm was assigned to
ylbenzimidazoles as HIV-1 RT inhibitors.
4-Hbenzimidazole and 7-Hbenzimidazole (J = 8.0 Hz). H-4
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955
Scheme 2. Reagents and
conditions: (i) EtOH,
H2SO4, reflux, 5 h;
(ii) NH2NH2·H2O, EtOH,
reflux, 8 h; (iii) R1R2C=O,
EtOH, reflux, 3 h.
and H-7 of the indole moiety appeared as doublets and the other with C-2 of the purine ring at δC
at δ = 6.95– 6.82 and 6.76 – 6.59 ppm (J ∼ 9.0 Hz), 148.9 ppm.
=
while H-7 gave a doublet of doublets in the region
δ = 7.02 – 6.84 ppm (J ∼ 9.0 and ∼ 2.5 Hz). The sin-
glets at δ = 3.81 – 3.70 ppm were assigned to OMe
groups, while the singlets at δ = 3.75 – 3.64 ppm were
attributed to methyl groups at C-2. H-6 of the pyri-
dine residue of 11 appeared as a doublet of doublets
at δ = 6.97 ppm (J = 8.8, 2.6 Hz). H-4 and H-5 of
the purine moiety of 12 gave doublets at δ = 9.05 and
8.90 ppm (J = 2.2 Hz), respectively. The 13C NMR
spectra of 9 – 12 were recorded (Experimental Sec-
tion), and compound 13 was selected for the 13C NMR
analysis. The spectrum showed higher field signals at
δ = 168.3 and 166.2 ppm which were assigned to
C=O and C-2 of benzothiazole, respectively. The res-
onances at δ = 156.1 and 154.1 ppm were attributed
to C-6 of the indole and to C-3a of the benzothiaz-
ole moieties. C-7a and C-2 of the indole appeared at
δ = 136.9 and 133.8 ppm, respectively. The signals
at δ = 125.6 and 121.9 ppm were assigned to C-5
and C-6 of the benzothiazole, while the signal at δ =
121.9 ppm was assigned to C-4 and C-7 of the same
ring. The resonances at δ = 118.9, 118.3, 111.7, and
101.3 ppm were attributed to C-4, C-3a, C-3, C-5, and
C-7 of the indole, respectively. The signals at δ = 55.8,
23.5, and 13.4 ppm were assigned to methoxy, methy-
lene and methyl groups. The purine derivative 12 was
selected for further spectroscopic analysis. From the
Next, other models of indomethacin derivatives
bearing imine derivatives via an acetohydrazide link-
age were prepared, aiming to evaluate their anti-HIV
activity. Esterfication of 1 with acidic EtOH afforded
the ester 14 (82 %) [31], which was converted into the
hydrazide 15 (64 %) [32] on treatment with hydrated
hydrazine. Treatment of 15 with various ketones gave
the imine derivatives 16 – 20 in 82, 85, 79, 78, and
85 % yield, respectively (Scheme 2).
The assignment of protons and carbons of the in-
domethacin backbone was deduced in comparison to
compounds 8 – 12. The 1H NMR spectrum of 14
showed a quartet at δ = 3.78 ppm (J = 7.1 Hz) and
a triplet at δ = 1.19 ppm, assigned to the ethyl protons
of the ester group. The signals had disappeared in the
spectrum of 15 and instead, three signals at δ = 10.38,
9.86, and 9.06 ppm were seen, attributed to NH groups.
Compounds 16 – 20 showed singlets at δ = 3.68, 3.36,
3.37, 3.47, and 3.44 ppm, assigned to the methylene
protons. In the 13C NMR spectra of 14 and 15, the
C=O carbon atoms of the ester and carbohydrazide
groups resonated at δ = 170.9 and 170.7 ppm, re-
spectively, while the amide carbon atom resonated at
δ = 168.3 ppm. Compounds 16 – 20 showed three res-
onances at δ = 170.0 – 174.0, 167.9 – 164.8 and 155.9 –
152.9 ppm, attributed to the NHNC=O, Camide=O and
C=N carbon atoms, respectively.
gradient-selected HMBC spectrum [30] CH-2 at δH
=
Further, treatment of 15 with phenyl isothiocyanate
or triethyl orthoformate in boiling EtOH afforded the
phenylcarbonothioyl-carbohydrazide 21 and the 1,2,4-
3.68 ppm showed two heteronuclear 2JC,H correlations:
one with C-3 of the indole ring at δC = 136.1 ppm
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N. A. Al-Masoudi et al. · Benzimidazole, Benzothiazole and Carbohyrazide Derivatives of Indomethacin
Table 1. In-vitro anti-HIV-1a and HIV-2b activity and cytotoxicity of compounds 8 – 22.
Entry
HIV-1 (IIIB)
HIV-2 (ROD)
CC50
SIe
(IIIB)
SIe
(ROD)
EC50 (µg mL−1 c
)
EC50 (µg mL−1 c
)
(µg mL−1 d
)
8
9
> 54.58
> 54.08
> 1.15
> 56.15
> 67.10
> 12.95
> 36.13
> 96.63
> 23.29
> 100
> 66.95
> 89.38
> 70.08
> 68.78
> 2.39
> 54.58
≥ 17.60
> 1.15
> 56.15
> 67.10
> 12.95
> 36.13
> 96.63
> 23.29
> 100
> 66.95
> 89.38
> 70.08
> 68.78
> 2.39
54.58
54.08
1.15
56.15
67.10
12.95
36.13
96.63
23.29
100
66.95
89.38
70.08
68.78
2.39
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
≤ 3
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
10
11
12
13
14
15
16
17
18
19
20
21
22
Nevirapine
AZT
0.050
0.0022
> 4.00
0.00094
> 4.00
> 25
> 80
> 11363
< 1
> 26596
a
b
c
Anti-HIV-1 activity measured with strain IIIB; anti-HIV-2 activity measured with strain ROD; compound concentration required to
d
achieve 50 % protection of MT-4 cells from the HIV-1- and 2-induced cytopathogenic effect; compound concentration that reduces the
viability of mock-infected MT-4 cells by 50 %; e SI: selectivity index (CC50/EC50).
Scheme 3. Synthesis of
indomethacin bearing
N-(phenylcarbonothio-
yl)acetohydrazide (21)
and oxadiazole (22)
functions.
oxadiazole analogs 22 in 78, and 62 % yield, respec- assay [33]. The results are summarized in Table 1, in
tively (Scheme 3). The structures of 21 and 22 were which the data for Nevirapine (BOE/BIRG587) [34]
confirmed by their 1H and 13C NMR spectra. The and azidothymidine (DDN/AZT) [35] were included
1H NMR spectrum of 21 showed two doublets at for comparison. Compound-induced cytotoxicity was
δ = 10.02 and 9.60 ppm (J = 4.8 Hz), attributed to also measured in MT-4 cells parallel with the antiviral
NH groups, which disappeared on D2O exchange. In activity.
the 13C NMR spectrum of 21, the signal at lower field
Compounds 9 and 10 were found to be the only
(δ = 187.3 ppm) was assigned to C=S, while the res-
onances at δ = 171.7 and 165.0 ppm were assigned to
NHNC=O and C=O (amide) groups, respectively. In
compounds in the series inhibiting HIV-2 and HIV-1
replication in a cell culture, respectively, which showed
EC50 values of ≥ 17.60 µg mL−1 and > 1.15 µg mL−1
with CC50 values of > 54.08 µg mL−1 and
> 1.15 µg mL−1, respectively, resulting in a se-
lectivity index of ≥ 3 and < 1, respectively.
1
the H NMR spectrum of 22, 5-H of the oxadiazole
moiety appeared as a singlet at δ = 9.34 ppm, while its
13C NMR spectrum showed a signal at δ = 153.0 ppm,
assigned to C-5 of the oxadiazole ring. The proton and
carbon signals of the indole backbone of 21 and 22
were deduced from a comparison with those of 8 – 12.
Based on the chemical structure of compounds 9
and 10, these molecules can be proposed to act as non-
nucleoside reverse transcriptase inhibitors (NNRTIs).
However, the activity spectrum that is limited to HIV-2
(in case of compound 9) is completely in contrast with
what was observed with NNRTIs.
In-vitro anti-HIV assay
Compounds 8 – 21 were tested for their in vitro anti-
HIV-1 (strain IIIB) and HIV-2 (strain ROD) activity in
In conclusion, the above data suggest that substitu-
human T-lymphocyte (MT-4) cells based on the MTT tion of the aromatic ring of the benzimidazole back-
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957
bone by a nitro group would engender the inhibitory 2-Cbenzimidazole), 138.9 (3a-Cbenzimidazole+7a-Cbenzimidazole
+
7a-Cindole), 135.9 (2-Cindole), 131.1, 130.7, 129.0,
activity on HIV-2 replication that is most exceptional,
while the substitution with a halogen atom (like chlo-
rine) would enhance the activity of HIV-1.
128.9, 122.9, 120.5 (Carom), 115.0 (4-Cbenzimidazole), 111.6
(3-Cindole + 5-Cindole), 101.2 (7-Cindole), 55.6 (OMe), 25.2
(CH2); 13.3 (Me). – HRMS ((+)-ESI): m/z = 479.9074
(calcd. 479.9100 for C25H20ClN3O2, [M]+).
Experimental Section
General
(4-Chlorophenyl)(6-methoxy-2-methyl-3-((4-nitrophenyl-1H-
benzoimidazol-2-yl)methyl)-1H-indol-1-yl)methanone (9)
Melting points are uncorrected and were measured on
a Bu¨chi melting point apparatus B-545 (Bu¨chi Labortech-
nik AG, Switzerland). NMR data were obtained on 400 and
600 MHz (1H) and 150.91 MHz (13C) spectrometers (Avance
III, Bruker, Germany) with TMS as internal standard and on
the δ scale in ppm. Heteronuclear assignments were verified
by 1H-13C COSY, or HMQC experiments. Microanalytical
data were obtained with a Vario, Elemental analyzer (Shi-
madzu, Japan). Mass spectra were recorded on EI (70 eV)
and FAB MAT 8200 spectrometers (Finnigan MAT, USA).
Microwave-assisted reactions were carried out in a CEM Fo-
cused Microwave Synthesis System (100 – 150 W). Silica gel
(0.040 – 0.063 mm) used for column chromatography and an-
alytical silica gel TLC plates 60 F254 were purchased from
Merck.
From 3-nitrobenzene-1,2-diamine (3) (153 mg). Yield:
488 mg (65 %); oil. – 1H NMR (CDCl3): δ = 7.98 –
7.61 (m, 4 H, Ar-H), 7.47 – 7.43 (m, 3 H, Ar-H), 6.97
(dd, 1 H, J = 9.0 Hz, 2.8 Hz, 5-Hindole), 6.85 (d, 1 H,
J = 9.0 Hz, 4-Hindole), 6.71 (d, 1 H, J = 2.6 Hz,
7-Hindole), 3.70 (s, 3 H, OMe), 3.75 (s, 2 H, CH2), 2.37
(s, 3 H, Me). – 13C NMR (CDCl3): δ = 168.3 (C=O),
156.0 (6-Cindole), 139.3 (4-Carom-Cl + 2-Cbenzimidazole), 139.2
(7a-Cbenzimidazole), 136.0 (7a-Cindole), 135.9 (2-Cindole
+
4-Carom−NO2), 133.8 (3a-Cbenzimidazole), 131.1, 130.7, 130.6,
129.2, 128.5, 122.1 (Carom), 119.4 (3a-Cindole + 4-Cindole
+ 5-Cbenzimidazole), 111.5 (3-Cindole), 101.3 (7-Cindole), 55.6
(OMe), 25.3 (CH2), 13.3 (Me). – HRMS ((+)-ESI): m/z =
474.9045 (calcd. 474.9076 for C25H19ClN4O4, [M]+).
(3-((4-Chloro-benzimidazol-2-yl)methyl)-6-methoxy-2-
methyl-1H-indol-1-yl)(4-chloro-phenyl)methanone (10)
General procedure for the preparation of the indometh-
acinyl-benzimidazole, -pyridine, -pyrimidine, and -benzo-
thiazole derivatives 6 – 13
From 3-chlorobenzene-1,2-diamine (4) (142 mg). Yield:
475 mg (65 %). – 1H NMR (CDCl3): δ = 7.72 (d, 2 H,
J = 6.6 Hz, 2-Harom-Cl + 6-Harom-Cl), 7.60 (dd, 1 H, J =
6.7 Hz, J = 2.5 Hz, 5-Hbenzimidazole), 7.50 (d, 2 H, J = 6.7 Hz,
3-Harom-Cl + 5-Harom-Cl), 7.25 (m, 2 H, 5-Hbenzimidazole
+ 6-Hbenzimidazole), 6.89 (dd, 1 H, J = 9.0 Hz, 2.8 Hz,
5-Hindole), 6.92 (d, 1 H, J = 8.9 Hz, 4-Hindole), 6.70 (d,
1 H, J = 2.7 Hz, 7-Hindole), 3.71 (s, 3 H, OMe), 3.66
(s, 2 H, CH2), 2.40 (s, 3 H, Me). – 13C NMR (CDCl3):
δ = 168.0 (C=O), 154.6 (6-Cindole), 139.2 (4-Carom-Cl
+ 7a-Cbenzimidazole), 138.4 (3a-Cbenzimidazole+7a-Cindole),
135.5 (2-Cindole), 131.0, 130.2, 129.1, 128.6, 122.7,
A mixture of indomethacin (1) (537 mg, 1.50 mmol) 1,2-
arenediamine (1.0 mmol), p-toluenesulfonic acid (p-TsOH)
(10 mg) and Al2O3 (20 mg) was thoroughly ground with a
pestle in a mortar at r. t. in an open atmosphere, then irra-
diated in MWI. After the reaction was completed, the mix-
ture was allowed to cool to r. t. and then partitioned between
CHCl3 (3×15 mL) and a dil. solution of NaHCO3 (15 mL).
The combined organic extracts were dried (Na2SO4), filtered
and evaporated to dryness. The crude product was purified on
a column of SiO2 (5 g) (eluents: hexane-EtOAc = 3 : 2 or, in
gradient, MeOH (0 – 10 %) and CHCl3) to give the desired
product.
120.2 (Carom), 113.9 (7-Cbenzimidazole), 111.2 (3-Cindole
+
5-Cindole), 101.0 (7-Cindole), 55.5 (OMe), 25.1 (CH2), 13.3
(Me). – C25H19Cl2N3O2: calcd. C 64.66, H 4.12, N 9.05;
found C 64.38, H 4.04, N 8.69.
(3-((Benzimidazol-2-yl)methyl)-6-methoxy-2-methyl-1H-
indol-1-yl)(4-chlorophenyl)methanone (8)
(3-((3H-Imidazo[4,5-b]pyridin-2-yl)methyl)-6-methoxy-
2-methyl-1H-indol-1-yl)(4-chlorophenyl)methanone (11)
From o-phenylenediamine (2) (108 mg). Yield: 398 mg
(62 %); oil. – 1H NMR (CDCl3): δ = 7.70 (d, 2 H,
J = 6.8 Hz, 2-Harom-Cl + 6-Harom-Cl), 7.66 (d, 2 H, J=
From 2,3-diaminopyridine (5) (109 mg). Yield: 459 mg
8.0 Hz, 4-Hbenzimidazole + 7-Hbenzimidazole), 7.51 (d, 2 H, J= (71 %). – 1H NMR (CDCl3): δ = 11.9 (br s., 1 H, NH),
6.8 Hz, 3-Harom-Cl + 5-Harom-Cl), 7.49 (d, 2 H, J = 8.0 Hz, 8.39 (d, 2 H, J = 8.5 Hz, 2.6 Hz, 6-Himidazol−pyridine), 7.59
5-Hbenzimidazole + 6-Hbenzimidazole), 7.02 (dd, 1 H, J = 9.0 Hz, (m, 3 H, 4-Hmidazol−pyridine + 2-Harom-Cl + 6-Harom-Cl), 7.42
2.8 Hz, 5-Hindole), 6.92 (d, 1 H, J = 9.0 Hz, 4-Hindole), 6.71 (m, 3 H, 3-Harom-Cl + 5-Harom-Cl + 5-Himidazol−pyridine),
(d, 1 H, J = 2.8 Hz, 7-Hindole), 3.81 (s, 3 H, OMe), 3.74 6.97 (dd, 1 H, J = 8.8 Hz, 2.6 Hz, 5-Hindole), 6.82 (d,
(s, 2 H, CH2), 2.40 (s, 3 H, Me). – 13C NMR (CDCl3): 1 H, J = 8.8 Hz, 4-Hindole), 6.59 (d, 1 H, J = 2.6 Hz,
δ = 168.2 (C=O), 155.9 (6-Cindole), 139.1 (4-Carom-Cl
+
7-Hindole), 3.74 (s, 3 H, OMe), 3.64 (s, 2 H, CH2), 2.30 (s,
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3 H, Me). – 13C NMR (CDCl3): δ = 168.3 (C=O), 155.9 der reflux for 3 h. After cooling, the solution was evapo-
(6-Cindole + 7a-Cimidazol−pyridine), 147.0 (2-Cimidazol−pyridine rated to dryness, and the residue was partitioned between
+ 6-Cimidazol−pyridine), 139.1 (4-Carom-Cl), 135.5 (2-Cindole CHCl3 (2 × 20 mL) and water (20 mL). The combined
+ 7a-Cindole), 131.1 (3-Cimidazol−pyridine), 130.9, 130.7, organic layers were dried (Na2SO4) and filtered, and the
127.0, 128.1, 122.0 (Carom), 111.3 (3-Cindole + 5-Cindole), filtrate was evaporated to dryness. The residue was puri-
101.2 (7-Cindole), 55.6 (OMe), 25.2 (CH2), 13.3 (Me). – fied by SiO2 column chromatography using a gradient of
C24H19ClN4O2: calcd. C 66.90, H 4.44, N 13.00; found MeOH (0 – 10 %) in CHCl3 as eluent to provide the desired
C 66.78, H 4.38, N 12.79.
product.
(3-((9H-Purin-8-yl)methyl)-6-methoxy-2-methyl-1H-indol-
1-yl)(4-chlorophenyl)methanone (12)
N-(4-tert-Butylcyclohexylidene)-2-(1-(4-chlorobenzoyl)-
6-methoxy-2-methyl-1H-indol-3-yl)acetohydrazide (16)
From 4,5-diaminopyrimidine (6) (110 mg). Yield: 376 mg
From 4-tert-butylcyclohexanone (196 mg). Yield: 416 mg
1
(58 %). – H NMR (CDCl3): δ = 9.05 (d, 1 H, J = 2.2 Hz,
(82 %); m. p. 101 – 105 ◦C. – 1H NMR ([D6]DMSO):
δ
4-Hpurine), 8.90 (d, 1 H, J = 2.2 Hz, 6-Hpurine), 7.65 (2 H,
J = 7.0 Hz, 2-Harom-Cl + 6-Harom-Cl), 7.46 (d, 2 H, J =
7.0 Hz, 3-Harom-Cl + 5-Harom-Cl), 6.95 (dd, 1 H, J = 8.9 Hz,
2.4 Hz, 5-Hindole), 6.84 (d, 1 H, J = 8.9 Hz, 4-Hindole), 6.67
(d, 1 H, J = 2.4 Hz, 7-Hindole), 3.81 (s, 3 H, OMe), 3.68
(s, 2 H, CH2), 2.38 (s, 3 H, Me). – 13C NMR (CDCl3):
δ = 168.3 (C=O), 156.0 (6-Cindole), 153.1 (7a-Cpurine); 148.9
(2-Cpurine + 6-Cpurine), 139.1 (4-Carom-Cl), 136.1 (2-Cindole
= 10.54 (s, 1 H, NH), 7.64 (dd, 2 H, J =
7.7 Hz, 1.8 Hz, 2-Harom-Cl + 6-Harom-Cl), 7.48 (dd,
2 H, J = 7.7 Hz, 1.8 Hz, 3-Harom-Cl + 5-Harom-Cl),
6.98 (d, 1 H, J = 2.4 Hz, 7-Hindole), 6.88 (d, 1 H,
J = 8.8 Hz, 4-Hindole), 6.69 (dd, 1 H, J = 8.8 Hz,
24 Hz, 5-Hindole), 3.81 (s, 3 H, OMe), 3.64 (s, 2 H,
CH2), 2.30 (s, 3 H, Me), 1.37 – 1.02 (m, 18 H, H-
tbut-cyclohexan). – 13C NMR ([D6]DMSO): δ = 170.0
+ 7a-Cindole), 131.2 (3a-Cpurine + 4-Cpurine + 2-Carom-Cl
6-Carom-Cl), 129.1, 128.2, 122.1 (Carom), 120.1 (3a-Cindole
+
+
(NHNC=O), 167.2 (C=O), 156.3 (6-Cindole
+ C=N),
138.1 (4-Carom-Cl), 133.9 (7a-Cindole), 134.0 (2-Cindole),
131.6, 130.2, 129.7 (Carom), 116.8 (3a-Cindole + 4-Cindole),
110.5 (3-Cindole), 109.0 (5-Cindole), 100.1 (7-Cindole),
55.1 (OMe), 46.9 (4-Ccyclohexan), 31.8 (CMe3), 27.1
(2,3,5,6-C6cyclohexan+CMe3), 13.1 (Me). – C29H34ClN3O3:
calcd. C 68.56, H 6.75, N 8.27; found C 68.36, H 6.68,
N 7.93.
4-Cindole), 111.6 (3-Cindole), 101.3 (7-Cindole), 55.7 (OMe);
23.5 (CH2); 13.3 (Me). – C23H18ClN5O2: calcd. C 63.96,
H 4.20, N 16.22; found C 63.69, H 4.11, N 16.01.
(3-(Benzothiazol-2-ylmethyl)-6-methoxy-2-methyl-1H-indol-
1-yl)(4-chlorophenyl)methanone (13)
From 2-aminobenzenethiol (7) (125 mg). Yield: 368 mg
(55 %); oil. – 1H NMR (CDCl3, 600 MHz, HMBC): δ =
8.17 – 7.90 (m, 2 H, 4-Hbenzothiazole + 7-Hbenzothiazole), 7.66
(d, 2 H, J = 8.9 Hz, 2-Harom-Cl + 6-Harom-Cl), 7.53 –
2-(1-Benzoyl-6-methoxy-2-methyl-1H-indol-3-yl)-Nꢀ-(1-(5-
methylphenyl)-2,2-dimethylpropylidene)acetohydrazide (17)
7.44 (4 H, 5-Hbenzothiazole + 6-Hbenzothiazole + 3-Harom-Cl
+
From 1-(5-methoxy-2-methylphenyl)-2,2-dimethylprop-
an-1-one (227 mg). Yield: 476 mg (85 %); m. p. 135 –
5-Harom-Cl), 6.95 (d, 1 H, J = 9.0 Hz, 2.4 Hz, 5-Hindole),
6.85 (d, 1 H, J = 9.0 Hz, 4-Hindole), 6.66 (d, 1 H, J =
2.4 Hz, 7-Hindole), 3.83 (s, 3 H, OMe), 3.70 (s, 2 H,
CH2), 2.38 (s, 3 H, Me). – 13C NMR (CDCl3): δ = 168.3
(C=O), 166.2 (2-Cbenzothiazole), 156.1 (6-Cindole), 154.1
◦
1
139 C. – H NMR ([D6]DMSO): δ = 10.60 (s, 1 H, NH),
7.86 (dd, 2 H, J = 6.8 Hz, 1.9 Hz, 2-Harom-Cl + 6-Harom-Cl),
7.54 (dd, 2 H, J = 6.8 Hz, 1.9 Hz, 3-Harom-Cl + 5-Harom-Cl),
7.17 (dd, 1 H, J = 8.4 Hz, 1.7 Hz, 4-Hindole), 7.08 (d,
1 H, J = 8.8 Hz, 3-Harom), 7.05 (d, 1 H, J = 2.4 Hz,
6-Harom), 6.97 (d, 1 H, J = 8.4 Hz, 5-Hindole), 6.86 (d,
1 H, J = 1.9 Hz, 7-Hindole), 6.63 (dd, 1 H, J = 8.6 Hz,
2.4 Hz, 4-Harom), 3.75, 3.73 (2xs, 6 H, 2xOMe), 3.36 (s, 2 H,
CH2); 2.34 (s, 3 H, Me), 1.32 (s, 6 H, CMe3). – 13C NMR
([D6]DMSO): δ = 170.2 (NHNC=O), 164.8 (C=O), 153.0
(6-Cindole + 5-Carom), 152.8 (C=N), 135.9 (4-Carom-Cl), 133.7
(7a-Cindole), 132.0 (2-Cindole), 130.4, 130.1, 129.0, 128.8,
128.3, 126.3 (Carom), 111.3 (3a-Cindole + 4-Cindole), 110.7
(5-Cindole + 6-Carom), 109.3 (4-Carom), 104.6 (3-Cindole),
100.7 (7-Cindole), 55.4 (2xOMe), 29.7 (CH2C=O), 26.5
(CMe3), 19.9, 11.6 (2xMe). – C32H34ClN3O45: calcd.
(3a-Cbenzothiazole), 139.3 (4-Carom-Cl), 136.9 (7a-Cindole
2-Cindole), 133.8 (7a-Cbenzothiazole), 131.2, 129.2, 127.6
(1-Carom-Cl 2-Carom-Cl 3-Carom-Cl 5-Carom-Cl+
+
+
+
+
6-Carom-Cl), 125.6 (5-Cbenzothiazole + 6-Cbenzothiazole), 121.9
(4-Cbenzothiazole + 7-Cbenzothiazole), 118.9 (4-Cindole), 118.3
(3a-Cindole), 111.7 (3-Cindole + 5-Cindole), 101.3 (7-Cindole),
55.8 (OMe), 23.5 (CH2), 13.4 (Me). – HRMS ((+)-ESI):
m/z = 446.9590 (calcd. 446.9594 for C25H19ClN2O2S,
[M]+).
General procedure for the preparation of the imine
derivatives of indomethacin 16 – 20
A solution of 15 (371 mg, 1.0 mmol) in EtOH (15 mL) C 68.62, H 6.12, N 7.50; found C 68.41, H 6.01,
containing an appropriate ketone (1.1 mmol) was heated un- N 7.21.
Unauthenticated
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N. A. Al-Masoudi et al. · Benzimidazole, Benzothiazole and Carbohyrazide Derivatives of Indomethacin
959
2-(1-(4-Chlorobenzoyl)-6-methoxy-2-methyl-1H-indol-3-yl)-
N-((4-methoxyphenyl)(phenyl)methylene)acetohydrazide
(18)
(Carom), 110.8 (4-Cindole + 3a-Cindole), 109.6 (5-Cindole),
104.4 (3-Cindole), 100.0 (7-Cindole), 54.8 (OMe), 31.5
(CH2C=O), 28.3 (CH2Ph), 11.7 (Me). – C33H28ClN3O3:
calcd. C 72.06, H 5.13, N 7.64; found C 71.89, H 5.04,
N 7.51.
From (4-methoxyphenyl)(phenyl)methanone (233 mg).
Yield: 447 mg (79 %); m. p. 142 – 145 ◦C. – 1H NMR
([D6]DMSO): δ = 9.08 (s, 1 H, NH), 7.86 – 6.62 (m,
16 H, Harom), 3.75 (2xs, 6 H, 2xOMe), 3.37 (s, 2 H,
CH2); 2.34 (s, 3 H, Me). – 13C NMR ([D6]DMSO):
2-(1-(4-Chlorobenzoyl)-6-methoxy-2-methyl-1H-indol-3-yl)-
N-(phenylcarbonothioyl)acetohydrazide (21)
A suspension of 15 (371 mg, 1.0 mmol) and phenyl isoth-
iocyanate (135 mg, 1.0 mmol) in EtOH (10 mL) was heated
under reflux for 6 h. The solvent was evaporated to dryness,
and the residue was worked up as in 20 to give 21 (297 mg,
δ = 170.7 (NHNC=O), 165.3 (C=O), 153.4 (6-Cindole
+
C=N + Carom-OMe), 137.8 (4-Carom-Cl), 136.8 (7a-Cindole),
134.2 (2-Cindole), 132.9, 132.5, 130.6, 130.3, 129.9, 129.3,
128.9 (Carom), 111.8 (4-Cindole + Carom + 3a-Cindole), 109.8
(5-Cindole), 105.8 (3-Cindole), 101.1 (7-Cindole), 55.9 (2 ×
OMe), 30.2 (CH2C=O), 12.1 (Me). – C33H28ClN3O4: calcd.
C 70.02, H 4.99, N 7.42; found C 69.78, H 4.92, N 7.21.
1
78 %). – H NMR ([D6]DMSO): δ = 10.02, 9.60 (2d, 2 H,
J = 4.8 Hz, NH), 7.99 – 6.61 (m, 12 H, Harom), 3.34 (s, 3 H,
OMe), 3.54 (s, 2 H, CH2), 2.31 (s, 3 H, Me). – 13C NMR
([D6]DMSO): δ = 187.3 (C=S=S), 171.7 (NHNC=O), 168.7,
165.0 (C=O), 139.1, 134.0, 131.3, 130.1, 129.7, 128.7,
128.3, 128.0 (Carom), 124.9 (3a-Cindole + 4-Cindole), 110.8
(3-Cindole), 103.9 (5-Cindole), 100.4 (5-Cindole), 55.3 (OMe),
29.7 (CH2), 11.6 (Me). – C26H22ClN3O3S: calcd. C 63.47,
N-(2-Amino-2-methyl-1-phenylpropylidene)-2-(1-
(4-chlorobenzoyl)-6-methoxy-2-methyl-1H-indol-3-yl)-N-
((4-methoxyphenyl)(phenyl)methylene)acetohydrazide (19)
From 2-amino-2-methyl-1-phenylpropan-1-one (179 mg). H 4.51, N 8.54; found C 63.21, H 4.47, N 8.17.
Yield: 403 mg (78 %). – 1H NMR ([D6]DMSO): δ =
10.79 (s, 1 H, NH), 8.69 (m, 2 H, NH2), 7.59 – 6.62
(m, 12 H, Harom), 3.72 (s, 3 H, OMe), 3.45 (s, 2 H,
CH2), 2.29 (s, 3 H, Me), 1.07, 1.03 (m, 6 H, 2xCMe2). –
13C NMR ([D6]DMSO): δ = 173.1 (NHNHC=O), 166.9
(3-(1,3,4-Oxadiazol-2-yl)methyl-6-methoxy-2-methyl-1H-
indol-1-yl)(4-chlorophenyl)methanone (22)
A mixture of 15 (371 mg, 1.0 mmol) and triethyl or-
thoformate (5 mL) was heated under reflux for 12 h. Af-
ter cooling, the solvent was evaporated, and the residue
was purified on a short SiO2 column. Elution, in gradient,
with MeOH (0 – 10 %) and CHCl3 as eluent provided 22
(305 mg, 62 %). – 1H NMR ([D6]DMSO): δ = 9.34 (s,
1 H, 5-Hoxadiazole), 8.03 – 6.63 (m, 7 H, Harom), 3.75 (s, 3 H,
OMe), 3.67 (s, 2 H, CH2), 2.21 (s, 3 H, Me). – 13C NMR
([D6]DMSO): δ = 169.1 (C=O), 165.5 (2-Coxadiazol), 162.7
(6-Cindole), 153.3 (5-Coxadiazol), 136.6, 133.8, 130.0, 129.4,
129.2, 128.3, 128.0 (Carom), 121.9 (3a-Cindole + 4-Cindole),
110.6 (3-Cindole), 109.4 (5-Cindole); 102.6 (C5indole), 55.1
(OMe), 19.8 (CH2), 11.5 (Me). – C20H16ClN3O3: calcd.
C 62.91, H 4.22, N 11.01; found C 62.69, H 4.16, N 10.76.
(C=O), 155.9 (6-Cindole + C=N, 136.4 (4-Carom-Cl
+
7a-Cindole + 2-Cindole), 130.2, 129.9, 129.7, 128.9, 128.8,
128.2 (Carom), 111.2 (4-Cindole + Carom + 3a-Cindole), 109.8
(5-Cindole), 102.2 (3-Cindole), 99.6 (7-Cindole), 56.0 (CMe3),
55.4 (OMe), 30.0 (CH2C=O), 24.4, 23.7 (CMe2), 12.2
(Me). – C29H29ClN4O3: calcd. C 67.37, H 6.86, N 10.84;
found C 67.06, H 5.48, N 10.57.
2-(1-(4-Chlorobenzoyl)-6-methoxy-2-methyl-1H-indol-3-yl)-
N-(1,2-diphenylethylidene)acetohydrazide (20)
From 1,2-diphenylethanone (215 mg). Yield: 467 mg
1
(85 %). – H NMR ([D6]DMSO): δ = 10.50 (s, 1 H, NH),
7.86 – 6.98 (m, 17 H, Harom), 3.69 (s, 3 H, OMe), 3.44 (s, 2 H,
CH2), 2.34 (s, 3 H, Me). – 13C NMR ([D6]DMSO): δ = 174.0
(NHNC=O), 167.9 (C=O), 160.6 (6-Cindole), 152.9 C=N),
Acknowledgement
We thank Mr. U. Haunz and Miss A. Friemel of the Chem-
141.8 (4-Carom-Cl + 1-Cbenzyl), 137.5 (7a-Cindole), 136.3 istry Department, University of Konstanz, Konstanz (Ger-
(2-Cindole), 129.6, 128.7, 128.5, 128.3, 128.1, 128.0, 126.4 many) for the NMR experiments.
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