Nitroimidazoles, part 3. Synthesis and anti-HIV activity of new N-alkyl-4-nitroimidazoles bearing benzothiazole and benzoxazole backbones

Article abstract of DOI:10.1515/znb-2007-0406

A series of 4-nitroimidazole derivatives bearing substituted piperazines (5, 8, 9, 12, 14, 16, 17, and 19 - 21) were synthesized with the aim to develop new non-nucleoside reverse transcriptase inhibitors (NNRTIs). The newly synthesized compounds were ass

Full text of DOI:10.1515/znb-2007-0406

Nitroimidazoles, Part 3. Synthesis and anti-HIV Activity of
New N-Alkyl-4-nitroimidazoles Bearing Benzothiazole and Benzoxazole
Backbones
Yaseen A. Al-Souda, Haitham Al-Sa’donia, Houssain A. S. Amajaoura, and
Najim A. Al-Masoudib
a Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
b Fachbereich Chemie, Universita¨t Konstanz, 78457 Konstanz, Germany
Reprint requests to Dr. N. A. Al-Masoudi. E-mail: dr@al-masoudi.de
Z. Naturforsch. 2006, 62b, 523 – 528; received May 29, 2006
A series of 4-nitroimidazole derivatives bearing substituted piperazines (5, 8, 9, 12, 14, 16, 17,
and 19 – 21) were synthesized with the aim to develop new non-nucleoside reverse transcriptase in-
hibitors (NNRTIs). The newly synthesized compounds were assayed against HIV-1 and HIV-2 in
MT-4 cells. All compounds are inactive, except compound 21 which showed inhibition of HIV-1
with EC50 0.20 µg/mL, and therapeutic indexes (SI) of 12.
Key words: anti-HIV Activity, Benzothiazoles, Benzoxazoles, 4-Nitroimidazoles, NNRTIs
Introduction
Nitro-substituted haloimidazoles are considered as
compounds with important biological activity as an-
tibacterial agents [1, 2], potential radiosensitizers [3]
and anticancer agents [4, 5]. Dacarbazine® (DTIC) [6]
is synthesized as an alkylating agent for inhibition of
de novo purine synthesis, while misonidazole 1 [7]
has been reported as a potential anticancer agent.
Other imidazole derivatives, such as clotrinazole [1-
(2-chlorotrityl)-1H-imidazole] [8, 9] and metronida-
zole (Flagyl) 2 [10], have been considered as potent
fungicides and/or used as antiprotozoal agents (espe-
cially for treatment of Trichomonas vaginalis, Enta-
moeba histolytica and Giardia lamblia). Capravirine,
(S-1153, 3) is an imidazole analogue with a high anti-
HIV inhibitory activity [11].
The facile replacement of the halogen substituent
in the nitro-substituted haloimidazoles prompted many
laboratories [12 – 18] to develop new high-yield syn-
theses leading to interesting imidazole compounds
bearing various alkylsulfanyl or alkylamino groups
via nucleophilic substitution of the halogen by N or
S nucleophiles. With the potential biological activity
in mind, we synthesized new substituted 4-nitroimid-
azoles and evaluated their HIV activity.
Results
Our recent work [19, 20] has focused on the sub-
stitution of the bromo group of 5-bromo-1-benzyl-
2-ethyl-4-nitroimidazole 4 [18] by various primary and
secondary amines as well as by alkylsulfanyl precur-
sors [13] to furnish potentially active analogues. In the
present work, compound 4 has been selected as start-
0932–0776 / 06 / 0400–0523 $ 06.00 © 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Unauthenticated
Download Date | 2/3/16 6:20 AM

524
Y. A. Al-Soud et al. · Nitroimidazoles, Part 3
Scheme 1.
ing material for the synthesis of new substituted imi- glet at δ = 8.67. The 13C NMR spectra of 8 and 9
dazole compounds via the nucleophilic displacement contained high-field signals at δ = 160.8 and 167.9
of the bromine group activated by an adjacent nitro which were attributed to C-10 of the oxazole and thia-
function. Treatment of 4 with piperazine in DMF af- zole rings, respectively. Carbon atom C-2 of the imida-
forded 5 (72 %), which gave 8 and 9 in 34 and 31 % zole ring resonated at δ = 140.0. The piperazine car-
yield, respectively, on reaction with 2-chlorobenzox- bon atoms were identified at δ = 48.4 and 46.4. Carbon
azole (6) and 2-chlorobenzothiazole (7), respectively, atoms C-4 and C-5 of the imidazole ring gave signals
in the presence of NaH/DMF.
at δ = 137.7 and 135.4. The 13C NMR spectra of 12
and 13 were similar to those of the analogues 8 and 9.
The carbon atoms of the triazole ring were assigned to
the signals at δ = 159.5 and 152.3 for 8 and δ = 152.2
and 145.1 for 9.
On the other hand, treatment of 5 with the 4-(1,2,4-
triazol-3-yl)benzyl chloride derivatives [21] 10 and 11
afforded, after purification, compounds 12 and 13 in 64
and 38 % yield, respectively.
Treatment of 4 with piperazine-1-carbaldehyde in
DMF afforded after chromatographicpurification com-
pound 14 (87%) (Scheme 1).
Next, our efforts have been focused on the N-
alkylation of 2-methyl-4-nitroimidazole (15) by in-
troduction of potential alkyl groups. Thus, treatment
The structures of 5 and 8 – 14 were identified by of 15 with 6 or 7 and NaH in DMF afforded, after
heteronuclear NMR spectroscopic methods including purification, compounds 16 and 17 in 41 and 46 %
1
HMBC spectra [22] and mass spectra. The H NMR yield, respectively. A similar treatment of 15 with the
spectra of 5, 8, 9 and 12 – 14 showed rather similar benzylic chlorides 10, 11 or 18 gave N1-benzylimid-
patterns. The resonances of the piperazine moiety ap- azoles 19 – 21 in 27, 38 and 40 % yield, respectively
peared as two broad singlets at δ = 3.89 – 2.65 and (Scheme 2). The constitution of 16, 17 and 19 – 21 was
δ = 3.51 – 2.56, the signal of the benzylic protons at derived from their NMR (1H, 13C) and mass spectra.
δ = 5.24 – 5.16. The aldehyde proton of 14 gave a sin- The HMBC spectrum of 21 showed 2JC,H coupling be-
Unauthenticated
Download Date | 2/3/16 6:20 AM

Y. A. Al-Soud et al. · Nitroimidazoles, Part 3
525
Scheme 2.
Table 1. In vitro anti-HIV-1a and HIV-2b of some new ni-
tween C-4 of the imidazole ring (δ = 136.4) and 5-H
(δ = 8.46). 3JC,H coupling was observed between C-4
and the methylene protons (CH2Ph) (δ = 5.32). 2JC,H
coupling was found between C-2’ of the triazole ring
troimidazoles.
Compound
8
Virus strain EC50 (µg/ml)c CC50 (µg/ml)d SIe
IIIB
> 14.9
> 16.2
> 15.9
> 16.6
> 15.0
> 15.2
> 14.3
> 15.6
> 85.1
> 117.0
> 28.8
> 22.4
> 96.1
> 101.0
> 102.0
> 118.0
> 14.2
> 14.6
0.20 0.08
> 2.9
16.48 1.32 < 1
16.48 1.32 < 1
17.18 1.15 < 1
17.18 1.15 < 1
16.75 1.75 < 1
16.75 1.75 < 1
15.78 1.09 < 1
97.05 13.97 < 1
97.05 13.97 < 1
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
(δ = 58.5) and 9’-H2 (δ = 2.94), and 3J
between C-2’ and 8’-H2 (δ = 1.74).
coupling
C,H
9
12
13
14
16
17
19
20
21
In vitro anti-HIV assay
Compounds 8, 9, 12 – 14, 16, 17 and 19 – 21 were
tested for their in vitro anti-HIV-1 (strain IIIB) and
HIV-2 (strain ROD) activity in human T-lymphocyte
(MT-4) cells. The results are summarized in Table 1, in
which the data for efavirenz [23] and capravirine [11]
are included for comparison purposes. Compound 21
was found to be the only compound in the series
inhibiting HIV-1 replication in cell culture. Com-
pound 21 showed an EC50 of 0.20 µg/mL and a CC50
of 2.40 µg/mL, resulting in a selectivity index of 12.
Based on the chemical structure and the fact that
compound 21 inhibits HIV-1, but not HIV-2 replica-
tion, this molecule can be proposed to act as an non-
nucleoside reverse transcriptase inhibitor (NNRTI).
This hypothesis was further confirmed by assaying the
compound against a typical NNRTI-resistant HIV-1
strain (double mutation in RT: K103N and Y181C).
Compound 21 completely lost its inhibitory activity
against this resistant strain.
117.0 4.2
< 1
46.88 19.95 < 1
46.88 19.95 < 1
≥ 96.1
< 1
< 1
< 1
< 1
< 1
< 1
12
< 1
13333
7857
≥ 96.1
≥ 102.0
≥ 102.0
14.8 0.50
14.8 0.50
2.4 0.1
2.8 0.1
40
ROD
IIIB
ROD
Efavirenz [23] IIIB
Capravirine [11] IIIB
0.003
0.0014
11
a
b
anti-HIV-1 activity measured with strain IIIB, anti-HIV-2 ac-
c
tivity measured with strain ROD, compound concentration re-
quired to achieve 50 % protection of MT-4 cells from the HIV-1- and
-2-induced cytopathogenic effect, d compound concentration that re-
duces the viability of mock-infected MT-4 cells by 50 %, e SI: selec-
tivity index (CC50/EC50).
without correction. 1H and 13C NMR spectra were measured
on a UltraShield TM NMR-300 MHz Bruker instrument with
TMS as internal standard and on the δ scale in ppm. Micro-
analytical data were obtained with a Vario Elementar appa-
Experimental Section
Melting points were measured on a Bu¨chi melting point ratus. EI and FAB mass spectra were measured on a GC-MS
¨
apparatus B-545 (BUCHI Labortechnik AG, Switzerland) Shimadzu QP-505A (Japan) spectrometer.
Unauthenticated
Download Date | 2/3/16 6:20 AM

526
Y. A. Al-Soud et al. · Nitroimidazoles, Part 3
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazine (5)
A solution of 4 (3.10 g, 10.0 mmol) in DMF (25 mL) and
1-[4-(1-Ethyl-5-methyl-1H-1,2,4-triazol-3-yl)benzyl-4-
1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl]piperazine (12)
◦
piperazine (1.03 g, 12.0 mmol) was stirred at 70 – 80 C for
This compound was prepared from 5 (0.32, 1.0 mmol)
and 10 (0.24 g, 1.0 mmol), analogously to ◦the preparation
of 8. Yield: 0.33 g (64 %). M. p. 152 – 154 C. – 1H NMR
(250 MHz, CDCl3): δ = 7.36 – 7.01 (m, 9H, ArH), 5.16,
5.01 (2xs, 4H, 2xCH2Ph), 3.20, 2.56 (2xbr s, 8H, piper-
azine), 4.16, 2.65 (2xq, J = 7.3 Hz, 2xCH2CH3), 2.68 (q, 2H,
J = 7.0 Hz, CH2CH3), 1.31 (t, 3H, CH2CH3). – 13C NMR
(62.9 MHz, CDCl3): δ = 159.5 (C-3’, triazole), 152.3 (C-5’,
triazole), 140.2 (C-2, imidazole), 138.9 (C-4, imidazole),
135.4 (2xC, Ar), 132.6 (C-5, imidazole), 130.0 – 125.6 (10
C, ar.), 48.4, 46.4 (4C, piperazine), 32.0 (CH2Ph), 49.2, 48.6
(4 C, piperazine), 46.4, 40.2 (2xCH2Ph), 43.5 (CH2CH3, tri-
azole), 20.1 (CH2CH3, imidazole), 13.8, 13.6 (2xCH2CH3),
11.8 (C5-Me). – MS (EI, 70 eV): m/z (%) = 514 (85) [M+].
– C28H34N8O2 (514.62): calcd. C 65.35, H 6.66, N, 21.77;
found C 65.07, H 6.49, N 21.53.
6 h. After cooling the precipitation was filtered and recrys-
tallized from EtOH to give 5 (2.27 g, 72 %). M. p. 228 –
231 ◦C. – 1H NMR (250 MHz, CDCl3): δ = 7.38 – 7.18
(m, 5H, ArH), 6.75 (br s, 1H, NH), 5.22 (s, 2H, CH2Ph),
3.09, 2.98 (2xbr s, 8H, piperazine), 2.56 (q, 2H, J = 7.5 Hz,
CH2CH3), 1.09 (t, 3H, CH2CH3). – 13C NMR (62.9 MHz,
CDCl3): δ = 145.7 (C-2), 139.4 (C-4); 137.0 (C-5), 129.6,
128.3, 127.0 (ar.), 46.6, 43.8 (4 C, piperazine), 41.0 (CH2Ph),
20.9 (CH2CH3), 11.3 (CH2CH3). – MS (EI, 70 eV): m/z (%)
= 315 (78) [M+]. – C16H21N5O2 (315.37): calcd. C 60.94,
H 6.71, N 22.21; found C 60.75, H 6.59, N 22.03.
2-[4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-
1-yl]benzoxazole (8)
To a solution of 5 (0.32 g, 1.0 mmol) in DMF (15 mL)
containing NaH (1.0 mmol) was added a solution of 6
(0.15 g, 1.0 mmol) in DMF (5 mL) and the mixture was
stirred at 23 ◦C for 48 h. The solvent was evaporated and the
residue brought to dryness and partitioned between CH2Cl2
(40 mL) and water (40 mL). The organic phase was dried
(Na2SO4), filtered and evaporated to dryness and the residue
was purified by chromatography (10 g), using CH2Cl2-
MeOH (9 : 1) as eluent to give 8 (0.15 g, 34 %). M. p. 145 –
147 ◦C. – 1H NMR (250 MHz, CDCl3): δ = 7.42 – 7.07
(m, 9H, ArH), 5.17 (s, 2H, CH2Ph), 3.91, 3.50 (2xbr s,
8H, piperazine), 2.68 (q, 2H, J = 7.0 Hz, CH2CH3), 1.33
(t, 3H, CH2CH3). – 13C NMR (62.9 MHz, CDCl3): δ =
160.8 (C-10), 148.2 (C-12, Ar-C), 145.3 (C-13, Ar-C), 140.0
(C-2), 137.7 (C-4), 135.4 (C-5), 129.2 – 109.2 (9 C, ar.), 48.7,
46.4 (4 C, piperazine), 45.2 (CH2Ph), 21.1 (CH2CH3), 11.4
(CH2CH3). – MS (EI, 70 eV): m/z (%) = 432 (59) [M+].
– C23H24N6O3 (432.48): calcd. C 63.88, H 5.59, N 19.43;
found C 63.57, H 5.46, N 19.21.
2-[4-((4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piper-
azin-1-yl)methyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]-triazolo-
[1,5-a]pyridine (13)
This compound was prepared from 5 (0.32, 1.0 mmol)
and 11 (0.25 g, 1.0 mmol), by following the same proce-
dure as for 8. Yield: 0.20 g (38 %). M. p. 148 – 150 ◦C.
–
1H NMR (250 MHz, CDCl3): δ = 8.20, 7.52 (2xd,
4H, J = 5.0 Hz, ArH), 7.38 – 7.04 (m, 5H, ArH), 5.16,
4.29 (2xs, 4H, 2xCH2Ph), 4.29 (m, 2H, 5’-H2, triazole),
3.24 (br s, 4H, piperazine), 2.65 (br s, 8H, 9’-H2, tria-
zole + piperazine + CH2CH3), 2.22 (m, 2H, 6’-H2, tria-
zole), 2.09 (m, 2H, 8’-H2, triazole), 1.35 (m, 2H, 7’-H2,
triazole), 1.30 (t, 3H, J = 7.2 Hz, CH2CH3). – 13C NMR
(62.9 MHz, CDCl3): δ = 152.2 (C-2’, triazole), 145.1
(C-10’, triazole), 140.8 (C-2, imidazole), 138.9 (C-4, imi-
dazole), 135.4 (2 C, ar.), 131.0.6 (C-5, imidazole), 130.9 –
125.7 (10C, ar.), 49.2, 47.9 (4C, piperazine), 45.5 (C-5’,
triazole), 46.4, 41.0 (2xCH2Ph), 29.7 (C-7’, triazole), 23.0
(C-9’, triazole), 22.1 (C-8’), 21.1 (C-6’, triazole), 18.7
(CH2CH3, imidazole), 11.4 (CH2CH3). – MS (EI, 70 eV):
m/z (%) = 526 (85) [M+]. – C29H34N8O2 (526.63):
calcd. C 66.14, H 6.51, N 21.28; found C 65.84, H 6.47,
N 21.11.
2-[4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-
1-yl]benzothiazole (9)
This compound was prepared from 5 (0.32, 1.0 mmol)
and 7 (0.17 g, 1.0 mmol), by following the same procedure
as for the preparation 8. Yield: 0.14 g (31 %). M. p. 123 –
125 ◦C. – 1H NMR (CDCl3): δ = 7.75 – 7.00 (m, 9H, ArH),
5.18 (s, 2H, CH2Ph), 3.89, 3.51 (2xbr s, 8H, piperazine),
2.68 (q, 2H, J = 7.0 Hz, CH2CH3), 1.31 (t, 3H, CH2CH3).
4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-
carbaldehyde (14)
–
13C NMR (62.9 MHz, CDCl3): δ = 167.9 (C-10), 145.4
(C-12, Ar-C), 145.1 (C-13, Ar-C), 140.0 (C-2), 137.4 (C-4),
A solution of 5 (0.34 g, 3.0 mmol) in DMF (30 mL) con-
135.4 (C-5), 135.3, 129.4 – 118.1 (ar.), 125.6 (C-12), 48.4, taining piperazine-1-carbaldehyde (0.93 g, 3.0 mmol) was
◦
46.4 (4 C, piperazine), 32.0 (CH2Ph), 21.1 (CH2CH3), 11.4 heated at 70 – 80 C for 6 h. After cooling overnight, the
(CH2CH3). – MS (EI, 70 eV): m/z (%) = 484 (88) [M+]. – cryst◦als were collected to give 14 (0.89 g, 87 %). M. p. 297 –
C23H24N6O2S (448.54): calcd. C 61.59, H 5.39, N 18.74; 299 C. – 1H NMR (250 MHz, CDCl3): δ = 8.67 (s, 1H,
found C 63.37, H 5.46, N 19.21.
CHO), 7.41 – 7.03 (m, 5H, ArH), 5.24, (s, 2H, CH2Ph),
Unauthenticated
Download Date | 2/3/16 6:20 AM

Y. A. Al-Soud et al. · Nitroimidazoles, Part 3
527
3.33, 3.07 (2xbr s, 8H, piperazine), 2.53 (q, J = 7.2 Hz, 13.3 (5’-Me, triazole), 11.8 (2-CH3, imidazole). – MS (EI,
CH2CH3), 1.14 (t, 3H, CH2CH3). – 13C NMR (62.9 MHz,
CDCl3): δ = 160.9 (CHO), 145.2 (C-2), 137.9 (C-4), 135.4
(C-5), 129.3, 128.4, 127.1, 123.7 (ar.), 49.6, 48.7, 46.3,
45.7 (4 C, piperazine), 40.2 (CH2Ph), 21.1 (CH2CH3), 11.4
(CH2CH3). – MS (EI, 70 eV): m/z (%) = 343 (75) [M+].
– C17H21N5O3(343.38): calcd. C 59.46, H 6.16, N 20.40;
found C 59.15, H, 6.08, N 12.75.
70 eV): m/z (%) = 260 (70) [M+]. – C16H18N6O2 (326.35):
calcd. C 58.88, H 5.56, N 25.75; found C 58.55, H 5.43,
N 25.53.
5,6,7,8-Tetrahydro-2-[4-((2-methyl-4-nitro-1H-imidazol-
1-yl-)methyl)phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (20)
This compound was prepared from 15 (0.13 g, 1.0 mmol)
and 11 (0.25 g, 1.0 mmol), by following the same p◦roce-
dure as for 8. Yield: 0.13 g (38 %). M. p. 148 – 150 C. –
1H NMR (250 MHz, CDCl3): δ = 8.16 (d, 2H, J = 8.2,
ArH), 7.71 (s, 1H, 5-H), 7.22 (d, 2H, J = 8.2, ArH), 7.32
(d, 2H, J = 8.2 Hz, ArH), 5.15 (s, 2H, CH2Ph), 4.25 (m,
2H, 5’-H2-triazole), 3.06 (m, 8’-H2, triazole), 2.41 (s, 3H,
2-Me, imidazole), 2.07 (m, 2H, 7’-H2, triazole), 2.03 (m,
2H, 6’-H2, triazole). – 13C NMR (62.9 MHz, CDCl3): δ =
160.1 (C-2’, triazole), 158.0 (C-9’, triazole), 145.0 (C-2,
imidazole), 138.0 (C-4, imidazole), 136.1 (C-Ar), 131.2
(C-5, imidazole), 127.6, 120.0 (5 C-Ar), 50.7 (CH2Ph), 47.5
(5’-CH2-5’, triazole), 29.7 (CH2-8’, triazole), 22.9 (CH2-7’,
triazole), 19.7 (CH2-6’, triazole), 13.3 (5’-Me, triazole). –
MS (EI, 70 eV): m/z (%) = 338 (85) [M+]. – C17H18N6O2
(338.36): calcd. C 60.34, H 5.36, N 24.84; found C 60.16,
H 5.19, N 24.49.
2-(2-Methyl-4-nitro-1H-imidazol-1-yl)benzoxazole (16)
To a solution of 15 (0.13 g, 1.0 mmol) in DMF (15 mL)
containing NaH (1.0 mmol) was added a solution of 6
(0.15 g, 1.0 mmol)◦in DMF (5 mL) and the mixture was
stirred at 120 – 130 C for 12 h. After cooling, the reaction
mixture was worked up as described for 8. Yield: 0.10 g
◦
(41 %). M. p. 182 – 184 C. – 1H NMR (250 MHz, CDCl3):
δ = 8.92 (s, 1H, 5-H), 7.87 – 7.83 (m, 3H, ArH), 7.51 – 7.48
(m, 2H, ArH), 2.79 (s, 3H, 2-CH3). – 13C NMR (62.9 MHz,
CDCl3): δ = 151.5 (C-2’), 149.1 (C-3a’), 146.8 (C-2), 146.5
(C-7a’), 140.3 (C-4), 126.2 (C-5), 126.2, 120.4, 120.2, 111.6
(ar.), 16.1 (2-CH3). – MS (EI, 70 eV): m/z (%) = 241
(68) [M+]. – C11H8N4O3 (244.21): calcd. C 54.10, H 3.30,
N 22.94; found C 53.93, H 3.18, N 22.67.
2-(2-Methyl-4-nitro-1H-imidazol-1-yl)benzothiazole (17)
6,7,8,9-Tetrahydro-2-[4-((2-methyl-4-nitro-1H-imidazol-1-
This compound was prepared from 15 (0.13 g, 1.0 mmol)
and 7 (0.17 g, 1.0 mmol), by following the same procedure as
for 16. Yield: 0.12 g (46 %). M. p. 220 – 222 ◦C. – 1H NMR
(250 MHz, CDCl3): δ = 8.26 (s, 1H, 5-H), 8.26 – 8.09 (m,
3H, ArH), 7.65 – 7.53 (m, 2H, ArH), 2.71 (s, 3H, 2-CH3).
yl-)methyl)phenyl]-5H-[1,2,4]-triazolo[1,5-a]azepine (21)
This compound was prepared from 15 (0.13 g, 1.0 mmol)
and 18 (0.13 g, 1.0 mmol), by following the same procedure
as for 8. Yield: 0.14 g, (40 %). M. p. 208 – 210 ◦C. – 1H NMR
(600 MHz, HMBC, CDCl3): δ = 8.46 (s, 1H, H-5), 7.95
(d, 2H, J = 8.1 Hz, ArH), 7.31 (d, 2H, J = 8.1 Hz, ArH),
5.32 (s, 2H, CH2Ph), 4.28 (m, 2H, 5’-H2-triazole), 2.94 (m,
2H, 9’-H2, triazole), 2.28 (s, 3H, 2-Me, imidazole), 1.84
(m, 2H, 6’-H2, triazole), 1.74 (m, 2H, 8’-H2, triazole), 1.64
(m, 2H, 7’-H2, triazole). – 13C NMR (150.0 MHz, CDCl3):
δ = 158.5 (C-2’, triazole), 158.1 (C-10’, triazole), 145.6
(C-2, imidazole), 136.4 (C-4, imidazole), 133.3 (C-Ar),
131.5 (C-5, imidazole), 128.2, 126.4, 123.0 (5 C-Ar), 51.0
(C-10’, triazole), 50.0 (CH2Ph), 47.5 (CH2-5’, triazole), 29.9
(CH2-7’, triazole), 27.6 (CH2-9’, triazole), 27.0 (CH2-8’,
triazole), 25.0 (CH2-6’, triazole), 13.3 (5’-Me, triazole). –
MS (EI, 70 eV): m/z (%) = 352 (70) [M+]. – C18H20N6O2
(352.39): calcd. C 61.35; H 5.72; N 23.85; found C 61.08,
H 5.63, N 23.57.
–
13C NMR (62.9 MHz, CDCl3): δ = 156.1 (C-2’), 149.9
(C-7a’), 146.0 (C-3a’), 146.0 (C-2), 134.2 (C-4), 127.8 (C-5),
126.9, 123.5, 123.2, 121.8 (ar.), 15.8 (2-CH3). – MS: m/z =
260 (M+). – C11H8N4O2S (260.27): calcd. C 50.76, H 3.10,
N 21.53; found C 50.54, H 2.98, N 21.42.
1-Ethyl-5-methyl-3-[((2-methyl-4-nitro-1H-imidazol-1-
yl)methyl)phenyl]-1H-1,2,4-triazole (19)
This compound was prepared from 15 (0.13 g, 1.0 mmol)
and 10 (0.24 g, 1.0 mmol), by following the same proce-
dure as for 8. Yield: 0.09 g (27 %). M. p. 166 – 168 ◦C.
–
1H NMR (250 MHz, CDCl3): δ = 8.46 (s, 1H, 5-H),
7.96 (d, 2H, J = 8.0 Hz, ArH), 7.32 (d, 2H, J = 8.0 Hz,
ArH), 5.33 (s, 2H, CH2Ph), 4.15 (q, 2H, J = 7.4 Hz,
CH2CH3), 2.44 (s, 3H, 2-Me, imidazole), 2.29 (s, 3H,
5’-Me, triazole), 1.36 (t, 3H, CH2CH3). – 13C NMR
(62.9 MHz, CDCl3): δ = 159.2 (C-3’, triazole), 153.0 (C-5’,
triazole), 145.6 (C-2, imidazole), 136.5 (C-4, imidazole),
136.4 (C-Ar); 131.5 (C-5, imidazole), 128.1, 126.4, 123.1
(5xC-Ar), 49.9 (CH2Ph), 43.2 (CH2CH3), 15.3 (CH2CH3),
Acknowledgements
Dr. Al-Soud would like to thank DAAD, Germany, for
supporting this project. Mr. Muhannad Musad of Al al-Bayt
University, Jordan, is greatfully acknowledged for the NMR
measurements.
Unauthenticated
Download Date | 2/3/16 6:20 AM

528
[1] E. Winkelmann, W. Raether, A. Sinharay, Arzneim.-
Y. A. Al-Soud et al. · Nitroimidazoles, Part 3
E. V. Aleksandrova, Chem. Heterocycl. Compd. 1998,
34, 1142.
Forsch./Drug Res. 1978, 28, 351.
[2] M. R. Grimmett, in Comprehensive Heterocyclic
Chemistry, Vol. 4, (Eds.: A. R. Katritzky, C. W. Rees),
Pergamon Press, Oxford, 1984, p. 498.
[3] G. E. Adams, E. D. Clarke, I. R. Flockhart, R. S. Ja-
cobs, D. S. Sehmi, I. J. Stratford, P. Wardman, M. E.
Watts, J. Parrick, R. G. Wallace, C. E. Smithen, Int. J.
Radiat. Biol. 1979, 35, 133.
[4] J. Morgenstern, R. Otto, S. Scheithaner, Germ. (East)
DD 260,062; Chem. Abstr. 1989, 110, 231634r.
[5] A. Breccia, R. Cavalleri in Nitroimidizoles: Chemistry,
Pharmacology and Clinical Application, Vol. 42 (Ed.:
G. E. Adams), Plenum Press, New York, 1982.
[6] J. L. Skibba, D. D. Beal, K. K. Whitnable, Cancer Res.
1970, 30, 147.
[7] J. E. Biskupiak, J. R. Grierson, J. S. Rasey, G. V. Mar-
tin, K. A. Krohn, J. Med. Chem. 1991, 34, 2165.
[8] J. Bartroli, M. Alguero, E. Boncompte, J. Forn,
Arzneim.-Forsch. 1992, 42, 832.
[9] I. Saji, K. Tamoto, H. Yamazaki, H. Aqui, Heterocycles
1981, 15, 943.
[10] C. Cosar, L. Julou, Ann. Inst. Pasteur Paris 1959, 96,
238.
[11] T. Fujiwara, A. Sato, M. El-Farrash, S. Miki,
K. Kabe, Y. Isaka, M. Kodama, Y. M. Wu, L. B. Chen,
H. Harada, H. Sugimoto, M. Hatanaka, Y. Hinuma, An-
timicrob. Agents Chemother. 1998, 42, 1340.
[12] P. M. Kochergin, L. A. Reznichenko, R. N. Girava,
[13] S. Kulkarni, M. R. Grimmett, L. R. Hanton, J. Simpson,
Aust. J. Chem. 1987, 40, 1399.
[14] A. K. S. B. Rao, C. G. Rao, B. B. Sigh, Synth. Commun.
1994, 24, 341.
[15] I. Wolska, T. Borowiak, S. Sobiak, Pol. J. Chem. 1994,
68, 1831.
[16] S. Sobiak, Pol. J. Chem. 1998, 72, 78.
[17] L. Zaprutko, M. Gajdzinski, W. Michalska, K. Pit Kil-
wicz, K. Lutomski, Z. Lukaszewski, U. Wrzeciono,
Pharmazie 1989, 44, 817.
[18] A. K. S. B. Rao, C. G. Rao, B. B. Singh, J. Org. Chem.
1992, 57, 3240.
[19] N. A. Al-Masoudi, Y. A. Al-Soud, A. Kalogerakis,
E. De Clercq, C. Paneccoque, Chem. Biodiver. 2006,
3, 515.
[20] Y. A. Al-Soud, N. A. Al-Masoudi, Synth. Commun.
2005, 35, 2258.
[21] Y. A. Al-Soud, R. F. Hala, N. A. Al-Masoudi, OPPI
2002, 34, 658.
[22] W. Willker, D. Leibfritz, W. Kerssbaum, W. Bermel,
Mag. Reson. Chem. 1993, 31, 287.
[23] S. D. Young, S. F. Britcher, L. O. Tran, L. S. Payne,
W. C. Lumma, T. A. Lyle, J. R. Huff, P. S. Anderson,
D. B. Olsen, S. S. Carroll, D. J. Pettibone, J. A. Obrien,
R. G. Ball, S. K. Balani, J. H. Lin, I. W. Chen, W. A.
Schleif, V. V. Sardana, W. J. Long, V. W. Byrnes, E. A.
Emini, Antimicrob. Agents Chemother. 1995, 39, 2602.
Unauthenticated
Download Date | 2/3/16 6:20 AM