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Arch. Pharm. Chem. Life Sci. 2010, 343, 397 – 403 N. S. Hamad et al. 397
Full Paper
Amino Acid Derivatives, Part 4: Synthesis and Anti-HIV Activity
of New Naphthalene Derivatives
Nawar S. Hamad1, Nahed H. Al-Haidery1, Iman A. Al-Masoudi2, Mey Sabri1, Luma Sabri1, and
Najim A. Al-Masoudi1
1Chemistry Department, College of Science, University of Basrah, Iraq
2College of Veterinary, University of Basrah, Basrah, Iraq
A new series of 2-(naphthalen-2-yloxy)-N-[(aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]
acetamides 5a–f was synthesized from naphthalene-derived glycine derivative 2via the hydrazi-
noacetamide analogs 4a–f. Alternatively, treatment of 4a with H2SO4afforded 2-(naphthalen-2-
yloxy)-N-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl) acetamide 6a. Alkylation or sulphonyla-
tion of 5a afforded the S-alkylated derivatives 7and 8, respectively. Interestingly, treatment of 3
with methoxide ion gave the triazine derivative 9. The synthesized compounds have been
screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. However, 7was
found to be the potent inhibitor in vitro for the replication of HIV-1 (EC50 = 0.20 lg/mL), suggest-
ing a new lead in the development of an antiviral agent.
Keywords: Amino acid derivatives / Anti-HIV activity / 2-Mercapto-1,2,4-triazole / Naphthalene / 1,3,4-Thiadiazole /
Received: November 29, 2009; Accepted: January 15, 2010
DOI 10.1002/ardp.200900293
Introduction
The global spread and fatal prognosis of human immuno-
deficiency virus (HIV) infection emphasize the urgent
need for effective antiretroviral therapies. The introduc-
tion of highly active antiretroviral therapy (HAART)
involving the use of drug combinations to treat AIDS, has
had a dramatic impact on the morbidity and mortality of
individuals infected by the HIV [1–3]. Kaletra, the first sec-
ond-generation protease inhibitor to reach drug status, is
a mixture of two protease inhibitors, lopinavir 1, [4, 5]
and ritonavir [6]. Lopinavir, which constitutes a peptide
backbone, was originally designed to diminish the inter-
actions of inhibitor with Val82 HIV-1 PR, a residue that is
often mutated in the drug-resistant strains of the virus
[3]. On the other hand, a new target for the development
of anti-HIV and antitumor therapies has been reported by
the use, in vivo and in vitro, of amino acid-derived hetero-
cycles. Such compounds are the lysyl amide prodrug of
2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole [7],
amino acid derivatives of paclitaxol [8], cysteine-modify-
ing agents [9], and isoquinoline carboxylic acid deriv-
atives as building blocks for HIV protease inhibitors [10].
It has been reported that certain compounds bearing a
thiadiazole and 1,2,4-triazole nucleus possess significant
anti-inflammatory activity [11–15]. In addition, it was
mentioned that [1,3,4]thiadiazoles exhibited various bio-
logical activities possibly due to the presence of the =N-C-
Correspondence: Najim A. Al-Masoudi, Chemistry Department, College
of Science, University of Basrah, Iraq.
E-mail: najim.al-masoudi@gmx.de
Fax: +964 770 570-0509 and +49 7531 34435
Abbreviation: Heteronuclear Multiple Bond Coherence (HMBC)
i2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. Structure of Lopinavir.
398 N. S. Hamad et al. Arch. Pharm. Chem. Life Sci. 2010, 343, 397– 403
S moiety [16]. In connection with our strategy in the syn-
thesis of new amino acid derivatives [17–19], we report
here the synthesis of new 1,2,4-triazolo-naphthalene and
thiadiazole derivatives derived from amino acid ana-
logues, and the evaluation of their anti-HIV activity.
Results and discussion
Chemistry
The amino acid derivative 2[19] has been selected as start-
ing material in our synthetic approach for the prepara-
tion of our potential target molecules. Thus, treatment of
2with hydrated hydrazine afforded the hydrazide 3[19].
Treatment of 3with aryl isothiocyanate in the presence
of Et3N afforded the carbamothioyl derivatives 4a–f in
75–86% yield. The 2-mercapto-1,2,4-triazole derivatives
5a–f were prepared in 65–73% yield via cyclization of 4a–
fin 4 N NaOH.
The structures of the newly synthesized compounds
were assigned by the NMR and mass spectra. The 1H-NMR
spectra of 4a–f showed common patterns for the aro-
matic protons appearing in the region d= 8.03–6.40 ppm.
The methylene groups (OCH2-) were found in the region d
= 4.51–4.60 ppm, while the NCH2group appeared as dou-
blet in the region d= 4.00–4.12 ppm (JCH, NH = 5.2 Hz). In
the13C-NMR spectra of 4a–f, the CH2O carbon appeared in
the region d= 67.2–66.4 ppm, whereas CH2N carbons res-
onated in the region d= 45.3–44.5 ppm. The higher-field
resonances in the region d= 168.4 to 169.9 ppm were
attributed to carbonyl C (C=O). Resonances in the region
d= 183.2–180.1 ppm could be assigned to the C=S carbons
of 4a–f, respectively. The carbons of the aromatic, naph-
thalene, and NHPh groups were assigned as well.
The1H-NMR spectra of 5a–f showed similar patterns for
the naphthalene and aromatic protons. The singlets at d
= 4.57–4.51 ppm were attributed to the OCH2protons,
while the doublets at d= 3.63–3.51 ppm were assigned to
the NCH2protons. In the 13C-NMR spectra of 5a–e, the res-
onance at d= 166.5, 166.4, 166.2, 166.5, and 166.1 ppm
were assigned to C=S, respectively. Compound 5f showed
a resonance at d= 162.0 ppm, which was attributed to the
C-SH rather than the C=S group (the latter group was
expected to appear at d= 180 ppm, due to the deshielding
of the benzyl group at N1triazol). C=N (C3triazol) resonated in
the region d= 156.9–156.5 ppm. Compound 5e was
selected for further NMR study, where HMBC (Heteronu-
clear Multiple Bond Coherence) spectrum [20] revealed a
2JC,H coupling between CH2O protons at d= 4.60 ppm and
C11=O at d= 168.4 ppm. Additionally, a 3JC,H coupling
between CH2O protons and C-2 at d= 155.2 ppm was
observed. Further, a 2JC,H coupling between C-13 at d=
46.9 ppm and C=N (C3triazol)atd= 156.6 ppm was assigned.
The structure of 5e was further confirmed by the gra-
dient selected 1H, 13C-HSQC spectrum in CDCl3by cou-
pling assignment between CH2-10, CH2-13 at d= 4.57 ppm
and d= 3.63 ppm, respectively, and OCH2, NCH2at d=
66.8 ppm and d= 46.9 ppm, respectively.
Next, the hydrazide 4a has been selected for further
treatment leading to a new cyclized product. Thus, reac-
tion of 4a with cold H2SO4led to the cyclization of the phe-
nylcarbamothioyl)hydrazinyl group, furnishing the thia-
i2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com
Scheme 1. Synthesis of compounds 4a–f,5a–f, and 6a.
Arch. Pharm. Chem. Life Sci. 2010, 343, 397 – 403 Synthesis and Anti-HIV Activity of Naphthalene Derivatives 399
diazole derivative 6a (62%). The structure of 6a was
assigned from the NMR and mass spectra. In the 13C-NMR
spectrum, C2thiadiazol resonated at higher field (d= 167.5
ppm) in comparison to C3triazol of 5a (d= 156.6 ppm). In addi-
tion, C5thiadiazol appeared at d= 151.6 ppm, while C5=S reson-
ated at a higher field (d= 166.4 ppm). Furthermore, the
HMBC-NMR spectrum revealed a 2JC,H coupling between
CH2-13 at d= 4.37 ppm and C2thiadiazol at d= 167.5 ppm.
Other models of a potential amide derivatives bearing
a substituted mercapto-1,2,4-triazole precursor was pre-
pared. Thus, treatment of 5a with 2-chloromethylbenz-
imidazole or p-toluenesulphonyl chloride in the presence
of base afforded, after purification, 7and 8in 72 and 70%
yield, respectively (Scheme 2). The structures of 7and 8
were confirmed by 1H-, 13C-NMR, and mass spectra. 1H-
NMR spectra of both compounds showed a similar NMR
pattern of 5a. In the 13C-NMR spectrum of 7, the reso-
nance at d= 140.4 ppm was assigned to C-2 of benzimid-
azole, while CH2S and C-13 resonated at d= 33.7 and d=
30.9 ppm, respectively. Similarly, carbons of 8as well as
the naphthalene and aromatic carbons were fully ana-
lyzed.
Interestingly, products tentatively identified as 3-
((naphthalene-2-yloxy)methyl)-4,5-dihydro-1,2,4-triazin-6-
one 9(67%) could be isolated from treatment of the
hydrazide derivative 3with the methoxide ion at 238C,
(Scheme 3). The structure of 9was assigned by the NMR
and mass spectra. In the 13C-NMR spectra of 8, the reso-
nances at the region d= 160.1 ppm was attributed to the
C6triazin=O group, while the signal at d= 154.1 ppm was
assigned to C2triazin (C=N). The HMBC-NMR spectrum of 9
showed a 2JC,H between CH2-10 protons at d= 3.98 ppm
and C=N at d= 154.1 ppm. CH2of the triazine ring
appeared at d= 41.5 ppm, while OCH2resonated at d=
73.0 ppm. The carbons of naphthalene were also
assigned.
In-vitro anti-HIV assay
Compounds 4a–f,5a–f, and 6a–9 were tested for their in-
vitro anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain ROD)
activity and monitored by the inhibition of the virus-
induced cytopathic effect in the human T-lymphocyte
(MT-4) cells, based on MTT assay [21]. The results are sum-
marized in Table 1, efavirenz [22] and capravirine [23] are
included for comparison. All the compounds are inactive
except for 6a and 7which showed EC50 values of 0.96
lg/mL and 0.20 lg/mL, respectively. The above data
showed no selective anti-HIV activity, although 5b
showed inhibitory activity against HIV-1 and HIV-2 with
EC50 value (>15.2 and 25.2 lg/mL, respectively), but with
low selectivity (SI = 3.5 and 2.1, respectively).
In conclusion, the structure-activity relationship (SAR)
suggested that the substitution of naphthalene bearing
amino acid precursors carrying various potential thiadi-
azole blocking group showed higher activity than those
of the corresponding substituted derivatives bearing
1,2,4-triazole derivatives. However, the anti-HIV activity
and the selectivity of these compounds are too limited to
perform extensive mode-of-action studies, but 7might be
considered as a new lead in the development of antiviral
agents as non-nucleoside reverse transcriptase inhibi-
tors.
i2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com
Scheme 2. Synthesis of compounds 7and 8.
Scheme 3. Synthesis of compound 9.
400 N. S. Hamad et al. Arch. Pharm. Chem. Life Sci. 2010, 343, 397– 403
Experimental
General
Melting points are uncorrected. NMR spectra were recorded at
250 and 600 MHz (1H), and 50.91 MHz (13C) with TMS as internal
standard on a dscale in ppm. EI and FAB mass spectra were meas-
ured on MAT8200 mass spectrometer (Finnigan) using 3-nitro-
phenol or glycerol as matrix.
Chemistry
2-Naphthalen-2-yloxy-acetic acid hydrazide 3
This compound was prepared according to the literature [19]
from methyl 2-naphthalen-2-yloxy-acetic acid ester 2and hydra-
zine hydrate.
General procedure for the synthesis of 2-
(naphthalenyloxy)-N-[2-oxo-2-
(arylcarbamothioyl)hydrazinyl)ethyl]acetamides 4a–f
To a solution of 3(270 mg, 1.0 mmol) in EtOH (10 mL), triethyl-
amine (0.51 g, 5.0 eq.) was added and cooled to 08C. The respec-
tive aryl isothiocyanate (1.0 mmol) was added in the cold and
stirred at room temperature for 5–6 h (completion of reaction
was confirmed by TLC). Water was added and the product
extracted twice using dichloromethane. The combined organic
layers were washed with brine and dried (Na2SO4), filtered, and
concentrated to give a solid product which was filtered and
recrystallized from EtOH affording 4a–f as white crystals.
2-(Naphthalenyloxy)-N-[2-oxo-2-
(phenylcarbamothioyl)hydrazinyl)ethyl]acetamide 4a
From phenylisothiocyanate (135 mg). Yield: 351 mg (86%), m. p.:
222–2268C; 1H-NMR (CDCl3)d: 7.85–6.83 (m, 12H, Ar-H), 4.60 (s,
2H, CH2-10), 4.10 (d, 2H, J= 5.5 Hz, CH2-14); 13C-NMR (CDCl3)d:
180.8 (C=S), 170.1 (C14=O), 168.4 (C11=O), 155.3 (C-2), 134.3, 129.4,
129.1, 128.1, 127.6, 126.7, 126.5, 124.4 (Ar-C), 118.1 (C3naphth.),
107.7 (C1naphth), 67.2 (C-10), 44.9. (C-13); MS m/z(FAB): 409 [M + H].
Anal. calcd. for C21H20N4O3S (408.47): C, 61.75; H, 4.94; N, 13.72.
Found: C, 61.55; H, 4.88; N, 13.52.
2-(Naphthalen-2-yloxy)-N-[2-oxo-2-(4-methylphenyl-
carbamothioyl)hydrazinyl)ethyl]acetamide 4b
From 4-methylbenzeneisothiocyanate (149 mg). Yield: 346 mg
(82%), m.p.: 197–2018C; 1H-NMR (CDCl3)d: 7.87–6.40 (m, 11H, Ar-
H), 4.58 (s, 2H, CH2-10), 4.11 (d, 2H, J= 5.5 Hz, CH2-13), 2.35 (s, 3H,
p-MePh); 13C-NMR (CDCl3)d: 181.1 (C=S), 170.3 (C14=O), 168.6
(C11=O), 155.5 (C-2), 137.0, 134.9, 129.4, 129.1, 128.0, 127.4, 126.3,
126.1, 125.0 (Ar-C), 118.0 (C1naphth.), 107.9 (C1naphth), 67.0 (C-10),
44.5. (C-13), 21.1 (p-MePh); MS m/z(FAB): 423 [M + H]. Anal. calcd.
for C22H22N4O3S (422.50): C, 62.54; H, 5.25; N, 13.26. Found: C,
62.29; H, 5.20; N, 12.94.
N-[2-(2-(4-Methoxyphenylcarbamothioyl)hydrazinyl)-2-
oxoethyl]-2-(naphthalene-2-yloxy) acetamide 4c
From 4-methoxybenzeneisothiocyanate (165 mg). Yield: 341 mg
(78%), m.p.: 178–1808C; 1H-NMR (CDCl3)d: 7.85–6.81 (m, 11H, Ar-
H), 4.55 (s, 2H, CH2-10), 4.10 (d, 2H, J= 5.3 Hz, CH2-13), 3.78 (s, 3H,
p-OMePh); 13C-NMR (CDCl3)d: 181.0 (C=S), 169.9 (C14=O), 168.7
(C11=O), 158.9 (C-OMePh), 155.7 (C-2), 129.8, 129.4, 128.0, 127.5,
126.5, 124.1, 125.0 (Ar-C), 118.0 (C3naphth), 113.6 (C3,5
OMe-Ph
), 107.3
(C1naphth), 66.4 (C-10), 55.2 (OMe-Ph), 44.8 (C-13); MS m/z(FAB): 439
[M + H]+. Anal. calcd. for C22H22N4O4S (438.50): C, 60.26; H, 5.05; N,
12.78. Found: C, 60.01; H, 4.97; N, 12.53.
N-[2-(2-(4-Bromophenylcarbamothioyl)hydrazinyl)-2-
oxoethyl]-2-(naphthalene-2-yloxy) acetamide 4d
From 4-bromophenylisothiocyanate (214 mg). Yield: 394 mg
(81%), m.p.: 230–2338C; 1H-NMR (CDCl3)d: 7.82–6.79 (m, 11H, Ar-
H), 4.57 (s, 2H, CH2-10), 4.05 (d, 2H, J= 5.2 Hz, CH2-13); 13C-NMR
(CDCl3)d: 181.3 (C=S), 170.0 (C14=O), 168.7 (C11=O), 155.6 (C-2),
137.3, 131.5, 129.6, 129.3, 127.8, 126.8, 124.3, 122.5 (Ar-C), 118.6
(C3naphth.), 105.9 (C1naphth), 66.8 (C-10), 45.6 (C-13); MS m/z(FAB): 488/
490 [M + H]+. Anal. calcd. for C21H19BrN4O3S (487.37): C, 51.75; H,
3.93; N, 11.50. Found: C, 51.43; H, 3.81; N, 11.39.
i2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com
Table 1. In-vitro anti-HIV-1§and HIV-2&of some new naphtha-
lene derivatives.
Com-
pound
Virus
strain
EC50
(lg/mL)
#
CC50
(lg/mL)
{
SI
p
4a III
B
>67.9 F67.9 a1
ROD >69.9 F69.9 a1
4b III
B
>91.4 91.4 € 14.4 a1
ROD >91.4 91.4 € 14.4 a1
4c III
B
>13.2 13.2 € 0.20 a1
ROD >13.2 13.2 € 0.20 a1
4d III
B
>31.2 31.2 € 2.23 a1
ROD >31.2 31.2 € 2.23 a1
4e III
B
>11.2 11.2 € 1.23 a1
ROD >11.2 11.2 € 1.23 a1
4f III
B
>67.0 F67.0 a1
ROD >67.0 F367.0 a1
5a III
B
>20.2 20.2 a1
ROD >20.2 20.2 a1
5b III
B
>15.2 53.2 € 2.1 3.5
ROD >25.2 53.2 € 2.1 2.1
5c III
B
>46.2 F46.2 a1
ROD >46.2 F46.2 a1
5d III
B
F10.2 10.2 a1
ROD F10.2 10.2 a1
5e III
B
>20.2 20.2 a1
ROD >20.2 20.2 a1
5f III
B
>28.5 28.5 a1
ROD >28.5 28.5 a1
6a III
B
>0.96 0.96 a1
ROD >2.92 2.92 a1
7III
B
>0.20 0.20 a1
ROD >2.2 2.2 a1
8III
B
ROD
>12.7
>12.7
12.7
>12.7
a1
a1
9III
B
ROD
>5.20
>5.20
5.20
5.20
a1
a1
Efavirenz III
B
0.003 40 13 333
Capravirine III
B
0.0014 11 7857
§ Anti-HIV-1 activity measured with strain IIIB; & Anti-HIV-2
activity measured with the strain ROD; # compound concentra-
tion required to achieve 50% protection of MT-4 cells from the
HIV-1- and -2-induced cytopathogenic effect; {compound con-
centration that reduces the viability of mock-infected MT-4 cells
by 50%; {SI: selectivity index (CC50/EC50).
Arch. Pharm. Chem. Life Sci. 2010, 343, 397 – 403 Synthesis and Anti-HIV Activity of Naphthalene Derivatives 401
N-[(4-(4-Chlorophenyl))-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl)methyl]-2-naphthalen-2-yloxy]acetamide 4e
From 4-chlorophenylisothiocyanate (170 mg). Yield: 336 mg
(76%), m.p.: 215–2188C; 1H-NMR (CDCl3)d: 7.98–7.21 (m, 9H, Ar-
H), 6.53 (d, 2H, J= 7.0 Hz, p-Cl-Ar-H), 4.51 (s, 2H, CH2-10), 4.00 (s,
2H, CH2-13); 13C-NMR (CDCl3)d: 180.1 (C=S), 169.8 (C14=O), 168.5
(C11=O), 155.2 (C-2), 135.7, 133.3, 131.2, 129.5, 129.1, 127.5, 126.6,
126.1, 123.8 (Ar-C), 118.5 (C3naphth.), 105.5 (C1naphth), 66.5 (C-10),
45.1 (C-13); MS m/z(FAB): 442/444 [M + H]+. Anal. calcd. for
C21H19ClN4O3S (442.92): C, 56.95; H, 4.32; N, 12.65. Found: C,
56.71; H, 4.27; N, 12.59.
N-[2-(2-(4-Benzylcarbamothioyl)hydrazinyl)-2-oxoethyl]-
2-(naphthalene-2-yloxy)acetamide 4f
From benzylisothiocyanate (225 mg). Yield: 316 mg (75%), m. p.:
169–1718C; 1H-NMR (CDCl3)d: 8.03–7.19 (m, 12H, Ar-H), 4.69 (s,
2H, CH2Ph), 4.58 (s, 2H, CH2-10), 4.05 (d, 2H, J= 5.2 Hz, CH2-13);
13C-NMR (CDCl3)d: 183.2 (C=S), 170.2 (C14=O), 168.8 (C11=O), 155.4
(C-2), 134.3, 129.4, 129.1, 128.1, 127.6, 126.7, 126.5, 124.4 (Ar-C),
118.1 (C3naphth.), 107.7 (C1naphth), 66.8 (C-10), 50.3 (CH2Ph), 45.3 (C-
13); MS m/z(FAB): 423 [M + H]+. Anal. calcd. for C22H22N4O3S
(422.50): C, 62.54; H, 5.25; N, 13.26. Found: C, 62.32; H, 5.19; N,
13.02.
General procedure for the synthesis of 2-(naphthalen-2-
yloxy)-N-[(aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl)methyl]acetamides 5a–f
A suspension of 4a–f (1.0 mmol) in EtOH (10 mL) was dissolved in
aq. 4 N NaOH (3 mL). The reaction mixture was gently refluxed
for 3 h, then concentrated to one third of its volume, cooled, fil-
tered, and the filtrate was adjusted to pH = 5–6 with dil. HOAc.
The white solid formed was filtered and recrystallized from
EtOH to give 5a–f.
2-(Naphthalen-2-yloxy)-N-[(4-phenyl-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-3-yl)methyl] acetamide 5a
From 4a (408 mg). Yield: 269 mg (69%), foam; 1H-NMR (CDCl3)d:
7.92–6.82 (m, 12H, Ar-H), 4.57 (s, 2H, CH2-10), 3.63 (s, 2H, CH2-13);
13C-NMR (CDCl3)d: 168.4 (C11=O), 166.5 (C=S), 156.6 (C3triazol), 155.2
(C-2), 133.5, 132.9, 129.4, 129.0, 128.2, 127.2, 126.6, 124.1 (Ar-C),
118.2 (C3naphth.), 105.9 (C1naphth), 66.8 (C-10), 46.9 (C-13); MS m/z
(FAB): 413 [M + Na]+. Anal. calcd. for C21H18N4O2S (390.46): C,
64.60; H, 4.65; N, 14.35. Found: C, 64.46; H, 4.58; N, 14.09.
2-(Naphthalen-2-yloxy)-N-[(5-thioxo-4-p-tolyl-4,5-
dihydro-1H-1,2,4-triazol-3-yl)methyl] acetamide 5b
From 4b (422 mg). Yield: 274 mg (65%), m. p.: 152–1558C;1H-NMR
(CDCl3)d: 8.01–6.10 (m, 11H, Ar-H), 4.53 (s, 2H, CH2-10), 3.55 (s,
2H, CH2-13); 13C-NMR (CDCl3)d: 168.6 (C11=O), 166.4 (C=S), 156.7
(C3triazol), 155.5 (C-2), 136.8, 133.1, 130.4, 129.5, 129.2. 128.0,
126.7, 124.0 (Ar-C), 118.5 (C3naphth.), 105.4 (C1naphth), 66.5 (C-10),
47.1 (C-13), 21.0 (MePh); MS m/z(FAB): 405 [M + H]+. Anal. calcd. for
C22H20N4O2S (404.48): C, 65.33; H, 4.98; N, 13.85. Found: C, 65.01;
H, 4.88; N, 13.62.
N-[(4-(4-Methoxyphenyl))-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl)methyl]-2-naphthalen-2-yloxy]acetamide 5c
From 4c (438 mg). Yield: 298 mg (71%), m.p.: 161–1638C; 1H-NMR
(CDCl3)d: 8.03–7.31 (m, 7H, Ar-H), 6.66 (d, 2H, J= 7.2 Hz, p-OMe-
Ar-H), 6.07 (d, 2H, J= 7.2 Hz, p-OMe-Ar-H), 4.51 (s, 2H, CH2-10), 3.53
(s, 2H, CH2-13); 13C-NMR (CDCl3)d: 168.5 (C11=O), 166.2 (C=S), 156.8
(C3triazol), 155.2 (C-2), 134.8, 129.5, 129.0, 127.5, 126.6, 126.2,
123.9, 122.5 (Ar-C), 118.6 (C3naphth.), 105.5 (C1naphth), 66.3 (C-10),
47.0 (C-13); MS m/z(FAB): 421 [M + H]+. Anal. calcd. for C22H20N4O3S
(420.48): C, 62.84; H, 4.79; N, 13.32. Found: C, 62.63; H, 4.68; N,
13.08.
N-[(4-(4-Bromophenyl))-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl)methyl]-2-naphthalen-2-yloxy]acetamide 5d
From 4d (487 mg). Yield: 259 mg (73%), m. p.: 179–1818C;1H-NMR
(CDCl3)d: 7.91–7.34 (m, 11H, Ar-H), 4.54 (s, 2H, CH2-10), 3.51 (s,
2H, CH2-13); 13C-NMR (CDCl3)d: 168.7 (C11=O), 166.5 (C=S), 158.8
(C-OMePh), 156.9 (C3triazol), 155.5 (C-2), 133.3, 129.6, 129.3. 128.0,
126.5, 126.1, 123.8 (Ar-C), 118.6 (C3naphth.), 114.1 (C-Ar), 105.8
(C1naphth), 66.6 (C-10), 47.3 (C-13), 55.3 (OMePh); MS m/z(FAB): 468/
470 [M + H]+. Anal. calcd. for C21H17BrN4O2S (469.35): C, 53.74; H,
3.65; N, 11.94. Found: C, 53.52; H, 3.57; N, 11.75.
N-[(4-(4-Chlorophenyl))-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl)methyl]-2-naphthalen-2-yloxy]acetamide 5e
From 4e (443 mg). Yield: 297 mg (70%), m. p.: 159–1618C;1H-NMR
(CDCl3)d: 7.96–7.23 (m, 9H, Ar-H), 6.19 (d, 2H, J= 7.0 Hz, p-Cl-Ar-
H), 4.52 (s, 2H, CH2-10), 3.51 (s, 2H, CH2-13); 13C-NMR (CDCl3)d:
168.5 (C11=O), 166.1 (C=S), 156.5 (C3triazol), 155.2 (C-2), 133.5, 135.1,
131.2, 129.5, 129.1, 127.4, 126.2, 123.9 (Ar-C), 118.2 (C3naphth.),
105.2 (C1naphth), 66.1 (C-10), 47.0 (C-13); MS m/z(FAB): 423/425 [M +
H]+. Anal. calcd. for C21H17ClN4O2S (424.90): C, 59.36; H, 4.03; N,
13.19. Found: C, 59.04; H, 3.95; N, 12.93.
N-[(4-Benzyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl)methyl)-2-(naphthalen-2-yloxy)] acetamide 5f
From 4f (422 mg). Yield: 271 mg (67%), m. p.: 162–1658C;1H-NMR
(CDCl3)d: 7.91–7.21 (m, 12H, Ar-H), 5.42 (s, 2H, CH2Ph), 4.54 (s,
2H, CH2-10), 3.51 (s, 2H, CH2-13); 13C-NMR (CDCl3)d: 162.0 (C-SH),
168.5 (C11=O), 156.7 (C3triazol), 155.4 (C-2), 135.1, 129.6, 129.2.
128.5, 127.2, 126.8, 123.9 (Ar-C), 118.5 (C3naphth.), 105.5 (C1naphth),
66.3 (C-10), 50.1 (CH2Ph), 47.5 (C-13); MS m/z(FAB): 427 [M + Na]+.
Anal. calcd. for C22H20N4O2S (404.48): C, 65.33; H, 4.98; N, 13.85.
Found: C, 64.97; H, 4.87; N, 13.68.
2-(Naphthalen-2-yloxy)-N-((5-(phenylamino)-1,3,4-
thiadiazol-2-yl)methyl)acetamide 6a
The hydrazide 4a (408 mg, 1.0 mmol) was added gradually with
stirring to an ice-cold conc. H2SO4(5 mL) and the reaction mix-
ture was further stirred for 4 h in an ice bath. It was then poured
into crushed ice and the resulting solution was adjusted to pH =
7–8 with a solution of NH4OH. The solid formed was filtered and
recrystallized from EtOH to give 6a (253 mg, 62%), m.p.: 232–
2358C; 1H-NMR (CDCl3)d: 8.01–6.84 (m, 12H, Ar-H), 4.52 (s, 2H,
CH2-10), 4.37 (s, 2H, CH2-13); 13C-NMR (CDCl3)d: 168.7 (C11=O),
167.5 (C2thiadiazol), 155.6 (C-2), 151.7 (C5thiadiazol), 139.7 (C1-NHAr),
129.8, 129.5. 127.5, 127.1, 122.4 (Ar-C), 118.6 (C3naphth.), 105.1
(C1naphth), 66.8 (C-10), 38.2 (C-13); MS m/z(FAB): 427 [M + Na]+. Anal.
calcd. for C22H20N4O2S (404.48): C, 65.33; H, 4.98; N, 13.85. Found:
C, 64.97; H, 4.87; N, 13.68.
i2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com
402 N. S. Hamad et al. Arch. Pharm. Chem. Life Sci. 2010, 343, 397– 403
N-((5-(Benzoimidazol-2-yl)methylthio)-4-phenyl-4H-
1,2,4-triazol-3-yl)methyl)-2-(naphthalen-2-
yloxy)acetamide 7
A mixture of 5a (390 mg, 1.08 mmol), 2-chloromethylbenzimid-
azole (1.0 mmol) and anhydr. K2CO3(210 mg, 1.5 mmol) in abs.
EtOH (30 mL) was stirred at 238C for 8 h. The mixture was filtered
and the filtrate was evaporated to dryness. The residue was
washed with water and recrystallized from EtOH to give 7(405
mg, 72%), m. p.: 228–2308C; 1H-NMR (CDCl3)d: 7.71–6.80 (m, 16H,
Ar-H), 4.64 (s, 2H, CH2-10), 4.29 (s, 2H, CH2-13), 4.09 (s, 2H, SCH2);
13C-NMR (CDCl3)d: 168.2 (C11=O), 155.0 (C-2), 150.5 (C3triazol), 148.4
(C5triazol), 140.2 (C2
benzimidazol
), 138.5, 134.5, 133.7, 132.9, 129.1,
130.1, 128.2, 127.8, 127.0, 126.1, 124.1 (Ar-C), 118.0 (C3naphth.),
105.6 (C1naphth), 67.0 (C-10), 33.7 (SCH2), 30.9 (C-13); MS m/z(FAB):
521 [M + H]+. Anal. calcd. for C29H24N6O2S (520.60): C, 66.90; H,
4.63; N, 15.14. Found: C, 65.78; H, 4.51; N, 15.89.
5-((2-Naphthalen-2-yloxy)acetamido)methyl-4-phenyl-
4H-1,2,4-triazol-3-yl-benzenesulphono thioate 8
To a solution of 5a (300 mg, 0.77 mmol) in pyridine (10 mL) was
added 4-toluenesulphonyl chloride (191 mg, 1.0 mmol) and the
solution was stirred at room temperature for 12 h. The reaction
mixture was poured into water and the precipitate formed was
filtered off and crystallized from MeOH to give 8(279 mg, 70%),
m.p.: 189–1928C; 1H-NMR (DMSO-d6)d: 8.07–7.17 (m, 17H, Ar-H),
4.71 (s, 2H, CH2-10), 4.37 (s, 2H, CH2-13); 13C-NMR (CDCl3)d: 168.9
(C11=O), 155.2 (C-2), 152.3 (C5triazol), 150.9 (C3triazol), 138.8 (CSO2ar),
134.7, 133.5, 129.9, 129.3, 128.7, 127.2, 126.5, 124.3 (Ar-C), 118.3
(C3naphth.), 105.7 (C1naphth), 67.8 (C-10), 31.3 (C-13); MS m/z(FAB): 518
[M + H]+. Anal. calcd. for C26H21N4O2S2(517.60): C, 60.33; H, 4.09;
N, 10.82. Found: C, 60.01; H, 3.98; N, 10.58.
3-((Naphthalene-2-yloxy)methyl)-4,5-dihydro-1,2,4-
triazin-6-one 9
A solution of 3(380 mg, 1.4 mmol) in 0.3 N NaOMe (10 mL) was
stirred at 238C for 24 h. After neutralization with HOAc, the sol-
ution was evaporated and the residue was partitioned between
CHCl3(2 6 20 mL) and water (20 mL). The combined organic
extracts were dried (Na2SO4), filtered, and evaporated to dryness.
The residue was poured onto a column of silica gel (10 g) using
MeOH (0–10%) and CHCl3as eluent (in a gradient) to give 9(240
mg, 67%), m.p.: 135–1378C; 1H-NMR (CDCl3)d: 10.21 (s, 1H, NH),
7.62–6.89 (m, 7H, Ar-H), 3.98 (s, 2H, CH2-10), 3.51 (s, 2H, CH2-triazin);
13C-NMR (CDCl3)d: 160.1 (C6triazin=O), 156.1 (C-2), 154.1 (C=N),
133.8, 129.6, 129.5, 126.7 (Ar-C), 118.5 (C3naphth.), 105.3 (C1naphth),
73.0 (C-10), 41.5 (C6triazin); MS m/z(FAB): 278 [M + Na]+. Anal. calcd.
for C14H13N3O2(255.1): C, 65.87; H, 5.13; N, 16.46. Found: C, 65.66;
H, 5.02; N, 16.21.
Anti-HIV assay
The compounds were tested for anti-HIV activity against replica-
tion of HIV-1 (III B) in MT-4 cells at varying concentrations from
100 nM by double dilution technique. The MT-4 cells were grown
in RPMI-1640 DM (Dutch modification) medium (Flow Lab,
Irvine, Scotland), supplemented with 10% (v/v) heat-inactivated
calf serum and 20 lg/mL gentamicin (E. Merck, Darmstadt, Ger-
many). HIV-1 (III B) was obtained from the culture supernatant of
HIV-1 infected MT-4 cell lines and the virus stocks were stored at
–708C until used. Anti-HIV assays were carried out in microtiter
plates filled with 100 lL of medium and 25 lL volumes of com-
pounds in triplicate so as to allow simultaneous evaluation of
their effects on HIV and mock infected cells. 50 lL of HIV at 100
CCID50 medium were added to either the HIV-infected or mock-
infected part of the microtiter tray. The cell cultures were incu-
bated at 378C in a humidified atmosphere of 5% CO2in air. Five
days after infection, the viability of mock and HIV-infected cells
was examined spectrophotometrically by the MTT method. The
EC50 (effective concentration of compound (nM) achieving 50%
protection in MT-4 cell lines against the cytopathic effect of HIV-
1), and CC50 (cytotoxic concentration of compound (lM) required
to reduce the viability of mock infected MT-4 cells by 50%) values
were calculated and reported.
We thank Prof. C. Pannecouque of Rega Institute for Medical Research,
Katholieke Universiteit Leuven, Belgium, for the anti-HIV screening.
Mr. U. Haunz of the Chemistry Department, University of Konstanz,
Germany, is acknowledged for the NMR experiments.
The authors have declared no conflict of interest.
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