Synthesis and anti-HIV activity of new chiral 1,2,4-triazoles and 1,3,4-thiadiazoles

Article abstract of DOI:10.1002/hc.20282

5-substituted 4-(4-chlorophenyl)-4H1,2,4-triazol-3-thiones 3 and 2-substituted 5-(4-chlorophenylamino)-1,3,4-thiadiazoles 4 were prepared from the intermediate thiosemicarbazides 2 under basic and acidic conditions, respectively. The thiosemicarbazides, i

Full text of DOI:10.1002/hc.20282

Heteroatom Chemistry
Volume 18, Number 3, 2007
Synthesis and Anti-HIV Activity of New Chiral
1,2,4-Triazoles and 1,3,4-Thiadiazoles
Tashfeen Akhtar,1 Shahid Hameed,1 Najim A. Al-Masoudi,2
and Khalid M. Khan3
1Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
2Formerly Fakulta¨t fu¨ r Chemie, Universita¨t Konstanz, Potfach 5560, D-78457 Konstanz, Germany
3HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
Received 30 May 2006
thiosemicarbazones were reported as specific an-
ABSTRACT: 5-substituted 4-(4-chlorophenyl)-4H-
tithyriod agents [1,2]; meanwhile some substi-
1,2,4-triazol-3-thiones
5-(4-chlorophenylamino)-1,3,4-thiadiazoles
3
and
2-substituted
were
tuted 1,3,4-thiadiazoles exhibited anticonvulsant
activity [3,4] and other pharmacological potency [5].
Other various 1,3,4-thiadiazole derivatives showed
remarkable potential biological activities such as an-
tibacterial [6], antimicrobial [7,8], and enzyme in-
hibition activities [9,10]. Although the synthesis of
these moieties is reported [6,11,12], the synthesis of
five membered chiral heterocycles is not well docu-
mented and only a few examples have been cited in
the literature [13,14].
Keeping in view that chiral drugs are highly se-
lective biological agents because of their reactivity
toward the specific enzymes, we report here the
synthesis of some chiral triazoles and thiadiazoles
derivatives with study of their HIV inhibitory activ-
ity, because of the specificity of such derivatives from
the chemical and bioactivity points of view.
4
prepared from the intermediate thiosemicarbazides 2
under basic and acidic conditions, respectively. The
thiosemicarbazides, in turn, were prepared by the
reaction of hydrazides 1 with 4-chlorophenylisothio-
cyanate in MeOH. Some of the new synthesized
compounds were assayed against HIV-1 and HIV-2 in
MT-4 cells. All the compounds were inactive except 3f,
which showed an EC50 value of 23.9 µg/mL and 9.9
µg/mL against HIV-1 and HIV-2 with a therapeutic
index of 3 and 7, respectively. It means that com-
pound 3f was cytotoxic to MT-4 cells at CC50 of 72.7
ꢀ
C
µg/mL in both strains.
2007 Wiley Periodicals, Inc.
Heteroatom Chem 18:316–322, 2007; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20282
INTRODUCTION
RESULTS AND DISCUSSION
Chemistry
Several heterocyles containing 1,2,4-triazoles and
1,3,4-thiadiazoles residues have been described
as potent chemotherapeutic agents. Recently, 3-
amino-, 3-nitro-, and 3-mercapto-1,2,4-triazoles as
well as 2,4-dihydro-3H-1,2,4-triazole-3-thiones and
The hydrazides 1, used in the synthesis of thiosemi-
carbazides, were prepared from L-amino acids, using
the sequence: N-tosylation [15], esterification, and
conversion to hydrazides on treatment with 80% hy-
drazine hydrate. The synthesized N-tosylamino acid
hydrazides 1a–h were treated with 4-chlorophenyl
isothiocyanate to yield thiosemicarbazides 2a–h,
Correspondence to: Shahid Hameed, Najim A. Al-Masoudi;
e-mail: shameed@qau.edu.pk, info@al-masoudi.de.
c
ꢀ
2007 Wiley Periodicals, Inc.
316

Synthesis and Anti-HIV Activity of New Chiral 1,2,4-Triazoles and 1,3,4-Thiadiazoles 317
SCHEME 1
which were used as key synthetic intermediates. IR
spectra of thiosemicarbazides exhibited characteris-
tic absorptions for C O and C S groups. H NMR
and mass spectral data were consistent with the
structure of the synthesized compounds.
signals. The polarimetric studies show that racem-
ization has not occurred during synthesis.
In the 13C NMR spectra of triazol-3-thiones of
type 5, the value close to δC 168 and δC 145–160 were
reported for C S (C-3) and C N (C-5), respectively
[16]. According to these data, 13C NMR shifts of δC
168.0–171.2 and δC 150.3–154.9 observed for com-
pounds 3a–g may be assigned to (C S) C-3 and C N
(C-5), respectively, of the thiadiazoles backbone as
shown in Scheme 1.
1
Cyclodehydration of the thiosemicarbazides
2a–h in basic medium leads to the 1,2,4-triazoles
3a–g, whereas acidic cyclodehydration gave 1,3,4-
thiadiazoles 4a–e,h. The synthesis of triazoles 3a–g
and thiadiazoles (4a–e,h) was indicated in their IR
spectra by the absence of carbonyl absorption. The
existence of triazoles (3a–g) in thione form was also
indicated in the IR spectra by the absence of SH
stretching in the characteristic region of 2550 cm−1
and presence of C S stretching in the region of
1200 cm−1. The 1H NMR spectrum of each com-
pound exhibited four doublets in the aromatic re-
gion, two for the 4-methylphenyl part and two for
4-chlorophenyl moiety in the compounds. The sig-
nal for NH of sulfonamide moiety was observed as
doublet in some cases and as a broad singlet in oth-
ers in the range of δ 6.74–8.34. The NH of the tri-
azole and thiadiaozle rings appeared deshielded as
expected in the range δ 12.61–13.87 and δ 8.14–10.13,
respectively. The signal for NH in case of triazoles
appearing downfield than δ 12.0, confirming the ex-
istence of the ring in thione form. The diastereotopic
effect of chiral center was also observed in the form
of complex splitting patterns for the nearby proton
In Vitro Anti-HIV Activity
Compounds 3a–f, 4a–e, and 4h 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 [17] and capravirine [18] were in-
cluded for comparison purposes. Compound 3f was
found to be the only compound from the series in-
hibiting HIV-1 replication in cell culture. Compound
3f showed an EC50 of 23.9 µg/mL against HIV-1
and 9.90 µg/mL against HIV-2 of CC50 of 72.7
1.4 µg/mL, resulting in selectivity index of 3 and 7,
respectively.
Based on the chemical structure and the fact that
compound 3f inhibits HIV-2, this molecule can be
proposed to act as a nonnucleoside reverse transcrip-
tase inhibitor.
Heteroatom Chemistry DOI 10.1002/hc

318 Akhtar et al.
TABLE 1 In Vitro Anti-HIV-1a and HIV-2b of Some New
added a solution of 4-chlorophenyl isothiocyanate
(5.9 mmol) in absolute MeOH (20 mL) stirring, and
the mixture was heated under reflux for 2–3 h. After
cooling, the resulting solid was filtered and recrys-
tallized from EtOH/water to give pure thiosemicar-
bazide 2.
Nitroimidazoles
Strain (µg/mL)c
(µg/mL)d
CC50
Virus
EC50
SIe
3a
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
IIIB
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>50.9 58.2 10.1
>48.1 58.2 10.1
>17.5 19.2 1.2
>19.4 19.2 1.2
>17.2 25.0 8.5
>18.1 25.0 8.5
<1
<1
<1
<1
<1
<1
≤ 1
<1
<1
<1
3
3b
1-[3-Methyl-2-(4-methylphenylsulfonamido)buta-
noyl]-4-(4-chlorophenyl)thiosemicarbazide
(2a).
3c
From 1a (1.59 g). Yield: 2.39 g (92%), mp 212–
3d
>105.0
>105.0
>66.0 74.3 8.6
>67.7 74.3 8.6
23.9 72.7 1.4
9.9 72.7 1.4
≥105.0
214◦C. IR (cm−1) νmax: 3461, 3379, 3273, 1649, 1335,
1
≥105.0
1265, 1157. H NMR (300 MHz, C3D6O, δ): 0.85 (d,
3e
3H, J = 6.7 Hz), 0.86 (d, 3H, J = 6.8 Hz), 2.02–2.09
(m, 1H), 2.40 (s, 3H), 3.47 (dd, 1H, J = 6.4 Hz,
6.5 Hz), 7.00 (d, 1H, J = 5.5 Hz), 7.35 (d, 2H,
J = 8.8 Hz), 7.41 (d, 2H, J = 8.1 Hz), 7.79 (d, 2H,
J = 8.7 Hz), 7.81 (d, 2H, J = 8.2 Hz), 8.95 (br s., 1H),
9.11 (bs, 1H), 9.76 (br s., 1H). EIMS (m/z): 327 (2.1),
226 (26.2), 171 (10.0), 170 (2.5), 169 (28.0), 155
(39.1), 127 (13.1), 111 (18.6), 91 (100.0), 65 (17.7).
3f
7
4a
>14.0 14.0 1.2
>12.4 14.0 1.2
<1
<1
1
4b
>125.0
>125.0
>125.0
>125.0
1
4c
>47.4 56.8 13.9
>67.5 56.8 13.9
>73.3 74.2 2.8
>70.6 74.2 2.8
>12.6 13.3 0.8
>12.5 13.3 0.8
>62.7 68.9 8.2
>65.9 68.9 8.2
<1
<1
<1
<1
<1
<1
<1
<1
4d
1-[4-Methyl-2-(4-methylphenylsulfonamido)penta-
4e
noyl]-4-(4-chlorophenyl)thiosemicarbazide
(2b).
From 1b (1.77 g). Yield: 2.46 g (89%), mp 159–
4h
161◦C. IR (cm−1) νmax: 3469, 3358, 3267, 1657, 1333,
ROD
IIIB
1
Efavirenz
Capravirine IIIB
0.003
0.0014
40
11
13,333 [17]
7,857 [18]
1248, 1161. H NMR (500 MHz, CD3OD, δ): 0.54 (d,
3H, J = 5.7 Hz), 0.81 (d, 3H, J = 6.1 Hz), 1.45–1.51
(m, 3H), 2.41 (s, 3H), 3.59 (br s., 1H), 7.31 (d, 2H,
J = 8.1 Hz), 7.38 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H,
J = 8.6 Hz), 7.76 (d, 2H, J = 8.2 Hz), 8.91 (br s., 1H),
9.18 (br s., 1H), 9.87 (br s., 1H). EIMS (m/z): 228
(8.3), 171 (17.8), 170 (3.4), 169 (51.3), 155 (32.3),
127 (6.2), 111 (27.5), 91 (96.0), 88 (100.0), 65 (23.9).
aAnti-HIV-1 activity measured with strain IIIB.
bAnti-HIV-2 activity measured with strain ROD.
cCompound concentration required to achieve 50% protection of MT-4
cells from the HIV-1- and 2-induced cytopathogenic effect.
dCompound concentration that reduces the viability of mock-infected
MT-4 cells by 50%.
eSI: Selectivity index (CC50/EC50).
1-[3-Methyl-2-(4-methylphenylsulfonamido)penta-
EXPERIMENTAL
noyl]-4-(4-chlorophenyl)thiosemicarbazide
(2c).
From 1c (1.76 g). Yield: 2.38 g (86%); mp 84–87◦C.
Melting points were recorded on a Gallenkamp melt-
ing point apparatus and are uncorrected. Specific
rotation [α] was measured as a solution in acetone
on ATAGO AP-100 automatic polarimeter. IR spec-
tra (cm−1) were recorded on FTX 3000 MX BioRad
Excalibar Series IR spectrophotometer, using KBr
IR (cm−1) νmax: 3465, 3387, 3271, 1663, 1338, 1239,
1
1155. H NMR (300 MHz, C3D6O, δ): 0.67 (t, 3H,
J = 7.8 Hz), 0.84 (d, 3H, J = 6.7 Hz), 1.02–1.25 (m,
1H), 1.41–1.55 (m, 1H), 1.68–1.85 (m, 1H), 2.40 (s,
3H), 3.72 (dd, 1H, J = 6.6 Hz, 9.9 Hz), 6.68 (d, 1H,
J = 9.8 Hz), 7.34 (d, 2H, J = 8.6 Hz), 7.36 (d, 2H,
J = 8.7 Hz), 7.68 (d, 2H, J = 8.2 Hz), 7.81 (d, 2H,
J = 8.2 Hz), 8.96 (s, 1H), 9.14 (s, 1H), 9.78 (s, 1H).
EIMS (m/z): 240 (100.0), 171 (3.7), 170 (6.5), 169
(12.1), 155 (85.1), 127 (6.4), 111 (15.5), 99 (18.8), 91
(73.8), 65 (15.1).
1
pellets. H NMR spectra were recorded on Bruker
(300 and 500 MHz) spectrometers, using TMS as
an internal standard. Mass spectra were measured
on a MAT-112-S spectrometer at 70 eV. Elemental
analysis was carried out on Leco CHNS-932 (USA)
Leco Corporation. 4-Chlorophenyl isothiocyanate
was synthesized by a reported procedure [19].
1-[3-Hydroxy-2-(4-methylbenzenesulfonamido)buta-
noyl]-4-(4-chlorophenyl)thiosemicarbazide
(2d).
General Procedure for the Synthesis of
Thiosemicarbazides(2a–h) [12]
From 1d (1.69 g). Yield: 2.21 g (82%), mp 192–
194◦C, IR (cm−1) νmax: 3397–3263, 1653, 1341, 1243,
1
To a solution of N-tosylamino acid hydrazide 1a–
h (5.90 mmol) in absolute MeOH (30 mL) was
1157. H NMR (500 MHz, CD3OD, δ): 1.03 (d, 3H,
J = 6.3 Hz), 2.40 (s, 3H), 3.64 (d, 1H, J = 4.5 Hz),
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Anti-HIV Activity of New Chiral 1,2,4-Triazoles and 1,3,4-Thiadiazoles 319
4.03–4.04 (m, 1H), 7.30 (d, 2H, J = 8.8 Hz), 7.36 (d,
J = 6.9 Hz), 7.61 (d, 2H, J = 8.2 Hz), 8.43 (s, 1H),
8.97 (s, 1H), 9.18 (s, 1H), 9.73 (s, 1H). EIMS (m/z):
200 (2.0), 171 (4.7), 170 (8.3), 127 (11.6), 111 (25.6),
91 (8.3), 75 (100.0).
2H, J = 8.1 Hz), 7.58 (d, 2H, J = 8.7 Hz), 7.77 (d,
2H, J = 8.2 Hz), 8.89 (s, 1H), 9.04 (s, 1H), 9.63 (s,
1H). EIMS (m/z): 228 (8.3), 171 (17.8), 170 (3.3), 169
(51.3), 155 (32.3), 127 (6.2), 111 (27.5), 91 (96.1), 88
(100.0), 65 (23.9).
General Procedure for the Synthesis of Triazoles
(3a–g)
1-[4-Methylthio-2-(4-methylbenzenesulfonamido)-
butanoyl]-4-(4-hlorophenyl)thiosemicarbazide (2e).
From 1e (1.87 g). Yield: 2.61 g (91%), mp: 200–
201◦C. IR (cm−1) νmax: 3463, 3351, 3253, 1661,
Thiosemicarbazide 2 (1.10 mmol) was added por-
tionwise to a solution of NaOH (5%, 30 mL), and the
reaction mixture was heated under reflux for 4 h.
After cooling, the mixture was filtered, and the fil-
trate was acidified with 6 N HCl to PH 2–3. The pre-
cipitated solid was filtered, washed thoroughly with
water, and recrystallized from EtOH/water.
1
1337, 1236, 1156. H NMR (500 MHz, CD3OD, δ):
1.80–1.86 (m, 1H), 1.90 (s, 3H), 1.92–1.98 (m, 1H),
2.25–2.31 (m, 1H), 2.39–2.46 (m, 4H), 3.83 (dd, 1H,
J = 5.5 Hz, 7.4 Hz), 7.31 (d, 2H, J = 8.7 Hz), 7.37
(d, 2H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.7 Hz), 7.72
(d, 1H, J = 7.6 Hz), 7.77 (d, 2H, J = 8.2 Hz), 8.93
(s, 1H), 9.07 (s, 1H), 9.69 (s, 1H). EIMS (m/z): 258
(18.8), 171 (19.3), 170 (4.1), 169 (51.9), 155 (15.4),
127 (5.8), 111 (27.3), 99 (2.8), 91 (78.1), 75 (27.0),
65 (16.2), 61 (100.0), 57 (2.4).
4-(4-Chlorophenyl)-5-(2-methyl-1-(p-toluenesulf-
onylamino)propyl)-2H-1,2,4-triazole-3-thione (3a).
From 2a (0.50 g). Yield: 0.41 g (85%), mp 100–
102◦C. [α]2D5 + 47◦ (c 1.2, acetone), IR (cm−1) νmax
:
1
3476, 3277, 1335, 1235, 1156. H NMR (500 MHz,
CD3OD, δ): 0.78 (d, 3H, J = 6.7 Hz), 0.81 (d, 3H, J =
6.7 Hz), 1.90–1.97 (m, 1H), 2.39 (s, 3H), 3.98 (dd,
1H, J = 7.1 Hz, 8.4 Hz), 6.99 (d, 1H, J = 8.4 Hz),
7.29 (d, 2H, J = 8.7 Hz), 7.35 (d, 2H, J = 8.1 Hz),
7.62 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H, J = 8.2 Hz),
12.62 (br s., 1H). 13C NMR (75 MHz, C3D6O, δ): 17.4
and 18.9 (CMe2), 20.9 (MeArSO2), 32.1 (CMe2), 55.2
(C5-CHN), 119.2 (NHAr-Cb,f), 126.7, 129.8, 130.0,
130.6 (Ar-C) , 132.5 (Ar-C-Cl), 135.2 (Ar-C-Me), 137.9
(Ar-C-SO2), 143.0 (Ar-C-N), 151.7 (C-5), 169.5 (C S).
Anal. Calcd for C19H21ClN4O2S2 (436.98): C, 52.22;
H, 4.84; N, 12.82. Found: C, 52.16; H, 4.79; N, 12.61.
1-[3-Mercapto-2-(4-methylbenzenesulfonamido)-
propanoyl]-4-(4-chlorophenyl)thiosemicarbazide (2f).
From 1f (1.71 g). Yield: 1.92 g (71%), mp 117–118◦C.
IR (cm−1) νmax: 3463, 3376, 3251, 2553, 1654, 1339,
1
1244, 1160. H NMR (300 MHz, C3D6O, δ): 2.39 (s,
3H), 3.63–3.71 (m, 2H), 4.29 (d, 1H, J = 6.4 Hz),
4.32 (bs, 1H), 7.0 (br s., 1H), 7.31 (d, 2H, J = 8.6 Hz),
7.37 (d, 2H, J = 8.2 Hz), 7.55 (d, 2H, J = 8.7 Hz),
7.58 (d, 2H, J = 8.1 Hz). EIMS (m/z): 171 (19.9), 155
(19.45), 107 (14.9), 91 (100.0), 65 (33.6).
1-[3-Hydroxy-2-(4-methylbenzenesulfonamido)-
propanoyl]-4-(4-chlorophenyl)thiosemicarbazide (2g).
From 1g (1.61 g). Yield: 1.91 g (73%), mp: 170–
172◦C. IR (cm−1) νmax: 3387–3235, 1665, 1337, 1155,
4-(4-Chlorophenyl)-5-(3-methyl-1-(p-toluenesul-
fonylamino)butyl)-2H-1,2,4-triazole-3-thione
(3b).
From 2b (0.52 g). Yield: 0.41 g (83%), mp 190–192◦C,
[α]2D5 + 27◦ (c 0.66, acetone), IR (cm−1) νmax: 3478,
3417, 1313, 1235, 1161. 1H NMR (500 MHz, CD3OD,
δ): 0.46 (d, 3H, J = 5.9 Hz), 0.72 (d, 3H, J = 6.0 Hz),
1.50–1.64 (m, 3H), 2.39 (s, 3H), 4.10 (br s., 1H), 4.12
(dd, 1H, J = 4.3 Hz, 8.4 Hz), 7.35 (d, 2H, J = 8.2
Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.60 (d, 2H, J = 8.2
Hz), 7.63 (d, 2H, J = 8.6 Hz), 12.61 (br s., 1H). 13C
NMR (75 MHz, C3D6O, δ): 20.4 (CHCMe2), 21.5
(MeArSO2), 22.7 (CHCMe2), 43.6 (CHCMe2), 47.9
(C5-CHN), 126.8, 129.7, 129.8, 130.4 (Ar-C), 130.8
(Ar-C-Cl), 136.9 (Ar-C-Me), 137.0 (Ar-C-SO2), 144.2
(Ar-C-NH, Ar-C-Me), 154.9 (C-5), 168.7 (C S). Anal.
Calcd for C20H23ClN4O2S2(451.01): C, 53.26; H, 5.14;
N, 12.42. Found: C, 53.13; H, 5.13; N, 12.36.
1
1246. H NMR (500 MHz, CD3OD, δ): 2.41 (s, 3H),
3.58 (dd, 1H, J = 6.7 Hz, 10.5 Hz), 3.70 (dd, 1H,
J = 5.5 Hz, 10.5 Hz), 3.79 (dd, 1H, J = 5.9 Hz, 6.2
Hz), 5.31 (br s., 1H), 7.30 (d, 2H, J = 8.7 Hz), 7.37
(d, 2H, J = 8.1 Hz ), 7.56 (d, 2H, J = 8.7 Hz), 7.77 (d,
2H, J = 8.2 Hz), 8.87 (s, 1H), 9.13 (s, 1H), 9.81 (s,
1H). EIMS (m/z): 240 (31.2), 171 (15.6), 170 (2.7),
169 (37.4), 155 (41.9), 127 (4.4), 111 (16.9), 99 (2.5),
91 (100.0), 75 (18.2), 65 (28.3).
1-[3-(1H-Imidazol-5-yl)-2-(4-methylphenyl-
sulfonamido)propanoyl]-4-(4-chlorophenyl)thiosemi-
carbazide (2h). From 1h (1.91 g). Yield: 2.47 g
(85%), mp: 176–178◦. IR (cm−1) νmax: 3421, 3361,
1
3297, 1658, 1336, 1244, 1156. H NMR (500 MHz,
CD3OD, δ): 2.39 (s, 3H), 3.13–3.21 (m, 2H), 4.85 (dd,
1H, J = 6.0 Hz, 9.0 Hz), 7.25 (s, 1H), 7.29 (d, 2H,
J = 8.1 Hz), 7.37 (d, 2H, J = 6.9 Hz), 7.43 (d, 2H,
4-(4-Chlorophenyl)-5-(2-methyl-1-(p-toluenesul-
fonylamino)butyl)-2H-1,2,4-triazole-3-thione
(3c).
From 2c (0.52 g). Yield: 0.41 g (83%), mp 122–124◦C.
Heteroatom Chemistry DOI 10.1002/hc

320 Akhtar et al.
From 2f (0.50 g). Yield: 0.31 g (63%), mp 141–143◦C,
[α]2D5 + 22◦ (c 0.53, CHCl3), IR (cm−1) νmax: 3287,
[α]2D5 +42◦ (c 1.01, CHCl3), IR (cm−1) νmax: 3473,
3217, 1336, 1239, 1158. 1H NMR (500 MHz, CD3OD,
δ): 0.64 (t, 3H, J = 7.4 Hz), 0.76 (d, 3H, J = 6.8 Hz),
0.79–0.88 (m, 1H), 1.39–1.54 (m, 1H), 1.68–1.79 (m,
1H), 2.39 (s, 3H), 3.98 (d, 1H, J = 6.9 Hz), 6.99 (br s.,
1H), 7.29 (d, 2H, J = 8.6 Hz), 7.36 (d, 2H, J = 8.2 Hz),
7.62 (d, 2H, J = 8.7 Hz), 7.64 (d, 2H, J = 8.2 Hz),
12.62 (br s., 1H). 13C NMR (75 MHz, C3D6O, δ):
1
3243, 2558, 1335, 1243, 1158. H-NMR (300 MHz,
C3D6O, δ): 2.41 (s, 3H), 3.74–3.83 (m, 2H), 4.19 (t,
1H, J = 6.4 Hz), 4.38 (br s., 1H), 7.07 (br s., 1H), 7.31
(d, 2H, J = 8.6 Hz), 7.33 (d, 2H, J = 7.9 Hz), 7.56
(d, 2H, J = 8.8 Hz) 7.57 (d, 2H, J = 8.0 Hz), 12.62
(br s., 1H). 13C NMR (75 MHz, DMSO-d6, δ): 18.9
(CH2SH), 21.8 (MeArSO2), 56.5 (C5-CHN), 116.5
(NHAr-Cb,f), 120.3, 125.9, 128.8, 129.4, 132.6 (Ar-C),
138.7 (Ar-C-SO2), 146.7 (Ar-C-NH, Ar-C-Me), 152.3
(C-5), 170.4 (C S). Anal. Calcd for C17H17ClN4O2S3
(440.99): C, 46.30; H, 3.89; N, 12.70. Found: C,
46.25; H, 3.79; N, 12.63.
14.8
(CHMeCH2CH3),
20.5
(CHMeCH2CH3),
24.2 (MeArSO2), 37.7 (CHMeCH2CH3), 51.1
(CHMeCH2CH3), 60.5 (C5-CHN), 119.0 (NHAr-Cb,f),
127.1, 128.6, 128.9, 129.2, 129.3 (Ar-C), 138.2 (Ar-
C-SO2), 143.1 144.2 (Ar-C-Me), 154.8 (C-5), 171.2
(C S). Anal. Calcd for C20H23ClN4O2S2(451.01): C,
53.26; H, 5.14; N, 12.42. Found: C, 53.31; H, 5.08; N,
12.31.
4-(4-Chlorophenyl-5-(2-hydroxy-1-(p-toluene-
sulfonylamino)propyl)-2H-1,2,4-triazole-3-thione (3g).
From 2g (0.49 g). Yield: 0.32 g (69%), mp 115–118◦C.
[α]2D5 + 63◦ (c 1.51, CHCl3), IR (cm−1) νmax: 3413,
4-(4-Chlorophenyl-5-(2-hydroxyl-1-(p-toluenesul-
fonylamino)propyl)-2H-1,2,4-triazole-3-thione (3d).
From 2d (0.50 g). Yield: 0.35 g (72%), mp 121–
1
3387, 3235, 1337, 1246, 1155. H NMR (300 MHz,
122◦C, [α]2D5 + 54◦ (c, 1.1, CHCl3), IR (cm−1) νmax
:
DMSO-d6, δ): 2.36 (s, 3H), 3.46 (dd, 1H, J = 6.5 and
10.1 Hz), 3.57 (dd, 1H, J = 8.7 Hz, 10.2 Hz), 3.83
(dd, 1H, J = 6.3 and 8.4 Hz), 5.22 (br s., 1H), 7.22
(d, 2H, J = 8.7 Hz), 7.31 (d, 2H, J = 8.1 Hz), 7.47 (d,
2H, J = 8.7 Hz), 7.63 (d, 2H, J = 8.1 Hz), 8.32 (br
s., 1H), 13.85 (br s., 1H). 13CNMR (75 MHz, C3D6O,
δ): 21.5 (MeArSO2), 51.1 (C5-CHN), 62.9 (CH2OH),
116.5 (NHAr-Cb,f), 127.0, 129.83, 130.0, 130.9, 132.4,
134.7 (Ar-C), 137.5 (Ar-C-SO2), 143.5 (Ar-C-NH,
Ar-C-Me), 151.2 (C-5), 168.0 (C S). Anal. Calcd for
C17H17ClN4O3S2 (424.92): C, 48.05; H, 4.03; N, 13.19.
Found: C, 47.96; H, 4.12; N, 13.09.
1
3418, 3365, 3271, 1339, 1241, 1158. H NMR (500
MHz, DMSO-d6, δ): 0.98 (d, 3H, J = 6.2 Hz), 2.36
(s, 3H), 3.66 (m, 1H), 3.80 (dd, 1H, J = 6.1 Hz,
6.2 Hz), 4.97 (d, 1H, J = 5.6 Hz), 6.74 (d, 2H, J = 8.1
Hz), 7.17 (br s., 1H), 7.31 (d, 2H, J = 8.0 Hz),
7.53 (d, 2H, J = 8.1 Hz), 7.61 (d, 2H, J = 8.7 Hz),
13.8 (s, 1H). 13C-NMR (75 MHz, CD3OD, δ): 17.6
(CHMeOH), 20.1 (MeArSO2), 54.4 (C5-CHN), 67.7
(CHMeOH), 126.9 (NHAr-Cb,f), 129.3, 129.4, 130.3,
132.0 (Ar-C), 135.6 (Ar-C-SO2), 137.2 (Ar-C-NH),
143.8 (Ar-C-Me), 150.1 (C-5), 168.3 (C S). Anal.
Calcd for C18H19ClN4O3S2(438.95): C, 49.25; H, 4.36;
N, 12.76. Found: C, 49.19, H, 4.31; N, 12.65.
General Procedure for the Synthesis of
Thiadiazoles (4a–e,h)
4-(4-Chlorophenyl-5-(3-methylthio-1-(p-toluene-
sulfonylamino)propyl)-2H-1,2,4-triazole-3-thione (3e).
From 2e (0.54 g). Yield: 0.41 g (79%), mp 105–107◦C,
[α]2D5 + 38◦ (c 0.90, CHCl3), IR (cm−1) νmax: 3417,
Thiosemicarbazide 2a–e,h (1.10 mmol) was added
portionwise to concentration H2SO4 (20 mL) at 0◦C
with continuous stirring. The reaction mixture was
stirred for 4 h at 23◦C and then allowed to stand
overnight. The mixture was neutralized with dilute
NaOH to give a precipitate as a crude solid, which
was filtered, washed with water, and recrystallized
from EtOH/water to afford the 1,3,4-thiadiazole
derivatives (4a–e,h).
1
3254, 1320, 1221, 1157. H NMR (500 MHz, C3D6O,
δ): 1.74 (s, 3H), 1.87–1.93 (m, 2H), 2.09–2.31 (m,
2H), 2.33 (s, 3H), 4.12 (dd, 1H, J = 7.0 and 13.7 Hz),
7.30 (d, 2H, J = 8.8 Hz), 7.31 (d, 2H, J = 8.2 Hz),
7.47 (d, 2H, J = 8.2 Hz), 7.61 (d, 2H, J = 8.8 Hz),
8.34 (d, 1H, J = 7.0 Hz), 13.87 (s, 1H). 13C NMR
(75 MHz, C3D6O, δ): 15.0 (SMe), 21.6 (MeArSO2),
29.7 (CH2CH2SMe), 33.1 (CH2CH2SMe), 48.0 (C5-
CHN), 127.0, 119.2 (NHAr-Cb,f), 129.6, 129.8, 130.4,
130.9 (Ar-C), 136.8 (Ar-C-SO2), 144.2 (Ar-C-NH,
Ar-C-Me), 153.7 (C-5), 168.7 (C S). Anal. Calcd for
C19H21ClN4O2S3 (469.04): C, 48.65; H, 4.51; N, 11.94.
Found: C, 48.59; H, 4.43; N, 11.86.
N-(4-Chlorophenyl-5-(2-methyl-1-(p-toluenesulfonyl-
amino)propyl)-1,3,4-thiadiazol-2-amine (4a). From
2a (0.50 g). Yield: 0.39 g (82%), mp 148–150◦C,
[α]2D5 + 35◦ (c 0.84, CHCl3), IR (cm−1) νmax: 3276,
1
3223, 1328, 1155. H NMR (500 MHz, C3D6O, δ):
0.83, 0.99 (2 × d, 6H, J = 6.7 Hz, CHMe2), 2.04–2.11
(m, 1H, CHMe2), 2.35 (s, 3H, MeArSO2), 4.44 (dd,
1H, J = 7.8 Hz, 8.5 Hz, NCHCHMe2), 7.07 (d, 1H,
J = 8.1 Hz, Cl-Ar-H), 7.23 (d, 2H, J = 8.1 Hz,
4-(4-Chlorophenyl-5-(2-mercapto-1-(p-toluene-
sulfonylamino)propyl)-2H-1,2,4-triazole-3-thione (3f).
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Anti-HIV Activity of New Chiral 1,2,4-Triazoles and 1,3,4-Thiadiazoles 321
Cl-Ar-H), 7.34 (d, 2H, J = 8.8 Hz, Me-Ar-H), 7.64
4.13–4.15 (m, 1H), 4.61 (dd, 1H, J = 3.6 Hz, 7.9 Hz),
6.93 (d, 1H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0), 7.37
(d, 2H, J = 8.6 Hz), 7.53 (d, 2H, J = 8.9 Hz), 7.74 (d,
2H, J = 8.2 Hz), 9.87 (br s., 1H). 13C NMR (75 MHz,
C3D6O, δ): 16.8 (CHMeOH), 21.0 (MeArSO2), 58.2
(C5-CHN), 75.0 (CHMeOH), 120.2 (NHAr-Cb,f),
125.6, 127.4, 129.2, 129.5 (Ar-C), 137.4 (Ar-C-SO2),
138.3 (Ar-C-NH), 143.0 (Ar-C-Me), 160.1 (C-5), 166.4
(C-2). Anal. Calcd for C18H19ClN4O3S2 (438.95): C,
49.25; H, 4.36; N, 12.76. Found: C, 49.33; H, 4.30; N,
12.81.
(d, 2H, J = 8.8 Hz, Me-Ar-H), 9.41 (br s., 1H, NH).
13C NMR (75 MHz, C3D6O, δ): 19.3 (CHMe2), 21.3
(MeArSO2), 33.3 (C-7), 59.9 (C-6), 119.2 (NHAr-Cb,f),
125.6, 127.2, 129.3, 129.7 (Ar-C), 140.0 (Ar-C-SO2),
142.5 (Ar-C-Me), 142.8 (Ar-C-NH), 162.1 (C-5), 164.8
(C-2). Anal. Calcd for C19H21ClN4O2S2 (436.98): C,
52.22; H, 4.84; N, 12.82. Found: C, 52.29; H, 4.82; N,
12.77.
N-(4-Chlorophenyl-5-(3-methyl-1-(p-toluene-
sulfonylamino)butyl)-1,3,4-thiadiazol-2-amine (4b).
From 2b (0.52 g). Yield: 0.39 g (79%), mp 208–210◦C,
[α]2D5 + 37◦ (c 0.88, CHCl3), IR (cm−1) νmax: 3315, 3227,
N-(4-Chlorophenyl-5-(3-methylthio)-1-(p-toluene-
sulfonylamino)propyl)-1,3,4-thiadiazol-2-amine (4e).
From 2e (0.54 g). Yield: 0.38 g (73%), mp 174–176◦C,
[α]2D5 + 74◦ (c 1.78, CHCl3), IR (cm−1) νmax: 3324,
1
1325, 1159. H-NMR (500 MHz, CD3OD, δ): 0.78 (d,
3H, J = 6.46 Hz), 0.85 (d, 3H, J = 6.5 Hz), 1.59–1.63
(m, 1H), 1.69 (dd, 2H, J = 7.0 Hz, 7.5 Hz), 2.28 (s,
3H), 4.71 (dd, 1H, J = 4.5 Hz, 7.8 Hz), 7.17 (br s.,
1H), 7.27 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.9
Hz), 7.64 (d, 2H, J = 8.3 Hz), 7.65 (d, 2H, J = 8.9
Hz), 9.51 (br s., 1H). 13C NMR (75 MHz, C3D6O,
δ): 19.3 (CHCMe2), 21.3 (CHCMe2, MeArSO2), 33.3
(CHCMe2), 59.9 (C5-CHN), 119.2 (NHAr-Cb,f), 125.6,
127.1, 129.3, 129.7 (Ar-C), 140.0 (Ar-C-SO2), 142.4
(Ar-C-NH), 142.8 (Ar-C-Me), 162.1 (C-5), 164.8
(C-2). Anal. Calcd for C20H23ClN4O2S2 (451.01): C,
53.26; H, 5.14; N, 12.42. Found: C, 53.37; H, 5.06; N,
12.37.
1
3221, 1335, 1154. H NMR (500 MHz, C3D6O, δ):
1.95 (s, 3H), 2.18 (m, 2H), 2.39–2.48 (m, 2H), 2.33
(s, 3H), 4.87 (dd, 1H, J = 7.9 Hz, 14.5 Hz), 7.20
(br s., 1H), 7.32 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H,
J = 8.8 Hz), 7.65 (d, 2H, J = 8.8 Hz), 7.69 (d, 2H,
J = 8.2 Hz), 8.14 (br s., 1H), 9.37 (bs, 1H). 13C NMR
(75 MHz, C3D6O, δ): 14.8 (SMe), 21.4 (MeArSO2),
29.6 (CH2CH2SMe), 34.5 (CH2CH2SMe), 52.5 (C5-
CHN), 119.2 (NHAr-Cb,f), 125.7, 127.1, 129.4, 129.9
(Ar-C), 138.4 (Ar-C-SO2), 139.9 (Ar-C-NH), 143.2
(Ar-C-Me), 162.7 (C-5), 165.0 (C-2). Anal. Calcd for
C19H21ClN4O2S3(469.04): C, 48.65; H, 4.51; N, 11.94.
Found: C, 48.57; H, 4.57; N, 11.87.
N-(4-Chlorophenyl-5-(2-methyl-1-(p-toluene-
sulfonylamino)butyl)-1,3,4-thiadiazol-2-amine (4c).
From 2c (0.52 g). Yield: 0.38 g (76%), mp 74–76◦C,
[α]2D5 + 72◦ (c 1.7, CHCl3), IR (cm−1) νmax: 3287,
3197, 1332, 1156. 1H NMR (500 MHz, CD3OD,
δ): 0.80–0.86 (m, 6H), 1.15–1.20 (m, 1H), 1.45–
1.50 (m, 1H), 1.71–1.74 (m, 1H), 3.72 (dd, 1H,
J = 6.70 Hz, 9.80 Hz), 6.74 (d, 1H, J = 9.80 Hz),
7.36 (d, 2H, J = 8.50 Hz), 7.59 (d, 2H, J = 8.13 Hz),
7.64 (d, 2H, J = 8.80 Hz), 7.68 (d, 2H, J = 8.17
Hz), 10.13 (br s., 1H). 13C NMR (75 MHz, C3D6O,
δ): 14.8 (CHMeCH2CH3), 20.5 (CHMeCH2CH3),
24.7 (MeArSO2), 37.7 (CHMeCH2CH3), 51.1
(CHMeCH2CH3), 60.4 (C5-CHN), 119.0 (NHAr-
Cb,f), 127.1, 128.6, 128.9, 129.3, 129.4 (Ar-C), 138.2
(Ar-C-SO2), 143.1 (Ar-C-NH, Ar-C-Me), 162.9 (C-5),
164.9 (C-2). Anal. Calcd for C20H23ClN4O2S2 (451.01):
C, 53.26; H, 5.14; N, 12.42. Found: C, 53.33; H, 5.18;
N, 12.33.
5-(2-(1H-Imidazol-4-yl)-1-(p-toluenesulfonyl-
amino)ethyl)-N-(4-chlorophenyl)-1,3,4-thiadiazol-2-
amine (4h). From 2h (0.54 g). Yield: 0.40 g (77%),
mp 247–248◦C (dec.), [α]D25 + 68◦ (c 1.62, CHCl3), IR
1
(cm−1) νmax: 3406, 3368, 3297, 1336, 1156. H NMR
(500 MHz, CD3OD, δ): 2.31 (s, 3H), 3.30–3.33 (m,
2H), 4.97 (dd, 1H, J = 6.0 Hz, 9.0 Hz), 7.15 (s, 1H),
7.23 (d, 2H, J = 8.10 Hz), 7.29 (d, 2H, J = 6.90 Hz),
7.48 (d, 2H, J = 6.9 Hz), 7.56 (d, 2H, J = 8.2 Hz),
8.40 (s, 1H), 9.47 (br s., 1H). 13C NMR (75 MHz,
CD3OD, δ): 21.4 (MeArSO2), 31.8 (CH2-imidazole),
53.4 (C5-CHN), 117.7 (imidazole-C), 119.2 (NHAr-
Cb,f), 125.7, 126.8, 129.4 (Ar-C), 130.9 (imidazole-C),
134.9 (imidazole-C), 138.1 (Ar-C-SO2), 139.9 (Ar-C-
NH), 143.1 (Ar-C-Me), 161.9 (C-5), 165.1 (C-2). Anal.
Calcd for C20H19ClN6O2S2(474.99): C, 50.57; H, 4.03;
N, 17.69. Found: C, 50.53; H, 4.06; N, 17.55.
1-(5-(4-Chlorophenylamino)-1,3,4-thiadiazol-2-yl)-
1-(p-toluenesulfonylamino)propan-2-ol (4d). From
2d (0.50 g). Yield: 0.32 g (67%), mp 180–182◦C, [α]D25
+ 28◦ (c 0.66, CHCl3). IR (cm−1) νmax: 3487, 3361,
REFERENCES
[1] Takaoka, M.; Manabe, S.; Yamoto, T.; Teranishi, M.,
Matsunuma, N.; Masuda, H.; Goto, N. J Vet Med Sci
1994, 56, 341–346.
1
3279, 1341, 1157. H NMR (500 MHz, C3D3O, δ):
1.10 (d, 3H, J = 6.3 Hz), 2.33 (s, 3H), 3.65 (br s., 1H),
Heteroatom Chemistry DOI 10.1002/hc

322 Akhtar et al.
[2] Kumamoto, T.; Toyooka, K.; Nishida, M.; Kuwahara,
H.; Yoshimura, Y.; Kawada, J.; Kubota, S. Chem
Pharm Bull 1990, 38, 2595–2596.
[3] Malawska, B. Curr Top Med Chem 2005, 5, 69–85,
and references therein.
[4] (a) Chapleo, C. B.; Myers, P. L.; Smith, A. C. B.;
Tulloch, I. F.; Turner, T.; Walter, D. S. J Med Chem
1987, 30, 951–954. (b) Chapleo, C. B.; Myers, P. L.;
Smith, A. C. B.; Tulloch, I. F.; Turner, T.; Walter, D.
S. J Med Chem 1988, 31, 7–11.
[5] Modzelewska-Banachiewicz, B.; Jagiello-Wojtowicz,
E.; Tokarzewska-Wielosz, E. Acta Pol Pharm 2000,
57, 199–204.
[6] Goswami, B. N.; Kataky, J. C. S.; Baruah, J. N. J
Heterocycl Chem 1984, 21, 1225–1229.
[7] Ulusoy, N.; Ates, O.; Kucukbasmac, O.; Kiraz, M.;
Yegenoglu, Y. Monatsh Chem 2003, 134, 465–
474.
[8] Turan-Zitouni, G.; Kaplancikli, Z. A.; Yildiz, M. T.;
Chevallet, P.; Kaya, D. Eur J Med Chem 2005, 40,
607–613.
[12] Zamani, K.; Faghihi, K.; Sangi, M. R.; Zolgharnein,
J. Turk J Chem 2003, 27, 119–125.
[13] Wang, Z.; Shi, H. J Heterocycl Chem 2001, 38, 355–
357.
[14] Elsharief, A. M. Sh.; Ghorab, M. M.; Al-Gaby, M. S.
A.; Mohamed, Sh. I.; Ammar, Y. A. Heteroatom Chem
2002, 13, 316–323.
[15] McChesney, E. W.; Kirkswamm, W. M. J A Chem Soc
1937, 59, 1116–1118.
[16] A-Masoudi, N. A.; Hassan, N. A.; Al-Soud, Y. A.;
Schmidt, P.; Gaafer, A. E.-D. M.; Weng, M.; Marino,
S.; Schoch, A.; Amer, A.; Jochims, J. C. J Chem
Soc Perkin Trans 1 1998, 947–953, and references
therein.
[17] Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne,
L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson,
P. S.; Olsen, D. B.; Carroll, S. S.; Pettibone, D. J:,
Obrien, J. A.; Ball, R. G.; Balani, S. K.; Lin, J. H.;
Chen, I. W.; Schleif, W. A.; Sardana, V. V.; Long,
W. J.; Byrnes, V. W.; Emini, E. A. Antimicrob Agents
Chemother 1995, 39, 2602–2605.
[9] Almajan, G. L.; Innocenti, A.; Puccetti, L.; Manole, G.;
Barbuceanu, S.; Saramet, I.; Scozzafava, A., Supuran,
C. T. Bioorg Med Chem Lett 2005, 15, 2347–2352.
[10] Messina, F., Botta, M.; Corelli, F.; Paladino, A.
Tetrahedron: Asymmetry 2000, 11, 4895–4901.
[11] Molina, P.; Tarraga, A.; Espinosa, A. Synthesis 1989,
923–929.
[18] Fujiwara, T.; Sato, A.; El-Farrash, M.; Miki, S.; Kabe,
K.; Isaka, Y.; Kodama, M.; Wu, Y. M.; Chen, L. B.;
Harada, H.; Sugimoto, H.; Hatanaka, M.; Hinuma,
Y. Antimicrob Agents Chemother 1998, 42, 1340–
1345.
[19] van der Kerk, G. J. M; Pluygers, C. W.; de Vries, G.
Org Synth, Coll 1973, 5, 273.
Heteroatom Chemistry DOI 10.1002/hc