Synthesis, anti-HIV activity and Molecular modeling study of 3-aryl-6-adamantylmethyl-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazole derivatives

Article abstract of DOI:10.1515/znb-2015-0032

A series of novel 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 6a-l were synthesized by a simple method with the aim of developing novel HIV non-nucleoside reverse transcriptase inhibitors. All the synthesized compounds were structurally confirmed by spectral analyses. The structure of 6a was unambiguously verified by X-ray structure determination. The synthesized compounds were evaluated for their anti-HIV activity and four analogs displayed moderate inhibitory activity with EC₅₀ values ranging from 10.10 to 12.40 μg mL^-1. Molecular docking of 6g with HIV-1 reverse transcriptase was studied to rationalize some structureactivity relationships (SARs).

Full text of DOI:10.1515/znb-2015-0032

Z. Naturforsch. 2015; aop
a,
Mahmood-ul-Hassan Khan, Shahid Hameed*, Muhammad Farman, Najim A. Al-Masoudi *
and Helen Stoeckli-Evans
Synthesis, anti-HIV activity and molecular modeling
study of 3-aryl-6-adamantylmethyl-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazole derivatives
DOI 10.1515/znb-2015-0032
Received February 12, 2015; accepted April 2, 2015
inhibitor [13, 14] and anti-inflammatory [15, 16]. These
biological activities are a driving force for the synthetic
chemists to focus on this important class of condensed
heterocycles. The activity may be enhanced by varying a
Abstract: A series of novel 3-aryl-6-adamantylmethyl- variety of derivatives on the triazolothiadiazole nucleus.
1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 6a–l were syn- In this respect, the adamantyl group is an excellent
[
thesized by a simple method with the aim of developing choice for incorporation with the triazolothiadiazole
novel HIV non-nucleoside reverse transcriptase inhibi- molecules due to the high lipophilicity of adamantine,
tors. All the synthesized compounds were structurally which in turn can modify the biological availability of
confirmed by spectral analyses. The structure of 6a was these molecules. Furthermore, the literature showed
unambiguously verified by X-ray structure determina- that adamantyl bearing heterocycles are renowned
tion. The synthesized compounds were evaluated for their due to their potential against bacterial [17] and malar-
anti-HIV activity and four analogs displayed moderate ial infections [18], cancer [19] and influenza [20]. In
inhibitory activity with EC values ranging from 10.10 to view of the reported antibacterial [21, 22], antifungal
5
0
–1
1
2.40 μg mL . Molecular docking of 6g with HIV-1 reverse [22] and anti-inflammatory [23] activities, two series of
transcriptase was studied to rationalize some structure- 5-(1-adamantyl)-2-aryl or alkylamino-1,2,4-triazolo[3,4-b]
activity relationships (SARs).
[1,3,4]thiadiazoles were synthesized.
In continuation of our study on the discovery of potent
Keywords: antiviral activity; crystal structure; cyclization; HIV-1 non-nucleoside reverse transcriptase inhibitors [24–
heterocycles; molecular modeling.
28] aiming to produce new generation inhibitors that cir-
cumvent the viral resistance, we designed a new series of
3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadi-
azoles 6a–l, in addition to studying their molecular docking
with the HIV reverse transcriptase amino acids. In addition,
the antifungal and antibacterial activities were screened.
1
Introduction
3,6-Disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
have received significant attention due to their enormous
biological activities, such as anticancer [1, 2], anti-
hypertensive [3], antiviral [4, 5], antimicrobial [6, 7], 2 Results and discussion
antibacterial [8–10], antifungal [11, 12], cholinesterase
The synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazoles 6a–l was carried out by
treatment of 4-amino-5-aryl-1,2,4-triazole-3-thiones 4a–l
with (adamant-1-yl)acetic acid 5 in the presence of phos-
phorus oxychloride [29]. The analogs 4a–l were prepared
aPresent address: Am Tannenhof 8, 78464 Konstanz, Germany.
Corresponding authors: Shahid Hameed, Department of
*
Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan,
e-mail: shameed@qau.edu.pk, shahidhameed@daad-alumni.de;
and Najim A. Al-Masoudi, Department of Chemistry, College
of Science, University of Basrah, Basrah, Iraq,
successively by reacting aryl hydrazides 3a–l with CS in
2
the presence of KOH followed by cyclization with hydra-
zine hydrate [30]. The aryl hydrazides 3a–l were synthe-
sized in turn from the substituted benzoic acids 1a–l via
esterification according to a reported protocol [31]. The
synthesis is summarized in Scheme 1.
e-mail: najim.al-masoudi@gmx.de
Mahmood-ul-Hassan Khan and Muhammad Farman: Department
of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
Helen Stoeckli-Evans: Institute of Physics, University of Neuchâtel,
Rue Emile-Argand 11, CH-2009 Neuchâtel, Switzerland
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ꢁꢁꢁꢂ
2ꢀ ꢀM.H. Khan et al.: Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
N
N
O
O
i. CS2, MeOH, KOH
ii. N2H4·H2O, reflux
SH
N2H4·H2O
reflux
OR'
NHNH2
N
NH2
R
R
R
3a−l
4a−l
1
a−l, R' = H
MeOH/
H
+
2a−l, R' = Me
POCl3, reflux
2
HO C
5
1
'
1
−4, 6
R
R
1−4, 6
N
N
3'
a
b
c
d
e
f
2-Me
3-Me
4-Me
2-F
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
g
h
i
5
N
S
R
2
3N
j
3-F
k
l
6a−l
4-F
Scheme 1:ꢁ Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 6a–l.
The structures of 6a–l were assigned from their IR, thiadiazoles. The base peak was observed at m/z ꢀ=ꢀ 135,
1
13
H, C NMR and mass spectra. The IR spectra were char- which corresponds to the adamantyl fragment of the
acterized by the disappearance of the NH broad signal molecules. The fragment observed at m/z ꢀ=ꢀ (200 + R)
2
1
in comparison to those of the analogs 4a–l. In the H was formed due to cleavage of the bond joining the ada-
NMR spectra, the multiplets and broad singlets in the mantylmethyl moiety to the triazolothiadiazole nucleus,
region δ ꢀ=ꢀ 1.60–2.06 ppm were assigned to 15 adamantyl while that at m/z ꢀ=ꢀ (102 + R) was due to cleavage of the
protons, whereas the 2 methylene protons appeared as a triazolothiadiazole nucleus. In addition to spectroscopic
singlet at δ ꢀ=ꢀ 2.74–2.83 ppm. The aromatic and methyl sub- characterizations, the structures of compounds 6a–l were
stituent protons were fully analyzed (cf. the Experimental further confirmed by single-crystal structure determina-
section), whereas aromatic protons in fluorine-substituted tion of 6a (Figs. 1 and 2). Selected bond lengths and bond
compounds (6d–f) showed split signals due to proton– angles are tabulated in Tables 1 and 2, respectively.
fluorine couplings (e.g. 6d showed J ꢀ=ꢀ 7.5, 1.8 Hz). In
H–F
13
the C NMR spectra, the adamantyl carbons appeared in
the region of δ ꢀ=ꢀ 28.4–42.3 ppm, while methylene carbons 2.1 In vitro anti-HIV activity
were resonated at δ ꢀ=ꢀ 46.6–46.8 ppm. The resonances
of aromatic carbon atoms of 6a–c, 6h–l appeared at the Compounds 6a–l were tested for their inhibitory activity
region δ ꢀ=ꢀ 123.0–140.5 ppm, whereas those of the fluorine- against HIV-1 (strain III ) and HIV-2 (strain ROD) I human
B
substituted analogs 6d–f resonated as doublets at the MT-4 cell cultures by the MTT assay [32, 33]. The results
region δ ꢀ=ꢀ 113.3–163.8 ppm due to carbon–fluorine cou- are compiled in Table 3, where the data for nevirapine [34]
plings. C-2 of 6d resonated as a doublet at δ ꢀ=ꢀ 159.9 ppm were included for comparison purposes. According to the
(
J
ꢀ=ꢀ 254 Hz), whereas C-3 of 6e appeared as a doublet at results, four analogs, namely 6a, 6b, 6d and 6g, inhib-
C2–F
δ ꢀ=ꢀ 162.9 ppm (JC3–F ꢀ=ꢀ 245 Hz). Further, C-4 of 6f appeared ited the replication of HIV-1 and HIV-2 with EC values
50
–1
as a doublet at δ ꢀ=ꢀ 163.8 ppm (JC4–F ꢀ=ꢀ 245 Hz). The reso- of ꢀ>ꢀ11.50, ꢀ>ꢀ14.90 and ꢀ>ꢀ12.40 μg mL , respectively, but no
nances observed at the regions δ ꢀ=ꢀ 143.0–146.9 and selectivity could be witnessed. From the SAR analysis, we
1
54.6–155.4 ppm were attributed for C-8 and C-3 of the found that the halogen residues on the aromatic ring at
triazolothiadiazole scaffold, respectively. The most down- ortho-position, e.g. in 6d and 6g or alkyl group at ortho-
field resonances between δ ꢀ=ꢀ 165.8 and 166.6 ppm were or meta-position as in 6a and 6b, were well tolerated in
assigned to C-6 of the triazolothiadiazole unit due to the the hydrophobic region of HIV reverse transcriptase and
substitution as well as the deshielding effect of the sulfur then showed higher activity than those of the derivatives
atom. In the EI-MS, the appearance of molecular ion peaks with other substituents of the same series of Scheme 1.
for all the compounds further confirmed the synthesis However, the anti-HIV activity and the selectivity of
of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4] these compounds are too limited to perform extensive
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M.H. Khan et al.: Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazolesꢀꢂꢁꢁꢁꢀ3
Fig. 1:ꢁMolecular structure of 6a in the crystal. Displacement ellipsoids are drawn at the 50 % probability level, H atoms as spheres with
arbitrary radii.
Table 2:ꢁSelected bond angles (deg) for 6a.
Angle
ꢀ
ꢀ
Angle
ꢀ
C(ꢃ)–S(ꢃ)–C(ꢊ) ꢄ
C(ꢊ)–N(ꢊ)–C(ꢇ) ꢄ
N(ꢃ)–N(ꢊ)–C(ꢊ) ꢄ
N(ꢃ)–N(ꢊ)–C(ꢇ) ꢄ
N(ꢃ)–C(ꢃ)–C(ꢃꢃ)ꢄ
N(ꢊ)–N(ꢃ)–C(ꢃ) ꢄ
N(ꢊ)–C(ꢊ)–N(ꢇ) ꢄ
N(ꢊ)–C(ꢇ)–N(ꢈ) ꢄ
ꢍꢅ.ꢅꢋ(ꢅ)ꢄ
ꢃꢉꢋ.ꢅꢋ(ꢃꢊ)ꢄ
ꢃꢃꢍ.ꢋꢌ(ꢃꢊ)ꢄ
ꢃꢇꢋ.ꢆꢆ(ꢃꢇ)ꢄ
ꢃꢊꢇ.ꢍꢃ(ꢃꢇ)ꢄ
ꢃꢉꢅ.ꢅꢃ(ꢃꢊ)ꢄ
ꢃꢃꢃ.ꢅꢌ(ꢃꢇ)ꢄ
ꢃꢉꢍ.ꢃꢉ(ꢃꢇ)ꢄ
N(ꢊ)–C(ꢇ)–C(ꢈ) ꢄ
N(ꢇ)–N(ꢈ)–C(ꢇ) ꢄ
N(ꢈ)–N(ꢇ)–C(ꢊ) ꢄ
N(ꢈ)–C(ꢇ)–C(ꢈ) ꢄ
S(ꢃ)–C(ꢃ)–N(ꢃ) ꢄ
S(ꢃ)–C(ꢃ)–C(ꢃꢃ)ꢄ
S(ꢃ)–C(ꢊ)–N(ꢊ) ꢄ
S(ꢃ)–C(ꢊ)–N(ꢇ) ꢄ
ꢃꢊꢈ.ꢃꢅ(ꢃꢇ)
ꢃꢉꢌ.ꢉꢌ(ꢃꢇ)
ꢃꢉꢋ.ꢊꢍ(ꢃꢇ)
ꢃꢊꢅ.ꢅꢊ(ꢃꢈ)
ꢃꢃꢆ.ꢍꢌ(ꢃꢃ)
ꢃꢃꢌ.ꢇꢉ(ꢃꢉ)
ꢃꢉꢌ.ꢉꢅ(ꢃꢃ)
ꢃꢇꢌ.ꢃꢈ(ꢃꢊ)
2
.2 In vitro antimicrobial activity
Compounds 6a–l were tested for their antimicrobial
potential against different fungal and bacterial strains. Six
fungal strains, namely Trichphyton longifusus, Candida
albicans, Aspergillus flavus, Microsporum canis, Fusarium
solani and Candida glabrata, were used to study antifun-
gal activity. Antibacterial activity was evaluated against
six bacterial strains, i.e. Escherichia coli, Bacillus subtilis,
Shigella flexneri, Staphylococcus aureus, Pseudomonas
ꢃ.ꢈꢉꢃ(ꢊ) aeruginosa and Salmonella typhi. The activities of the
ꢃ.ꢇꢉꢉ(ꢊ) synthesized compounds were found to be non-significant
Fig. 2:ꢁPacking of molecules of 6a in the crystal.
Table 1:ꢁSelected bond lengths (Å) for 6a.
Bond
ꢀ
ꢀ
Bond
ꢀ
S(ꢃ)–C(ꢃ)ꢄ
S(ꢃ)–C(ꢇ)ꢄ
N(ꢃ)–N(ꢊ)ꢄ
N(ꢃ)–C(ꢃ)ꢄ
N(ꢊ)–C(ꢊ)ꢄ
N(ꢊ)–C(ꢇ)ꢄ
ꢃ.ꢅꢆꢇꢅ(ꢃꢈ)ꢄ
ꢃ.ꢅꢊꢋꢌ(ꢃꢆ)ꢄ
ꢃ.ꢇꢅꢅꢌ(ꢃꢅ)ꢄ
ꢃ.ꢊꢍꢍꢈ(ꢃꢌ)ꢄ
ꢃ.ꢇꢋꢋꢇ(ꢃꢌ)ꢄ
ꢃ.ꢇꢅꢉꢈ(ꢃꢌ)ꢄ
N(ꢇ)–N(ꢈ)
N(ꢇ)–C(ꢊ)
N(ꢈ)–C(ꢇ)
C(ꢃ)–C(ꢃꢃ) ꢄ
C(ꢇ)–C(ꢈ)
C(ꢃꢃ)–C(ꢃꢊ)ꢄ
ꢄ
ꢄ
ꢄ
ꢃ.ꢇꢃꢋ(ꢊ)
at non-toxic concentrations against the tested fungi and
ꢃ.ꢈꢍꢌ(ꢊ)
bacteria.
ꢄ
ꢃ.ꢈꢆꢈ(ꢊ)
ꢃ.ꢋꢈꢍ(ꢊ)
2
.3 Molecular modeling study
mode-of-action studies, and 6b might be considered as a The molecular docking was performed using Sꢁꢂꢁꢃ-X 1.1
new lead in the development of antiviral agents as a non- [35] and the docking results were shown by PꢁMOL [36].
nucleoside reverse transcriptase inhibitor.
In the docking study, X-ray crystal structure of HIV reverse
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ꢁꢁꢁꢂ
4ꢀ ꢀM.H. Khan et al.: Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
a
b
Table 3:ꢁIn vitro anti-HIV-1 and HIV-2 activities of the adamantyl-
methyl-triazolothiadiazole analogs 6a–l.
a selectivity of adamantyl-triazolothiadiazole 6g in its
binding to the enzyme pocket (Fig. 3). Detailed analysis
of the binding mode showed that the aromatic ring of 6g
points toward the aromatic ring of the Tyr179 residue appar-
ently developing π–π stacking interactions with the two
residues. The triazolothiadiazole backbone is located in
the middle of the binding pocket, anchoring the nitrogen
Entry
ꢀ
Virus ꢀ
strain
EC ꢀ
CC ꢀ
SIe
5
0
c
50
–
ꢁ
–ꢁ
d
(μg mL )
(μg mL )
ꢂa
ꢂb
ꢂc
ꢂd
ꢂe
ꢂf
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
III
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ>ꢄꢃꢃ.ꢋꢉꢄ
ꢄ>ꢄꢃꢃ.ꢋꢉꢄ
ꢄ>ꢄꢃꢉ.ꢌꢉꢄ
ꢄ>ꢄꢃꢉ.ꢌꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢈ.ꢌꢉꢄ
ꢄ>ꢄꢃꢈ.ꢌꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢆꢋ.ꢇꢇꢄ
ꢄ>ꢄꢆꢋ.ꢇꢇꢄ
ꢄ>ꢄꢃꢊ.ꢈꢉꢄ
ꢄ>ꢄꢃꢊ.ꢈꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢊꢈ.ꢅꢉꢄ
ꢄ>ꢄꢊꢈ.ꢅꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢉ.ꢉꢋꢄ
ꢄ≥ꢄꢃꢃ.ꢋꢉꢄ
ꢄ≥ꢄꢃꢃ.ꢋꢉꢄ
ꢄ≥ꢄꢃꢉ.ꢌꢉꢄ
ꢄ≥ꢄꢃꢉ.ꢌꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ≥ꢄꢃꢈ.ꢌꢉꢄ
ꢄ≥ꢄꢃꢈ.ꢌꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢆꢋ.ꢇꢇꢄ
ꢄ<ꢄ or Xꢃ
ꢄ<ꢄ or Xꢃ
ꢄ<ꢄ or Xꢃ
B
ROD
B
III
ROD
ꢄ<ꢄ or Xꢃ atom N-3 and the sulfur atom of 6g in a favorable position
III
Xꢃ
Xꢃ
B
for hydrogen bonding with Lys101 and Lys100, respectively,
of the reverse transcriptase enzyme. Overall, the combina-
tion of hydrophobic interaction and π stacking appears to
ROD
III
ꢄ<ꢄ or Xꢃ
ꢄ<ꢄ or Xꢃ
B
ROD
III
Xꢃ govern the binding of 6g with HIV reverse transcriptase.
B
ROD
Xꢃ
ꢄ<ꢄꢃ
ꢄ<ꢄꢃ
III
B
ROD
ꢆꢋ.ꢇꢇꢄ
3
Conclusion
ꢂg
ꢂh
ꢂi
III
ꢄ≥ꢄꢃꢊ.ꢈꢉꢄ
ꢄ≥ꢄꢃꢊ.ꢈꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢊꢈ.ꢅꢉꢄ
ꢄ>ꢄꢊꢈ.ꢅꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢃꢊꢋ.ꢉꢄ
ꢄ>ꢄꢈꢄ
ꢄ<ꢄ or Xꢃ
ꢄ<ꢄ or Xꢃ
B
ROD
III
Xꢃ The 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]
B
ROD
Xꢃ
thiadiazoles 6a–l were synthesized in a multistep
III
Xꢃ
B
sequence in high yields. The structures of the synthesized
ROD
Xꢃ
compounds were established using spectroscopic tech-
ꢂj
III
Xꢃ
B
ROD
Xꢃ niques; compound 6a was confirmed by single-crystal
ꢂk
ꢂl
III
Xꢃ
B
structure determination. The activity against HIV-1 and
ROD
Xꢃ
HIV-2 revealed that 6b was the most active candidate in
III
Xꢃ
B
the series. The antimicrobial activity of the synthesized
ROD
Xꢃ
Nevirapineꢄ
ꢄ
III
ꢄ>ꢄꢍꢉ compounds was also evaluated against different fungal
B
ROD
ꢄ>ꢄꢈꢄ
ꢄ>ꢄꢈꢄ
ꢄ<ꢄꢃ
and bacterial strains, but no activity was observed at non-
toxic concentrations against the tested fungi and bacteria.
a
b
Anti-HIV-1 activity measured with strain III . Anti-HIV-2 activity meas-
B
c
ured with strain ROD. Compound concentration required to achieve
5
0 % protection of MT-4 cells from HIV-1- and HIV-2-induced cytopath-
d
ogenic effects. Compound concentration that reduces the viability of
4
Experimental section
e
mock-infected MT-4 cells by 50 %. Selectivity index (CC /EC ).
50
50
4
.1 General
transcriptase (RT) enzyme (PDB: 1dtt) was obtained from
Protein Data Bank (http://www.rcsb.org) [37].
Melting points of the synthesized compounds were meas-
Compound 6g has been selected for the docking mod- ured in open capillaries using Stuart SMP3 melting point
eling study, since its binding energy score is –9.2, indicating apparatus (Barloworld Scientific Ltd, Staffordshire, UK)
OH
Tyr179
Tyr186
1'
H
N
N
N
H
5
Lys100
3'
N
S
2
N
Cl
3
Glu131
H
Pro319
N
Lys101
H
Fig. 3:ꢁ Docked conformation of 6g showing two hydrogen bondings: Lys101 with N3 of the thiadiazole ring and Lys100 with the sulfur
atom of the same ring. It also exhibited hydrophobic interactions between the phenyl group at C-3′ of the triazole moiety and Tyr179 of the
reverse transcriptase enzyme.
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M.H. Khan et al.: Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazolesꢀꢂꢁꢁꢁꢀꢃ
and are uncorrected. The IR spectra were recorded on a Hadaman.), 2.05 (br s, 3H, Hadaman.), 2.47 (s, 3H, Ar-Me), 2.80 (s,
Schimadzu Fourier Transform Infrared spectrophotom- 2H, CH ), 7.32 (m, 1H, Harom.), 7.44 (m, 1H, Harom.), 8.15–8.17
2
1
13
13
eter (Model 270, Japan). The H and CNMR spectra were (m, 2H, Harom.). – C NMR (75 MHz, CDCl ) δ ꢀ=ꢀ 21.5 (CH ),
3
3
recorded on a Bruker Avance 300 MHz NMR spectrometer 28.5, 33.9, 36.5, 42.3 (10 ꢀ×ꢀ Cadaman), 46.8 (CH ), 123.4, 125.7,
2
(
Bruker, Reinstetten, Germany) and signals calibrated to 126.9, 128.8, 131.1, 138.7 (6 ꢀ×ꢀ Carom.), 146.4 (Ctriazolothiad.-8),
the residual solvent signals. The EI mass spectrometry 155.0 (Ctriazolothiad.-3), 165.9 (Ctriazolothiad.-6). – EI-MS: m/z
+
was carried out using Agilent Technologies 6890N (GC) (%) ꢀ=ꢀ 364 (26) [M] , 230 (3), 135 (100), 117 (30), 107 (13), 93
with an inert selective detector 5973 mass spectrometer (36), 79 (52). – C H N S (364.51): C 69.20, H 6.64, N 15.37;
2
1
24
4
(
Agilent Technologies, San Diego, USA). The reagents found C 69.00, H 6.55, N 15.39.
used were of analytical grade, while the solvents were
purified before use.
4
.2.3 3-(4-Methylphenyl)-6-adamantylmethyl-1,2,
-triazolo[3,4-b]-1,3,4-thiadiazole (6c)
4
4
.2 General procedure for the synthesis
of 3-aryl-6-adamantylmethyl-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazoles 6a–l
From 4c (186 mg). Yield: 285 (87 %); m.p. 190–192 °C. – IR
–1
1
(
ATR, cm ): υ ꢀ=ꢀ 3027, 2898, 2847, 1527, 1456. – H NMR
max
(
300 MHz, CDCl ): δ ꢀ=ꢀ 1.62–1.76 (m, 12H, Hadaman.), 2.04 (br
3
A mixture of 4a–l (0.90 mmol) and (adamant-1-yl)acetic s, 3H, Hadaman.), 2.44 (s, 3H, Ar-Me), 2.79 (s, 2H, CH ), 7.34
acid 5 (175 mg, 0.90 mmol) in phosphorus oxychloride (d, 2H, J ꢀ=ꢀ 8.1 Hz, Harom.), 8.23 (d, 2H, J ꢀ=ꢀ 8.1 Hz, Harom.).
2
1
3
(
5 mL) was heated under reflux for 4 h. The reaction – C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 21.6 (CH ), 28.5, 33.9, 36.5,
3
3
mixture was cooled to room temperature, poured into 42.3 (10 ꢀ×ꢀ Cadaman.), 46.7 (CH ), 123.0, 126.3, 129.6, 140.5
2
crushed ice and neutralized with solid potassium carbon- (6 ꢀ×ꢀ Carom.), 146.4 (Ctriazolothiad.-8), 154.8 (C
-3), 165.9
triazolothiad.
+
ate and potassium hydroxide until the pH was 8. The pre- (Ctriazolothiad.-6). – EI-MS: m/z (%) ꢀ=ꢀ 364 (36) [M] , 230 (3),
cipitated products were filtered, washed with excess water 135 (100), 117 (30), 107 (12), 93 (32), 79 (41). – C H N S
2
1
24
4
and purified by silica gel column chromatography, using (364.51): C 69.20, H 6.64, N 15.37; found C 68.95, H 6.51, N
n-hexane-ethyl acetate (7:3) as eluent to give the desired 15.13.
products 6a–l.
4
.2.4 3-(2-Fluorophenyl)-6-adamantylmethyl-1,2,
4
.2.1 3-(2-Methylphenyl)-6-adamantylmethyl-1,2,
4-triazolo[3,4-b]-1,3,4-thiadiazole (6d)
4
-triazolo[3,4-b]-1,3,4-thiadiazole (6a)
From 4d (189 mg). Yield: 252 mg (76 %); m.p. 175–176 °C
–1
From 4a (186 mg). Yield: 272 mg (83 %); m.p. 186–187 °C. – IR (ATR, cm ): υ ꢀ=ꢀ 3021, 2899, 2847, 1531, 1460, 1228.
max
–1
1
1
–
IR (ATR, cm ): υ ꢀ=ꢀ 3040, 2899, 2844, 1527, 1459. – H – H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.60–1.74 (m, 12H, Hadaman.),
max 3
NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.61–1.77 (m, 12H, Hadaman.), 2.02 (br s, 3H, Hadaman.), 2.75 (s, 2H, CH ), 7.24–7.35 (m, 2H,
3
2
2
.04 (br s, 3H, Hadaman.), 2.60 (s, 3H, Ar-Me), 2.76 (s, 2H, Harom.), 7.52 (m, 1H, Harom.), 8.02 (dt, 1H, JH–F ꢀ=ꢀ 7.5, 1.8 Hz,
1
3
13
CH ), 7.34–7.46 (m, 3H, Harom.), 7.86 (m, 1H, Harom.). –
C
Harom.). – C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 28.5, 33.9, 36.5, 42.2
2
3
NMR (75 MHz, CDCl ) δ ꢀ=ꢀ 21.2 (CH ), 28.4, 33.9, 36.5, 42.3 (10 ꢀ×ꢀ Cadaman.), 46.7 (CH ), 114.2 (d, J ꢀ=ꢀ 13.0 Hz, Carom.-3),
3
3
2
C–F
(
1
1
(
–
10 ꢀ×ꢀ Cadaman.), 46.7 (CH ), 125.0, 125.9, 129.5, 130.2, 131.3, 116.6(d, JC–F ꢀ=ꢀ20.3Hz, Carom.-1), 124.5(d, JC–F ꢀ=ꢀ3.8Hz, Carom.-5),
2
38.1 (6 ꢀ×ꢀ Carom.), 146.9 (Ctriazolothiad.-8), 154.6 (Ctriazolothiad.-3), 130.3 (d, JC–F ꢀ=ꢀ 2.3 Hz, Carom.-6), 132.2 (d, JC–F ꢀ=ꢀ 8.3 Hz,
+
65.8 (Ctriazolothiad.-6). – EI-MS: m/z (%) ꢀ=ꢀ 364 (36) [M] , 230 Carom.-4), 143.0 (Ctriazolothiad.-8), 155.2 (Ctriazolothiad.-3), 159.9
3), 189 (26), 135 (100), 117 (30), 107 (12), 93 (28), 79 (36). (d, JC–F ꢀ=ꢀ 254 Hz, C -2), 166.0 (Ctriazolothiad.-6). – EI-MS: m/z
arom.
+
C H N S (364.51):C 69.20, H 6.64, N 15.37; found C 69.09, (%) ꢀ=ꢀ 368 (37) [M] , 234 (4), 135 (100), 121 (25), 107 (6), 93
2
1
24
4
H 6.58, N 15.48.
(12), 79 (12). – C H FN S (368.47): C 65.19, H 5.74, N 15.21;
found C 64.93, H 5.66, N 15.03.
20 21 4
4
.2.2 3-(3-Methylphenyl)-6-adamantylmethyl-1,2,
4
-triazolo[3,4-b]-1,3,4-thiadiazole (6b)
4.2.ꢃ 3-(3-Fluorophenyl)-6-adamantylmethyl-1,2,
4
-triazolo[3,4-b]-1,3,4-thiadiazole (6e)
From 4b (186 mg). Yield: 287 mg (88 %); m.p. 178–180 °C.
–1
–
IR (ATR, cm ): υ ꢀ=ꢀ 3035, 2896, 2843, 1533, 1445. – From 4e (189 mg). Yield: 298 mg (90 %); m.p. 196–198 °C.
max
1
–1
H NMR (300 MHz, CDCl , ppm): δ ꢀ=ꢀ 1.63–1.77 (m, 12H, – IR (ATR, cm ): υ ꢀ=ꢀ 3030, 2899, 2847, 1525, 1454, 1199.
3
max
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ꢁꢁꢁꢂ
6ꢀ
ꢀM.H. Khan et al.: Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
– 1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.63–1.77 (m, 12H, Hadaman.), – H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.61–1.75 (m, 12H, Hadaman.),
1
3
3
2
.05 (br s, 3H, Hadaman.), 2.82 (s, 2H, CH ), 7.20 (m, 1H, 2.03 (br s, 3H, Hadaman.), 2.80 (s, 2H, CH ), 7.44–7.47 (m, 2H,
2
2
1
3
Harom.), 7.52 (m, 1H, Harom.), 8.10 (m, 1H, Harom.), 8.17 (m, 1H, Harom.), 8.24 (m, 1H, Harom.), 8.35 (m, 1H, Harom.). – C NMR
13
Harom.). – C NMR (75 MHz, CDCl ) δ ꢀ=ꢀ 28.5, 34.0, 36.5, 42.3 (75 MHz, CDCl ): δ ꢀ=ꢀ 28.5, 33.9, 36.4, 42.3 (10 ꢀ×ꢀ Cadaman.),
3
3
(
1
10 ꢀ×ꢀ Cadaman.), 46.8 (CH ), 113.3 (d, J ꢀ=ꢀ 24.0 Hz, Carom.-2), 46.7 (CH ), 124.3, 126.2, 127.4, 130.1, 130.2, 134.9 (6 ꢀ×ꢀ Carom.),
2
C
–
F
2
17.2 (d, JC–F ꢀ=ꢀ 21.0 Hz, Carom.-4), 122.0 (d, JC–F ꢀ=ꢀ 3.0 Hz, 144.9 (Ctriazolothiad.-8), 155.4 (C
-3), 166.6 (C
-6).
triazolothiad.
triazolothiad.
+
+
Carom.-6), 127.7 (d, JC–F ꢀ=ꢀ 9.0 Hz, Carom.-5), 130.7 (d, JC–F ꢀ=ꢀ 8.3 – EI-MS: m/z (%) ꢀ=ꢀ 386 (5) [M+2] , 384 (14) [M] , 139 (7),
Hz, Carom.-1), 145.2 (Ctriazolothiad.-8), 155.4 (Ctriazolothiad.-3), 162.9 137 (23), 135 (100), 107 (13), 93 (39), 79 (61). – C H ClN S
20
21
4
(
d, JC–F ꢀ=ꢀ 245 Hz, Carom.-3), 166.6 (Ctriazolothiad.-6). – EI-MS: m/z (384.93): C 62.41, H 5.50, N 14.56; found C 62.23, H 5.43, N
+
(
%) ꢀ=ꢀ 368 (19) [M] , 135 (100), 121 (33), 107 (12), 93 (33), 79 14.39.
(
44). – C H FN S (368.47): C 65.19, H 5.74, N 15.21; found C
2
0
21
4
6
4.90, H 5.53, N 15.11.
4
.2.9 3-(4-Chlorophenyl)-6-adamantylmethyl-1,2,
-triazolo[3,4-b]-1,3,4-thiadiazole (6i)
4
4
.2.6 3-(4-Fluorophenyl)-6-adamantylmethyl-1,2,
-triazolo[3,4-b]-1,3,4-thiadiazole (6f)
4
From 4i (204 mg). Yield: 319 mg (92 %); m.p. 250–252 °C.
IR (ATR, cm ): υ ꢀ=ꢀ 3029, 2897, 2847, 1531, 1451, 1082.
–1
–
–
2
max
From 4f (189 mg). Yield: 279 mg (84 %); m.p. 200–201 °C. –
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.63–1.77 (m, 12H, Hadaman.),
–1
1
3
IR (ATR, cm ): υ ꢀ=ꢀ 3033, 2898, 2850, 1537, 1456, 1220. – H
max
.05 (br s, 3H, Hadaman.), 2.81 (s, 2H, CH ), 7.50–7.54 (m, 2H,
2
NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.61–1.75 (m, 12H, Hadaman.), 2.03
3
13
Harom.), 8.29–8.33 (m, 2H, Harom.). – C NMR (75 MHz, CDCl ):
3
(
br s, 3H, Hadaman.), 2.78 (s, 2H, CH ), 7.19–7.24 (m, 2H, Harom.),
2
δ ꢀ=ꢀ 28.5, 34.0, 36.4, 42.3 (10 ꢀ×ꢀ Cadaman.), 46.8 (CH ), 124.3,
13
2
8
.32–8.37 (m, 2H, Harom.). – C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 28.5,
3
1
27.5, 129.2, 136.2 (6 ꢀ×ꢀ Carom.), 145.4 (Ctriazolothiad.-8), 155.2
3
3.9, 36.4, 42.3 (10 ꢀ×ꢀ Cadaman.), 46.8 (CH ), 116.1 (d, J ꢀ=ꢀ 22.5
2 C–F
(
C
-3), 166.4 (C
-6). – EI-MS: m/z (%) ꢀ=ꢀ 386
triazolothiad.
triazolothiad.
Hz, Carom.-3 + Carom.-5), 122.1 (d, JC–F ꢀ=ꢀ 3.0 Hz, Carom.-1), 128.4
+
+
(
9
6) [M+2] , 384 (17) [M] , 139 (8),137 (22), 135 (100), 107 (11),
(
d, JC–F ꢀ=ꢀ 8.3 Hz, Carom.-2 + Carom.-6), 145.4 (Ctriazolothiad.-8),
3 (30), 79 (40). – C H ClN S (384.93): C 62.41, H 5.50,
N 14.56; found C 62.20, H 5.44, N 14.33.
20 21 4
1
55.1 (Ctriazolothiad.-3), 163.8 (d, JC–F ꢀ=ꢀ 245 Hz, Ar C-4), 166.3
+
(Ctriazolothiad.-6). – EI-MS: m/z (%) ꢀ=ꢀ 368 (22) [M] , 135 (100), 121
(38), 107 (12), 93 (31), 79 (33). – C H FN S (368.47): C 65.19,
20 21 4
H 5.74, N 15.21; found C 64.89, H 5.68, N 15.01.
4
.2.1ꢄ 3-(2-Bromophenyl)-6-adamantylmethyl-1,2,
-triazolo[3,4-b]-1,3,4-thiadiazole (6j)
4
4
.2.7 3-(2-Chlorophenyl)-6-adamantylmethyl-1,2,
-triazolo[3,4-b]-1,3,4-thiadiazole (6g)
4
From 4j (244 mg). Yield: 317 mg (82 %); m.p. 222–224 °C.
–1
–
IR (ATR, cm ): υ ꢀ=ꢀ 3035, 2895, 2847, 1528, 1456, 1042.
max
1
From 4g (204 mg). Yield: 295 (85 %); m.p. 211–213 °C. – IR – H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.61–1.75 (m, 12H, Hadaman),
3
–1
1
(
ATR, cm ): υ ꢀ=ꢀ 3026, 2898, 2847, 1525, 1454, 1036. – H 2.03 (br s, 3H, Hadaman), 2.75 (s, 2H, CH ), 7.43 (m, 1H, Harom.),
m
a
x
2
1
3
NMR(300MHz,CDCl ):δꢀ=ꢀ1.61–1.75(m,12H,Hadaman.),2.03(br 7.49 (m, 1H, Harom.), 7.71–7.79 (m, 2H, Harom.). – C NMR (75
3
s, 3H, Hadaman.), 2.74 (s, 2H, CH ), 7.41–7.53 (m, 2H, Harom.), 7.58 MHz, CDCl ): δ ꢀ=ꢀ 28.5, 34.0, 36.5, 42.3 (10 ꢀ×ꢀ Cadaman.), 46.6
2
3
13
(
m, 1H, Harom.), 7.78 (m, 1H, Harom.). – C NMR (75 MHz, CDCl ): (CH ), 123.2, 127.4, 127.6, 131.9, 132.4, 133.7 (6 ꢀ×ꢀ Carom.), 145.5
3 2
δ ꢀ=ꢀ 28.5, 34.0, 36.5, 42.2 (10 ꢀ×ꢀ Cadaman.), 46.7 (CH ), 125.3, 127.0, (Ctriazolothiad.-8), 154.8 (Ctriazolothiad.-3), 166.0 (C
-6).
2
triazolothiad.
+
+
1
30.5, 131.7, 132.0, 133.9 (6 ꢀ×ꢀ Carom.), 145.1 (Ctriazolothiad.-8), 155.0 – EI-MS: m/z (%) ꢀ=ꢀ 430 (10) [M+2] , 428 (9) [M] ,183 (6),
(
C
-3), 166.0 (Ctriazolothiad.-6). – EI-MS: m/z (%) ꢀ=ꢀ 386 (3) 181 (6), 135 (100), 107 (13), 93 (37), 79 (58). – C H BrN S
triazolothiad.
20 21
4
+
+
[
M+2] , 384 (13) [M] , 139 (12),137 (37), 135 (100), 107 (15), 93 (429.38): C 55.95, H 4.93, N 13.05; found C 55.74, H 4.79, N
(
47), 79 (36). – C H ClN S (384.93): C 62.41, H 5.50, N 14.56; 12.88.
20 21 4
found C 62.23, H 5.43, N 14.39
4
.2.11 3-(3-Bromophenyl)-6-adamantylmethyl-1,2,
4
.2.8 3-(3-Chlorophenyl)-6-adamantylmethyl-1,2,
-triazolo[3,4-b]-1,3,4-thiadiazole (6h)
4-triazolo[3,4-b]-1,3,4-thiadiazole (6k)
4
From 4k (244 mg). Yield: 336 mg (87 %); m.p. 235–237 °C.
–1
From 4h (204 mg). Yield: 308 mg (89 %); m.p. 200–202 °C. – IR (ATR, cm ): υ ꢀ=ꢀ 3030, 2899, 2848, 1543, 1451, 1055.
max
–1
1
–
IR (ATR, cm ): υ ꢀ=ꢀ 3012, 2898, 2842, 1535, 1463, 1034. – H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.64–1.78 (m, 12H, Hadaman),
max 3
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Download Date | 6/22/15 7:22 AM

M.H. Khan et al.: Synthesis of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazolesꢀꢂꢁꢁꢁꢀ7
2
.06 (br s, 3H, Hadaman), 2.83 (s, 2H, CH ), 7.42 (m, 1H, H ), Acknowledgments: This work was financially supported
2
arom.
1
3
7
.63 (m, 1H, Harom.), 8.32 (m, 1H, Harom.), 8.54 (m, 1H, Harom.). – C by Higher Education Commission (HEC) of Pakistan
NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 28.5, 34.0, 36.5, 42.3 (10 ꢀ×ꢀ Cadaman.), through a PhD fellowship to Mahmood-ul-Hassan Khan
3
4
6.8 (CH ), 123.0, 124.7, 127.7, 129.1, 130.5, 133.1 (6 ꢀ×ꢀ Carom.), under “Indigenous Ph. D. 5000 Fellowship Program”. We
2
1
44.9 (Ctriazolothiad.-8), 155.4 (C
-3), 166.6 (Ctriazolothiad.-6). thank Professor C. Pannecouque of Rega Institute for Med-
triazolothiad.
+
+
–
EI-MS: m/z (%) ꢀ=ꢀ 430 (2) [M+2] , 428 (2) [M] , 183 (9), 181 ical Research, Katholieke Universiteit, Leuven, Belgium,
(
8), 135 (100), 107 (13), 93 (34), 79 (81). – C H BrN S (429.38): for the anti-HIV screening.
20 21 4
C 55.95, H 4.93, N 13.05; found C 55.68, H 4.82, N 12.79.
4
.2.12 3-(4-Bromophenyl)-6-adamantylmethyl-1,2,
References
4
-triazolo[3,4-b]-1,3,4-thiadiazole (6l)
[
1] B. S. Holla, K. N. Poojary, B. S. Rao, M. K. Shivananda, Eur. J.
Med. Chem. 2ꢄꢄ2, 37, 511.
From 4l (244 mg). Yield: 325 mg (84 %); m.p. 246–248 °C.
[
2] Y. A. Al-Soud, N. A. Al-Masoudi, R. Loddo, P. La Colla, Arch.
Pharm. 2ꢄꢄ8, 341, 365.
–1
–
–
IR (ATR, cm ): υ ꢀ=ꢀ 3033, 2896, 2847, 1531, 1451, 1065.
max
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.63–1.77 (m, 12H, Hadaman.),
1
3
[3] Z. Y. Zhang, M. Li, L. Zhao, Z. M. Li, R. A. Liao, Chin. J. Org.
Chem. 1993, 13, 397.
2
.05 (br s, 3H, Hadaman), 2.81 (s, 2H, CH ), 7.67–7.70 (m, 2H,
2
13
Harom.), 8.23–8.26 (m, 2H, Harom.). – C NMR (75 MHz, CDCl ):
δ ꢀ=ꢀ 28.5, 34.0, 36.5, 42.3 (10 ꢀ×ꢀ Cadaman.), 46.8 (CH ), 124.6,
[4] I. Khan, S. Hameed, N. A. Al-Masoudi, N. A. Abdul-Reda,
J. Simpson, Z. Naturforsch. 2ꢄ1ꢃ, 70b, 47.
3
2
[
5] N. A. Al-Masoudi, Y. A. Al-Soud, Nucleos. Nucleot. Nucl Acids
1
24.7, 127.7, 132.2 (6 ꢀ×ꢀ Carom.), 145.4 (Ctriazolothiad.-8), 155.3
2
ꢄꢄ8, 27, 1034.
(C
-3), 166.5 (C
-6). – EI-MS: m/z (%) ꢀ=ꢀ 430
triazolothiad.
triazolothiad.
[
[
6] M. A. Al-Omar, Molecules 2ꢄ1ꢄ, 15, 502.
+
+
(6) [M+2] , 428 (6) [M] , 183 (8), 181 (8), 135 (100), 107 (14),
9
7] M. Ashok, B. S. Holla, J. Pharmacol. Toxicol. 2ꢄꢄ7, 2, 256.
3 (39), 79 (56). – C H BrN S (429.38): calcd. C 55.95, H
.93, N 13.05; found C 55.70, H 4.84, N 12.91.
[8] M. Z. Maqsood, M. Hanif, M. Rafiq, M. Saleem, S. Zaib,
A. A. Khan, M. Iqbal, J. Iqbal, N. H. Rama, S.-Y. Seo, K.-H. Lee,
Bull. Korean Chem. Soc. 2ꢄ12, 33, 4180.
2
0
21
4
4
[
9] N. S. A. M. Khalil, Eur. J. Med. Chem. 2ꢄꢄ7, 42, 1193.
[
[
[
[
10] Y. A. Ammar, M. M. Ghorab, A. M. El-Sharief, S. I. Mohamed,
4
.3 Crystal structure determination of 6a
Heteroatom Chem. 2ꢄꢄ2, 13, 199.
11] V. Mathew, J. Keshavayya, V. P. Vaidya, D. Giles, Eur. J. Med.
Chem. 2ꢄꢄ7, 42, 823.
Suitable single crystals of compound 6a were obtained as
colorless blocks from chloroform. Data were collected on
a Stoe Image Plate Diffraction System diffractometer with
graphite-monochromatized MoK radiation (λ ꢀ=ꢀ 0.71073
Å). The structure was solved by Direct Methods and
12] H. M. Hirpara, V. A. Sodha, A. M. Trivedi, B. L. Khatri, A. R.
Parikh, Indian J. Chem. 2ꢄꢄ3, 42B, 1756.
13] I. Khan, S. M. Bakht, A. Ibrar, S. Abbas, S. Hameed, J. M. White,
U. A. Rana, S. Zaib, M. Shahid, J. Iqbal, RSC Adv. 2ꢄ1ꢃ, 5,
α
2
1249.
2
refined by full-matrix least-squares procedures on F with [14] I. Khan, A. Ibrar, S. Zaib, S. Hameed, J. Simpson, J. Iqbal,
the Sꢄꢅꢃꢆꢇ/ꢃ-97 software package. Hydrogen atoms were
placed in idealized positions and included as constrained
into the refinement, while all other atoms were refined
with anisotropic displacement parameters.
Bioorg. Med. Chem. 2ꢄ14, 22, 6163.
[
15] N. Chindananda, B. Poojary, V. Sumangala, N. S. Chetty,
T. Arulmoli, Eur. J. Med. Chem. 2ꢄ12, 51, 124.
[
16] L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev. 2ꢄ13, 113,
3
516.
Crystal structure data: C H N S, M ꢀ=ꢀ 364.50, color-
2
1
24
4
r
[17] A. A. El-Emam, K. A. Alrashood, M. A. Al-Omar, A.-M. S.
3
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Z. Naturforsch.ꢀ
ꢀ2015 | Volume x | Issue x(b)
Graphical synopsis
Mahmood-ul-Hassan Khan, Shahid
Hameed, Muhammad Farman,
Najim A. Al-Masoudi and Helen
Stoeckli-Evans
Synthesis, anti-HIV activity and
molecular modeling study of
OH
Tyr179
Tyr186
1
N
'
H
N
N
H
5
Lys100
3
'
N
S
2
N
Cl
3
Glu131
H
3
-aryl-6-adamantylmethyl-[1,2,4]
Pro319
N
Lys101
H
triazolo[3,4-b][1,3,4]thiadiazole
derivatives
DOI 10.1515/znb-2015-0032
Z. Naturforsch. 2015; x(x)b: xxx–xxx
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