A solvent free, four-component synthesis and 1,3-dipolar cycloaddition of 4(H)-pyrans with nitrile oxides: Synthesis and discovery of antimycobacterial activity of enantiomerically pure 1,2,4-oxadiazoles

Article abstract of DOI:10.1016/j.ejmech.2012.04.021

Four-component reactions of (R)-1-(1-phenylethyl)tetrahydro-4(1H)- pyridinone, aromatic aldehydes and malononitrile in a 1:2:1 molar ratio in the presence of solid sodium ethoxide under solvent free conditions afforded an inseparable mixture of two diastereomeric 4(H)-pyrans in near quantitative yields. These compounds upon 1,3-dipolar cycloaddition with nitrile oxides furnished two enantiomerically pure 1,2,4-oxadiazoles in moderate yields, which were screened for in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the compounds screened, compound 10h was found to be the most active in vitro with a MIC value of 0.07 and 0.14 μM against MTB and MDR-TB respectively.

Full text of DOI:10.1016/j.ejmech.2012.04.021

European Journal of Medicinal Chemistry 53 (2012) 416e423
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
A solvent free, four-component synthesis and 1,3-dipolar cycloaddition
of 4(H)-pyrans with nitrile oxides: Synthesis and discovery of antimycobacterial
activity of enantiomerically pure 1,2,4-oxadiazoles
Abdulrahman I. Almansour , Raju Suresh Kumar , Natarajan Arumugam , Dharmarajan Sriram b
a
a
,
a
*
a
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science e Pilani, Hyderabad Campus, Jawahar Nagar,
b
Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 February 2012
Received in revised form
Four-component reactions of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehydes
and malononitrile in a 1:2:1 molar ratio in the presence of solid sodium ethoxide under solvent free
conditions afforded an inseparable mixture of two diastereomeric 4(H)-pyrans in near quantitative
yields. These compounds upon 1,3-dipolar cycloaddition with nitrile oxides furnished two
enantiomerically pure 1,2,4-oxadiazoles in moderate yields, which were screened for in vitro activity
against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB).
Among the compounds screened, compound 10h was found to be the most active in vitro with a MIC
5
April 2012
Accepted 12 April 2012
Available online 21 April 2012
Keywords:
value of 0.07 and 0.14
m
M against MTB and MDR-TB respectively.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Antitubercular activity
Mycobacterium tuberculosis
Multi-drug resistant tuberculosis
1
,3-Dipolar cycloaddition
Pyrans
,2,4-Oxadiazoles
1
1
. Introduction
decades, except the recently introduced fluoroquinolones [8,9],
which testifies to the lack of significant research in this area in the
pharmaceutical industry. Hence the development of new drugs,
capable of overcoming MDR- and XDR-TB, to efficiently treat this
disease is imperative.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB),
has become an important world-wide public health problem with
one-third of theworld’s population infected by the TB bacillus. About
9
million people, mostly from developing countries, develop active
Pyran derivatives occupy an important place in the realm of
natural and synthetic organic chemistry, because of their biological
and pharmacological properties as antisterility and anticancer
agents [10,11]. Polyfunctionalised dihydropyran is a common
structural unit in a number of natural products such as secoiridoid
monoterpenes and biogenetically related indole alkaloids [12,13].
2-Amino-3-cyano-4H-pyrans possess photochemical activity [14],
and the synthesis of 4H-pyran in recent years has attracted
considerable interest as an important intermediate for the
construction of many heterocycles. The 4H-pyran ring can also be
transformed into pyridine systems which are also pharmacologi-
cally important [15,16].
TB yearly, and the death toll is about 2 million in each year [1,2]. The
pathogenic synergyof tuberculosis with HIV [3] enhances the overall
incidence of TB in HIV-positive patients by 50 times relative to the
rate for HIV-negative individuals [4]. Single agent TB therapy rapidly
leads to drug-resistant organisms [5], while multi-drug treatment
needs to be prolonged as MTB divides slowly and it is metabolically
capable of becoming drug insensitive and/or bacilli may become
sequestered [6,7]. The emergence of multi-drug and extensively
drug-resistant tuberculosis (MDR-TB and XDR-TB) further aggra-
vates the problems associated with TB treatment, as patients could
become virtually untreatable using currentlyavailable anti-TB drugs.
Furthermore, no new drugs have been introduced in the last four
The 1,2,4-oxadiazole ring system, known as an ester isostere
[
17], is prevalent in various biologically interesting benzodiazepine
receptor ligands [18,19], muscarinic receptor agonists (1, Fig. 1)
20e22] and 5HT
receptor antagonists (2, Fig. 1) [23]. Marine
[
3
*
Corresponding author. Tel.: þ966 4675907; fax: þ966 4675992.
alkaloids, phidianidines A (3, R ¼ Br) and B (3, R ¼ H) (Fig. 1) iso-
E-mail addresses: sraju@ksu.edu.sa, drrajusureshkumar@gmail.com (R. Suresh
Kumar).
lated from the aeolid opisthobranch Phidiana militaris exhibit high
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.04.021

A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
417
Fig. 1. Examples of biologically active 1,2,4-oxadiazoles.
cytotoxicity against tumour and nontumor mammalian cell lines in
in vitro assays [24]. 1,2,4-Oxadiazoles have also been found to
possess analgesic [25], anti-inflammatory [26] and antitumour [27]
activities. These observations lead to the conclusion that 1,2,4-
oxadiazoles satisfy the definition of privileged scaffolds, that is,
molecular frameworks that are able to bind to a diverse array of
receptors [28]. Molecules with piperidine sub-structure possesses
analgesic [29,30], anti-inflammatory [29], central nervous system
the cases, the product was obtained as a mixture of two diaste-
reomers of 8 with almost similar R values, which could not be
f
separated through column chromatography. However, the products
1
were identified from the H NMR spectrum of the mixture and the
ratio of diastereomers was calculated from the intensities of the
singlets due to H-4 of major and minor isomers of 8b respectively
occurring at 3.91 and 3.84 ppm. The other notable signals of the
2
diastereomers of 8b are: a singlet from the NH protons at 4.57 ppm,
(
CNS) depressant [31e33], local anaesthetic [31,34], anticancer [35],
two singlets at 6.81 and 6.84 ppm from the arylmethylidene
and antimicrobial activities [36].
hydrogen, doublets and multiplets in the region, 2.76e3.31 ppm
Recently, we have initiated a research programme aimed at
studying the application of multi-component, domino and cyclo-
addition reactions to the construction of novel heterocycles
2 2
and 3.52e3.75 ppm, due to 5-CH and 7-CH protons of the major
and minor isomers. The doublets at 1.20 ppm (J ¼ 6.6 Hz) and
1.27 ppm (J ¼ 7.2 Hz) are due to the methyl protons of the phenyl-
ethyl group. The signals for CH hydrogen of the mixture overlap and
appear as a quartet at 3.42 ppm (J ¼ 6.6 Hz). The methyl hydrogens
of the aryl rings appear as singlets at 2.31, 2.33 and 2.34 ppm and
the aromatic hydrogens appear as a multiplet at 6.93e7.30 ppm.
With the diastereomeric mixture of 4(H)-pyrans (8aee) in our
hand, next our aim is to synthesize oxadiazole derivatives using
eC^N functionality as the dipolarophile. The 1,3-dipolar cycloaddi-
tion of nitrile oxide, generated in situ from N-hydroxyarylimidoyl
chlorideand triethylamine, totheinseparablediastereomericmixture
of 2-amino-4-aryl-6-[(R)-1-phenylethyl]-8-[(E)-1-arylmethylidene]-
5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridine-3-carbonitriles 8aee
(Scheme 2) furnished two diastereomeric 1,2,4-oxadiazoles 9 and
10, which could be separated through column chromatography using
petroleum ether/ethyl acetate as eluent. These enantiomerically pure
oxadiazoles 9 and 10 were obtained in 30e38% and 15e29% yields
respectively.
[37e42], and their screening for antimycobacterial activities, which
has unearthed several compounds with activities comparable to or
superior to those of some of the currently employed first-line drugs
for TB [43e51]. In this context, we report here our findings on the
antitubercular properties of enantiomerically pure hybrid hetero-
cycles incorporating piperidine, pyran and oxadiazoles.
2
. Chemistry
In the present investigation, the reaction of (R)-1-(1-
phenylethyl)tetrahydro-4(1H)-pyridinone 5, a series of aromatic
aldehydes 6 and malononitrile 7 in a 1:2:1 molar ratio in the
presence of solid sodium ethoxide under solvent free condition
afforded a mixture of two diastereomers of tetrahydro-4H-pyrano
[3,2-c]pyridine-3-carbonitriles
8 in near quantitative yields
(
94e97%) (Scheme 1, Table 1). Enantiomerically pure (R)-1-(1-
phenylethyl)tetrahydro-4(1H)-pyridinone 5, required for this
investigation, was prepared from 1-methyltetrahydro-4(1H)-pyr-
idinone 4 following a literature procedure [52]. A mixture of (R)-1-
The cycloadducts were characterized by one- and two-
1
dimensional NMR spectroscopic data as illustrated for 9a. The
H
NMR spectrum of 9a has a singlet at 4.36 ppm readily assignable to
H-4, whose C,H-COSY correlation assigns 40.8 ppm to C-4. The H-4
shows HMBCs (Fig. 2) with (i) C-5 at 50.4 ppm and (ii) C-4a at
114.0 ppm. Further, H-4 also shows HMBCs with (i) C-3 at 74.1 ppm,
(
1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehyde
and malononitrile in solid sodium ethoxide was ground well in
a semimicro boiling tube at ambient temperature for about 2e3 min
and after completion of the reaction, water (50 mL) was added to
the mixture and the product was filtered and dried in vacuo. In all
0
(ii) C-2 at 156.6 ppmand(iii) C-5 of theoxadiazole ring at 175.9 ppm.
2
The C,H-COSY spectrum assigns the 5-CH hydrogens to a doublet at
Scheme 1. Synthesis of 4(H)-pyrans 8.

418
A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
Table 1
Diastereomeric ratio and yield of compounds 8aee.
duplicate. The MDR-TB clinical isolate was resistant to the first-line
anti-TB drugs, isoniazid, rifampicin and ethambutol. The MIC,
defined as the minimum concentration of the compound required
to completely inhibit the bacterial growth, the MIC values of the
synthesized compounds and the standard drugs for comparison are
reported in Table 2.
Comp
Ar
Ratio of diastereomers of 8
Yield of 8 (RR) þ (RS) (%)
a
b
c
d
e
C
6
H
5
1:0.6
1:0.4
1:0.9
1:0.9
1:0.9
96
97
95
96
94
p-MeC
o-ClC
o,p-Cl
6
H
4
6
H
4
2
C
6
H
3
In the first phase of screening against MTB, all the compounds
showed excellent in vitro activity with MIC ranging from 0.07 to
1-Naphthyl
1
8.80
with MIC of less than 5.22
dard, ethambutol (MIC: 7.64
10h) were found to be more active against MTB than isoniazid
(MIC: 0.36 M). Compound 10h was found to be the most active
in vitro with MIC of 0.07 M against MTB displaying 1.7, 5.1, 67.3 and
m
M. Twelve compounds (9b, 9deh, 10aej) inhibited MTB
M and are more potent than the stan-
M). Three compounds (9h, 10f and
3
.02 (J ¼ 15.9 Hz) and a multiplet at 3.32e3.37 ppm. The 5-CH
hydrogens show a HMBC with a carbon at 49.7 ppm assigning it to C-
. From C,H-COSY spectrum, the doublet and a multiplet at 3.76
hydro-
2
m
m
7
(
J ¼ 14.1 Hz) and 3.32e3.37 ppm can be assigned to 7-CH
2
m
gens, which show HMBC with C-8a at 139.9 ppm. The benzylidene
hydrogen H-9 appears as a singlet at 6.97 ppm, the C,H-COSY of
which assigns the signal at 123.1 ppm to C-9. The carbon signal at
m
109 times greater activity than rifampicin, isoniazid, ciprofloxacin
and ethambutol respectively.
0
1
66.7 ppm can be assigned to C-3 of oxadiazole ring. The methine
and methyl hydrogens of 1-phenylethylamine appear as a quartet
and a doublet at 3.47 and 1.17 ppm (J ¼ 6.6 Hz) and the aromatic
hydrogens appearas multiplets at 7.06e8.03 ppm. The assignmentof
hydrogen and carbon signals of 10a has also been done by similar
Subsequently, compounds having MIC < 3
against MDR-TB, which inhibited MDR-TB with MIC ranging from
0.14 to 5.54 M. All the twelve compounds screened were found to
be more active than isoniazid (MIC: 11.38 M), ciprofloxacin (MIC:
37.73 M) and ethambutol (MIC: 61.18 M). Eleven compounds
with MIC ꢁ 2.60 were more active than rifampicin (MIC: 3.80 M).
Compounds 9h and 10h display the maximum activity in vitro with
MIC of 0.14 M against MDR-TB, being 27.1, 81.3, 269.5 and 437
mM were evaluated
m
m
m
m
1
13
straightforward considerations. The H and C chemical shifts of 9a
and 10a are depicted in Figs. 3 and 4 respectively.
m
The absolute configuration atC-4 of9 and10 could not bededuced
from NMR data alone. However, no compound belonging to 9 and 10
afforded crystals suitable for X-ray crystallographic study rendering
the assignment of their complete stereochemistry difficult. To obtain
crystals suitable for X-raycrystallographic structure determination to
deduce the absolute configuration at C-4, the cycloadduct 10 was
acetylated with acetic anhydride (Scheme 3). However, the product
m
times more potent than rifampicin, isoniazid, ciprofloxacin and
ethambutol respectively.
In general, oxadiazoles belonging to the diastereomer 10 display
enhanced activity (2e4 times) relative to the diastereomer 9 against
MTB disclosing that the activity is sensitive to the stereochemistry
of the pyran. On the contrary, the activities of the diastereomers of
each compound tested against MDR-TB appear to be insensitive to
their stereochemistry, in the range of compounds investigated, as
evident from the fact that their MIC values are equal.
11 was obtained as a viscous liquid impeding X-ray crystallographic
study. Hence, with a view to arriving at the most likely relative
configuration at C-4, optimization of the cycloadducts 9a and10a was
done using AM1 calculations (Arguslab 4.0.1). From the optimized
geometries, it is clear that the two diastereomers have almost equal
energy (ꢀ1,53,115.0997 kcal/mol and ꢀ1,53,115.0153 kcal/mol),
showing that both the isomers are almost equally stable. This is also
evident from the formation of the diastereomers, 9 and 10 in most
cases in approximately equal amounts Scheme 2.
4. Conclusion
The present investigation describes a facile access to highly
functionalised 4H-pyrans from (R)-1-(1-phenylethyl)tetrahydro-
4(1H)-pyridinone, a series of aromatic aldehydes and malononitrile
using solid sodium ethoxide under solvent free conditions in near
quantitative yields and their chemoselective 1,3-dipolar cycload-
dition with nitrile oxides furnishing two enantiomerically pure
1,2,4-oxadiazoles in moderate yields. These novel oxadiazoles
showed excellent in vitro activity against M. tuberculosis H37Rv
(MTB) and multi-drug resistant M. tuberculosis (MDR-TB). The novel
oxadiazole derivatives discovered in this study may provide valu-
able therapeutic intervention for the treatment of tuberculosis.
Although the tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitriles
8aeepossess two dipolarophilic functionalities, viz. eC]CandeC^N,
nitrile oxide adds preferentially to the cyano functionality furnishing
only the 1,2,4-oxadiazoles, 9 and 10 showing that this reaction
proceeds chemoselectively. The cycloadduct 12 arising from the
addition of nitrile oxide to C]C was not formed, even when an excess
of nitrile oxide was used (Scheme 4).
3
. Biological results and discussion
5. Experimental
The enantiomerically pure 1,2,4-oxadiazoles, 9 and 10, bearing
diastereomeric relationship, were screened for their in vitro anti-
mycobacterial activity against MTB and MDR-TB by agar dilution
method similar to that recommended by the National Committee
for Clinical Laboratory Standards for the determination of MIC in
5.1. General methods
The melting points were measured using open capillary tubes
and are uncorrected. H, C and two-dimensional NMR spectra
1
13
Scheme 2. Synthesis of enantiomerically pure oxadiazoles 9 and 10.

A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
419
Fig. 2. Selected HMBCs of 9a.
were recorded on a Bruker 300 MHz instrument in CDCl
as internal standard. Chemical shifts are given in parts per million
-scale) and the coupling constants are given in hertz. IR spectra
were recorded on a JASCO FT IR instrument (KBr pellet in case of
solids and CHCl in case of liquids). Elemental analyses were per-
3
using TMS
Fig. 4. 1H and 13C chemical shifts of 10a.
(d
boiling tube at ambient temperature for about 2e3 min. After
completion of the reaction as evident from TLC, water (50 mL) was
added to the reaction mixture and the product was filtered, washed
with water, and dried in vacuo.
3
formed on a Perkin Elmer 2400 Series II Elemental CHNS analyser.
Mass spectra were recorded on JEOL-DX303 HF mass spectrometer.
Column chromatography was performed on silica gel (230e400
mesh) using petroleum ethereethyl acetate as eluent. Optical
rotation values were measured using an autopol IV automatic
5
5
.2.1. 2-Amino-4-phenyl-6-(1-phenylethyl)-8-[(E)-phenylmethylidene]-
,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (8a)
[dr ¼ 1:0.6]
ꢂ
polarimeter at sodium D line at 25 C. Ten fold serial dilutions of
1
Obtained as pale yellow solid; H NMR (300 MHz, CDCl
d, J ¼ 6.6 Hz, CH ),1.19 (d, J ¼ 7.2 Hz, CH ), 2.77e3.31 (m, 5-CH
-CH ), 3.40e3.43 (m, CH), 3.52e3.88 (m, 5-CH and 7-CH
s, 1H, H-4), 3.95 (s, 1H, H-4), 4.59 (s, NH ), 6.85e7.39 (m, aromatic),
3
):
d
H
1.18
and
each test compound/drug were incorporated into Middlebrook
(
7
(
3
3
2
7
H11 agar medium with OADC Growth Supplement. Inoculum of
2
2
2
), 3.93
M. tuberculosis H37Rv were prepared from fresh Middlebrook 7H11
2
agar slants with OADC Growth Supplement adjusted to 1 mg/mL
7.83 (s, H-9).
ꢀ
2
(
wet weight) in Tween 80 (0.05%) saline diluted to 10 to give
7
a concentration of approximately 10 cfu/mL. A 5
mL amount of
5
.2.2. 2-Amino-4-(4-methylphenyl)-8-[(E)-(4-methylphenyl)
methylidene]-6-(1-phenylethyl)-5,6,7,8-tetrahydro-4H-pyrano
bacterial suspension was spotted into 7H11 agar tubes containing
1
0-fold serial dilutions of drugs per mL. The tubes were incubated
[
3,2-c]pyridine-3-carbonitrile (8b) [dr ¼ 1:0.4]
ꢂ
at 37 C, and final readings were recorded after 28 days. The
1
Obtained as white solid; H NMR (300 MHz, CDCl
3
):
d
H
1.20 (d,
and 7-
), 3.84
2
), 6.81 (s, H-9), 6.84 (s, H-
minimum inhibitory concentration (MIC) is defined as the
minimum concentration of compound required to give complete
inhibition of bacterial growth.
J ¼ 6.6 Hz, CH ), 1.27 (d, J ¼ 7.2 Hz, CH
CH
), 3.42 (q, J ¼ 6.6 Hz, CH), 3.52e3.75 (m, 5-CH
s, 1H, H-4), 3.91 (s, 1H, H-4), 4.57 (s, NH
3
3
), 2.76e3.31 (m, 5-CH
2
2
2
and 7-CH
2
(
9), 6.93e7.30 (m, aromatic).
5.2. General procedure for the synthesis of pyrans (8aee)
5
.2.3. 2-Amino-4-(2-chlorophenyl)-8-[(E)-(2-chlorophenyl)
A mixture of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone
1 mmol), aromatic aldehyde (2 mmol), and malononitrile
1 mmol), in solid sodium ethoxide was ground well in a semimicro
methylidene]-6-(1-phenylethyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]
pyridine-3-carbonitrile (8c) [dr ¼ 1:0.9]
(
(
1
Obtained as pale yellow solid; H NMR (300 MHz, CDCl
3
):
), 2.79e3.30 (m, 5-CH
and 7-CH
), 6.82e7.40 (m, aromatic and H-9).
H
d 1.14
(
d, J ¼ 6.6 Hz, CH
and 7-CH ), 3.36e3.54 (m, CH, 5-CH
and NH
3
), 1.18 (d, J ¼ 6.9 Hz, CH
3
2
2
2
2
), 4.66e4.80 (m, CH
2
5.2.4. 2-Amino-4-(2,4-dichlorophenyl)-8-[(E)-(2,4-dichlorophenyl)
methylidene]-6-(1-phenylethyl)-5,6,7,8-tetrahydro-4H-pyrano
[
3,2-c]pyridine-3-carbonitrile (8d) [dr ¼ 1:0.9]
1
Obtained as pale yellow solid; H NMR (300 MHz, CDCl
3
):
d
H
1.17
(
d, J ¼ 6.6 Hz, CH
and 7-CH ), 3.06e3.50 (m, CH, 5-CH
), 6.73e7.45 (m, aromatic and H-9).
3
), 1.18 (d, J ¼ 6.3 Hz, CH
3
), 2.73e2.84 (m, 5-CH
), 4.60 (s, NH ), 4.68
2
2
2
and 7-CH
2
2
(
s, NH
2
5
6
3
.2.5. 2-Amino-4-(1-naphthyl)-8-[(E)-1-naphthylmethylidene]-
-(1-phenylethyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-
-carbonitrile (8e) [dr ¼ 1:0.9]
1
Obtained as solid; H NMR (300 MHz, CDCl
3
):
), 3.28e3.32 (m, CH),
), 4.64 (s, NH ), 6.83e8.24 (m,
H
d 0.98e1.02 (m,
CH
3
3
), 2.64e3.22 (m, 5-CH
2 2
and 7-CH
.37e3.60 (m, CH, 5-CH
2
and 7-CH
2
2
Fig. 3. 1H and 13C chemical shifts of 9a.
aromatic and H-9).

420
A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
Scheme 3. Acetylation of oxadiazole 10.
5.3. General procedure for the synthesis of 1,2,4-oxadiazoles 9 and 10
(m, 2H, aromatic). 13C NMR (75 MHz, CDCl
0.7, 61.8, 74.4, 114.8, 122.6, 126.8, 126.9, 127.0, 127.3, 127.4, 128.0,
3 C
): d 20.0, 40.6, 49.0,
5
To a solution of 4H-pyran 8 (1 mmol) in benzene (5 mL), N-
hydroxyarylcarboximidoyl chloride (1 mmol) was added and the
mixture stirred at room temperature. A solution of triethylamine
128.2,128.3,128.5,128.6,129.0,130.7,136.3,139.9,143.2,144.1,156.8,
þ
166.7, 175.9. EI-MS: m/z 564.74 (M ). Anal. Calcd for C37
H N
32 4
2
O : C,
78.70; H, 5.71; N, 9.92. Found: C, 78.75; H, 5.66; N, 9.96.
(
1 mmol) in benzene (3 mL) was added dropwise to the above
0
mixture and the stirring was continued for 7e8 h. After completion
of the reaction as evident from TLC, the resulting mixture was
filtered to remove the triethylamine hydrochloride, the solvent
evaporated in vacuo and the residue subjected to flash column
chromatography on silica gel using petroleum ether/ethyl acetate
5.3.3. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-phenyl-6-
[(R)-1-phenylethyl]-8-[(E)-1-phenylmethylidene]-5,6,7,8-
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (9b)
ꢂ
Obtained as white solid (0.075 g, 37%); mp ¼ 184e185 C;
[a
]
D
¼ þ139.0 (c 0.20, CHCl
3
); IR (KBr): 1091, 1290, 1369, 1407, 1533,
ꢀ
1 1
(
5:1 v/v) to obtain enantiomerically pure 9 and 10.
1635, 1678, 2924, 3451 cm ; H NMR (300 MHz, CDCl
H, J ¼ 6.3 Hz, CH ), 2.98 (d, 1H, J ¼ 16.2 Hz, H-5a), 3.27e3.33 (m,
2H, H-5b and H-7a), 3.44 (q, 1H, J ¼ 6.3 Hz, CH), 3.73 (d, 1H,
J ¼ 14.1 Hz, H-7b), 4.78 (s, 1H, H-4), 6.53 (br s, 2H, NH ), 6.95 (s, 1H,
H-9), 7.06e7.36 (m,15H, aromatic), 7.41 (d, 2H, J ¼ 8.1 Hz, aromatic),
3 H
): d 1.18 (d,
3
3
5
3
.3.1. 4-Phenyl-6-[(R)-1-phenylethyl]-8-[(E)-1-phenylmethylidene]-
0
-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-4H-pyrano
2
[
3,2-c]pyridin-2-amine (9a)
Obtained as white solid (0.069 g, 36%); mp ¼ 174e175 C;
¼ þ142.8 (c 0.20, CHCl ); IR (KBr): 1093, 1290, 1362, 1409, 1537,
ꢂ
13
7.95 (d, 2H, J ¼ 8.1 Hz, aromatic). C NMR (75 MHz, CDCl
3 C
): d 20.1,
[
a
]
D
3
40.9, 50.1, 50.9, 62.7, 74.2, 114.7, 122.5, 125.9, 126.9, 127.0, 127.1,
127.3, 127.9, 128.2, 128.3, 128.5, 128.6, 128.8, 128.9, 136.2, 136.7,
ꢀ
1 1
1
3
2
635, 1676, 2920, 3452 cm ; H NMR (300 MHz, CDCl
3
):
), 3.02 (d, 1H, J ¼ 15.9 Hz, H-5a), 3.32e3.37 (m,
H, H-5b and H-7a), 3.47 (q, 1H, J ¼ 6.6 Hz, CH), 3.76 (d, 1H,
), 6.97 (s, 1H,
H-9), 7.06e7.45 (m, 18H, aromatic), 8.00e8.03 (m, 2H, aromatic).
H
d 1.17 (d,
þ
H, J ¼ 6.6 Hz, CH
3
140.0, 143.4, 144.0, 156.7, 165.9, 176.1. EI-MS: m/z 599.10 (M ). Anal.
Calcd for C37H31ClN O : C, 74.17; H, 5.22; N, 9.35. Found: C, 74.12; H,
4 2
5.26; N, 9.30.
J ¼ 14.1 Hz, H-7b), 4.36 (s, 1H, H-4), 6.56 (br s, 2H, NH
2
1
3
0
C NMR (75 MHz, CDCl
23.1, 126.5, 127.0, 127.3, 127.4, 128.0, 128.1, 128.2, 128.3, 128.5,
28.6, 128.8, 129.2, 130.0, 130.7, 136.1, 139.9, 142.8, 144.0, 156.6,
3
):
d
C
19.8, 40.8, 49.7, 50.4, 62.1, 74.1, 114.0,
5.3.4. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-phenyl-6-[(R)-
1-phenylethyl]-8-[(E)-1-phenylmethylidene]-5,6,7,8-tetrahydro-4H-
pyrano[3,2-c]pyridin-2-amine (10b)
1
1
1
7
þ
ꢂ
66.7, 175.9. EI-MS: m/z 564.60 (M ). Anal. Calcd for C37
H
32
N
4
O
2
: C,
Obtained as white solid (0.052 g, 26%); mp ¼ 163e164 C;
8.70; H, 5.71; N, 9.92. Found: C, 78.76; H, 5.76; N, 9.85.
[
1
a
]
D
¼ ꢀ102.7 (c 0.20, CHCl
3
); IR (KBr): 1093, 1292, 1367, 1409, 1535,
ꢀ
1 1
3 H
633, 1679, 2921, 3450 cm ; H NMR (300 MHz, CDCl ): d 1.20 (d,
5
3
.3.2. 4-Phenyl-6-[(R)-1-phenylethyl]-8-[(E)-1-phenylmethylidene]-
-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-4H-pyrano
3H, J ¼ 6.6 Hz, CH ), 2.89 (d, 1H, J ¼ 16.4 Hz, H-5a), 3.21 (d, 1H,
3
0
J ¼ 16.4 Hz, H-5b), 3.43 (q, 1H, J ¼ 6.6 Hz, CH), 3.61 (d, 1H,
J ¼ 14.1 Hz, H-7a), 3.78 (d, 1H, J ¼ 14.1 Hz, H-7b), 4.27 (s, 1H, H-4),
[3,2-c]pyridin-2-amine (10a)
Obtained as viscous liquid (0.046 g, 24%); [
a
]
D
¼ ꢀ115.2 (c 0.23,
2
6.51 (br s, 2H, NH ), 6.98e7.35 (m, 16H, H-9 and aromatic), 7.40 (d,
13
CHCl
3
CH
3
); IR (CHCl
3
): 1095, 1292, 1365, 1408, 1535, 1633, 1678, 2923,
H NMR (300 MHz, CDCl ):
1.20 (d, 3H, J ¼ 6.6 Hz,
), 2.91 (d, 1H, J ¼ 16.4 Hz, H-5a), 3.23 (d, 1H, J ¼ 16.4 Hz, H-5b),
2H, J ¼ 8.6 Hz, aromatic), 7.94 (d, 2H, J ¼ 8.6 Hz, aromatic). C NMR
ꢀ
1 1
450 cm
;
3
d
H
(75 MHz, CDCl ): 20.0, 40.6, 49.1, 50.9, 61.9, 74.3, 115.0, 122.6,
3
d
C
3
125.9, 127.0, 127.3, 128.0, 128.2, 128.3, 128.6, 128.9, 129.0, 136.2,
3
.44 (q,1H, J ¼ 6.6 Hz, CH), 3.64 (d,1H, J ¼ 14.1 Hz, H-7a), 3.79 (d,1H,
J ¼ 14.1 Hz, H-7b), 4.28 (s, 1H, H-4), 6.54 (br s, 2H, NH ), 6.99e7.02
m, 3H, H-9 and aromatic), 7.16e7.45 (m, 16H, aromatic), 7.99e8.02
136.7, 140.0, 143.4, 144.0, 156.9, 165.9, 176.1. EI-MS: m/z 599.02
þ
2
(M ). Anal. Calcd for C37
H31ClN
4
O
2
: C, 74.17; H, 5.22; N, 9.35. Found:
(
C, 74.23; H, 5.27; N, 9.28.
Scheme 4. Non formation of isoxazoline 12.

A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
421
Table 2
Minimum inhibitory concentrations (
m
M) of compounds 9 and 10 against mycobacterial species.
0
Yield (%)a
(RR or RS)b
Comp
Ar
Ar
MTB
MDR-TB
MTB
MDR-TB
9
10 (RS or RR)b
9
10
a
b
c
d
e
f
g
h
C
C
6
H
H
5
C
6
H
5
36
37
38
37
30
30
32
33
30
32
e
24
26
18
15
27
28
26
25
28
29
e
11.07
5.22
10.54
2.49
1.23
0.60
1.11
0.27
18.80
8.94
e
NT
NT
NT
1.24
1.23
0.60
0.57
0.14
NT
NT
e
2.76
2.60
5.28
0.64
0.63
0.15
0.57
0.07
4.71
4.48
0.12
0.36
4.71
7.64
5.54
2.60
NT
1.24
1.23
0.60
0.57
0.14
NT
6
5
p-ClC
C H
6 5
p-ClC
6 5
C H
p-ClC
6 5
C H
p-ClC
C H
6 5
6
6
6
6
6
H
4
H
4
H
4
H
4
H
4
p-MeC
p-MeC
o-ClC
o-ClC
o,p-Cl
o,p-Cl
1-Naphthyl
6
H
H
4
6
4
6
H
H
4
6
4
2
2
C
C
6
H
H
3
3
6
i
j
1-Naphthyl
p-ClC
e
NT
Rifampicin
Isoniazid
Ciprofloxacin
Ethambutol
e
e
e
e
3.80
11.38
37.73
61.18
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
MTB: Mycobacterium tuberculosis; MDR-TB: multi-drug resistant Mycobacterium tuberculosis; NT: not tested.
a
Isolated yield.
b
The absolute configurations of these diastereomers at C-4 not distinctly assigned.
þ
5
6
.3.5. 4-(4-Methylphenyl)-8-[(E)-1-(4-methylphenyl)methylidene]-
-[(R)-1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
165.9, 176.2. EI-MS: m/z 626.80 (M ). Anal. Calcd for C39
H35ClN
4
O
2
:
0
C, 74.69; H, 5.62; N, 8.93. Found: C, 74.75; H, 5.68; N, 8.87.
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (9c)
Obtained as white solid (0.071 g, 38%); mp ¼ 186e187 C;
¼ þ126.0 (c 0.20, CHCl ); IR (KBr): 1091, 1292, 1366, 1409, 1536,
ꢂ
0
5.3.8. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methylphenyl)-
8-[(E)-1-(4-methylphenyl)methylidene]-6-[(R)-1-phenylethyl]-5,6,7,8-
tetrahydro-4H-pyrano[3,2-c]-pyridin-2-amine (10d)
[
1
a
]
D
3
ꢀ
1 1
630, 1679, 2921, 3451 cm ; H NMR (300 MHz, CDCl
3 H
): d 1.21 (d,
3
H, J ¼ 6.6 Hz, CH
3
), 2.28 (s, 1H, CH ), 2.32 (s, 1H, CH ), 2.99 (d, 1H,
3
3
Obtained as viscous liquid (0.030 g, 15%); [
CHCl ); IR (CHCl ): 1093, 1290, 1368, 1408, 1537, 1631, 1679, 2924,
3454 cm H NMR (300 MHz, CDCl ):
1.20 (d, 3H, J ¼ 6.8 Hz,
CH ), 2.31 (s, 1H, CH ), 2.36 (s, 1H, CH
a
]
D
¼ ꢀ106.2 (c 0.21,
J ¼ 15.9 Hz, H-5a), 3.22e3.33 (m, 2H, H-5b and H-7a), 3.45 (q, 1H,
J ¼ 6.6 Hz, CH), 3.76 (d, 1H, J ¼ 14.1 Hz, H-7b), 4.31 (s, 1H, H-4), 6.53
3
3
ꢀ
1 1
;
3
d
H
13
(
br s, 2H, NH
NMR (75 MHz, CDCl
14.5,122.3,126.4,127.0,127.3,127.4,127.8,128.3,128.6,128.8,128.9,
29.2,130.7,130.9,133.4,136.4,136.7,140.0,141.1,143.5,156.6,166.7,
2
), 6.91 (s, 1H, H-9), 6.96e8.02 (m, 18H, aromatic).
C
3
3
3
), 2.87 (d, 1H, J ¼ 16.2 Hz, H-
3
):
d
C
19.2, 21.1, 21.2, 40.5, 50.1, 51.0, 62.7, 74.4,
5a), 3.20 (d, 1H, J ¼ 16.2 Hz, H-5b), 3.42 (q, 1H, J ¼ 6.6 Hz, CH), 3.63
(d, 1H, J ¼ 14.1 Hz, H-7a), 3.82 (d, 1H, J ¼ 14.1 Hz, H-7b), 4.22 (s, 1H,
1
1
2
H-4), 6.50 (br s, 2H, NH ), 6.95 (s, 1H, H-9), 7.01e7.20 (m, 9H,
þ
176.0. EI-MS: m/z 592.60 (M ). Anal. Calcd for C39
36
H N
4
O
2
: C, 79.03;
aromatic), 7.40 (d, 2H, J ¼ 8.6 Hz, aromatic), 7.53e7.55 (m, 2H,
H, 6.12; N, 9.45. Found: C, 79.08; H, 6.18; N, 9.50.
aromatic), 7.71e7.73 (m, 2H, aromatic), 7.94 (d, 2H, J ¼ 8.6 Hz,
13
3 C
aromatic). C NMR (75 MHz, CDCl ): d 19.2, 21.1, 21.2, 40.1, 49.2,
5
6
.3.6. 4-(4-Methylphenyl)-8-[(E)-1-(4-methylphenyl)methylidene]-
-[(R)-1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
50.9, 61.8, 74.5, 114.7, 122.5, 125.9, 126.9, 127.4, 127.9, 128.2, 128.6,
0
128.8,128.9,129.0,129.1,129.2,130.9,136.4,136.7,136.8,141.1,156.9,
þ
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (10c)
Obtained as viscous liquid (0.034 g, 18%); [
CHCl ); IR (CHCl ): 1094, 1292, 1365, 1410, 1534, 1631, 1678, 2925,
H NMR (300 MHz, CDCl ):
1.20 (d, 3H, J ¼ 6.8 Hz,
), 2.31 (s,1H, CH ), 2.36 (s,1H, CH
), 2.89 (d,1H, J ¼ 16.5 Hz, H-5a),
165.9, 176.5. EI-MS: m/z 626.92 (M ). Anal. Calcd for C39
H35ClN
4
O
2
:
a]
D
¼ ꢀ114.4 (c 0.19,
C, 74.69; H, 5.62; N, 8.93. Found: C, 74.63; H, 5.67; N, 8.86.
3
3
ꢀ
1 1
3
CH
451 cm
;
3
d
H
5.3.9. 4-(2-Chlorophenyl)-8-[(E)-1-(2-chlorophenyl)methylidene]-
0
3
3
3
6-[(R)-1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
3
.21 (d,1H, J ¼ 16.5 Hz, H-5b), 3.43 (q,1H, J ¼ 6.8 Hz, CH), 3.64 (d,1H,
J ¼ 14.3 Hz, H-7a), 3.82 (d, 1H, J ¼ 14.3 Hz, H-7b), 4.23 (s, 1H, H-4),
.52 (br s, 2H, NH ), 6.95 (s, 1H, H-9), 7.01e8.01 (m, 18H, aromatic).
C NMR (75 MHz, CDCl ): 19.2, 21.1, 21.2, 40.1, 49.1, 50.8, 61.8, 74.5,
14.2,122.4,126.2,126.9,127.2,127.4,127.9,128.2,128.6,128.8,128.9,
29.0,129.2,130.6,130.9,133.5,136.4,136.8,141.2,143.4,156.8,166.6,
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (9e)
Obtained as viscous liquid (0.055 g, 30%); [
CHCl ); IR (CHCl ): 1092, 1294, 1367, 1407, 1537, 1635, 1676, 2920,
3452 cm H NMR (300 MHz, CDCl ):
1.13 (d, 3H, J ¼ 6.6 Hz,
CH
), 2.98 (d, 1H, J ¼ 16.5 Hz, H-5a), 3.09 (d, 1H, J ¼ 14.1 Hz, H-7a),
3.37 (q, 1H, J ¼ 6.6 Hz, CH), 3.52e3.57 (m, 2H, H-5b and H-7b), 5.10
(s, 1H, H-4), 6.62 (br s, 2H, NH
), 6.84 (d, 1H, J ¼ 7.8 Hz, aromatic),
6.96e8.04 (m, 18H, H-9 and aromatic). C NMR (75 MHz, CDCl
0.2, 41.0, 50.0, 50.4, 62.3, 72.8,114.6,120.1,126.2,127.0,127.2,127.3,
a
]
D
¼ þ161.0 (c 0.23,
6
2
3
3
1
3
ꢀ1 1
;
3
d
C
3
d
H
1
1
3
þ
176.1. EI-MS: m/z 592.72 (M ). Anal. Calcd for C39
H N
36 4
2
O : C, 79.03;
2
13
H, 6.12; N, 9.45. Found: C, 79.10; H, 6.05; N, 9.51.
3 C
): d
2
0
5
.3.7. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-
127.4, 128.1, 128.2, 128.3, 128.6, 129.3, 129.5, 130.2, 130.7, 133.4,
þ
methylphenyl)-8-[(E)-1-(4-methylphenyl)methylidene]-6-[(R)-1-
133.8, 134.4, 139.7, 143.5, 157.1, 166.7, 175.8. EI-MS: m/z 632.73 (M ).
phenylethyl]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridin-2-amine (9d)
Anal. Calcd for C37
70.20; H, 4.83; N, 8.91.
2 4 2
H30Cl N O : C, 70.14; H, 4.77; N, 8.84. Found: C,
ꢂ
Obtained as white solid (0.074 g, 37%); mp ¼ 192e193 C;
[
1
a
]
D
¼ þ134.4 (c 0.20, CHCl
3
); IR (KBr): 1093, 1291, 1365, 1406, 1536,
ꢀ1 1
630, 1675, 2922, 3450 cm ; H NMR (300 MHz, CDCl
3
):
d
H
1.21 (d,
5.3.10. 4-(2-Chlorophenyl)-8-[(E)-1-(2-chlorophenyl)methylidene]-
6-[(R)-1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (10e)
0
3
H, J ¼ 6.6 Hz, CH
3
), 2.29 (s, 1H, CH ), 2.32 (s, 1H, CH ), 2.98 (d, 1H,
3
3
J ¼ 16.5 Hz, H-5a), 3.22e3.32 (m, 2H, H-5b and H-7a), 3.45 (q, 1H,
J ¼ 6.6 Hz, CH), 3.75 (d, 1H, J ¼ 13.8 Hz, H-7b), 4.30 (s, 1H, H-4), 6.49
Obtained as viscous liquid (0.050 g, 27%); [
CHCl ); IR (CHCl ): 1091, 1292, 1366, 1409, 1539, 1633, 1677, 2922,
3453 cm H NMR (300 MHz, CDCl ):
1.19 (d, 3H, J ¼ 6.6 Hz,
CH
), 2.98 (d, 1H, J ¼ 17.0 Hz, H-5a), 3.37 (d, 1H, J ¼ 17.0 Hz, H-5b),
3.42e3.57 (m, 3H, CH, H-7a and H-7b), 5.02 (s, 1H, H-4), 6.61 (br s,
a
]
D
¼ ꢀ134.7 (c 0.18,
13
(
br s, 2H, NH
NMR (75 MHz, CDCl
14.5, 122.3, 125.9, 126.4, 127.0, 127.4, 127.8, 128.3, 128.6, 128.8,
28.9, 129.2, 133.3, 136.5, 136.6, 136.7, 140.0, 141.1, 143.5, 156.7,
2
), 6.90 (s, 1H, H-9), 6.96e7.96 (m, 17H, aromatic).
C
3
3
ꢀ
1 1
3
):
d
C
20.2, 21.1, 21.2, 40.5, 50.2, 51.0, 62.8, 74.3,
;
3
d
H
1
1
3

422
A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
2
(
1
1
H, NH
75 MHz, CDCl
26.3, 126.9, 127.2, 127.3, 127.4, 128.0, 128.1, 128.5, 128.6, 128.8,
29.5, 130.2 130.4,130.7,133.5,133.9,134.5,139.7,143.3, 157.3,166.7,
2
), 6.99 (s, 1H, H-9), 7.01e8.03 (m, 18H, aromatic). 13C NMR
): 19.7, 40.2, 49.1, 50.3, 61.4, 73.0, 114.8, 120.1,
131.0, 133.0, 133.2, 133.6, 134.1, 134.6, 139.7, 143.1, 157.1, 166.8, 175.5.
þ
3
d
C
EI-MS: m/z 702.61 (M ). Anal. Calcd for C37H28Cl N O : C, 63.26; H,
4 4 2
4.02; N, 7.98. Found: C, 63.30; H, 4.09; N, 7.92.
þ
0
175.7. EI-MS: m/z 632.59 (M ). Anal. Calcd for C37
H30Cl
2
N
4
O
2
: C,
5.3.15. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2,4-
7
0.14; H, 4.77; N, 8.84. Found: C, 70.21; H, 4.68; N, 8.80.
dichlorophenyl)-8-[(E)-1-(2,4-dichlorophenyl)methylidene]-6-[(R)-1-
phenylethyl]-5,6,7,8-tetrahydro-4H-pyrano-[3,2-c]-pyridin-2-amine (9h)
5
3
5
.3.11. 4-(2-Chlorophenyl)-8-[(E)-1-(2-chlorophenyl)methylidene]-
-[3 -(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-6-[(R)-1-phenylethyl]-
,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridin-2-amine (9f)
Obtained as viscous liquid (0.063 g, 33%); [
CHCl ); IR (CHCl ): 1114, 1295, 1357, 1408, 1529, 1633, 1683, 2923,
3442 cm H NMR (300 MHz, CDCl ):
1.19 (d, 3H, J ¼ 6.5 Hz,
CH
), 2.90 (d, 1H, J ¼ 16.2 Hz, H-5a), 3.10 (d, 1H, J ¼ 14.1 Hz, H-7a),
3.36 (q, 1H, J ¼ 6.5 Hz, CH), 3.44e3.48 (m, 2H, H-5b and H-7b), 5.03
(s, 1H, H-4), 6.62 (br s, 2H, NH
a
]
D
¼ þ124.6 (c 0.21,
0
3
3
ꢀ
1 1
;
3
d
H
Obtained as viscous liquid (0.058 g, 30%); [
CHCl ); IR (CHCl ): 1090, 1291, 1366, 1409, 1538, 1633, 1676, 2924,
H NMR (300 MHz, CDCl ):
1.13 (d, 3H, J ¼ 6.6 Hz,
), 2.97 (d, 1H, J ¼ 16.5 Hz, H-5a), 3.09 (d, 1H, J ¼ 14.1 Hz, H-7a),
a
]
D
¼ þ142.4 (c 0.22,
3
3
3
ꢀ
1 1
3
CH
3
449 cm
;
3
d
H
2
), 6.76 (d, 1H, J ¼ 8.4 Hz, aromatic),
3
6.89 (s, 1H, H-9), 6.98 (dd, 1H, J ¼ 8.1, 1.8 Hz, aromatic), 7.16e7.37
.37 (q, 1H, J ¼ 6.6 Hz, CH), 3.52e3.57 (m, 2H, H-5b and H-7b), 5.09
(m, 9H, aromatic), 7.42 (d, 2H, J ¼ 8.4 Hz, aromatic), 7.95 (d, 2H,
1
3
(
s, 1H, H-4), 6.61 (br s, 2H, NH
2
), 6.83 (d, 1H, J ¼ 7.5 Hz, aromatic),
J ¼ 8.4 Hz, aromatic). C NMR (75 MHz, CDCl
3 C
): d 20.2, 40.8, 50.0,
13
6
.96e7.97 (m, 17H, H-9 and aromatic). C NMR (75 MHz, CDCl
3
):
d
C
50.5, 62.7, 72.2, 114.4, 119.1, 125.6, 126.5, 127.2, 127.8, 128.4, 128.5,
128.6, 128.9, 129.2, 130.8, 131.0, 132.8, 133.2, 133.4, 133.9, 134.5,
136.8, 139.7, 140.0, 143.2, 157.1, 166.0, 175.7. EI-MS: m/z 736.80 (M ).
1
1
1
9.2, 40.4, 50.0, 50.4, 62.3, 72.8,114.3,120.1,125.3,125.8,126.2,127.1,
27.3, 127.5, 128.0,128.2, 128.3, 128.4, 128.6, 128.8, 128.9, 129.0,
29.3, 129.5, 130.2, 133.4, 133.8, 134.3, 136.8, 139.7, 143.4, 157.2,
þ
5 4 2
Anal. Calcd for C37H27Cl N O : C, 60.31; H, 3.69; N, 7.60. Found: C,
60.23; H, 3.76; N, 7.67.
þ
165.9,175.9. EI-MS: m/z 666.95 (M ). Anal. Calcd for C37
H29Cl
3
N
4
O
2
:
C, 66.53; H, 4.38; N, 8.39. Found: C, 66.46; H, 4.33; N, 8.46.
0
5
.3.16. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2,4-
5
3
5
.3.12. 4-(2-Chlorophenyl)-8-[(E)-1-(2-chlorophenyl)methylidene]-
-[3 -(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-6-[(R)-1-phenylethyl]-
,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridin-2-amine (10f)
dichlorophenyl)-8-[(E)-1-(2,4-dichlorophenyl)methylidene]-6-[(R)-1-
phenylethyl]-5,6,7,8-tetrahydro-4H-pyrano-[3,2-c]-pyridin-2-amine (10h)
0
Obtained as viscous liquid (0.047 g, 25%); [
CHCl ); IR (CHCl ): 1114, 1294, 1359, 1406, 1530, 1632, 1680, 2923,
3445 cm H NMR (300 MHz, CDCl ):
1.18 (d, 3H, J ¼ 6.6 Hz,
CH
), 2.92 (d, 1H, J ¼ 16.7 Hz, H-5a), 3.34 (d, 1H, J ¼ 16.7 Hz, H-5b),
3.40e3.50 (m, 3H, CH, H-7a and H-7b), 4.94 (s, 1H, H-4), 6.60 (br s,
2H, NH ), 6.91e7.51 (m, 14H, H-9 and aromatic), 7.94 (d, 2H,
a
]
D
¼ ꢀ108.6 (c 0.19,
Obtained as viscous liquid (0.055 g, 28%); [
CHCl ); IR (CHCl ): 1089, 1294, 1365, 1406, 1537, 1635, 1678, 2921,
H NMR (300 MHz, CDCl ):
1.19 (d, 3H, J ¼ 6.6 Hz,
), 2.97 (d, 1H, J ¼ 16.7 Hz, H-5a), 3.37 (d, 1H, J ¼ 16.7 Hz, H-5b),
a]
D
¼ ꢀ118.5 (c 0.24,
3
3
ꢀ
1 1
3
3
;
3
d
H
ꢀ
1 1
3
CH
451 cm
;
3
d
H
3
3
3
2
CDCl
1
1
.42e3.57 (m, 3H, CH, H-7a and H-7b), 5.01 (s, 1H, H-4), 6.60 (br s,
2
13
13
H, NH
):
26.9, 127.3, 127.4, 127.9, 128.2, 128.5, 128.9, 129.0, 129.5, 130.2,
30.3, 130.9, 133.4, 133.9, 134.4, 136.7, 139.7, 143.2, 157.4, 165.9,
2
), 6.99e7.96 (m, 18H, H-9 and aromatic). C NMR (75 MHz,
J ¼ 8.4 Hz, aromatic). C NMR (75 MHz, CDCl
3 C
): d 19.6, 40.8, 48.9,
3
d
C
19.7, 40.5, 49.1, 50.3, 61.4, 72.9, 115.0, 120.1, 125.8, 126.3,
50.1, 61.3, 72.5, 114.3, 119.3, 125.7, 126.7, 127.1, 127.2, 127.8, 128.3,
128.6, 128.8, 129.0 129.3, 129.4, 131.0, 132.9, 133.2, 133.6, 134.0,
134.6, 136.9, 139.7, 143.0, 157.2, 166.0, 175.6. EI-MS: m/z 736.68
þ
þ
175.9. EI-MS: m/z 667.08 (M ). Anal. Calcd for C37
H29Cl
3
N
4
O
2
: C,
(M ). Anal. Calcd for C37
H27Cl
5
N
4
O
2
: C, 60.31; H, 3.69; N, 7.60.
6
6.53; H, 4.38; N, 8.39. Found: C, 66.59; H, 4.31; N, 8.45.
Found: C, 60.38; H, 3.62; N, 7.68.
5
.3.13. 4-(2,4-Dichlorophenyl)-8-[(E)-1-(2,4-dichlorophenyl)
5.3.17. 4-(1-Naphthyl)-8-[(E)-1-(1-naphthyl)methylidene]-6-[(R)-
1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
0
0
methylidene]-6-[(R)-1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-
5
-yl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridin-2-amine (9g)
Obtained as viscous liquid (0.058 g, 32%); [
¼ þ112.0 (c 0.24,
CHCl ); IR (CHCl ): 1093, 1290, 1362, 1407, 1535, 1630, 1676, 2923,
H NMR (300 MHz, CDCl ):
1.18 (d, 3H, J ¼ 6.6 Hz,
), 2.90 (d, 1H, J ¼ 16.2 Hz, H-5a), 3.10 (d, 1H, J ¼ 14.1 Hz, H-7a),
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (9i)
ꢂ
a
]
D
Obtained as pale yellow solid (0.055 g, 30%); mp ¼ 124e125 C;
¼ þ156.0 (c 0.21, CHCl ); IR (KBr): 1089, 1291, 1365, 1402, 1531,
3
3
[
a
]
D
3
ꢀ
1
1
ꢀ1 1
3
CH
449 cm
;
3
d
H
3 H
1634,1676, 2922, 3454 cm ; H NMR (300 MHz, CDCl ): d 0.93 (d,
3
3H, J ¼ 6.6 Hz, CH ), 2.76 (d, 1H, J ¼ 16.1 Hz, H-5a), 3.06 (d, 1H,
3
3
(
6
.35 (q, 1H, J ¼ 6.6 Hz, CH), 3.43e3.48 (m, 2H, H-5b and H-7b), 5.02
s, 1H, H-4), 6.66 (br s, 2H, NH
), 6.76 (d, 1H, J ¼ 8.1 Hz, aromatic),
.89 (s, 1H, H-9), 6.97 (dd, 1H, J ¼ 8.1, 2.0 Hz, aromatic), 7.14e8.03
J ¼ 14.0 Hz, H-7a), 3.25 (q, 1H, J ¼ 6.6 Hz, CH), 3.41 (d, 1H,
J ¼ 16.1 Hz, H-7a), 3.53 (d, 1H, J ¼ 14.0 Hz, H-7b), 5.35 (s, 1H, H-4),
2
2
6.67 (br s, 2H, NH ), 6.96e7.99 (m, 23H, H-9 and aromatic), 8.07 (d,
13
13
(
6
1
m, 14H, aromatic). C NMR (75 MHz, CDCl
2.7, 72.3, 114.8, 119.0, 126.5, 127.1, 127.2, 127.8, 128.3, 128.6, 128.7,
29.2, 130.8, 132.8, 133.1, 133.4, 134.0, 134.5, 139.7, 143.3, 157.0,
3
):
d
C
20.2, 49.9, 50.5,
1H, J ¼ 8.7 Hz, aromatic), 8.37 (d, 1H, J ¼ 8.1 Hz, aromatic). C NMR
(75 MHz, CDCl ): 19.9, 41.8, 50.3, 51.1, 62.3, 74.2, 120.6, 122.8,
3
d
C
124.9, 125.0, 125.5, 125.7, 125.8, 125.9, 126.2, 126.4, 126.9, 127.1,
127.2, 127.3, 127.6, 128.0, 128.2, 128.4, 128.5, 128.6, 128.8, 128.9,
þ
166.7,175.5. EI-MS: m/z 702.48 (M ). Anal. Calcd for C37
4 4 2
H28Cl N O :
C, 63.26; H, 4.02; N, 7.98. Found: C, 63.34; H, 4.08; N, 7.90.
129.0,130.7,130.9,131.7,131.9,133.2,133.4,139.6,143.2,157.2,166.6,
þ
176.1. EI-MS: m/z 664.88 (M ). Anal. Calcd for C45
H
36
N
4
O
2
: C, 81.30;
5
.3.14. 4-(2,4-Dichlorophenyl)-8-[(E)-1-(2,4-dichlorophenyl)
H, 5.46; N, 8.43. Found: C, 81.38; H, 5.52; N, 8.48.
0
methylidene]-6-[(R)-1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-
5
-yl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridin-2-amine (10g)
Obtained as viscous liquid (0.047 g, 26%); [
¼ ꢀ128.0 (c 0.25,
CHCl ); IR (CHCl ): 1090, 1292, 1364, 1405, 1538, 1632, 1679, 2925,
H NMR (300 MHz, CDCl ):
1.18 (d, 3H, J ¼ 6.6 Hz,
), 2.93 (d, 1H, J ¼ 16.8 Hz, H-5a), 3.35 (d, 1H, J ¼ 16.8 Hz, H-5b),
5.3.18. 4-(1-Naphthyl)-8-[(E)-1-(1-naphthyl)methylidene]-6-[(R)-
1-phenylethyl]-3-(3 -phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-
0
a
]
D
3
3
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (10i)
ꢀ1
1
ꢂ
3
CH
447 cm
;
3
d
H
Obtained as pale yellow solid (0.051 g, 28%); mp ¼ 112e113 C;
3
[a
]
D
¼ ꢀ132.4 (c 0.20, CHCl ); IR (KBr): 1088, 1289, 1366, 1405, 1534,
3
ꢀ1 1
3
2
CDCl
.41e3.55 (m, 3H, CH, H-7a and H-7b), 4.96 (s, 1H, H-4), 6.62 (br s,
1630,1675, 2924, 3455 cm ; H NMR (300 MHz, CDCl
3H, J ¼ 6.6 Hz, CH ), 2.68 (d,1H, J ¼ 16.5 Hz, H-5a), 3.22e3.31 (m, 2H,
CH and H-5b), 3.41 (d, 1H, J ¼ 14.1 Hz, H-7a), 3.64 (d, 1H, J ¼ 14.1 Hz,
H-7b), 5.24 (s, 1H, H-4), 6.64 (br s, 2H, NH ), 6.69e7.97 (m, 23H, H-9
3 H
): d 0.89 (d,
13
H, NH
):
27.2, 127.3, 127.8, 128.3, 128.4, 128.7, 128.8, 129.3, 129.4, 130.8,
2
), 6.91e8.03 (m, 17H, H-9 and aromatic). C NMR (75 MHz,
3
3
C
d 19.7, 41.1, 49.0, 50.1, 61.2, 72.5, 114.6, 119.2, 126.7, 127.1,
1
2

A.I. Almansour et al. / European Journal of Medicinal Chemistry 53 (2012) 416e423
423
and aromatic), 8.09 (d, 1H, J ¼ 7.2 Hz, aromatic), 8.24 (d, 1H,
[7] T.B. Agerton, S.E. Valway, R.J. Blinkhorn, K.L. Shilkret, R. Reves, W.W. Schluter,
B. Gore, C.J. Pozsik, B.B. Plikaytis, C. Woodley, I.M. Onorato, Clin. Infect. Dis. 29
13
J ¼ 7.8 Hz, aromatic). C NMR (75 MHz, CDCl
1.1, 61.4, 74.3, 120.5, 122.7, 124.9, 125.1, 125.4, 125.6, 125.9, 126.0,
26.1, 126.5, 126.6, 127.0, 127.1, 127.2, 127.7, 127.9, 128.1, 128.4, 128.5,
28.8,129.0,129.1,130.6,131.6,131.9,133.2,133.5,139.5,142.9,157.0,
3 C
): d 19.5, 40.6, 49.3,
(1999) 85.
5
1
[8] P.R. Mohapatra, Am. J. Respir. Crit. Care Med. 170 (2004) 920.
[9] H.L. Rieder, Lancet 373 (2009) 1148.
[
[
[
10] Y. Morianka, K. Takahashi, Jpn. Kokai 17 (1977) 498.
11] J.B. Montandon, F.J. Zijlstra, J.H.P. Wilson, J. Int. Tissue React. 11 (1989) 107.
12] L.-F. Tietze, Angew. Chem., Int. Ed. Engl 22 (1983) 828 and references cited
therein.
1
þ
166.5, 176.0. EI-MS: m/z 664.72 (M ). Anal. Calcd for C45H N O : C,
36 4 2
8
1.30; H, 5.46; N, 8.43. Found: C, 81.37; H, 5.39; N, 8.50.
[
13] S. Hatakeyama, N. Ochi, H. Numata, S. Takano, J. Chem. Soc., Chem. Commun.
(
1988) 1202.
0
5
8
.3.19. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(1-naphthyl)-
-[(E)-1-(1-naphthyl)methylidene]-6-[(R)-1-phenylethyl]-5,6,7,8-
[
14] C.N. Ocallaghan, T.B.H. Mcmurry, J. Chem. Res. (S) 8 (1999) 457.
[15] J.L. Marco, N. Martin, A.M. Grau, C. Seoane, A. Albert, F.H. Cano, Tetrahedron 50
1994) 3509.
(
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (9j)
Obtained as pale yellow solid (0.062 g, 32%); mp ¼ 114e115 C;
¼ þ152.6 (c 0.20, CHCl ); IR (KBr): 1101, 1288, 1367, 1407, 1533,
[
16] A. Albert, F.H. Cano, N. Martin, A. Ramos, M. Rodriguez, J.L. Segara, C. Seoane,
ꢂ
J. Chem. Soc., Perkin Trans. 1 (1997) 3401.
[17] J. Saunders, A.M. MacLeod, K. Merchant, G.A. Showell, R.J. Snow, L.J. Street,
R. Baker, J. Chem. Soc., Chem. Commun. (1988) 1618.
18] F. Watjen, R. Baker, M. Engelstoff, R. Herbert, A. MacLeod, A. Knight,
K. Merchant, J. Moseley, J. Saunders, C.J. Swain, E. Wong, J.P. Springer, J. Med.
Chem. 32 (1989) 2282.
[
a
]
D
3
ꢀ
1 1
1
3
633,1679, 2925, 3470 cm ; H NMR (300 MHz, CDCl ): d 0.92 (d,
3 H
[
H, J ¼ 6.6 Hz, CH ), 2.75 (d, 1H, J ¼ 16.2 Hz, H-5a), 3.06 (d, 1H,
3
J ¼ 14.1 Hz, H-7a), 3.24 (q, 1H, J ¼ 6.6 Hz, CH), 3.40 (d, 1H,
J ¼ 16.2 Hz, H-7a), 3.52 (d, 1H, J ¼ 14.1 Hz, H-7b), 5.33 (s, 1H, H-4),
[19] W.R. Tully, C.R. Gardner, R.J. Gillespie, R. Westwood, J. Med. Chem. 34 (1991)
060.
2
6
(
2
.63 (br s, 2H, NH ), 6.95e7.01 (m, 5H, H-9 and aromatic), 7.20e7.91
[
20] J. Saunders, M. Cassidy, S.B. Freedman, E.A. Harley, L.L. Iversen, C. Kneen,
A.M. MacLeod, K.J. Merchant, R.J. Snow, R. Baker, J. Med. Chem. 33 (1990)
1128.
21] B.S. Orlek, F.E. Balaney, F. Braun, M.S.G. Clark, M.S. Hadley, J. Hatcher, G.J. Riley,
H.E. Rosenberg, H.J. Wadsworth, P. Wyman, J. Med. Chem. 34 (1991) 2726.
22] L.J. Street, R. Baker, T. Book, C.O. Kneen, A.M. MacLeod, K.J. Merchant,
G.A. Showell, J. Saunders, R.H. Herbert, S.B. Freedman, E.A. Harley, J. Med.
Chem. 33 (1990) 2690.
23] C.J. Swain, R. Baker, C. Kneen, J. Moseley, J. Saunders, E.M. Seward,
G. Stevenson, M. Beer, J. Stanton, K. Watlina, J. Med. Chem. 34 (1991) 140.
24] M. Carbone, Y. Li, C. Irace, E. Mollo, F. Castelluccio, A. Di Pascale, G. Cimino,
R. Santamaria, Y.W. Guo, M. Gavagnin, Org. Lett. 13 (2011) 2516.
25] R.M. Srivastava, A. Lima, O.S. Viana, M.J.C. Silva, M.T.J.A. Catanho, J.O.F. Morais,
Bioorg. Med. Chem. 11 (2003) 1821.
m, 17H, aromatic), 8.06 (d, 1H, J ¼ 8.7 Hz, aromatic), 8.35 (d, 1H,
13
J ¼ 8.1 Hz, aromatic). C NMR (75 MHz, CDCl
1.0, 62.3, 74.1, 120.6, 122.7, 124.9, 125.0, 125.5, 125.7, 125.8, 125.9,
26.2, 126.4 126.8, 127.1, 127.6, 128.0, 128.4, 128.5, 128.9, 131.6, 131.9,
33.1, 133.4, 136.7, 139.6, 143.1, 157.1, 165.8, 176.2. EI-MS: m/z 698.50
3 C
): d 19.8, 41.3, 50.3,
[
[
5
1
1
(
þ
4 2
M ). Anal. Calcd for C45H35ClN O : C, 77.30; H, 5.05; N, 8.01.
Found: C, 77.24; H, 4.98; N, 8.08.
[
[
[
0
5
8
.3.20. 3-[3 -(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(1-naphthyl)-
-[(E)-1-(1-naphthyl)methylidene]-6-[(R)-1-phenylethyl]-5,6,7,8-
tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (10j)
Obtained as pale yellow solid (0.056 g, 29%); mp ¼ 109e110 C;
¼ ꢀ121.5 (c 0.19, CHCl ); IR (KBr): 1087, 1288, 1367, 1407, 1536,
[26] P. Afiatpour, R.M. Srivastava, M.L. Oliveira, E.J. Barreiro, Braz. J. Med. Biol. Res.
ꢂ
27 (1994) 1403.
[27] N.M.M. Bezerra, S.P. De Oliveira, R.M. Srivastava, J.R. De Silva, II Farmaco 60
[
1
a
]
D
3
(2005) 955.
ꢀ
1 1
632,1678, 2926, 3457 cm ; H NMR (300 MHz, CDCl
3
):
), 2.68 (d, 1H, J ¼ 16.5 Hz, H-5a), 3.21e3.31 (m,
H, CH and H-5b), 3.41 (d, 1H, J ¼ 14.1 Hz, H-7a), 3.65 (d, 1H,
), 6.70e7.02
m, 4H, H-9 and aromatic), 7.17 (d, 1H, J ¼ 6.9 Hz, aromatic),
.36e7.91 (m, 18H, aromatic), 8.09 (d, 1H, J ¼ 8.4 Hz, aromatic), 8.24
d
H
0.86 (d,
[28] For a review of the application of the privileged scaffold concept to drug
discovery, see: M.E. Welsch, S.A. Snyder, B.R. Stockwell Curr. Opin. Chem. Biol.
3
2
H, J ¼ 6.6 Hz, CH
3
1
4 (2010) 347.
29] G.J. Richardo, B.C. Juan, R.A. Mario, M. Rolder, C.R. Peinado, Fernando Spen. 47
1979) 168.
[30] B.R. Jerom, K.H. Spencer, Eur. Pat. Appl. EP 277794, 1998.
[
J ¼ 14.1 Hz, H-7b), 5.24 (s, 1H, H-4), 6.63 (br s, 2H, NH
2
(
(
7
[
[
[
31] R.V. Perumal, M. Adiraj, P. Shanmugapandian, Indian Drugs 38 (2001) 156.
32] C.R. Ganellin, R.G. Spickett, J. Med. Chem. 8 (1965) 619.
33] M. Nikolov, D. Stefanara, D. Chardanov, Acta. Nerv. Super. 16 (1974) 264.
13
(
d, 1H, J ¼ 8.7 Hz, aromatic). C NMR (75 MHz, CDCl
9.3, 51.2, 61.5, 74.3, 120.6, 122.7, 125.0, 125.1, 125.5, 125.7, 125.8,
26.0, 126.1, 126.2, 126.6, 126.7, 127.1, 127.8, 127.9, 128.4, 128.5,
28.9, 131.7, 131.9, 133.3, 133.5, 136.7, 139.5, 157.1, 165.8, 176.2. EI-
3 C
): d 19.6, 40.3,
4
1
[34] R.E. Hangenbach, H. Gysin, Experientia 8 (1952) 184.
[
[
35] B. Heana, V. Dobre, I. Niculesar-Duvaz, J. Prakt. Chem. 327 (1985) 667.
36] I.G. Mobio, A.T. Soldatenkov, V.O. Federov, E.A. Ageer, N.D. Sergeeva, S. Lin,
E.E. Stashenko, N.S. Prostakov, E.I. Andreeva, Khim.-Farm. Zh. 23 (1989) 421.
1
þ
MS: m/z 698.74 (M ). Anal. Calcd for C45
H35ClN
4
O
2
: C, 77.30; H,
[37] M. Ashraf Ali, R. Ismail, T.S. Choon, R. Suresh Kumar, H. Osman, N. Arumugam,
A.I. Almansour, K. Elumalai, A. Singh, Bioorg. Med. Chem. Lett. 22 (2012) 508.
5
.05; N, 8.01. Found: C, 77.37; H, 5.11; N, 8.07.
[
[
[
38] R. Suresh Kumar, H. Osman, S. Perumal, J.C. Menendez, M. Ashraf Ali, R. Ismail,
T.S. Choon, Tetrahedron 67 (2011) 3132.
39] R. Suresh Kumar, M. Ashraf Ali, H. Osman, R. Ismail, T.S. Choon, Y.K. Yoon,
A.C. Wei, S. Pandian, E. Manogaran, Bioorg. Med. Chem. Lett. 21 (2011) 3997.
40] M. Ashraf Ali, R. Ismail, T.S. Choon, Y.K. Yoon, A.C. Wei, S. Pandian, R. Suresh
Kumar, H. Osman, E. Manogaran, Bioorg. Med. Chem. Lett. 20 (2010) 7064.
41] R. Suresh Kumar, S. Perumal, Tetrahedron Lett. 48 (2007) 7164.
42] R. Suresh Kumar, S. Perumal, H.B. Kagan, R. Guillot, Tetrahedron: Asymmetry
Acknowledgements
This project was supported by Research Center, College of
Science, King Saud University.
[
[
18 (2007) 170.
[
[
43] S. Michael Rajesh, R. Suresh Kumar, L.A. Libertsen, S. Perumal, P. Yogeeswari,
D. Sriram, Bioorg. Med. Chem. Lett. 21 (2011) 3012.
44] M. Ashraf Ali, R. Ismail, T.S. Choon, E. Manogaran, R. Suresh Kumar, H. Osman,
J. Govindasamy, R. Yadav, G. Yadav, R. Kour, S. Vyas, J. Enzyme Inhib. Med.
Chem. 27 (2012) 155.
45] R. Suresh Kumar, S. Perumal, K.A. Shetty, P. Yogeeswari, D. Sriram, Eur. J. Med.
Chem. 45 (2010) 124.
46] R. Suresh Kumar, S.M. Rajesh, S. Perumal, D. Banerjee, P. Yogeeswari,
D. Sriram, Eur. J. Med. Chem. 45 (2010) 411.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmech.2012.04.021.
[
[
[
References
47] R. Suresh Kumar, S. Michael Rajesh, S. Perumal, P. Yogeeswari, D. Sriram,
Tetrahedron: Asymmetry 21 (2010) 1315.
[
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