Novel quinoline and naphthalene derivatives as potent antimycobacterial agents

Article abstract of DOI:10.1016/j.ejmech.2010.01.024

We have designed and synthesized both the quinoline and naphthalene based molecules influenced by the unique structural make-up of mefloquine and TMC207, respectively. These compounds were evaluated for their anti-mycobacterial activity against drug sensi

Full text of DOI:10.1016/j.ejmech.2010.01.024

European Journal of Medicinal Chemistry 45 (2010) 1854–1867
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original Article
Novel quinoline and naphthalene derivatives as potent antimycobacterial agents
Ram Shankar Upadhayaya a, Jaya Kishore Vandavasi a, Ramakant A. Kardile a, Santosh V. Lahore a,
Shailesh S. Dixit a, Hemantkumar S. Deokar a, Popat D. Shinde a, Manash P. Sarmah a,
,
Jyoti Chattopadhyaya b
*
a Institute of Molecular Medicine, Pune 411 057, Maharashtra, India
b Program of Bioorganic Chemistry, Institute of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
We have designed and synthesized both the quinoline and naphthalene based molecules influenced by
the unique structural make-up of mefloquine and TMC207, respectively. These compounds were eval-
uated for their anti-mycobacterial activity against drug sensitive Mycobacterium tuberculosis H37Rv in
Received 25 November 2009
Received in revised form
8 January 2010
Accepted 12 January 2010
Available online 20 January 2010
vitro at single-dose concentration (6.25
M. tuberculosis H37Rv 99%, 90%, 98% and 91% respectively. Minimum inhibitory concentration of
compounds 22, 23, 26 and 27 was found to be 6.25 g/mL. Our molecular modeling and docking studies
mg/mL). The compounds 22, 23, 26 and 27 inhibited the growth of
m
of designed compounds showed hydrogen bonding with Glu-61, Tyr-64 and Asn-190 amino acid residues
at the putative binding site of ATP synthase, these interactions were coherent as shown by Mefloquine
and TMC207, where hydrogen bonding was found with Tyr-64 and Glu-61 respectively. SAR analysis
indicates importance of hydroxyl group and nature of substituents on piperazinyl-phenyl ring was
critical in dictating the biological activity of newly synthesized compounds.
Keywords:
ATP synthase
Naphthalene
Quinoline
TMC207
Mefloquine
Anti-tuberculosis drugs
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
patient is much more significant than those of the HIV-negative
patient [1]. The emergence of multi-drug resistant TB (MDR-TB) [7]
Tuberculosis has become a primary health threat to the
mankind. Mycobacterium tuberculosis is a very successful pathogen,
which causes tuberculosis and is the greatest single infectious
cause of mortality worldwide, killing approximately two million
people annually [1]. It is estimated that, one third of world pop-
ulation is infected with latent TB [2]. The pathogenic synergy
between TB and HIV is alarming [3–5]. HIV-positive patients are 50
times more susceptible to TB infection than that of HIV-negative
individuals [6], also the progression rate of latent TB in HIV-positive
and extensive drug resistant TB (XDR-TB) [8] is a new threat to the
public health [9] and has created an urgent need to develop new
anti-mycobacterial therapeutics to treat this deadly disease.
However, new anti-tubercular drugs with new mechanisms of
action have not been developed in last 40 years. Quinoline-based
compounds [10–13] and fluoroquinolones [14,15] are known to
display anti-TB activity [10–13]. Quinoline-based well-known drug
mefloquine is widely used for the prophylaxis of chloroquine-
resistant Plasmodium falciparum malaria [16,17]. Mefloquine is also
known for its antibacterial [18] and anti-tubercular activity [19–22]
(H37Rv MIC range: 8–16
mg/mL or 21.1–42.2 mM) [23] and its
Abbreviations: ATP, adenosine triphosphate; DCM, dichloromethane; DMF,
N,N-dimethyl formamide; DMSO, dimethyl sulphoxide; EAA, ethyl acetoacetate; GI,
growth index; HIV, human immunodeficiency virus; H2O2, hydrogen peroxide;
m-CPBA, meta-chloroperbenzoic acid; MDR, multi-drug resistance; MIC, minimum
inhibitory concentration; mp, melting point; MeOH, methanol; NaH, sodium
hydride; NBS, N-bromosuccinimide; NE, North-East; NMR, nuclear magnetic reso-
nance; NW, North-West; POCl3, phosphorus oxychloride; PBr3, phosphorus tri-
bromide; PPA, polyphosphoric acid; SAR, structure–activity relationship; SE,
South-East; SW, South-West; TB, tuberculosis; THF, tetrahydorfuran; TLC, thin layer
chromatography; WHO, World Health Organisation; XDR, extensive drug resis-
tance; (NOTE: All amino acid numbering corresponds to Mycobacterium tuberculosis
ATP synthase subunits A and C. Subunit type shown in superscript.).
analogs have displayed moderate [24] to submicromolar [25] anti-
TB activity. Mefloquine and its derivatives are known to act as
purine receptor antagonists [26] and it’s only prokaryotic target
known so far is F0F1Hþ ATPase in Streptococcus pneumoniae [27].
The possible reason of anti-TB activity of mefloquine might be due
to sequence identity (w27%) and similarity (50%) of ATP synthase
(subunit a and c, P63654 and P63691) of M. tuberculosis with the
ATP synthase (subunit a and c, P0A2Y8 and P0A307; all sequences
were retrieved from Uniprot database) of S. pneumoniae. Another
possible reason of using mefloquine for treating intracellular
pathogen could be its property, to reach 80 times greater
* Corresponding author. Tel.: þ46 18 4714577; fax: þ46 18 554495.
E-mail address: jyoti@boc.uu.se (J. Chattopadhyaya).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.024

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1855
concentrations in tissues than the concentration achieved in serum
and in addition has a long half-life [28]. Andries et al. have recently
reported [29] a potent anti-TB molecule, diarylquinoline TMC207
and is targeted to the proton pump of M. tuberculosis ATP synthase
and have inhibited mycobacterial growth effectively (H37Rv MIC of
conformationally-constrained indeno[2,1-c]quinoline analogs [34]
based on modification of SW and NW hemispheres of TMC207.
Conformationally constrained indeno[2,1-c]quinoline analogs
were designed (Fig. 2) to diminish the conformational flexibility
which will decrease the entropic penalty for complex formation
and enhance the binding affinity to the putative target ATP syn-
thase by covalently locking the C4 center of the quinoline moiety
in SW hemisphere with the C20 center of the phenyl ring in NW
hemisphere so as to enhance the binding affinity to the target.
Most active compound from conformationally-constrained series
is an oxime of indeno[2,1-c]quinoline which showed MIC of
TMC207: 0.06 mg/mL or 0.01 mM). As mefloquine and TMC207 both
target ATP synthase, we argued that a synthesis of new types of
molecules incorporating the molecular features of both of meflo-
quine and TMC207 might produce a new ‘‘hit’’ against M. tubercu-
losis. Thus, we planned to synthesize two series of molecules based
on this strategy (Fig. 1), modified quinoline series (compounds 9–
19) and modified naphthalene series (compounds 22–30). Ram-
amurthy et al. reported [30] the synthesis and anti-tubercular
activity of bioisosters N(2-naphthyl)glycine hydrazide analogs and
N-(6-quinolyl)glycine hydrazide, and found that N(2-naph-
thyl)glycine hydrazide analogs possess potent inhibitory activity
against M. tuberculosis H37Rv at concentrations ranging from 0.5 to
0.39 mg/mL [34].
As a part of our on-going anti-TB research program, we herein
report design, synthesis and anti-mycobacterial activity of novel
quinoline and naphthalene derivatives influenced by structure of
TMC207 and mefloquine (Fig. 1) to explore new class of potent anti-
TB agents.
10.0 mg/mL whereas N-(6-quinolyl)glycine hydrazide analogs did
not show anti-tubercular activity. A series of naphthalene-1,4-
dione derivatives was synthesized and evaluated for their in vitro
anti-mycobacterial activity against H37Rv strain and most effective
2. Chemistry
2.1. Synthesis of quinoline derivatives (9–19)
compounds had MIC of 3.13
99% [31].
mg/mL and growth inhibition of
Quinoline derivatives (9–19) were prepared as shown in Scheme
1 and Scheme 2. 4-Bromoaniline (1) was heated with ethyl ace-
toacetate (EAA) and polyphosphoric acid (PPA) at 170 ꢀC to give
alcohol 2 (30%). Alcohol 2 when treated with PBr3 in dry DMF gave
4,6-dibromo quinoline 3 in moderate yield (50%). 4,6-di-Bromo-
quinoline 3, was subjected to n-BuLi treatment in dry THF at ꢁ78 ꢀC
followed by addition of pyridine-4-carboxaldehyde to give alcohol
4 (55%). We tried to synthesize epoxide 5 from alcohol 4 by two
different methods. Alcohol 4 was treated with (a) epi-chlorohydrin
in presence of dry DMF and NaH, and (b) epi-chlorohydrin in
presence of dry acetone and K2CO3, but both the methods failed to
give us desired key intermediate compound 5. Then we changed
the electrophile from epi-chlorohydrin to epi-bromohydrin. Alcohol
4 was treated with epi-bromohydrin in dry DMF in presence of NaH
to obtain epoxide 5, but yield was poor (3%). Hence we attempted to
synthesize epoxide 5 from O-allyl ether 6, followed by oxidation to
give epoxide 5. O-allyl ether 6 was synthesized in good yield (70%)
from alcohol 4 by treating with allyl bromide and NaH in dry DMF.
Epoxidation of O-allyl 6 with (a) m-CPBA in dry DCM and (b) 10% aq.
NaOH in 30% H2O2 were tried, but were not successful. Again we
devised our synthetic strategy to synthesize the target compounds
9–19 by exploiting halohydrin reaction on compound 6. Compound
6 (Scheme 2) was initially treated with acetone:water (3:1, v/v) in
presence of NBS to furnish compound 7 (12%) along with the
undesirable di-bromo compound 8 in 38%. Yield of desired
compound 7 was improved by changing the solvent system to
THF:water (1:1, v/v) in presence of NBS to give compound 7 in 24%
and di-bromo compound 8 in 32% yield. We optimized the yield of
compound 7 by changing the solvent ratio of THF:water to 4:1, v/v
and by adding a drop of conc. H2SO4 to obtain compound 7 in 45%
We have previously reported [32,33] design, synthesis and
biological activity of novel quinoline derivatives against
M. tuberculosis, based on molecular dissection (NE, SE and SW
hemisphere modifications) of the TMC207 (Fig. 1). Our initial
results showed that NE (hydroxyl and N,N0 dimethyl amine) and
SE (naphthyl) hemispheres are critical for anti-mycobacterial
activity of TMC207. Different amine substitutions at NE, SE and
SW hemispheres have also displayed good anti-mycobacterial
activity [32,33]. We have also recently reported a new class of
Modified Quinoline Series
N
OH
O
R
Br
N
CH3
Inactive
N
OH
N
N
H
OH
W
E
Br
N
CF3
O
N
CF3
S
TMC207
Mefloquine
H37Rv MIC: 0.06 µg/mL (0.01 µM)
H37Rv MIC: 8-16 µg/mL (21.1- 42.2 µM)
Plasmodium falciparum
MIC: 4.91 µg/mL (13 µM)
Modified Naphthalene Series
OH
OH
N
OH
Br
Br
O
R
N
N
N
N
N
N
IMM 39
IMM 35
H37Rv MIC: 6.25 µg/mL (13.4 µM)
Fig. 2. Structures of conformationally constrained active molecules, oxime (IMM 39)
and alcohol (IMM 35) [34].
Fig. 1. Design of quinoline and naphthalene series based on Mefloquine and TMC207.

1856
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
OH
N
Br
N
us desired key intermediate compound 7 in sufficient quantity to
proceed further in our synthetic scheme. Compound 7 (white solid)
decomposes (becomes pinkish) after couple of weeks even after
storing at ꢁ5 ꢀC. Hence target compounds 9–19 (Fig. 3) were
synthesized immediately from the key intermediate 7 by refluxing
it with appropriate amine in a protic polar solvent, iso-propanol,
and anhydrous K2CO3 for 10–12 h under nitrogen atmosphere in
moderate yields (24–60%).
Br
Br
Br
(i)
(ii)
NH2
2
3
1
(iii) 55%
OH
N
N
2.2. Synthesis of naphthalene derivatives (22–30)
O
O
Br
Br
Naphthalene series target molecules 22–30 were synthesized
using procedure as shown in Scheme 3. Etherification of alcohol
20 [36] with epi-chlorohydrin using NaH as a base in dry DMF
gave oxirane 21 (52%). Nucleophilic opening of the oxirane ring in
21 was carried out by treating compound 21 with appropriate
aryl-piperazines [37] in refluxing iso-propanol for 16 h to furnish
the target compounds 22–30 (Fig. 4) in moderate yields
(23–44%).
(iv) or (v) No reaction
(vi) 3%
N
N
5
4
(vii) 70%
N
X
O
(viii) or (ix) No reaction
Br
3. Pharmacology
N
3.1. Antimycobacterial activity
6
Scheme 1. Reagents and conditions: (i) EAA, PPA, 170 ꢀC, 6 h; 30% (ii) dry DMF, PBr3
(2 eq), 0 ꢀC; 8 h; 50% (iii) dry THF, n-BuLi (1.1 eq), ꢁ78 ꢀC, pyridine-4-carboxaldehyde
(1.5 eq), 30 min; 55% (iv) dry DMF, NaH (1.5 eq), epi-chlorohydrin (1.2 eq), rt, 2 h (v) dry
Acetone, K2CO3 (1.2 eq), epi-chlorohydrin (1.2 eq), 80 ꢀC, 2 h (vi) dry DMF, NaH (1.5 eq),
epi-bromohydrin (2 eq), 0 ꢀC to rt, 15 min; 3% (vii) dry DMF, NaH (1.5 eq), allyl bromide
(1.2 eq), 0 ꢀC, 30 min; 70% (viii) dry DCM, m-CPBA (3 eq), rt, 30 min (ix) 10% aq. NaOH,
30% v/v H2O2, rt, 24 h.
Two different series of compounds 9–19 and 22–30 were
evaluated for the anti-mycobacterial activity and the results are
summarized in Table 1. These compounds were screened against
M. tuberculosis H37Rv (ATCC 27294) in triplicate at the single
concentration of 6.25
mg/mL for inhibitory activity by BACTEC 460
radiometric methods [38,39]. It was found that naphthalene
series compounds (22–30) possess superior anti-TB activity than
the quinoline series compounds (9–19). Graphs of growth index
(GI) on the day basis for compounds 22, 23, 26 and 27 in
comparison to Isoniazid were plotted as shown in Fig. 5. Graphs
in Fig. 5 reveal that for compound 22 the mycobacterial load
and compound 8 in 14%. It is known in the literature that the
reactivity of NBS could be increased by adding catalytic amount of
acid, which could form hydrogen bond with nitrogen, and thereby
enhance the electrophilicity of the bromine [35]. This method gave
OH
Br
N
N
O
Br
O
Br
Br
Br
(i) or (ii) or (iii)
+
6
N
N
8 (14%)
7 (45%)
(iv)
OH
N
O
R1
Br
N
9 - 19
9: R1 = Imidazolyl (33%); 10: R1 = 1,2,4-trizolyl (24%); 11: R1 = Pyrazolyl (25%);
-1,2,4-trizolyl (24%);
12: R1 = 5-Amino-1,2,4-trizolyl (47%); 13: R1 = 3-Amino
14: R1 = 1-(Pyridin-2-yl) piperazinyl (42%); 15: R1 = 3-Methyl pyrazolyl (25%);
16: R1 = 2-Methoxy ethanamine (35%); 17: R1 = 2-(Methyl amino ethanol) (60%);
18: R1 = 5-Amino- tetrazolyl (39%);19: R1= Ethane-1,2-diamine (42%)
Scheme 2. Reagents and conditions: (i) Acetone:H2O (3:1), NBS (1.1 eq); rt, 1 h, for 7, 12%; 8, 38% (ii) THF:H2O (1:1), NBS (1.1 eq), rt, 1 h; for 7, 24%; 8, 32% (iii) THF:H2O (4:1), NBS
(1.1 eq), H2SO4 (cat), rt, 30 min; for 7, 45%; 8, 14% (iv) 2-propanol, R1H (1 eq), reflux, 10–12 h; 24–60%.

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1857
never increased and showed gradual decrease from day 3 to day
11. Compounds 22, 23, 26 and 27 inhibited H37Rv 99% (ꢂ0.65),
90% (ꢂ2.40), 98% (ꢂ2.68) and 91% (ꢂ6.79) respectively (Table 1).
Figs. 5 and 6 shows that compounds 22, 23, 26 and 27 possess
good anti-mycobacterial activity and are comparable to standard
N
OH
N
O
N
Br
N
first front-line drug Isoniazid at concentration 6.25
mg/mL and
9
under identical experimental conditions. The activity profile of
compounds 22, 23, 26 and 27 suggest that each compound has
a bactericidal effect as there is no growth in treated control.
Based on the primary growth inhibition activity, compounds 22,
23, 26 and 27 were selected to determine minimum inhibitory
N
N
OH
N
N
N
OH
O
O
N
N
Br
Br
N
N
concentration (MIC) against H37Rv and was found to be 6.25 mg/
10
11
mL for 22, 23, 26 and 27 (Table 2).
N
OH
N
OH
H
N
H
N
H
N
O
O
N
3.2. Cytotoxicity
N
NH
Br
N
Br
N
Cell viability in the presence and absence of test compounds was
determined by Mossman’s MTT assay [40–42] at two different
N
N
concentrations 1 and 10 mg/mL for the most active compounds (22,
12
13
N
23, 26 and 27) from our data set. The results are presented as
percentage cell viability (Table 3). Cytotoxicity results of 22, 23, 26
and 27 (Table 3) suggest that these compounds are not cytotoxic to
host cells at the given concentrations, except compound 23, which
is least safe (cell viability 64%) to human monocytic cells.
N
N
N
OH
OH
OH
N
N
OH
N
N
O
O
O
N
O
O
O
Br
Br
Br
Br
N
N
N
N
N
N
4. Results and discussion
15
14
N
OH
H
N
Based on our strategy of modifying TMC207 having resemblance
with Mefloquine we have presented new class of anti-TB
compounds in order to understand SAR and develop new anti-TB
compounds. Table 1 revels that quinoline based compounds did not
show good anti-TB activity. Target compounds with heteroaromatic
ring containing 2 to 4 nitrogen atoms (9, 10, 11, 12, 13, 15 and 18), or
aliphatic amines (14, 16, 17 and 19) did not show biological activity
may be due to lack of proper interactions with crucial amino acids
at the binding site.
It is interesting to note that the substituents on the piperazine-
phenyl ring are playing important role in determining the biolog-
ical activity of naphthalene series compounds 22–30. From Table 1
it is clear that compound 22 having 3-methoxy and compound 23
having 2-methoxy group shows excellent activity (99% and 90%
inhibition respectively). Change in the position of methoxy group in
compounds 22 and 23 is not showing much effect on its anti-TB
activity. When we have 3-trifluoro group on phenyl ring
N
O
OH
Br
16
17
N
OH
H
N
H
N
N
NH2
N
Br
HN
N
18
19
Fig. 3. Structures of quinoline series compounds (9–19).
OH
OH
(i)
O
O
O
R1
(ii)
20
21
22 - 30
22: R1 = 4-(3-Methoxy-phenyl)-piperazin-1-yl (30%);
23: R1 = 4-(2-Methoxy-phenyl)-piperazin-1-yl (42%);
24: R1 =4-(3-Trifluromethyl-phenyl)-piperazin-1-yl (31%);
25: R1 = 4-(3,4-Dichloro-phenyl)-piperazin-1-yl (39%);
26: R1 = 4-Benzhydryl-piperazin-1-yl (37%);
27: R1 = 4-Benzyl-piperazin-1-yl (44%);
28: R1 = 4-(pyridin-2-yl)piperazin-1-yl (42%);
29: R1 = 4-(4-Fluro-phenyl)-piperazin-1-yl (28%);
30: R1 = 4-(4-Chloro-phenyl)-piperazin-1-yl (23%)
Scheme 3. Reagents and conditions: (i) dry DMF, NaH (1.2 eq), epi-chlorohydrin (2 eq), rt, 16 h; 52% (ii) 2-propanol, R1H (1 eq), reflux, 16 h; 23–44%.

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R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
OMe
MeO
OH
OH
OH
OH
OH
N
N
N
N
N
OH
N
O
O
O
O
O
N
N
N
N
N
O
N
CF3
Cl
Cl
22
24
26
23
OH
N
O
N
25
OH
N
O
N
F
27
N
OH
N
O
N
Cl
28
29
30
Fig. 4. Structures of naphthalene series compounds (22–30).
(compound 24), biological activity is lost. Molecules having 4-flu-
oro (compound 29), 4-chloro (compound 30) and 3,4-dichloro
group (compound 25) on phenyl ring dose not show anti-TB
activity. Also when phenyl ring is replaced by pyridyl ring in
compound 28, dose not display activity against M. tuberculosis.
While molecules having benzhydryl group (compound 26) and
benzyl group (compound 27) displays good activity. This analysis
suggests that the electronic nature of substituent on piperazine-
phenyl ring, probably modulates activity profile of these series of
compounds. Substituents which increase electron density
(methoxy) on the piperazine-phenyl ring (compounds 22 and 23)
or when phenyl ring is replaced by alkylaryl group (compounds 26
and 27) molecules showed excellent activity. While electron
withdrawing substituents on the piperazine-phenyl ring, like
trifluoro (compound 24), 3,4-dichloro (compound 25), 4-fluoro
(compound 29) and 4-chloro (compound 30) dose not show anti-TB
activity. Similarly, compound 28 having pyridyl ring instead of
phenyl ring was inactive, as it is known that the nitrogen polarizes
4.1. Docking studies
Designed molecules having fragmental similarity with TMC207
and Mefloquine were docked on previously known putative
binding site of ATP synthase of M. tuberculosis [43]. The function of
the ATP-synthase enzyme depends upon the ability of subunit
a (81–250) and subunit c (1–81) to transfer proton through binding
site residues [43]. The binding site of ATP synthase is composed of
highly conserved and charged residues and located in between
cavity formed by subunit a (Arg-186 and Asn-190) and subunit c
(Glu-61, Tyr-64, Phe-65 and Leu-68). Docking study was carried out
using Glide XP, which docks ligand accurately at the binding site
[44] and details of docking procedure and methodology are given in
Supplementary data. All molecules docked at the same binding site
and in similar fashion. Their affinity towards the binding site can be
judged by the energetic and structural features analysis at the
binding site. The molecular docking studies showed that some
compounds have high binding affinity, while some had low affinity
towards binding site. The detailed analysis of docking energies
(Table 4) and poses of the compounds helped us to find out the
the
p-system of pyridine, resulting in decreased electron density on
the ring carbons.

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1859
Table 1
(ꢁ5.98) and Ecoul (ꢁ0.81) interaction energies, in addition it lacked
hydrogen bonding with any amino acid at the binding site. From
docking study it can be seen that active compounds (22, 23, 26 and
27) have lower XP Glide docking score (ꢁ10.58, ꢁ10.77, ꢁ11.50 and
ꢁ9.94 respectively) and lower interaction energies when compared
with the inactive compound 25. Thus for a compound to retain its
biological activity, it should form crucial hydrogen bonding with
critical amino acid (Glu-61, Tyr-64, Asn-190) residue at the binding
site, Similar kind of interactions were observed with Mefloquine
and TMC207, where they formed hydrogen bonding with Tyr-64
and Glu-61 binding site residues respectively. The lipophilic van der
Walls (EvdW) and coulomb (Ecoul) interactions, were also found in
accordance with biological activity. The docking study showed the
importance of binding energies and hydrogen bonding between
ligand and crucial amino acid residues of proton transfer chain for
biological activity.
In vitro anti-mycobacterial activity against M. tuberculosis H37Rv (at 6.25
m
g/mL).
clogP
Compounds
% Inhibition
9
10
11
12
13
14
15
16
17
18
19
22
23
24
25
26
7
10
9
22
15
4
2.0
1.72
2.40
2.14
2.41
3.48
2.67
2.14
2.03
1.11
0.97
5.73
5.73
6.96
7.32
7.42
6.07
4.83
6.10
6.67
ꢁ0.8a
8
19
13
20
5
99
90
11
4
98
91
23
14
5
27
28
29
30
5. Conclusion
We have synthesized two series of molecules influenced by
TMC207 and Mefloquine, among these compounds 22, 23, 26 and
27 were found to be active against M. tuberculosis on the basis of
preliminary biological results through in vitro BACTEC-460 radio-
metric method. Naphthalene series compounds displayed excellent
anti-mycobacterial activity as compared to quinoline series
compounds and had MIC less than mefloquine. Nature of substit-
uents on piperazine-phenyl ring in naphthalene series was found to
play an important role in determining biological activity.
Compounds having electron donating groups on piperazine-phenyl
ring (naphthalene series) showed good anti-mycobacterial activity,
while compounds having electron withdrawing groups on pipera-
zine-phenyl ring were inactive. Docking calculations revealed that
hydrogen bonding interactions played crucial role in demonstrating
biological activity.
Isoniazid
99
a
From PubChem (http://pubchem.ncbi.nlm.nih.gov/).
possible reason for the difference in their bioactivity: Most active
compound 22 (99% inhibition) showed lower ꢁ10.58 docking score.
Visual analysis of the docked compound 22 (Fig. 7 A) showed that
naphthalene nucleus resides in the pocket formed by the Glu-61
(2.288 Å), Tyr-64 (2.458 Å) and Phe-65 (2.523 Å), the phenyl ring
adjacent to ethereal linkage fits in the close vicinity of Glu-61
(2.785 Å) and Tyr-64 (2.091 Å). Compound 22 showed crucial
hydrogen bonding interaction of hydroxyl group with Asn-190
(2.130 Å). 3-Methoxy group of 22 on piperazine-phenyl ring
showed additional weak interactions with the binding site resi-
dues, which contributed to the van der Walls and columbic inter-
action energies. Compound 23 (Fig. 7 B) is structurally similar to 22,
except difference between the position of methoxy group (on
piperazine-phenyl ring) -ortho and –meta respectively. Although
hydroxyl group of compound 23 made a hydrogen bonding inter-
action with a key amino acid residue Glu-61 (1.909 Å) (instead of
Asn-190 in 22), its docking score was ꢁ10.77 (ꢁ10.58 for 22)
showed good activity i.e. 90% inhibition, which is slightly less than
22. From docking studies it can be concluded that shifting of
methoxy group (from meta to ortho) leads to more restricted
geometry (RMSD between 22 and 23 was 3.353 Å) than 22, which
might cause lesser interactions with the binding site residues and
thus lead to possible slight decrease in the activity of compound 23.
Compound 27 having benzyl group on piperazine also followed
similar binding pattern and its hydroxyl group showed hydrogen
bonding interaction with Tyr-64 (2.063 Å) at the binding site. When
benzyl group was replaced by bulkier benzhydryl group
(compound 26, Fig. 7 D), it docked in similar fashion making
hydrogen bonding interaction of its hydroxyl group with Glu-61
(2.179 Å). Compound 27 showed 91% inhibition of M. tuberculosis
while compound 26 showed 98% inhibition. Replacing benzyl
group (compound 27) on the piperazine ring by the bulkier benz-
hydryl group, leads to the extended geometry (RMSD between 26
and 27 was 2.737 Å) at the binding site and increase in interactions
with the binding site, which could be the reason for higher docking
score and better biological activity of 26 as compared to 27. When
the piperazine-phenyl ring had halogens as substituents (24, 25, 29
and 30) biological activity was dramatically reduced, although they
docked in similar way (RMSD between 25 and 24, 29, 30 was
1.099 Å, 1.085 Å, 0.781 Å respectively). The docked complex of 25
(Fig. 7C), showed higher docking score (ꢁ6.67), higher EvdW
6. Experimental
6.1. Chemistry
All chemicals and reagents used were of reagent grade. Purifi-
cation and drying of reagents and solvents was carried out accord-
ing to literature procedure [45]. Thin layer chromatographic
analyses were performed on E-Merck 60 F 254 precoated aluminum
thin layer chromatographic plates. All air-sensitive reactions were
carried out under nitrogen atmosphere. Melting points were
determined on a Bu¨chi melting point B-540 instrument and are
uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
Biospin 400 MHz spectrometer in the indicated solvents (TMS as an
internal standard). The values of chemical shifts are expressed in
d
ppm and the coupling constants J in hertz (Hz). Mass spectra were
recorded on API 2000 LC/MS/MS system spectrometer.
6.1.1. 6-Bromo-2-methylquinolin-4-ol (2)
p-Bromoaniline (5.0 g, 29.1 mmol), PPA (14.73 g, 43.7 mmol) and
EAA (7.55 mL, 58.1 mmol) were heated at 170 ꢀC for 6 h under
nitrogen atmosphere. Reaction was allowed to come to room
temperature and quenched with aqueous 20% NaOH solution so
that pH becomes 7. Precipitated solid was washed with water
(3 ꢃ 100 mL) and dried under vacuum to obtain pure white solid
compound 2 (2.1 g, 30%); mp 257–260 ꢀC. 1H NMR (400 MHz,
DMSO-d6):
d 2.33 (s, 3H, Ar–CH3), 5.96 (s, 1H, Ar–H), 7.46 (d,
J ¼ 8.8 Hz, 1H, Ar–H), 7.75 (dd, J ¼ 8.8, 2.4 Hz, 1H, Ar–H), 8.10 (d,
J ¼ 2.4 Hz, 1H, Ar–H), 11.80 (br-s, 1H, D2O exchangeable, Ar–OH). 13
C
NMR (100.6 MHz, DMSO-d6):
d 19.5 (Ar–CH3), 108.5 (Ar–C), 115.6
(Ar–C), 120.6 (Ar–C), 125.6 (Ar–C), 126.8 (Ar–C), 134.3 (Ar–C), 138.9

1860
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1000
900
800
700
600
500
400
300
200
100
0
Control (no inhibitor added)
30
Isoniazid
Compound 22
20
Compd 22
Isoniazid
10
0
-100
0
1
2
3
4
5
6
7
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9 10 11 12
Days
Days
Control (no inhibitor added)
Isoniazid
1000
900
800
700
600
500
400
300
200
100
0
90
80
70
60
50
40
30
20
10
0
Compound 23
Compd 23
Isoniazid
-100
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
Days
Days
1000
900
800
700
600
500
400
300
200
100
0
40
Control (no inhibitor added)
Isoniazid
30
20
10
0
Compound 26
Compd 26
Isoniazid
-100
0
1
2
3
4
5
6
7
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9 10 11 12
Days
Days
1000
900
800
700
600
500
400
300
200
100
0
125
100
75
50
25
0
Control (no inhibitor added)
Isoniazid
Compound 27
Compd 27
Isoniazid
-100
0
1
2
3
4
5
6
7
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9 10 11 12
Days
Days
Fig. 5. Day-wise growth index of MTB after single-dose administration at the day-one of infection.
(Ar–C), 150.8 (Ar–C), 175.0 (Ar–C). ESI-MS m/z of 238.0, 240.0
[M þ H]þ was obtained for a calculated mass of 237.99, 239.98.
concentrated under reduced pressure to obtain a sticky mass as
a crude product. This crude product was purified by column chro-
matography (silica gel 100–200 mesh, eluent: 3% ethyl acetate in
hexane) to afford pure 3 (0.062 g, 50%) as an off white solid, mp 94–
6.1.2. 4,6-Dibromo-2-methylquinoline (3)
6-Bromo-2-methylquinolin-4-ol (2, 0.100 g, 0.420 mmol) was
dissolved in dry DMF (5 mL), PBr3 (0.17 mL, 0.22 mmol) was added
drop wise at 0 ꢀC over 30 min under nitrogen atmosphere and
stirred at room temperature for 8 h. Reaction was quenched by ice
and extracted with ethyl acetate (2 ꢃ 10 mL). The combined organic
layer was washed with water (2 ꢃ 10 mL), brine (1 ꢃ 10 mL), and
dried over anhydrous sodium sulfate. Organic layer was filtered and
96 ꢀC. 1H NMR (400 MHz, CDCl3):
d 2.69 (s, 3H, Ar–CH3), 7.61 (s, 1H,
Ar–H), 7.77 (dd, J ¼ 9.0, 2.1 Hz, 1H, Ar–H), 7.85 (d, J ¼ 9.0 Hz, 1H, Ar–
H), 8.29 (d, J ¼ 2.1 Hz,1H, Ar–H). 13C NMR (100.6 MHz, CDCl3):
d 24.9
(Ar–CH3), 120.9 (Ar–C), 126.4 (Ar–C), 127.1 (Ar–C), 128.6 (Ar–C),
130.7 (Ar–C), 132.5 (Ar–C), 133.7 (Ar–C), 146.8 (Ar–C), 159.2 (Ar–C).
[M þ H]þ ¼ for C10H7Br2N. ESI-MS m/z of 301.80, 303.80 [M þ H]þ
was obtained for a calculated mass of 301.90, 303.90.

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1861
100
MIC
6.25
12.5
10.0
7.5
80
60
40
20
0
MIC
6.25
MIC
6.25
5.0
MIC
0.25
MIC
6.25
2.5
0.0
Fig. 6. % TB growth under influence of untreated control, compounds (22, 23, 26 and 27) and Isoniazid.
6.1.3. (6-Bromo-2-methylquinolin-4-yl)(pyridin-4-yl)methanol (4)
n-Butyl lithium (1.6 M, 0.137 mL, 0.22 mmol) was added to the
compound 3 (0.1 g, 0.33 mmol) in dry THF at ꢁ78 ꢀC and stirred for
30 min. The solution of pyridine-4-carboxaldehyde (0.035 mL,
0.36 mmol) was added at ꢁ78 ꢀC over 2 min, and stirred for 30 min.
Reaction was quenched with aqueous NH4Cl (3 mL). Ice-cold water
was added to reaction mixture and extracted with ethyl acetate
(2 ꢃ 10 mL). The combined organic layer was washed with water
(2 ꢃ 10 mL), brine (1 ꢃ 10 mL) and dried over anhydrous sodium
sulfate. Organic layer was filtered and concentrated under reduced
pressure to obtain a sticky mass as a crude product. This crude
product was purified by column chromatography (Silica gel 100–
200 mesh, eluent: 2.5% methanol in DCM) to afford 4 (0.056 g, 55%)
as off white solid, mp 200–204 ꢀC. 1H NMR (400 MHz, CD3OD):
Ar–H), 7.33–7.42 (m, 1H, Ar–H), 7.69 (dd, J ¼ 9.0, 2.0 Hz, 1H, Ar–H),
7.87 (d, J ¼ 9.0 Hz, 1H, Ar–H), 8.10 (dd, J ¼ 9.3, 2.0 Hz, 1H, Ar–H),
8.51–8.85 (m, 2H, Ar–H). 13C NMR (100.6 MHz, CDCl3):
d 25.4 (Ar–
CH3), 43.8 (epoxy–CH2), 44.0 (epoxy–CH2), 50.6 (epoxy–CH), 69.9
(OCH2), 70.4 (OCH2), 79.2 (Ar–CHO–), 79.3 (Ar–CHO–),120.0 (Ar–C),
120.4 (Ar–C), 120.6 (Ar–C), 121.3 (Ar–C), 121.5 (Ar–C), 121.7 (Ar–C),
121.8 (Ar–C), 125.1 (Ar–C), 125.2 (Ar–C), 125.8 (Ar–C), 125.9 (Ar–C),
130.8 (Ar–C), 131.2 (Ar–C), 132.6 (Ar–C), 132.8 (Ar–C), 143.7 (Ar–C),
143.9 (Ar–C), 146.9 (Ar–C), 147.0 (Ar–C), 148.1 (Ar–C), 148.3 (Ar–C),
150.1 (Ar–C), 159.0 (Ar–C), 159.3 (Ar–C). ESI-MS m/z of 384.90,
386.70 [M þ H]þ was obtained for a calculated mass of 385.06,
387.05.
6.1.5. 4-(Allyloxy(pyridin-4-yl)methyl)-6-bromo-2-
d
2.71 (s, 3H, Ar–CH3), 4.63 (s, 1H, D2O exchangeable, OH), 6.37 (s,
methylquinoline (6)
1H, CH(OH)), 7.47 (dd, J ¼ 4.5, 1.6 Hz, 2H, Ar–H), 7.58 (s, 1H, Ar–H),
7.78 (dd, J ¼ 9.0, 2.1 Hz,1H, Ar–H), 7.86 (d, J ¼ 9.0 Hz,1H, Ar–H), 8.29
(d, J ¼ 2.1 Hz, 1H, Ar–H), 8.49 (dd, J ¼ 4.7, 1.6 Hz, 2H, Ar–H). 13C NMR
Sodium hydride (0.007 g, 0.33 mmol) was added to solution of
compound 4 (0.1 g, 0.30 mmol) in dry DMF (2 mL) at 0 ꢀC and
stirred for 30 min. Allyl bromide (0.041 mL, 0.45 mmol) was added
at 0 ꢀC and stirred at room temperature for 30 min. Reaction was
quenched by ice and extracted with ethyl acetate (2 ꢃ 10 mL). The
combined organic layer was washed with water (2 ꢃ 10 mL) fol-
lowed by brine (1 ꢃ 10 mL) and dried over anhydrous sodium
sulfate. Organic layer was filtered and concentrated under reduced
pressure to obtain a sticky mass as a crude product. This crude
product was purified by column chromatography (silica gel 100–
200 mesh, eluent: 1% MeOH in DCM) to afford 6 (0.083 g, 70%) as off
(100.6 MHz, CD3OD):
d 24.9 (Ar–CH3), 72.3 (Ar–CHOH), 120.9
(Ar–C), 122.8 (Ar–C), 123.4 (Ar–C), 126.7 (Ar–C), 128.1 (Ar–C), 131.2
(Ar–C), 134.1 (Ar–C), 147.7 (Ar–C), 149.6 (Ar–C), 150.3 (Ar–C), 154.2
(Ar–C), 161.2 (Ar–C). ESI-MS m/z of 329.00, 330.80 [M þ H]þ was
obtained for a calculated mass of 329.03, 331.02.
6.1.4. 6-Bromo-2-methyl-4-((oxiran-2-ylmethoxy)
(pyridin-4-yl)methyl)quinoline (5)
Compound 4 (0.5 g, 1.51 mmol) was dissolved in dry DMF
(10 mL), epi-bromohydrin (0.26 mL, 3.03 mmol) was added, cooled
to 0 ꢀC, sodium hydride (0.054 g, 0.25 mmol) was added portion
wise. Reaction was stirred at 0 ꢀC for 30 min, quenched by ice and
extracted with ethyl acetate (2 ꢃ 50 mL). The combined organic
layer was washed with water (2 ꢃ 25 mL) and brine (2 ꢃ 25 mL).
Organic layer was dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum to obtain a sticky mass as a crude
product. Crude product was purified by column chromatography
(silica gel 100–200 mesh, eluent: 1% MeOH in DCM) to give
compound 5 (0.020 g, 3%) as a sticky mass. 1H NMR (400 MHz,
white solid, mp 118–120 ꢀC. 1H NMR (400 MHz, CDCl3):
d 2.73 (s,
3H, Ar–CH3), 4.00–4.12 (m, 2H, OCH2), 5.23–5.37 (m, 2H, CH]CH2),
5.90 (s,1H, OCH), 5.91–6.03 (m,1H, OCH2CHCH2), 7.28 (d, J ¼ 6.0 Hz,
2H, Ar–H), 7.37 (s, 1H, Ar–H), 7.71 (dd, J ¼ 9.0, 2.0 Hz,1H, Ar–H), 7.89
(d, J ¼ 7.9 Hz, 1H, Ar–H), 8.12 (d, J ¼ 2.0 Hz, 1H, Ar–H), 8.57 (dd,
J ¼ 4.5, 1.5 Hz, 2H, Ar–H). 13C NMR (100.6 MHz, CDCl3):
d 25.4 (Ar–
CH3), 70.4 (OCH2), 77.9 (Ar–CHO–), 118.3 (CH2]CH), 120.0 (Ar–C),
121.5 (Ar–C), 121.6 (Ar–C), 125.3 (Ar–C), 125.9 (Ar–C), 131.2 (Ar–C),
132.8 (Ar–C), 133.5 (CH2 ¼ CHCH2O), 144.2 (Ar–C), 147.0 (Ar–C),
148.6 (Ar–C), 150.1 (Ar–C), 159.3 (Ar–C).
ESI-MS m/z of 369.00, 370.80 [M þ H]þ was obtained for
a calculated mass of 369.06, 371.06.
CDCl3):
d
2.53 (dd, J ¼ 4.8, 2.7 Hz, 0.5H, epoxy–CH), 2.62 (dd, J ¼ 4.8,
2.7 Hz, 0.5H, epoxy–CH), 2.71 (s, 3H, Ar–CH3), 2.75–2.82 (m, 1H,
epoxy–CH2), 3.16–3.27 (m, 1H, epoxy–CH2), 3.34–3.48 (m, 1H,
OCH2), 3.81–3.91 (m, 1H, OCH2), 5.95 (s, 1H, OCH), 7.22–7.32 (m, 2H,
Table 3
Cytotoxic effects of tested compounds on human monocytic cell line U937, 24 h and
72 h after treatment.
Compounds
% Cell viability
10 g/mL
Table 2
MIC of compounds against M. tuberculosis H37Rv.
m
1 mg/mL
Compounds
MIC (
m
g/mL)
MIC (
mM/mL)
24 h
72 h
24 h
72 h
22
23
26
27
6.25
6.25
6.25
6.25
12.96
12.96
11.53
13.41
22
23
26
27
82
81
74
77
63
62
70
74
100
81
93
100
64
79
77
71

1862
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
Table 4
Glide docking energies of compounds 22, 23, 25, 26 and 27.
Molecule
XP Glide Score
EvdW
Ecoul
22
23
25
26
27
ꢁ10.58
ꢁ10.77
ꢁ6.67
ꢁ10.15
ꢁ9.98
ꢁ5.98
ꢁ10.98
ꢁ9.67
ꢁ2.48
ꢁ5.10
ꢁ0.81
ꢁ2.60
ꢁ2.46
ꢁ11.50
ꢁ9.94
EvdW ¼ lipophilic van der Waals energy (kcal/mol), Ecoul ¼ coulomb energy (kcal/
mol).
6.1.6. 1-Bromo-3-((6-bromo-2-methylquinolin-4-yl)
(pyridin-4-yl)methoxy)propan-2-ol (7) and 6-bromo-4-((2,3-
dibromopropoxy)(pyridin-4-yl)methyl)-2-methylquinoline (8)
Compound 6 (0.1 g, 0.27 mmol) and N-bromosuccinimide
(0.05 g, 0.32 mmol) was dissolved in THF:H2O (4:1, v/v, 10 mL), few
drops of conc. sulphuric acid were added and stirred for 10 min. The
reaction was quenched by water and extracted with ethyl acetate
(2 ꢃ 10 mL). The combined organic layer was washed with water
(2 ꢃ 10 mL), brine (1 ꢃ 10 mL) and dried over anhydrous sodium
sulfate. Organic layer was filtered and concentrated under reduced
pressure to obtain a sticky mass as a crude product. This crude
product was purified by column chromatography (silica gel 100–
200 mesh, eluent: 3% MeOH in DCM) to afford 7 (0.056 g, 45%) as off
white solid and 8 (0.020 g, 14%) as a sticky solid.
Data for 7: mp 75 ꢀC. 1H NMR (400 MHz, CD3OD):
d 2.67 (s, 1H,
Ar–CH3), 2.74 (s, 2H, Ar–CH3), 3.40–3.74 (m, 2H, Br–CH2), 3.75–3.90
(m, 2H, O–CH2), 3.92–4.10 (m, 1 H, Br–CH2), 4.15–4.30 (m, 1H,
CH(OH)), 6.16 (s, 0.5H, OCH), 6.17 (s, 0.5H, OCH), 7.50 (d, J ¼ 4.8 Hz,
2H, Ar–H), 7.68 (s,1H, Ar–H), 7.78 (dd, J ¼ 9.0, 2.0 Hz,1H, Ar–H), 7.87
(d, J ¼ 9.0 Hz,1H, Ar–H), 8.28–8.38 (m,1H, Ar–H), 8.50 (d, J ¼ 4.0 Hz,
2H, Ar–H) total 18H in a diastereomeric ratio 2: 1. 13C NMR
(100.6 MHz, CDCl3):
d 25.3 (Ar–CH3), 52.59 (CHOH), 52.65 (CHOH),
63.54 (CH2–Br), 63.56 (CH2–Br), 70.4 (OCH2CHOH), 70.5 (OCH2
-
CHOH), 79.74 (Ar–CHO–), 79.85 (Ar–CHO–), 120.19 (Ar–C), 120.21
(Ar–C), 121.5 (Ar–C), 121.62 (Ar–C), 121.65 (Ar–C), 121.8 (Ar–C),
125.07 (Ar–C), 125.12 (Ar–C), 125.7 (Ar–C), 125.91 (Ar–C), 125.95
(Ar–C), 131.0 (Ar–C), 132.90 (Ar–C), 132.93 (Ar–C), 143.47 (Ar–C),
143.52 (Ar–C),143.6 (Ar–C),146.82 (Ar–C),146.9 (Ar–C),148.26 (Ar–
C), 148.3 (Ar–C), 149.9 (Ar–C), 159.26 (Ar–C), 159.28 (Ar–C). ESI-MS
m/z of 466.90, 469.00 [M þ H]þ was obtained for a calculated mass
of 466.98, 468.98.
Data for 8: 1H NMR (400 MHz, CDCl3):
d 2.73 (s, 3H, Ar–CH3),
2.78–3.93 (m, 3H, BrCH2–CHBr, OCH2CHBr), 3.97 (dd, J ¼ 10.6, 4.2 Hz,
0.5H, Br–CH), 4.04 (dd, J ¼ 10.4, 4.3 Hz, 0.5H, Br–CH), 4.26–4.34 (m,
1H, OCH2CHBr), 5.92 (s, 1H, OCH), 7.25–7.32 (m, 2H, Ar–H), 7.35 (d,
J ¼ 2.0 Hz, 1H, Ar–H), 7.67–7.75 (m, 1H, Ar–H), 7.86–7.95 (m, 1H, Ar–
H), 8.12 (dd, J ¼ 9.8, 2.0 Hz, 1H, Ar–H), 8.55–8.63 (m, 2H, Ar–H). 13C
NMR (100.6 MHz, CDCl3): d 25.4 (Ar–CH3), 32.0 (CH2–Br), 32.2 (CH2–
Br), 47.8 (CH–Br), 48.0 (CH–Br), 70.2 (OCH2), 70.4 (OCH2), 79.9 (Ar–
CHO–), 120.3 (Ar–C), 121.5 (Ar–C), 121.6 (Ar–C), 121.8 (Ar–C), 122.0
(Ar–C), 122.7 (Ar–C), 125.2 (Ar–C), 126.0 (Ar–C), 126.1 (Ar–C), 131.2
(Ar–C), 133.0 (Ar–C), 143.2 (Ar–C), 147.1 (Ar–C), 147.8 (Ar–C), 147.9
(Ar–C), 150.2 (Ar–C), 159.3 (Ar–C). ESI-MS m/z of 528.60, 530.50
[M þ H]þ was obtained for a calculated mass of 528.89, 530.89.
6.1.7. Representative procedure A, for compounds 9–19: 1-((6-
bromo-2-methylquinolin-4-yl)(pyridin-4-yl)methoxy)-3-(1H-
imidazol-1-yl)propan-2-ol (9)
Compound 7 (0.1 g, 0.21 mmol), imidazole (0.029 g, 0.42 mmol)
and anhydrous potassium carbonate (0.059 g, 0.42 mmol) was
refluxed in 2-propanol (8 mL) for 16 h. 2-Propanol was evaporated
under reduced pressure to obtain sticky mass, which was diluted
with ethyl acetate (20 mL) washed with water, brine (1 ꢃ 10 mL)
and dried over anhydrous sodium sulfate. Organic layer was filtered
Fig. 7. Molecules 22, 23, 25 and 26 in the binding site of M. tuberculosis ATP synthase.
EvdW and Ecoul interactions are shown in blue and hydrogen bonding in red color (For
interpretation of the references to colour in this figure legend, the reader is referred to
the web version of this article).

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1863
and concentrated under reduced pressure to obtain sticky mass as
a crude product. Crude product was purified by column chroma-
tography (silica gel 100–200 mesh, eluent: 3.5% methanol in DCM)
to afford 9 (0.032 g, 33%) as off white solid, mp 174–176 ꢀC. 1H NMR
7.84–7.94 (m, 1H, Ar–H), 8.00–8.12 (m, 1H, Ar–H), 8.52–8.62 (m, 2H,
Ar–H) total 21H in
(100.6 MHz, CDCl3):
a
diastereomeric ratio 1: 1.5. 13C NMR
25.3 (Ar–CH3), 50.3 (HN–CH2), 52.3 (HN–
d
CH2), 68.22 (CHOH), 68.28 (CHOH), 69.7 (CHOH), 71.4 (OCH2), 71.5
(OCH2), 71.52 (OCH2), 71.57 (OCH2), 79.8 (Ar–CHO–), 79.84 (Ar–
CHO–), 120.1 (Ar–C), 120.21 (Ar–C), 121.6 (Ar–C), 125.1 (Ar–C),
125.71 (Ar–C), 125.76 (Ar–C), 125.8 (Ar–C), 130.9 (Ar–C), 131.1 (Ar–
C), 132.9 (Ar–C), 143.13 (Ar–C), 143.16 (Ar–C), 143.7 (Ar–C), 146.7
(Ar–C), 146.8 (Ar–C), 148.03 (Ar–C), 148.05 (Ar–C), 148.17 (Ar–C),
148.3 (Ar–C), 148.4 (Ar–C), 149.8 (Ar–C), 149.9 (Ar–C), 159.27 (Ar–
C), 159.29 (Ar–C), 163.3 (Ar–C). ESI-MS m/z of 469.00, 471.40 [M]þ
was obtained for a calculated mass of 469.09, 471.09.
(400 MHz, CDCl3):
d 2.70 (s, 3H, Ar–CH3), 3.33–3.76 (m, 3H, OCH2
and 1H D2O exchangeable OH), 3.85–4.20 (m, 3H, NCH2, CHOH),
5.88 (s, 0.5H, OCH), 5.90 (s, 0.5H, OCH), 6.86 (s, 2H, Ar–H), 7.15–7.47
(m, 4H, Ar–H), 7.63–7.80 (m, 1H, Ar–H), 7.80–8.00 (m, 1H, Ar–H),
8.09 (d, J ¼ 8.0 Hz, 1H, Ar–H), 8.55 (s, 2H, Ar–H) total 21H in
a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 25.3 (Ar–
CH3), 50.5 (N–CH2), 69.2 (CHOH), 71.3 (OCH2), 80.0 (Ar–CHO–), 80.1
(Ar–CHO–), 119.8 (Ar–C), 120.1 (Ar–C), 121.5 (Ar–C), 121.6 (Ar–C),
121.7 (Ar–C), 125.0 (Ar–C), 125.8 (Ar–C), 128.3 (Ar–C), 131.1 (Ar–C),
132.9 (Ar–C), 137.4 (Ar–C), 143.6 (Ar–C), 146.9 (Ar–C), 148.3 (Ar–C),
150.0 (Ar–C), 159.3 (Ar–C). ESI-MS m/z of 452.80, 455.00 [M þ H]þ
was obtained for a calculated mass of 453.09, 455.09.
6.1.11. 1-(1H-1,2,4-Triazol-3-ylamino)-3-((6-bromo-2-
methylquinolin-4-yl)(pyridin-4-yl) methoxy)propan-2-ol (13)
Procedure A, yield 24%. Off white solid; mp 179–182 ꢀC. 1H NMR
(400 MHz, CDCl3): d 2.68 (s, 1H, Ar–CH3), 2.71 (s, 2H, Ar–CH3), 3.46–
6.1.8. 1-((6-Bromo-2-methylquinolin-4-yl)(pyridin-4-yl)methoxy)-
3-(1H-1,2,4-triazol-1-yl) propan-2-ol (10)
3.67 (m, 2H, NHCH2), 3.96–4.33 (m, 4H, OCH2, CHOH, 1H D2O
exchangeable OH), 4.91 (d, J ¼ 10.2 Hz, 1H D2O exchangeable, NH),
5.87 (s, 1H, OCH), 7.21–7.32 (m, 5H, 1H D2O exchangeable, Ar–NH),
7.40 (d, J ¼ 5.6 Hz, 0.5H, Ar–H), 7.60–7.76 (m, 1.5H, Ar–H), 7.83–7.92
(m, 1H, Ar–H), 8.01–8.10 (m, 1H, Ar–H), 8.48–8.59 (m, 2H, Ar–H)
total 20H in a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz,
Procedure A, yield 24%. Off white solid; mp 163–165 ꢀC. 1H NMR
(400 MHz, CDCl3):
d 2.71 (s, 1.5H, Ar–CH3), 2.72 (s, 1.5H, Ar–CH3),
3.50–3.63 (m, 2H, OCH2), 3.92 (br-s, 1H, D2O exchangeable, OH),
4.16–4.50 (m, 3H, NCH2, CHOH), 5.89 (s, 1H, OCH), 7.19–7.33 (m, 3H,
Ar–H), 7.64–7.77 (m, 1H, Ar–H), 7.82–7.88 (m, 2H, Ar–H), 8.00–8.20
(m, 2H, Ar–H), 8.56 (t, J ¼ 5.0 Hz, 2H, Ar–H) total 20H in a diaste-
CDCl3):
d 25.31 (Ar–CH3), 25.38 (Ar–CH3), 50.0 (HN–CH2), 52.0
(HN–CH2), 68.7 (CHOH), 70.03 (CHOH), 70.06 (CHOH), 71.03
(CHOH), 71.03 (OCH2), 71.07 (OCH2), 71.41 (OCH2), 71.43 (OCH2),
80.0 (Ar–CHO–), 120.18 (Ar–C), 120.21 (Ar–C), 121.45 (Ar–C), 121.49
(Ar–C), 121.5 (Ar–C), 121.6 (Ar–C), 121.65 (Ar–C), 125.03 (Ar–C),
125.05 (Ar–C), 125.09 (Ar–C), 125.7 (Ar–C), 125.82 (Ar–C), 125.85
(Ar–C), 131.0 (Ar–C), 131.22 (Ar–C), 131.26 (Ar–C), 132.9 (Ar–C),
143.2 (Ar–C), 143.4 (Ar–C), 143.54 (Ar–C), 143.58 (Ar–C), 143.6 (Ar–
C), 146.7 (Ar–C), 146.94 (Ar–C), 146.99 (Ar–C), 147.9 (Ar–C), 148.1
(Ar–C), 148.3 (Ar–C), 149.9 (Ar–C), 150.1 (Ar–C), 155.51 (Ar–C), 159.2
(Ar–C), 159.29 (Ar–C), 159.33 (Ar–C), 163.4 (Ar–C). ESI-MS m/z of
469.20, 471.30 [M þ H]þ was obtained for a calculated mass of
469.10, 471.10.
reomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 25.4 (Ar–CH3),
52.4 (N–CH2), 68.7 (CHOH), 71.2 (OCH2), 79.96 (Ar–CHO–), 80.04
(Ar–CHO–), 120.2 (Ar–C), 121.40 (Ar–C), 121.43 (Ar–C), 121.6 (Ar–C),
125.1 (Ar–C), 125.8 (Ar–C), 131.15 (Ar–C), 131.2 (Ar–C), 132.9 (Ar–C),
143.46 (Ar–C), 143.54 (Ar–C),144.0 (Ar–C), 144.1 (Ar–C),146.87 (Ar–
C), 146.89 (Ar–C), 146.94 (Ar–C), 148.1 (Ar–C), 149.8 (Ar–C), 149.9
(Ar–C), 150.0 (Ar–C), 150.1 (Ar–C), 151.7 (Ar–C), 151.8 (Ar–C), 159.2
(Ar–C), 159.3 (Ar–C). ESI-MS m/z of 453.80, 455.90 [M þ H]þ was
obtained for a calculated mass of 454.09, 456.09.
6.1.9. 1-((6-Bromo-2-methylquinolin-4-yl)(pyridin-4-yl)methoxy)-
3-(1H-pyrazol-1-yl) propan-2-ol (11)
Procedure A, yield 25%. Off white solid; mp 135–137 ꢀC. 1H NMR
6.1.12. 1-((6-Bromo-2-methylquinolin-4-yl)(pyridin-4-
(400 MHz, CDCl3):
d
2.72 (s, 1.5H, Ar–CH3), 2.73 (s, 1.5H, Ar–CH3),
yl)methoxy)-3-(4-(pyridin-2-yl) piperazin-1-yl)propan-2-ol (14)
3.32–3.64 (m, 2H, OCH2), 3.99–4.12 (br-s, 0.5H, D2O exchangeable,
OH), 4.12–4.38 (m, 3.5H, 0.5H D2O exchangeable, NCH2), 5.85 (s,
0.5H, Ar-CH-O-), 5.86 (s, 0.5H, Ar-CH-O-), 6.20 (t, J ¼ 2.0 Hz, 0.5H,
Ar-H), 6.25 (t, J ¼ 2.0 Hz, 0.5H, Ar-H), 7.26–7.41 (m, 4H), 7.47 (d,
J ¼ 2.0 Hz, 0.5H), 7.51 (d, J ¼ 2.0 Hz, 0.5H), 7.70 (dd, J ¼ 4.0, 2.0 Hz,
0.5H), 7.72 (dd, J ¼ 4.4, 2.0 Hz, 0.5H), 7.90 (dd, J ¼ 9.0, 3.3 Hz, 1H),
8.07 (dd, J ¼ 4.8, 2.0 Hz, 1H), 8.57 (d, J ¼ 5.9 Hz, 2H) total 21H in
Procedure A, yield 42%. Off white solid; mp 149–151 ꢀC. 1H NMR
(400 MHz, CDCl3):
d 2.35–2.56 (m, 4H, CH2N(CH2)2), 2.67–2.95 (m,
5H, Ar–CH3, NCH2CHOH), 3.20–3.81 (m, 7H, OCH2, N(CH2)2, 1H D2O
exchangeable OH), 3.92–4.25 (m, 1H, CHOH), 5.97 (s, 0.5H, OCH),
5.98 (s, 0.5H, OCH), 6.62 (d, J ¼ 6.6 Hz, 2H, Ar–H), 7.22–7.40 (m, 3H,
Ar–H), 7.40–7.58 (m, 1H, Ar–H), 7.67–7.83 (m, 1H, Ar–H), 7.85–8.03
(m, 1H, Ar–H), 8.06–8.33 (m, 2H, Ar–H), 8.59 (s, 2H, Ar–H) total 30H
a diastereomeric ratio 1:1. 13C NMR (100.6 MHz, CDCl3):
d
25.3 (Ar–
in a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 25.3
CH3), 53.9 (N–CH2), 54.1 (N–CH2), 69.6 (CHOH), 70.9 (OCH2), 71.0
(OCH2), 79.9 (Ar–CHO–), 105.4 (Ar–C), 105.5 (Ar–C), 120.06 (Ar–C),
120.08 (Ar–C), 121.5 (Ar–C), 121.6 (Ar–C), 121.7 (Ar–C), 125.1 (Ar–C),
125.8 (Ar–C), 125.82 (Ar–C), 125.9 (Ar–C), 130.5 (Ar–C), 131.10 (Ar–
C), 131.16 (Ar–C), 131.20 (Ar–C), 132.7 (Ar–C), 132.8 (Ar–C), 139.7
(Ar–C), 139.74 (Ar–C), 143.6 (Ar–C), 143.7 (Ar–C), 146.9 (Ar–C), 147.0
(Ar–C), 148.2 (Ar–C), 150.0 (Ar–C), 159.2 (Ar–C), 159.25 (Ar–C). ESI-
MS m/z of 452.80, 454.90 [M þ H]þ was obtained for a calculated
mass of 453.09, 455.09.
(Ar–CH3), 45.1 (Py–N–CH2CH2), 52.9 (Py–N–CH2CH2), 60.43 (Py–N–
CH2CH2), 60.47 (Py–N–CH2CH2), 66.10 (CHOH), 66.14 (CHOH), 71.9
(OCH2), 72.1 (OCH2), 79.9 (Ar–CHO–), 107.0 (Ar–C), 113.4 (Ar–C),
119.9 (Ar–C), 121.6 (Ar–C), 121.64 (Ar–C), 121.8 (Ar–C), 125.2 (Ar–C),
125.3 (Ar–C), 126.1 (Ar–C), 126.15 (Ar–C), 131.10 (Ar–C), 132.7 (Ar–
C), 137.4 (Ar–C), 143.95 (Ar–C), 144.01 (Ar–C), 147.0 (Ar–C), 147.8
(Ar–C), 148.4 (Ar–C), 150.0 (Ar–C), 159.2 (Ar–C). ESI-MS m/z of
548.40, 550.50 [M þ H]þ was obtained for a calculated mass of
548.17, 550.16.
6.1.10. 1-(1H-1,2,4-Triazol-5-ylamino)-3-((6-bromo-2-
6.1.13. 1-((6-Bromo-2-methylquinolin-4-yl)(pyridin-4-
yl)methoxy)-3-(3-methyl-1H-pyrazol-1-yl)propan-2-ol (15)
Procedure A, yield 25%. Off white solid; mp 144–146 ꢀC. 1H NMR
methylquinolin-4-yl)(pyridin-4-yl) methoxy)propan-2-ol (12)
Procedure A, yield 47%. Off white solid; mp 199–201 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
2.70 (s, 0.75H, Ar–CH3), 2.73 (s, 2.30H, Ar–CH3),
(400 MHz, CDCl3): d 2.15–2.23 (m, 3H, pyrazole–CH3), 2.72 (s, 3H,
3.45–3.70 (m, 2H, CH2NH), 3.90–4.40 (m, 5H, OCH2, CHOH, 2H D2O
exchangeable OH, NH), 4.77 (d, J ¼ 7.2 Hz, 1H, D2O exchangeable,
Ar–NH), 5.88 (s, 1H, OCH), 7.20–7.33 (m, 3H, Ar–H), 7.37–7.50 (m,
0.5H, Ar–H), 7.60–7.68 (m, 0.5H, Ar–H), 7.69–7.77 (m, 1H, Ar–H),
Ar–CH3), 3.27–3.70 (m, 2H, OCH2), 3.97–4.37 (m, 4H, NCH2, CHOH,
1H D2O exchangeable OH), 5.70–6.12 (m, 2H, OCH, pyrazole-H),
7.10–7.42 (m, 4H, Ar–H), 7.62–7.79 (m, 1H, Ar–H), 7.90 (d, J ¼ 9.0 Hz,
1H, Ar–H), 8.00–8.15 (m, 1H, Ar–H), 8.57 (s, 2H, Ar–H) total 23H in

1864
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d
10.96
(Ar–C), 125.6 (Ar–C), 129.6 (Ar–C), 130.9 (Ar–C), 131.1 (Ar–C), 132.9
(Ar–C), 132.95 (Ar–C), 143.3 (Ar–C), 143.46 (Ar–C), 143.5 (Ar–C),
146.8 (Ar–C), 146.84 (Ar–C), 148.06 (Ar–C), 148.1 (Ar–C), 149.8 (Ar–
C), 149.9 (Ar–C), 149.96 (Ar–C), 159.3 (Ar–C), 165.3 (Ar–C), 166.1
(Ar–C). ESI-MS m/z of 470.20, 472.30 [M þ H]þ was obtained for
a calculated mass of 470.09, 472.09.
(Pyrazole–CH3), 11.0 (Pyrazole–CH3), 13.46 (Pyrazole–CH3), 13.48
(Pyrazole–CH3), 25.4 (Ar–CH3), 50.2 (N–CH2), 50.3 (N–CH2), 53.5
(N–CH2), 53.7 (N–CH2), 69.8 (CHOH), 69.85 (CHOH), 70.7 (OCH2),
70.9 (OCH2), 70.98 (OCH2), 71.01 (OCH2), 79.97 (Ar–CHO–), 80.0
(Ar–CHO–), 80.1 (Ar–CHO–), 104.98 (Ar–C), 105.05 (Ar–C), 105.3
(Ar–C), 120.1 (Ar–C), 121.5 (Ar–C), 121.55 (Ar–C), 121.58 (Ar–C),
121.7 (Ar–C), 121.74 (Ar–C), 121.8 (Ar–C), 125.1 (Ar–C), 125.9 (Ar–C),
125.96 (Ar–C), 131.2 (Ar–C), 132.9 (Ar–C), 138.73 (Ar–C), 138.78 (Ar–
C), 139.11 (Ar–C), 139.16 (Ar–C), 143.67 (Ar–C), 143.71 (Ar–C), 143.73
(Ar–C), 147.01 (Ar–C), 147.03 (Ar–C), 148.26 (Ar–C), 148.3 (Ar–C),
148.34 (Ar–C),149.2 (Ar–C),149.3 (Ar–C),150.1 (Ar–C),159.3 (Ar–C).
ESI-MS m/z of 467.20, 469.30 [M þ H]þ was obtained for a calcu-
lated mass of 467.11, 469.11.
6.1.17. 1-(2-Aminoethylamino)-3-((6-bromo-2-methylquinolin-4-
yl)(pyridin-4-yl)methoxy) propan-2-ol (19)
Procedure A, yield 42%. Off white solid; mp 107–109 ꢀC. 1H
NMR (400 MHz, CDCl3):
d 2.10 (s, 1H, NH), 2.55–2.89 (m, 6H,
Ar–CH3, NH2CH2, OH), 2.90–3.10 (m, 2H, NHCH2), 3.31–3.56 (m,
2H, OCH2), 3.82–4.15 (m, 1H, CHOH), 4.46–5.20 (m, 4H, NH2,
NHCH2CHOH), 5.80–6.05 (m, 1H, OCH), 7.28–7.43 (m, 3H, Ar–H),
7.55–7.78 (m, 1H, Ar–H), 7.80–7.94 (m, 1H, Ar–H), 8.04–8.23 (m,
1H, Ar–H), 8.41–8.68 (m, 2H, Ar–H) total 25H in a diastereomeric
6.1.14. 1-((6-Bromo-2-methylquinolin-4-yl)(pyridin-4-
yl)methoxy)-3-(2-methoxyethylamino)propan-2-ol (16)
Procedure A, yield 35%. Off white solid; mp 116–118 ꢀC. 1H NMR
ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 25.3 (Ar–CH3), 40.0
(NH2–CH2), 49.0 (NH–CH2), 51.8 (NH–CH2CHOH), 68.6 (CHOH),
72.3 (OCH2), 79.8 (Ar–CHO–), 119.9 (Ar–C), 121.6 (Ar–C), 121.7
(Ar–C), 125.1 (Ar–C), 126.0 (Ar–C), 131.2 (Ar–C), 132.7 (Ar–C), 143.9
(Ar–C), 146.9 (Ar–C), 148.4 (Ar–C), 150.0 (Ar–C), 159.3 (Ar–C). ESI-
MS m/z of 445.00, 446.90 [M þ H]þ was obtained for a calculated
mass of 445.12, 447.12.
(400 MHz, CDCl3):
d 2.02 (br-s, 2H, D2O exchangeable, OH, NH),
2.55–2.95 (m, 7H, Ar–CH3, CH2NHCH2), 3.32 (s, 3H, OCH3), 3.40–
3.70 (m, 4H, OCH2, CH3OCH2), 3.89–4.09 (m, 1H, CHOH), 5.92 (s, 1H,
OCH), 7.26–7.40 (m, 3H, Ar–H), 7.71 (dd, J ¼ 8.4, 1.9 Hz, 1H, Ar–H),
7.90 (d, J ¼ 9.0 Hz,1H, Ar–H), 8.13 (dd, J ¼ 8.3, 1.9 Hz,1H, Ar–H), 8.58
(d, J ¼ 5.7 Hz, 2H, Ar–H) total 26H in a diastereomeric ratio 1:1. 13C
NMR (100.6 MHz, CDCl3):
d
25.3 (Ar–CH3), 48.7 (HN–CH2CH2), 51.66
6.1.18. 2-((Naphthalen-1-yl(phenyl)methoxy)methyl)oxirane (21)
Alcohol 20 [36] (0.05 g, 0.21 mmol) was dissolved in dry
(OHCHCH2NH), 51.70 (OHCHCH2NH), 58.7 (OCH3), 67.9 (CHOH),
68.0 (CHOH), 70.6 (CH3OCH2), 72.2 (OCH2CHOH), 79.9 (Ar–CHO–),
120.0 (Ar–C), 121.6 (Ar–C), 121.7 (Ar–C), 121.8 (Ar–C), 125.2 (Ar–C),
125.9 (Ar–C), 126.0 (Ar–C), 131.1 (Ar–C), 132.8 (Ar–C), 143.9 (Ar–C),
146.9 (Ar–C), 148.4 (Ar–C), 150.0 (Ar–C), 159.3 (Ar–C). ESI-MS m/z of
460.20, 462.00 [M þ H]þ was obtained for a calculated mass of
460.12, 462.12.
DMF (0.5 mL), cooled to
0
ꢀC, sodium hydride (0.006 g,
0.25 mmol) was added portion wise, cooling bath was removed
and reaction was stirred at room temperature for 30 min. epi-
Chlorohydrin (0.032 mL, 0.42 mmol) was added and stirring was
continued for further 16
h at room temperature. Reaction
mixture was concentrated under reduced pressure; ice-cold
water was added and extracted with ethyl acetate (2 ꢃ 10 mL).
The combined organic layer was washed with water (2 ꢃ 10 mL)
and brine (1 ꢃ 10 mL). Organic layer was dried over anhydrous
sodium sulfate, filtered and concentrated to obtain a sticky mass
as a crude product. This crude product was purified by column
chromatography (silica gel 100–200 mesh, eluent: ethyl acetate,
hexane; gradient elution) to give oxirane 21 (0.032 g, 52%) as
6.1.15. 1-((6-Bromo-2-methylquinolin-4-yl)(pyridin-4-
yl)methoxy)-3-((2-hydroxyethyl) (methyl)amino)propan-2-ol (17)
Procedure A, yield 60%. Viscous compound. 1H NMR (400 MHz,
CDCl3):
d 2.32 (s, 4H, NCH3, 1H D2O exchangeable, OH), 2.42–2.68
(m, 5H, CH2N(CH3)CH2, 1H D2O exchangeable, OH), 2.72 (s, 1.5H,
Ar–CH3), 2.73 (s, 1.5H, Ar–CH3), 3.43–3.68 (m, 4H, OCH2, OHCH2),
3.91–4.05 (m, 1H, CHOH), 5.93 (s, 1H, OCH), 7.25–7.32 (m, 3H, Ar–
H), 7.69–7.74 (m, 1H, Ar–H), 7.89 (d, J ¼ 9.0 Hz, 1H, Ar–H), 8.14 (dd,
J ¼ 6.5, 1.9 Hz, 1H, Ar–H), 8.58 (d, J ¼ 5.8 Hz, 2H, Ar–H) total 26H in
a colorless liquid. 1H NMR (400 MHz, CDCl3):
d
2.56 (dd, J ¼ 5.0,
2.6 Hz, 0.5H, epoxy–CH2), 2.66 (dd, J ¼ 5.0, 2.6 Hz, 0.5H, epoxy–
CH2), 2.77 (t, J ¼ 4.6 Hz, 0.5H, epoxy–CH2), 2.80 (t, J ¼ 4.6 Hz,
0.5H, epoxy–CH2), 3.22–3.30 (m, 1H, epoxy–CH), 3.52 (dd,
J ¼ 11.4, 6.0 Hz, 0.5H, epoxy–CH2), 3.57 (dd, J ¼ 11.5, 5.5 Hz,
0.5H, OCH2), 3.82 (dd, J ¼ 2.9, 1.6 Hz, 0.5H, OCH2), 3.85 (dd,
J ¼ 2.9, 1.9 Hz, 0.5H, OCH2), 6.17 (s, 1H, OCH), 7.23–7.30 (m, 1H,
Ar–H), 7.31–7.37 (m, 2H, Ar–H), 7.42–7.55 (m, 5H, Ar–H), 7.66 (d,
J ¼ 7.0 Hz, 1H, Ar–H), 7.81–7.92 (m, 2H, Ar–H), 8.08–8.17 (m, 1H,
a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 25.3 (Ar–
CH3), 42.5 (N–CH3), 59.0 (OHCH2), 59.5 (NCH2CH2), 60.3
(NCH2CHOH), 60.4 (NCH2CHOH), 67.3 (CHOH), 72.1 (OCH2), 72.3
(OCH2), 79.9 (Ar–CHO), 120.0 (Ar–C), 121.6 (Ar–C), 121.7 (Ar–C),
125.2 (Ar–C), 126.0 (Ar–C), 131.1 (Ar–C), 132.7 (Ar–C), 144.0 (Ar–C),
146.9 (Ar–C), 148.5 (Ar–C), 149.9 (Ar–C), 159.2 (Ar–C). ESI-MS m/z of
460.30, 462.00 [M þ H]þ was obtained for a calculated mass of
460.12, 462.12.
Ar–H) total 18H in
(100.6 MHz, CDCl3):
a
diastereomeric ratio 1: 1. 13C NMR
44.2 (epoxy OCH2), 44.4 (epoxy OCH2),
d
50.9 (epoxy OCH), 50.96 (epoxy OCH), 69.6 (OCH2), 70.0 (OCH2),
81.7 (OCH), 81.8 (OCH), 124.0 (Ar–C), 124.2 (Ar–C), 125.18 (Ar–C),
125.2 (Ar–C), 125.4 (Ar–C), 125.5 (Ar–C), 125.7 (Ar–C), 125.98
(Ar–C), 126.03 (Ar–C), 127.2 (Ar–C), 127.4 (Ar–C), 127.5 (Ar–C),
127.55 (Ar–C), 128.3 (Ar–C), 128.5 (Ar–C), 128.54 (Ar–C), 128.6
(Ar–C), 131.0 (Ar–C), 131.03 (Ar–C), 133.9 (Ar–C), 133.96 (Ar–C),
136.4 (Ar–C), 136.5 (Ar–C), 141.0 (Ar–C), 141.1 (Ar–C). ESI-MS m/z
of 217.20 [M ꢁ 73]þ was obtained for a calculated mass of
217.10.
6.1.16. 1-(1H-Tetrazol-5-ylamino)-3-((6-bromo-2-methylquinolin-
4-yl)(pyridin-4-yl)methoxy) propan-2-ol (18)
Procedure A, yield 39%. Off white solid; mp 186–188 ꢀC. 1H NMR
(400 MHz, CDCl3):
d 1.67 (br-s, 1H, D2O exchangeable, NH), 2.68 (s,
1H, Ar–CH3), 2.72 (s, 2H, Ar–CH3), 3.33–3.75 (m, 3H, NHCH2, OCH2),
4.25–4.49 (m, 2H, OCH2, 1H D2O exchangeable, OH), 4.50–4.70 (m,
1H, CHOH), 5.15–5.35 (m, 1H, D2O exchangeable, tetrazole-NH),
5.75–5.95 (m, 1H, OCH), 7.05–7.24 (m, 2H, Ar–H), 7.26–7.45 (m, 1H,
Ar–H), 7.55–7.75 (m, 1H, Ar–H), 7.76–7.95 (m, 1H, Ar–H), 7.96–8.20
(m, 1H, Ar–H), 8.42–8.62 (m, 2H, Ar–H) total 20H in a diastereo-
6.1.19. Representative procedure B, for compounds 22–30: 1-(4-(3-
methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yl
meric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 25.3 (Ar–CH3), 48.8
(HN–CH2), 55.3 (HN–CH2), 68.6 (CHOH), 69.8 (CHOH), 70.7 (OCH2),
79.8 (Ar–CHO–), 79.9 (Ar–CHO–), 120.2 (Ar–C), 121.4 (Ar–C), 121.44
(Ar–C), 121.49 (Ar–C), 121.6 (Ar–C), 121.7 (Ar–C), 124.9 (Ar–C), 125.0
(phenyl)methoxy)propan-2-ol (22)
Oxirane 21 (0.05 g, 0.17 mmol) and 1-(3-methoxy phenyl)-
piperazine (0.045 g, 0.17 mmol) were dissolved in 2-propanol

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
1865
(5 mL) and the mixture was refluxed for 16 h. Reaction mixture
was concentrated under reduced pressure to get thick liquid as
a crude product. Crude product was purified by column chroma-
tography (eluent: ethyl acetate, hexane; gradient elution) to obtain
pure 22 (0.025 g, 30%) as a off-white sticky compound. 1H NMR
(Ar–C), 127.3 (Ar–C), 127.5 (Ar–C), 128.3 (Ar–C), 128.5 (Ar–C), 128.6
(Ar–C), 128.7 (Ar–C), 129.5 (Ar–C), 130.9 (Ar–C), 131.0 (Ar–C), 131.1
(Ar–C), 131.2 (Ar–C), 131.5 (Ar–C), 131.8 (Ar–C), 133.98 (Ar–C), 134.0
(Ar–C), 136.7 (Ar–C), 136.74 (Ar–C), 141.18 (Ar–C), 141.2 (Ar–C), 151.2
(Ar–C). ESI-MS m/z of 520.90 [M þ H]þ was obtained for a calcu-
lated mass of 521.24.
(400 MHz, CDCl3):
d 2.45–2.65 (m, 4H, N–CH2, piperazine–CH2),
2.68–2.81 (m, 2H, piperazine–CH2), 3.08–3.30 (m, 4H, piperazine–
CH2), 3.37–3.52 (m, 1H, D2O exchangeable, OH), 3.52–3.70 (m, 2H,
OCH2), 3.80 (s, 3H, OCH3), 3.94–4.12 (m, 1H, OHCH), 6.10 (s, 0.5H,
ArCH–O), 6.11 (s, 0.5H, ArCH–O), 6.32–6.50 (m, 2H, Ar–H), 6.53 (d,
J ¼ 8.2 Hz, 1H, Ar–H), 7.18 (t, J ¼ 8.2 Hz, 1H, Ar–H), 7.23–7.30 (m,
1H, Ar–H), 7. 32 (t, J ¼ 7.5 Hz, 2H, Ar–H), 7.37–7.53 (m, 5H, Ar–H),
7.56–7.65 (m, 1H, Ar–H), 7.77–7.92 (m, 2H, Ar–H), 8.10–8.15 (m, 1H,
6.1.22. 1-(4-(3,4-Dichlorophenyl)piperazin-1-yl)-3-(naphthalen-1-
yl(phenyl)methoxy) propan-2-ol (25)
Procedure B, yield 39%. Sticky compound. 1H NMR (400 MHz,
CDCl3):
d 2.35–2.62 (m, 5H, N–CH2, piperazine –CH2, 1H D2O
exchangeable, OH), 2.65–2.75 (m, 2H, piperazine–CH2), 3.07–3.20
(m, 4H, piperazine –CH2), 3.55–3.68 (m, 2H, OCH2), 3.95–4.06 (m,
1H, CHOH), 6.09 (s, 0.5H, Ar–CHO–), 6.10 (s, 0.5H, Ar–CHO–), 6.70
(dd, J ¼ 9.0, 2.8 Hz, 1H, Ar–H), 6.93 (d, J ¼ 2.8 Hz, 1H, Ar–H), 7.22–
7.24 (m, 1H, Ar–H), 7.29–7.34 (m, 2H, Ar–H), 7.37–7.53 (m, 6H, Ar–
H), 7.55–7.62 (m, 1H, Ar–H), 7.78–7.89 (m, 2H, Ar–H), 8.05–8.15 (m,
1H, Ar–H) total 30H in a diastereomeric ratio 1: 1. 13C NMR
Ar–H) total 34H in
(100.6 MHz, CDCl3):
a
diastereomeric ratio 1: 1. 13C NMR
49.0 (piperazine–CH2), 53.2 (piperazine–
d
CH2), 55.1 (OCH3), 60.7 (NCH2), 66.4 (CHOH), 66.43 (CHOH), 71.7
(OCH2), 71.8 (OCH2), 82.1 (Ar–CHO–), 82.2 (Ar–CHO–), 102.4
(Ar–C), 104.4 (Ar–C), 108.8 (Ar–C), 124.2 (Ar–C), 125.2 (Ar–C), 125.5
(Ar–C), 125.6 (Ar–C), 125.7 (Ar–C), 125.96 (Ar–C), 125.98 (Ar–C),
127.3 (Ar–C), 127.5 (Ar–C), 128.3 (Ar–C), 128.52 (Ar–C), 128.55
(Ar–C), 128.7 (Ar–C), 129.74 (Ar–C), 131.05 (Ar–C), 131.08 (Ar–C),
133.96 (Ar–C), 133.98 (Ar–C), 136.67 (Ar–C), 136.73 (Ar–C), 141.2
(Ar–C), 152.5 (Ar–C), 160.5 (Ar–C). ESI-MS m/z of 483.30 [M þ H]þ
was obtained for a calculated mass of 483.26.
(100.6 MHz, CDCl3): d 48.6 (piperazine–CH2) 52.9 (piperazine–CH2),
60.6 (NCH2), 66.5 (CHOH), 66.54 (CHOH), 71.7 (OCH2), 71.75 (OCH2),
82.15 (Ar–CHO–), 82.17 (Ar–CHO–), 115.2 (Ar–C), 117.1 (Ar–C), 122.1
(Ar–C), 124.2 (Ar–C), 125.2 (Ar–C), 125.5 (Ar–C), 125.6 (Ar–C), 125.7
(Ar–C), 125.97 (Ar–C), 125.98 (Ar–C), 127.3 (Ar–C), 127.5 (Ar–C),
128.3 (Ar–C), 128.53 (Ar–C), 128.57 (Ar–C), 128.7 (Ar–C), 130.3 (Ar–
C), 131.03 (Ar–C), 131.06 (Ar–C), 132.7 (Ar–C), 133.95 (Ar–C), 133.97
(Ar–C), 136.63 (Ar–C), 136.7 (Ar–C), 141.13 (Ar–C), 141.14 (Ar–C),
150.5 (Ar–C).
6.1.20. 1-(4-(2-Methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-
yl(phenyl)methoxy)propan-2-ol (23)
Procedure B, yield 42%. Brownish sticky compound. 1H NMR
ESI-MS m/z of 521.10 [M þ H]þ was obtained for a calculated
mass of 521.18.
(400 MHz, CDCl3):
d 2.42–2.70 (m, 4H, N–CH2, piperazine–CH2),
2.72–2.91 (m, 2H, piperazine–CH2), 2.96–3.31 (m, 5H, 1H D2O
exchangeable, piperazine–CH2, OH), 3.55–3.68 (m, 2H, OCH2), 3.85
(s, 3H, OCH3), 3.95–4.10 (m,1H, CHOH), 6.10 (s, 0.5H, Ar–CHO–), 6.11
(s, 0.5H, Ar–CHO–), 6.85 (d, J ¼ 7.8 Hz, 1H, Ar–H), 6.90–6.96 (m, 2H,
Ar–H), 6.97–7.09 (m, 1H, Ar–H), 7.20–7.28 (m, 1H, Ar–H), 7.29–7.35
(m, 2H, Ar–H), 7.35–7.53 (m, 5H, Ar–H), 7.54–7.64 (m, 1H, Ar–H),
7.73–7.92 (m, 2H, Ar–H), 8.10 (d, J ¼ 6.7 Hz, 1H, Ar–H) total 34H in
6.1.23. 1-(4-Benzhydrylpiperazin-1-yl)-3-(naphthalen-1-
yl(phenyl)methoxy)propan-2-ol (26)
Procedure B, yield 37%. Off-white sticky solid. 1H NMR
(400 MHz, CDCl3):
d 2.00–2.57 (m, 9H, NCH2, piperazine–CH2, 1H
D2O exchangeable, OH), 2.55–2.69 (m, 2H, piperazine –CH2), 3.48–
3.59 (m, 2H, O–CH2), 3.89–4.00 (m, 1H, CHOH), 4.19 (s, 1H, NCH),
6.06 (s, 0.5H, Ar–CHO–), 6.07 (s, 0.5H, Ar–CHO–), 7.13–7.19 (m, 2H,
Ar–H), 7.20–7.25 (m, 4H, Ar–H), 7.26–7.32 (m, 3H, Ar–H), 7.36–7.49
(m, 9H, Ar–H), 7.52 (d, J ¼ 7.1 Hz, 1H, Ar–H), 7.75–7.88 (m, 2H, Ar–
H), 8.02–8.10 (m, 1H, Ar–H) total 38H in a diastereomeric ratio 1: 1.
a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 50.6
(piperazine–CH2), 53.4 (piperazine–CH2), 55.3 (piperazine–CH2),
60.8 (N–CH2), 66.3 (CHOH), 66.36 (CHOH), 71.8 (O–CH2), 71.9 (O–
CH2), 82.1 (Ar–CHO–), 111.1 (Ar–C), 118.1 (Ar–C), 120.9 (Ar–C), 122.9
(Ar–C), 124.24 (Ar–C), 124.27 (Ar–C), 125.2 (Ar–C), 125.5 (Ar–C),
125.7 (Ar–C),125.73 (Ar–C), 125.95 (Ar–C), 125.97 (Ar–C), 127.3 (Ar–
C), 127.5 (Ar–C), 128.3 (Ar–C), 128.5 (Ar–C), 128.52 (Ar–C), 128.7
(Ar–C), 131.09 (Ar–C), 131.12 (Ar–C), 133.97 (Ar–C), 133.98 (Ar–C),
136.74 (Ar–C),136.79 (Ar–C),141.1 (Ar–C),141.25 (Ar–C),141.26 (Ar–
C), 152.2 (Ar–C). ESI-MS m/z of 483.14 [M þ H]þ was obtained for
a calculated mass of 483.26.
13C NMR (100.6 MHz, CDCl3):
d 51.9 (piperazine–CH2), 53.5
(piperazine–CH2), 60.7 (NCH2), 66.20 (CHOH), 66.26 (CHOH), 71.8
(OCH2), 71.9 (OCH2), 76.14 (NCH), 82.1 (Ar–CHO–), 124.23 (Ar–C),
124.26 (Ar–C), 125.2 (Ar–C), 125.5 (Ar–C), 125.66 (Ar–C), 125.71
(Ar–C), 125.92 (Ar–C), 125.94 (Ar–C), 126.9 (Ar–C), 127.3 (Ar–C),
127.4 (Ar–C), 127.8 (Ar–C), 128.2 (Ar–C), 128.3 (Ar–C), 128.43 (Ar–C),
128.47 (Ar–C), 128.5 (Ar–C), 128.6 (Ar–C), 131.09 (Ar–C), 131.11 (Ar–
C), 133.95 (Ar–C), 133.97 (Ar–C), 136.7 (Ar–C), 136.8 (Ar–C), 141.3
(Ar–C), 142.66 (Ar–C), 142.67 (Ar–C).
6.1.21. 1-(Naphthalen-1-yl(phenyl)methoxy)-3-(4-(3-
(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-ol (24)
Procedure B, yield 31%. Sticky compound. 1H NMR (400 MHz,
ESI-MS m/z of 542.80 [M]þ was obtained for a calculated mass of
542.29.
CDCl3):
d 2.43–2.64 (m, 4H, NCH2, piperazine–CH2), 2.68–2.82 (m,
2H, piperazine–CH2), 2.90–3.40 (m, 5H, piperazine–CH2, 1H D2O
exchangeable, OH), 3.55–3.68 (m, 2H, OCH2), 3.95–4.08 (m, 1H,
CHOH), 6.10 (s, 0.5H, Ar–CHO–), 6.11 (s, 0.5H, Ar–CHO–), 6.90–7.06
(m, 1H, Ar–H), 7.06–7.16 (m, 2H, Ar–H), 7.20–7.29 (m, 1H, Ar–H),
7.30–7.39 (m, 3H, Ar–H), 7.40–7.54 (m, 5H, Ar–H), 7.55–7.63 (m, 1H,
Ar–H), 7.77–7.92 (m, 2H, Ar–H), 8.03–8.17 (m,1H, Ar–H) total 31H in
6.1.24. 1-(4-Benzylpiperazin-1-yl)-3-(naphthalen-1-
yl(phenyl)methoxy)propan-2-ol (27)
Procedure B, yield 44%. Sticky-compound. 1H NMR (400 MHz,
CDCl3):
d 2.21–2.57 (m, 9H, N–CH2, piperazine –CH2, 1H D2O
exchangeable, OH), 2.58–2.74 (br-s, 2H, piperazine–CH2), 3.49 (s,
2H, O–CH2), 3.53–3.63 (m, 2H, CH2), 3.87–4.02 (m, 1H, CHOH), 6.07
(s, 0.5H, Ar–CHO–), 6.08 (s, 0.5H, Ar–CHO–), 7.19–7.29 (m, 5H, Ar–
H), 7.29–7.35 (m, 3H, Ar–H), 7.35–7.49 (m, 5H, Ar–H), 7.55 (d,
J ¼ 7 Hz, 1H, Ar–H), 7.73–7.89 (m, 2H, Ar–H), 7.99–8.11 (m, 1H, Ar–
H) total 34 H in a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz,
a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 48.6
(piperazine–CH2), 53.0 (piperazine–CH2), 60.7 (NCH2), 66.5
(CHOH), 66.6 (CHOH), 71.7 (OCH2), 71.8 (OCH2), 82.19 (Ar–CHO–),
82.21 (Ar–CHO–), 112.05 (Ar–C), 112.09 (Ar–C), 112.13 (Ar–C), 112.17
(Ar–C), 115.79 (Ar–C), 115.83 (Ar–C), 115.86 (Ar–C), 115.9 (Ar–C),
118.7 (Ar–C), 122.9 (Ar–C), 124.2 (Ar–C), 125.2 (Ar–C), 125.5 (Ar–C),
125.63 (Ar–C), 125.66 (Ar–C), 125.7 (Ar–C), 125.98 (Ar–C), 126.0
CDCl3):
d 53.0 (piperazine–CH2), 60.7 (NCH2), 63.0 (OCH2), 66.2
(CHOH), 66.3 (CHOH), 71.8 (OCPh), 71.9(OCPh), 82.1 (Ar–CHO–),
124.25 (Ar–C), 124.27 (Ar–C), 125.2 (Ar–C), 125.5 (Ar–C), 125.7 (Ar–

1866
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 45 (2010) 1854–1867
C), 125.72 (Ar–C), 125.94 (Ar–C), 125.96 (Ar–C), 127.0 (Ar–C), 127.3
(Ar–C), 127.5 (Ar–C), 128.2 (Ar–C), 128.3 (Ar–C), 128.48 (Ar–C),
128.51 (Ar–C), 128.7 (Ar–C), 129.2 (Ar–C), 131.1 (Ar–C), 131.12 (Ar–
C), 134.0 (Ar–C), 136.7 (Ar–C), 136.8 (Ar–C), 138.0 (Ar–C), 141.3
(Ar–C).
82.06 (Ar–CHO–), 117.1 (Ar–C), 124.1 (Ar–C), 124.3 (Ar–C), 125.1 (Ar–
C),125.5 (Ar–C),125.6 (Ar–C),125.64 (Ar–C),125.9 (Ar–C),125.91 (Ar–
C),127.2 (Ar–C),127.4 (Ar–C),128.2 (Ar–C),128.4 (Ar–C),128.5 (Ar–C),
128.6 (Ar–C), 128.8 (Ar–C), 130.97 (Ar–C), 131.0 (Ar–C), 133.87 (Ar–C),
133.89 (Ar–C),136.61 (Ar–C),136.67 (Ar–C),141.1 (Ar–C),149.6 (Ar–C).
ESI-MS m/z of 487.10 [M þ H]þ was obtained for a calculated
mass of 487.22.
ESI-MS m/z of 467.21 [M þ H]þ was obtained for a calculated
mass of 467.27.
6.1.25. 1-(Naphthalen-1-yl(phenyl)methoxy)-3-(4-(pyridin-2-
yl)piperazin-1-yl)propan-2-ol (28)
6.2. Biological methods
Procedure B, yield 42%. Sticky-solid. 1H NMR (400 MHz, CDCl3):
6.2.1. Microbiology
d
2.37–2.60 (m, 4H, NCH2, piperazine–CH2), 2.64–2.76 (m, 2H,
All compounds 9–19, 22–30 and drug references were dissolved
in DMSO at a concentration of 6.25
until used.
m
g/mL and were stored at w4 ꢀC
piperazine–CH2), 3.45–3.66 (m, 7H, piperazine–CH2, OCH2, 1H D2O
exchangeable, OH), 3.95–4.07 (m,1H, CHOH), 6.08(s, 0.5H, Ar–CHO–),
6.09 (s, 0.5H, Ar–CHO–), 6.61 (dd, J ¼ 7.0, 5.8 Hz, 2H, Ar–H), 7.20–7.24
(m,1H, Ar–H), 7.27–7.34 (m, 2H, Ar–H), 7.36–7.51 (m, 6H, Ar–H), 7.53–
7.61 (m, 1H, Ar–H), 7.75–7.87 (m, 2H, Ar–H), 8.03–8.11 (m, 1H, Ar–H),
8.14–8.23 (m, 1H, Ar–H) total 31H in a diastereomeric ratio 1: 1. 13C
6.2.2. Cytotoxicity
The cells (human monocytic cell line U937) were plated in flat-
bottomed 96 well plates (1 ꢃ 105 cells/mL), cultured for 1 h in
controlled atmosphere (CO2 5% at 37 ꢀC), and non-adherent cells
were washed by gentle flushing with RPMI 1640. Adherent cells
were cultured in the presence of medium alone, Tween 20 (3%) (live
and dead controls, respectively) or different concentration of
compounds (depending upon the solubility) in a triplicate assay
(Table 3). After completion of the experiment protocol 10 mL of MTT
solution (5 mg/mL solution in Phosphate Buffer Saline) was added
in each well. Plates were incubated for 3 h in CO2 incubator at 37 ꢀC.
NMR (100.6 MHz, CDCl3): d 45.1 (piperazine–CH2), 53.0 (piperazine–
CH2), 60.8 (NCH2), 66.3 (CHOH), 66.4 (CHOH), 71.7 (OCH2), 71.75
(OCH2), 82.06 (Ar–CHO–), 82.08 (Ar–CHO–), 107.0 (Ar–C), 113.3 (Ar–
C),124.1 (Ar–C),125.1 (Ar–C),125.5 (Ar–C),125.6 (Ar–C),125.7 (Ar–C),
125.90 (Ar–C), 125.91 (Ar–C),127.2 (Ar–C), 127.4 (Ar–C), 128.2 (Ar–C),
128.44(Ar–C),128.47(Ar–C),128.6(Ar–C),130.97(Ar–C),131.0(Ar–C),
133.87 (Ar–C), 133.89 (Ar–C),136.61 (Ar–C),136.68 (Ar–C), 137.4 (Ar–
C), 141.1 (Ar–C), 147.8 (Ar–C), 159.3 (Ar–C).
ESI-MS m/z of 454.30 [M þ H]þ was obtained for a calculated
mass of 454.25.
Then 100 mL solubilizing solution (0.4 M HCl in isopropanol) was
added to solubilize the formazan crystals formed by the surviving
cells. Finally the absorbance was read at 600 nm in a micro plate
reader (Bio-Rad-i Mark) using acidified isopropanol as blank.
6.1.26. 1-(4-(4-Fluorophenyl)piperazin-1-yl)-3-(naphthalen-1-
yl(phenyl)methoxy)propan-2-ol (29)
Procedure B, yield 28%. Sticky-solid. 1H NMR (400 MHz, CDCl3):
2.45–2.59 (m, 4H, NCH2, piperazine–CH2), 2.69–2.80 (m, 2H,
piperazine–CH2), 2.97–3.30 (m, 5H, piperazine –CH2, 1H D2O
exchangeable, OH), 3.53–3.67 (m, 2H, OCH2), 3.94–4.08 (m, 1H,
CHOH), 6.09 (s, 0.5H, Ar–CHO–), 6.10 (s, 0.5H, Ar–CHO–), 6.82–6.89
(m, 2H, Ar–H), 6.92–7.00 (m, 2H, Ar–H), 7.26–7.28 (m, 1H, Ar–H),
7.29–7.35 (m, 2H, Ar–H), 7.37–7.52 (m, 5H, Ar–H), 7.52–7.62 (m, 1H,
Ar–H), 7.78–7.91 (m, 2H, Ar–H), 8.04–8.14 (m, 1H, Ar–H) total 31H
Acknowledgement
We thank Dr. Anjlina Wali, Institute of Molecular Medicine, for
cytotoxicity study of compounds. We thank Uppsala University,
Sweden for valuable scientific support through JC. Generous
financial support from the European Union (Project No. 222965,
Project name: New approaches to target Tuberculosis, Call identi-
fier: FP7-Health-2007-B) and TCG Life Sciences, Kolkata for funding
the collaboration are also gratefully acknowledged.
in a diastereomeric ratio 1: 1. 13C NMR (100.6 MHz, CDCl3):
d 50.1
(piperazine–CH2), 53.2 (piperazine–CH2), 60.7 (NCH2), 66.4
(CHOH), 66.5 (CHOH), 71.7 (OCH2), 71.8 (OCH2), 82.13 (Ar–CHO–),
82.14 (Ar–CHO–), 115.3 (Ar–C), 115.5 (Ar–C), 117.7 (Ar–C), 117.8 (Ar–
C), 124.2 (Ar–C), 125.2 (Ar–C), 125.5 (Ar–C), 125.6 (Ar–C), 125.7 (Ar–
C), 125.94 (Ar–C), 125.97 (Ar–C), 127.3 (Ar–C), 127.5 (Ar–C), 128.3
(Ar–C), 128.5 (Ar–C), 128.54 (Ar–C), 128.7 (Ar–C), 131.04 (Ar–C),
131.07 (Ar–C), 133.94 (Ar–C), 133.96 (Ar–C), 136.7 (Ar–C), 136.73
(Ar–C), 141.16 (Ar–C), 141.17 (Ar–C), 147.7 (Ar–C), 147.8 (Ar–C), 155.9
(Ar–C), 158.3 (Ar–C).
Appendix. Supplementary data
Supplementary material associated with this paper can be
found, in the online version, at doi:10.1016/j.ejmech.2010.01.024.
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