Amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: Synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities

Article abstract of DOI:10.1016/j.ejmech.2012.03.019

Three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. The synthesized compounds were tested for in vitro antimalarial activity against chloroquine

Full text of DOI:10.1016/j.ejmech.2012.03.019

European Journal of Medicinal Chemistry 52 (2012) 230e241
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted
8-aminoquinolines: Synthesis and evaluation of anti-infective, b-haematin
inhibition and cytotoxic activities
,
,e
Kirandeep Kaur a, Meenakshi Jain a, Shabana I. Khan c d, Melissa R. Jacob c, Babu L. Tekwani c
,
,
Savita Singh b, Prati Pal Singh b, Rahul Jain a
*
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India
b Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India
c National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, USA
d Department of Pharmacognosy, School of Pharmacy, University of Mississippi, MS 38677, USA
e Department of Pharmacology, School of Pharmacy, University of Mississippi, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino
acids, dipeptides and pseudodipeptides have been synthesized. The synthesized compounds were tested
for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium
falciparum strains, in vitro cytotoxicity in mammalian kidney cells (Vero), in vitro antileishmanial activity
Received 14 February 2012
Received in revised form
9 March 2012
Accepted 11 March 2012
Available online 21 March 2012
against Leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of
b-haematin
formation. The promising compounds were also evaluated for in vivo blood-schizontocidal antimalarial
activity against Plasmodium berghei infected mice. The analogues 55 and 101 produced highest anti-
malarial activities, in vitro. Analogues 52 and 59 exhibited promising antileishmanial and broad spec-
trum of antifungal activities, respectively.
Keywords:
8-Aminoquinolines
Malaria
Antimicrobial
Synthesis
Ó 2012 Elsevier Masson SAS. All rights reserved.
b-Haematin inhibition
1. Introduction
metabolism (for example, conversion to 2, Fig. 1), and its toxic side
effects, specifically haemolytic anaemia, particularly in patients
Malaria is one of the major life-threatening parasitic diseases in
the tropical and subtropical regions of the world. Worldwide, there
are at least 300 million acute cases of malaria and more than 1e2
million die each year, mainly due to Plasmodium falciparum infec-
tion [1,2]. The malaria problem is further exacerbated by the spread
of drug resistant P. falciparum strains [3e5]. In this context, the
development of safe and effective antimalarial drugs preventing
transmission, in addition to curing patients becomes an important
strategy towards achieving an effective control of malaria.
Currently, primaquine (PQ, 1, Fig. 1), composed of an 8-
aminoquinoline (8-AQ) structural framework, is one of the avail-
able transmission blocking antimalarial drugs. It displays a marked
activity against gametocytes of all species of Plasmodium affecting
humans, including chloroquine-resistant P. falciparum [6,7].
However, the use of 1 is restricted and limited due to its extensive
having glucose-6-phosphate dehydrogenase deficiency [8,9].
The therapeutic index profile of 1 has been improved by struc-
tural modification/manipulation of the aminoalkyl side-chain
resulting in its decreased metabolic inactivation. As examples of
such improvement, several side-chain modified analogues of 1
have been synthesized [10e20]. A large number of these derivatives
have displayed improved activity/toxicity ratios compared to 1. We
have earlier reported that 2-tert-butylprimaquine (BPQ, 3, Fig. 1)
exhibit potent blood-schizontocidal antimalarial activity [21]. The
BPQ possibly eliminates a putative oxidative metabolic pathway
known for several quinoline ring-containing antimalarial drugs,
including quinine by the placement of a metabolically stable tert-
butyl group at the C-2 position of the ring. We also demonstrated
the ability of 3 to inhibit
b-haematin formation, in vitro by forming
a complex with haem with a stoichiometry of 1:1, resulting in
haem-induced haemolysis, thereby providing evidence of the
biochemical pathway responsible for its antimalarial action [22].
The present study was aimed to design, synthesize and evaluate
in vitro and in vivo antimalarial activity, cytotoxicity in the
* Corresponding author. Tel.: þ91 172 229 2024; fax: þ91 172 221 4692.
E-mail address: rahuljain@niper.ac.in (R. Jain).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.03.019

K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
231
O
O
O
N
N
N
NH
NH
NH
NH2
OH
NH2
O
3. 2-tert-Butylprimaquine (BPQ)
1. Primaquine (PQ)
2. Carboxyprimaquine
Fig. 1. Structure of 8-aminoquinolines.
mammalian cells, inhibition of
b
-haematin formation, and in vitro
pseudopeptides, amino acid residues can also be linked through
a/
antileishmanial and antimicrobial activity of amino acid, dipeptides
b/g-CO2H or NH2 groups, thereby rendering them more resistant to
and pseudodipeptides conjugates (Fig. 2) of PQ (1) and BPQ (3).
enzymatic cleavage. Most of these modifications led to changes in
the hydrophilic or hydrophobic properties, electronic distributions,
and geometric/topochemical structure of the resulting compounds.
In addition to the synthesis of dipeptide conjugates, we also plan-
ned to evaluate the effect of linkage between 8-AQs and amino
acids on the antimalarial activity and synthesized pseudodipeptide
conjugates of 8-AQs (101e124, Series 3, Fig. 2). The synthetic
strategy for pseudodipeptide conjugates involves linking of 8-QAs
2. Results and discussion
Earlier, we have reported the synthesis of 8-AQs conjugated to
amino acids containing a free terminal amino group [13]. Herein,
we report synthesis of 8-AQs conjugates (Series 1, Fig. 2) by
coupling the side-chain amino group of the amino acids through
a covalent linkage to the terminal amino group of 8-AQs. We have
found earlier that the attachment of cationic amino acids to 8-AQs
enhances the antimalarial activity. Therefore, cationic amino acids
like, lysine (Lys) and ornithine (Orn) were selected to synthesize the
target compounds. The amino acids were adequately protected at
to anionic amino acids (Asp or Glu) through their side-chain
CO2H group. This is followed by a coupling reaction through their
NH2 group with cationic amino acids (Lys, Arg, or Orn).
b
/
g
a
-
-
2.1. Chemistry
the a-NH2 and a-CO2H group to allow specific reaction with the
side-chain NH2 group. These analogues (9e12, Series 1, Scheme 1)
allowed us to observe the effect of both free CO2H and NH2 groups
on the antimalarial activity.
The earlier studies from our laboratory have shown that the
amino acid conjugates of 8-AQs containing cationic amino acids
exhibit higher activities as compared to those containing anionic
and lipophilic amino acids [13,15]. The enhanced activities of 8-AQs
conjugated with cationic amino acids could be explained by the fact
that these compounds possibly accumulate in the acidic food
vacuole of the parasite, increasing their ability to complex with
The reaction of 1 or 3 [21] with the suitably protected D/L-amino
acids 4 in the presence of 1,10-carbonyldiimidazole (CDI) in anhy-
drous dichloromethane (CH2Cl2) afforded fully protected conju-
gates 5e8 in moderate yield (31e42%). The yield of reaction was
low due to the formation of bis-adducts as the by-product in
35e40% yield. The complete deprotection of 5e8 was achieved in
one or two steps depending upon the nature of the protecting
groups. In cases involving combination of carbobenzyloxy (Z) and
methyl ester groups (compounds 5 and 7), Z group was first
removed using PdeC/H2 followed by removal of ester group with
6 N HCl to provide 9 and 11. In contrast, tert-butoxycarbonyl (t-Boc)
and tert-butyl ester protecting groups in compounds 6 and 8 were
removed in one-step by using 6 N HCl to provide analogues 10 and
12 (Scheme 1).
haem, leading to inhibition of b-haematin (BH) formation. More
recently, a study on the effects of cationic amino acids on the BH
inhibition confirms the importance of basicity [23]. Therefore, in
principle, an increase in the basicity of conjugates should increase
their accumulation in the parasitic food vacuole to an even greater
extent, resulting in an increase in BH inhibition and antimalarial
activity. To further explore the scope and validity of this hypothesis,
we synthesized cationic dipeptide conjugates of 8-AQs (49e60,
Series 2, Fig. 2).
The pseudopeptides are a class of compounds in which an amide
linkage is modified by chemical changes such as, modification of
the carbonyl group of amide bond by reduction, thionation or by
changing the linkage between the consecutive amino acids. In
The reaction of 1 or 3 with suitably orthogonally protected
-amino acids in the presence of 1,3-diisopropylcarbodiimide
(DIC) in CH2Cl2 readily provided carbamates 13e24.
The Fmoce -Arg(Pmc)-OH having orthogonal protecting
D/
L
D
groups, 9-fluorenylmethyloxycarbonyl (Fmoc) and 2,2,5,7,8-
pentamethylchroman-6-sulfonyl (Pmc) was used for the
synthesis of Arg containing conjugates. Whereas, for all other
conjugates, amino acids with Z as the side-chain amino pro-
tecting group and t-Boc as the
a-amino protecting group were
O
O
O
N
R1
N
R1
N
R1
NH
R2
O
NH
R2
NH
NH2
CO2H
H
N
H
N
H
N
H
N
H
N
NH2
N
H
NH2
n
n
O
R2
O
CO2H O
O
Series 1
Series 2
Series 3
Fig. 2. General structure of synthesized 8-aminoquinoline conjugates.

232
K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
O
O
N
R
N
R
NH
NH
HN Boc/Z
HN Boc/Z
H
N
H
N
i
NH2
H2N
t
t
CO2- Bu/Me
+
CO2- Bu/Me
n
n
31-42%
O
1. R = H
n = 3 or 4
5-8
3.
R = C(CH3)3
4
81-95%
ii, iii
O
N
R
NH
NH2
H
N
H
N
CO2H
n
O
9-12
Scheme 1. Reagents and conditions: (i) CDI, DCM, rt, 8 h; (ii) PdeC/H2, MeOH, rt, 4 h; (iii) 6 N HCl, rt, 5 h.
used. All products were obtained in good yields (88e97%),
except for -Arg conjugates, which were obtained in 72e81%
yields due to a complex multi-step purification procedure.
Depending upon their nature, -NH2 protecting group in 13e24
was removed using acidic or basic conditions. For example, in
compounds 13e16, 18e22 and 24, the N- -Boc group was
removed by using 4 N HCl in methanol (MeOH), followed by
neutralization reaction with the aqueous NH4OH solution to
generate 25e28, 30e34 and 36. On the other hand, the Fmoc
group in 17 and 23 was removed by using 20% piperidine in
CH2Cl2 to afford 29 and 35. The coupling reaction of 25e36 with
analogue 84). We also observed degradation of the product,
resulting in lower yield. Therefore, an alternate deprotection
strategy for compounds 78, 81, 86, 90, 93, 95, 96, 98, and 99 was
adopted. The Z group was cleaved first by hydrogenolysis as
described earlier, followed by acidolysis of tert-butyl ester group
using 4 N HCl. While, for compounds 92, 94, 97 and 100, removal of
t-Boc and tert-butyl ester groups was achieved in a one-step by
using 4 N HCl (Scheme 3).
D
a
a
2.2. Biological activity
protected
D
/
L
-amino acids in the presence of DIC in CH2Cl2
2.2.1. Antiprotozoal activity, cytotoxicity, and inhibition of
haematin (BH) formation
b-
afforded protected dipeptide conjugates 37e48. In the cases of Z
group containing conjugates 37e40 and 43e46, deprotection
was achieved by hydrogenolysis with PdeC/H2. It is important to
mention that the removal of Z group in Arg containing dipep-
tides required a longer reaction time (7 h) and lower yield
(74e78%) compared to Lys and Orn conjugates (4 h, 80e85%
yield). The acidolysis reaction with 4 N HCl in MeOH cleanly
cleaved the t-Boc group of dipeptides 42 and 48. While, dipep-
tide conjugates 41 and 47 containing both Z and Pmc groups
were deprotected in two steps. In these cases, Z group was first
removed (Pd/C-H2) followed by removal of Pmc group by using
8 N HCl in MeOH (Scheme 2).
Determination of in vitro antimalarial activity was based on the
assay of plasmodial LDH activity [24]. The antimalarial activities of
all synthesized analogues are reported as IC50 values against
chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains
of P. falciparum inTables 1e3. Invitrocytotoxicityof all the analogues
was determined against mammalian kidney cell line (Vero) up to
a highest concentration of 23.8 mg/mL by neutral red assay [25,26].
None of the compounds were found to exhibit cytotoxic effects
indicating a selectivity of antimalarial action. The synthesized
conjugates were also assayed for inhibition of BH formation
according to a procedure reported earlier [27]. The antileishmanial
activities of the conjugates were evaluated in vitro against Leish-
mania donovani promastigotes by Alamar Blue assay [28,29].
8-AQs (9e12, Series 1) were either inactive or possessed weak
in vitro antimalarial activity. Compound 12 exhibited weak inhibi-
8-Aminoquinolines 1 or 3 upon reaction with the suitable
orthogonally protected
carboxyl group in the presence of the DIC in CH2Cl2 produced
compounds 61e68. The N- -Fmoc group in 61e68 was removed
using 20% piperidine. The latter compounds 69e76, upon reaction
with the appropriately protected -amino acids in the presence of
DIC afforded fully protected pseudodipeptide conjugates 77e100.
The amino and carboxyl protecting groups in the compounds
77e100 were removed under different conditions and reagents
depending upon the nature of the protecting groups. In cases
involving compounds 77, 79, 80, 82, 85, 88, and 90, both t-Boc and
tert-butyl ester groups were easily removed by using 33% HBr in
acetic acid in 30 min. However, the application of same strategy for
removing Z and tert-butyl ester groups in a one-step led to an
increased reaction time of 2 h (for analogues 83 and 89) and 6 h (for
D/L-amino acids containing a side-chain free
a
tion of the BH formation with an IC50 value of 250 mM. Compounds
D
/L
9e12 were inactive against L. donovani. These results indicate that
the presence of free CO2H, in addition to the desired free NH2 group
at the terminal position of the 8-AQs is detrimental for anti-
protozoal activity (Table 1).
Of all the dipeptide conjugates 49e60 (Series 2), the most active
were 55 (IC50 ¼ 0.63 and 0.40
respectively) and 56 (IC50 ¼ 0.97 and 0.82
strains, respectively) containing -Lyse
sequences, respectively. Analogues containing
either inactive or weakly active (IC50 ¼ 3.3e4.76
m
g/mL against D6 and W2 strains,
g/mL against D6 and W2
-Lys and -Arge -Arg
-amino acids were
g/mL), except for
m
L
L
L
L
D
m

K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
233
O
O
O
i
N
R1
N
R1
N
R1
ii
NH
NH
R2
NH
R2
H
N
H
N
72-97%
73-90%
N Boc/Fmoc
NH2
NH2
H
O
13-24
O
1. R1 = H
3. R1 = C(CH3)3
25-36
iii
82-91%
O
O
N
R1
N
R1
NH
R4
O
NH
R2
O
iv
74-85%
H
N
H
H
N
NH2
N
N
H
N
H
Boc/Z
O
49-60
R4
O
R3
37-48
R1 = H/C(CH3)3
R2 = Lys(Z)/Arg(Z)2/Arg(Pmc)/Orn(Z)
R3 = Lys(Z)/Arg(Z)2/Orn(Z)/Orn(Boc)
R4 = Lys/Arg/Orn
Scheme 2. Reagents and conditions: (i) DIC, Boc/FmocNH-CH(R2)-CO2H, DCM, 0 ꢀCert, 4 h; (ii) 4 N methanolic HCl, rt, 45 min, 20% NH4OH or 20% piperidine in DCM, rt, 20 min; (iii)
DIC, Boc/ZNH-CH(R3)-CO2H, DCM, 0 ꢀCert, 4 h; (iv) PdeC/H2, MeOH, rt, 4e7 h or 4 N methanolic HCl, rt, 45 min or 8 N methanolic HCl, rt, 8 h.
analogue 53 (R ¼ H, R1 ¼
and 1.7 g/mL against D6 and W2 strains, respectively. Some
analogues inhibited BH formation with IC50 values ranging between
D
-Arg), which exhibited IC50 values of 1.3
R1 ¼
D
-Lys), and 56 [R ¼ C(CH3)3, R1 ¼
L
-Arg] were most active
m
against L. donovani with IC50 values of 4, 3.5 and 9
mg/mL, respec-
tively, while remaining compounds were either inactive or
moderately active (Table 2).
32 and 618
m
M. Compounds 51 (R ¼ H, R1 ¼ -Orn), 52 (R ¼ H,
L
O
O
O
ii
i
83-91%
N
R1
N
R1
N
R1
70-79%
NH
NH
NH
H
N
H
N
t
t
NH2
CO2 Bu
CO2 Bu
n
n
O
NH2
O
HN Fmoc
1. R1 = H
3.
R1 = C(CH3)3
61-68
69-76
83-95%
iii
O
O
N
R1
N
R1
NH
R2
NH
R3
iv
H
N
O
H
N
H
H
N
Boc/Z
N
N
H
NH2
n
n
76-98%
t
O
CO2 Bu
O
CO2HO
77-100
101-124
n = 1 or 2
R1 = H/C(CH3)3
R2 = Lys(Boc)/Lys(Z)/Arg(Z)2/Orn(Boc)
R3 = Lys/Arg/Orn
t
Scheme 3. Reagents and conditions: (i) DIC, FmocNH-CH[(CH2)nCO2H]-CO2 Bu, DCM, 0 ꢀCert, 4 h; (ii) 20% piperidine in DCM, rt, 20 min; (iii) DIC, Boc/ZNH-CH(R2)-CO2H, DCM,
0
ꢀCert, 4 h; (iv) 33% HBr-CH3CO2H, 0 ꢀCert, 30 mine6 h or PdeC/H2, MeOH, rt, 4 h or 4 N HCl, rt, 5 h.

234
K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
Table 1
In vitro antimalarial (P. falciparum) and antileishmanial (L. donovani) activity, cytotoxicity, and
b
-haematin (BH) inhibition of 8-aminoquinoliness (9e12) (Series 1).
O
N
R
NH
NH2
H
N
H
N
CO2H
n
O
Compd. no.
R
n
P. falciparum (D6)
P. falciparum (W2)
Cytotoxicityd (Vero)
BH inhibitione
IC50 M)
L. donovani
b
IC50
(m
g/mL)
SIc
IC50
(m
g/mL)
SIc
IC50
(m
g/mL)
(m
IC50
(
mg/mL)
IC90 (mg/mL)
a
a
9
H
H
4
3
4
3
(
(
(
(
L
)
)
NAf
NA
NA
4.2
2.0
e
e
e
NA
NA
NA
4.76
2.8
e
e
e
NC
NC
NC
NC
NC
>1000
>1000
>1000
250
NA
NA
NA
NA
19.9
NA
NA
NA
NA
NA
10
11
12
PQ
D
C(CH3)3
C(CH3)3
L)
D
)
>5.5
>11.9
5
>8.5
>1000
Selectivity index (SI) is the ratio of IC50 in Vero cells to IC50 in P. falciparum (D6 or W2).
a
IC50 is the sample concentration that kills 50% cells compared to vehicle control.
IC90 is the sample concentration that kills 90% cells compared to vehicle control.
b
c
Chloroquine: IC50 ¼ 0.014 microg/mL, SI ¼ 1700 (D6 clone); IC50 ¼ 0.1
m
g/mL, SI ¼ 238 (W2 clone). Artemisinin: IC50 ¼ 0.015
m
g/mL, SI ¼ 1565 (D6 clone); IC50 ¼ 0.009
mg/
mL, SI ¼ 2644 (W2 clone).
d
NC, not cytotoxic up to (23.8 mg/mL).
e
BH inhibition activity: Chloroquine: IC50 ¼ 80
Amphotericin B: IC50 ¼ 0.19 g/mL, IC90 ¼ 0.35 g/mL.
NA, Not active. “e”, Not tested.
mM, BPQ: IC50 ¼ 2.9
m
M, PQ: IC50>1000
m
M. Antileishmanial activity: Pentamidine: IC50 ¼ 1
m
g/mL, IC90 ¼ 3.8
mg/mL.
m
m
f
Among the analogues 101e124 (Series 3), 101 (R ¼ H, R1 ¼
Lys, n ¼ 1) emerged as the most potent antimalarial with IC50
values of 0.13 and 0.26 g/mL against D6 and W2 strains,
respectively, and it exhibited high selectivity index (SI >91e183).
M) was
M). These results clearly
L
-
indicate that the potent blood-schizontocidal antimalarial
activity of 101 is probably due to a disturbance in haem catabo-
lism pathway in the malarial parasite. Of the remaining
m
compounds, only 105 (R ¼ H, R1 ¼
[R ¼ C(CH3)3, R1 ¼ -Arg, n ¼ 1] possessed moderate antimalarial
activity (IC50 ¼ 1.8e2.6 g/mL). Compound 113 [R ¼ C(CH3)3,
L
-Arg, n ¼ 2) and 120
Inhibition of BH formation by analogue 101 (IC50 ¼ 5.8
m
D
16-fold higher than that of CQ (IC50 ¼ 80
m
m
Table 2
In vitro antimalarial (P. falciparum) and antileishmanial (L. donovani) activity, cytotoxicity, and
b-haematin (BH) inhibition of 8-aminoquinoliness (49e60) (Series 2).
O
N
R
NH
R1
O
H
N
NH2
N
H
O
R1
Compd. no
R
R1
P. falciparum (D6)
P. falciparum (W2)
Cytotoxicityd (Vero)
BH inhibitione
IC50 M)
L. donovani
SIc
IC50
(
m
g/mL)
SIc
>8.5
>5.0
IC50
(
m
g/mL)
(m
IC50
(
mg/mL)
IC90 (mg/mL)
a
a
b
IC50
(
m
g/mL)
49
50
51
52
53
54
55
56
57
58
59
60
PQ
H
H
H
H
H
H
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
(
(
(
(
(
(
(
(
(
(
(
(
L
L
L
)
)
)
)
)
)
)
)
)
2.0
NA
>11.9
e
2.8
4.76
NA
NA
1.7
4.76
0.4
0.82
2.0
2.8
NA
3.3
2.8
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
618
81
>1000
310
32
420
NAf
NA
4
3.5
17
40
19
9
20
NA
20
20
19.9
NA
NA
20
7
36
NA
39
31
NA
NA
34
38
NA
NA
e
e
D
D
D
NA
e
e
1.3
NA
>18.3
e
>14
>5.0
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
L
L
L
0.63
0.97
2.5
4.76
NA
>37.7
>24.5
>9.5
>5.0
e
>59.5
>29.0
>11.9
>8.5
e
73
53
85
D
D
D
)
)
)
>1000
>1000
39
4.76
2.0
>5.0
>11.9
>7.21
>8.5
>1000
Selectivity index (SI) is the ratio of IC50 in Vero cells to IC50 in P. falciparum (D6 or W2).
a
IC50 is the sample concentration that kills 50% cells compared to vehicle control.
IC90 is the sample concentration that kills 90% cells compared to vehicle control.
b
c
Chloroquine: IC50 ¼ 0.014 microg/mL, SI ¼ 1700 (D6 clone); IC50 ¼ 0.1
m
g/mL, SI ¼ 238 (W2 clone). Artemisinin: IC50 ¼ 0.015
m
g/mL, SI ¼ 1565 (D6 clone); IC50 ¼ 0.009
mg/
mL, SI ¼ 2644 (W2 clone).
d
NC, not cytotoxic up to (23.8 mg/mL).
e
BH inhibition activity: Chloroquine: IC50 ¼ 80
Amphotericin B: IC50 ¼ 0.19 g/mL, IC90 ¼ 0.35 g/mL.
NA, Not active. “e”, Not tested.
m
M, BPQ: IC50 ¼ 2.9
m
M, PQ: IC50 >1000
m
M. Antileishmanial activity: Pentamidine: IC50 ¼ 1
mg/mL, IC90 ¼ 3.8
mg/mL.
m
m
f

K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
235
Table 3
In vitro antimalarial (P. falciparum) and antileishmanial (L. donovani) activity, cytotoxicity, and
b
-haematin (BH) inhibition of 8-aminoquinoliness (101e124) (Series 3).
O
R1
N
R
O
NH
NH2
NH
H
N
n
O
CO2H
Compd. no.
R
R1
n
P. falciparum (D6)
P. falciparum (W2)
Cytotoxicityd (Vero)
IC g/mL)
BH inhibitione
IC50 M)
5.8
L. donovani
SIc
IC50
(
m
g/mL)
SIc
(m
(m
IC50
(m
g/mL)
IC90 (mg/mL)
a
a
b
IC50
(
m
g/mL)
50
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
PQ
H
H
H
H
H
H
H
H
H
H
H
H
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
Lys
Arg
Orn
1
1
1
2
2
2
1
1
1
2
2
2
1
1
1
2
2
2
1
1
1
2
2
2
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
L
L
L
L
L
L
)
)
)
)
)
)
)
)
)
)
)
)
0.13
3.0
e
>183
0.26
2.9
e
>91.5
>8.2
e
NC
NC
e
NAf
NA
e
NA
NA
e
>7.9
120
e
e
e
e
e
NA
1.8
NA
2.4
3.2
NA
NA
NA
NA
3.8
3.3
2.7
NA
2.3
NA
NA
1.8
2.5
NA
NA
NA
2.0
NA
1.8
NA
3.2
4.2
NA
NA
NA
NA
2.8
2.8
3.0
NA
2.0
NA
NA
2.6
3.4
NA
NA
NA
2.8
e
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NA
NA
NA
NA
20.1
NA
20.1
NA
NA
9.4
NA
20
NA
NA
NA
NA
NA
NA
NA
NA
NA
19.9
NA
NA
NA
NA
33
NA
36
NA
NA
31
>13.2
>13.2
e
e
>1000
160
210
>1000
>1000
>1000
>1000
131
D
D
D
D
D
D
>9.9
>7.4
>7.4
>5.6
e
e
e
e
e
e
e
e
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
H
L
L
L
L
L
L
)
)
)
)
)
)
>6.2
>7.2
>8.8
>8.5
>8.5
>7.9
e
115
40
NA
36
e
>1000
96
>1000
>1000
127
>1000
>1000
>1000
>1000
>1000
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
>10.3
>11.9
e
e
D
D
D
D
D
D
)
)
)
)
)
)
e
e
>13.2
>9.5
>9.1
>7
e
e
e
e
e
e
>11.9
>8.5
Selectivity index (SI) is the ratio of IC50 in Vero cells to IC50 in P. falciparum (D6 or W2).
a
IC50 is the sample concentration that kills 50% cells compared to vehicle control.
IC90 is the sample concentration that kills 90% cells compared to vehicle control.
b
c
Chloroquine: IC50 ¼ 0.014 microg/mL, SI ¼ 1700 (D6 clone); IC50 ¼ 0.1
m
g/mL, SI ¼ 238 (W2 clone). Artemisinin: IC50 ¼ 0.015
m
g/mL, SI ¼ 1565 (D6 clone); IC50 ¼ 0.009
mg/
mL, SI ¼ 2644 (W2 clone).
d
NC, not cytotoxic up to (23.8 mg/mL).
e
BH inhibition activity: Chloroquine: IC50 ¼ 80
Amphotericin B: IC50 ¼ 0.19 g/mL, IC90 ¼ 0.35 g/mL.
NA, Not active. “e”, Not tested.
m
M, BPQ: IC50 ¼ 2.9
m
M, PQ: IC50 >1000
m
M. Antileishmanial activity: Pentamidine: IC50 ¼ 1
mg/mL, IC90 ¼ 3.8
mg/mL.
m
m
f
R1 ¼
L
-Lys, n ¼ 1] possessed considerable antileishmanial activity
exhibited 100% curative activity (6/6 cures) at a primary test dose of
100 mg/kg. While, 51 (OrneOrn conjugate, 4/6 cures), 55 (LyseLys
conjugate, 5/6 cures), 56 (ArgeArg conjugate, 5/6 cures) and 120
with an IC50 value of 9.4
m
g/mL (Table 3).
The results of in vivo blood-schizontocidal antimalarial activity
evaluation of selected analogues in Plasmodium berghei mouse
malaria model are summarized in Table 4. Analogues 49 and 101
(Aspe
D-Arg conjugate, 4/6 cures) produced suppressive activity
and partial cure; remaining analogues were inactive at 100 mg/kg
Table 4
In vivo (P. berghei) antimalarial activity of selected 8-aminoquinolines.
Compd. no.
P. bergheia,b,c
(10 mg/kg/day ꢁ 4, oral)
(25 mg/kg/day ꢁ 4, oral)
(50 mg/kg/day ꢁ 4, oral)
(100 mg/kg/day ꢁ 4, oral)
49
51
55
56
57
58
101
117
120
2/6
e
6/6
e
6/6
e
(6/6) Curative
(4/6) Active
(5/6) Active
(5/6) Active
(0/6) Inactive
(0/6) Inactive
(6/6) Curative
(0/6) Inactive
(4/6) Active
e
e
e
e
e
e
e
e
e
e
e
e
4/6
e
6/6
e
6/6
e
e
e
e
“e”, Not tested.
a
The term ‘curative’ indicates complete elimination of malaria parasites from the body, and animals survive up to day D þ 60.
b
The term ‘active’ indicates that all of the treated animals show negative parasitaemia up to D þ 7. However, by D þ 60, some mice die, and some survive with complete
elimination of parasitaemia as indicated by numbers given in parentheses.
c
The term ‘inactive’ indicates that the treated animals show positive parasitaemia either on D þ 4 or D þ 7 and usually die by D þ 14.

236
K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
Table 5
In vitro antibacterial activities of 8-aminoquinolines.
Compd. no.
S. aureus
MRSA
M. intracellulare
E. coli
MICb
g/mL)
MBCc
g/mL)
IC50
MICb
g/mL)
MBCc
g/mL)
IC50
MICb
g/mL)
MBCc
g/mL)
IC50
MICb
g/mL)
MBCc
g/mL)
a
a
a
a
IC50
(
m
g/mL)
(
m
(
m
(
m
g/mL)
(
m
(
m
(
m
g/mL)
(
m
(
m
(
m
g/mL)
(
m
(m
56
59
60
113
114
ed
11.16
e
e
e
7
5.96
NA
NA
NA
10
10
NA
NA
NA
20
20
NA
NA
NA
NAe
NA
10
NA
NA
NA
NA
20
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
15
NA
NA
NA
20
NA
NA
NA
NA
NA
20
e
20
e
e
e
e
e
e
e
15
NA
a
IC50 ¼ the concentration (
m
g/mL) that affords 50% growth inhibition.
b
c
MIC, minimum inhibitory concentration (the lowest concentration in
m
g/mL that allows no detectable growth).
g/mL that kills the organism).
MBC, minimum bactericidal concentration (the lowest concentration in
“e”, not tested.
NA, no activity at the highest test concentration of 20
m
d
e
m
g/mL. Ciprofloxacin: IC50 ¼ 0.12
m
g/mL, MIC ¼ 0.50
m
g/mL, MBC ¼ 50
m
g/mL (Sa); IC50 ¼ 0.09
m
g/mL, MIC ¼ 0.31
mg/
mL, MBC ¼ 2.5
m
g/mL (MRSA); IC50 ¼ 0.3 g/mL, MIC ¼ 0.63
m
m
g/mL, MBC ¼ 2.5 g/mL (Mi), IC50 ¼ 0.003
m
m
g/mL, MIC ¼ 0.016
m
g/mL, MBC ¼ 0.016
mg/mL (Ec).
with all mice dying by D þ 14. The analogues 49 and 101 were also
curative (6/6 cures) at the lower test doses (50 and 25 mg/kg), and
exhibited suppressive activity at the lowest tested dose of 10 mg/kg
producing 2/6 and 4/6 cures, respectively.
and 5.9
respectively. Analogue 59 was also active against S. aureus dis-
playing IC50 value of 11.6 g/mL, and MIC and MBC of 20 g/mL.
Another analogue 60 of the series was active against
M. intracellulare with IC50 of 10 g/mL, and MIC of 20 g/mL but was
not bactericidal. Analogues 113 and 115 (Series 3) were moderately
active against E. coli exhibiting an IC50 value of 15 g/mL, but none
were bactericidal at 20 g/mL.
The antifungal activities of the selected conjugates are
summarized in Table 6 along with the positive control amphoter-
icin B. None of the conjugates was active against Aspergillus fumi-
gatus (data not shown). All of the conjugates 49e60 (Series 2)
exhibited good activity against Cryptococcus neoformans with IC50
mg/mL, MIC value of 10 mg/mL, and MBC value of 20 mg/mL,
m
m
m
m
2.2.2. Antimicrobial activities
The conjugates were also tested for their antibacterial properties
against Staphylococcus aureus ATCC 29213, methicillin-resistant S.
aureus ATCC 43300 (MRSA), Mycobacterium intracellulare ATCC
23068, Escherichia coli ATCC 35218, and Pseudomonas aeruginosa
ATCC 27853. Susceptibility testing was performed using a modified
version of the CLSI (formerly NCCLS) methods [30e34], while
M. intracellulare was tested using a modified method of Franzblau
et al. [35].
The antibacterial activities of selected conjugates 56, 59, 60, 113
and 114 are reported in Table 5, including the positive control
ciprofloxacin. The remaining conjugates were inactive (data not
included). None of the conjugates was active against P. aeruginosa
(data not shown). The analogues 56 and 59 (Series 2) possessed
m
m
values ranging between 2.5 and 7
56 of the series (IC50 ¼ 2.5 g/mL, MIC ¼ 5
cidal at 5 g/mL. The analogues 52, 54, 55, 57 and 60 exhibited IC50
values of 3.5 g/mL, and MIC and MFC of 5 g/mL. Except for 56
(IC50 ¼ 10 g/mL), all other conjugates were inac-
mg/mL. The most active analogue
m
mg/mL) was also fungi-
m
m
m
mg/mL, MIC ¼ 20
m
tive against C. albicans. Analogue 59 showed moderate activity
against Candida glabrata and Candida krusei with IC50 values
promising activity against MRSA exhibiting IC50 values of 7 mg/mL
Table 6
In vitro antifungal activities of 8-aminoquinolines.
Compd. no.
C. albicans
C. glabrata
C. krusei
C. neoformans
MICb
g/mL)
MFCc
g/mL)
IC50
MICb
g/mL)
MFCc
g/mL)
IC50
MICb
g/mL)
MFCc
g/mL)
IC50
MICb
g/mL)
MFCc
g/mL)
a
a
a
a
IC50
(
m
g/mL)
(
m
(
m
(
m
g/mL)
(
m
(
m
(
m
g/mL)
(
m
(
m
(
m
g/mL)
(
m
(m
49
50
51
52
53
54
55
56
57
58
59
60
107
109
113
114
115
116
117
118
121
122
NAd
NA
NA
NA
NA
NA
NA
15
NA
NA
NA
NA
NA
NA
NA
NA
15
NA
NA
NA
NA
NA
NA
NA
20
NA
NA
NA
NA
NA
NA
NA
NA
20
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
20
ee
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
7
10
10
10
5
10
5
5
5
5
10
10
5
10
10
5
20
20
20
20
20
10
20
20
10
20
5
10
5
5
5
5
10
10
5
10
10
5
20
20
20
20
20
10
NA
e
4.5
5.5
3.5
7.0
3.5
3.5
2.5
3.5
6.5
3.55
3.5
4.5
7
3.5
15
4
15
15
15
4.86
15.19
e
e
e
e
e
e
e
e
12.42
e
20
e
20
e
7.08
e
10
e
10
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
13.68
NA
20
NA
20
NA
NA
NA
NA
NA
NA
NA
a
IC50 ¼ the concentration (
mg/mL) that affords 50% growth inhibition.
MIC, minimum inhibitory concentration (the lowest concentration in
MFC, minimum fungicidal concentration (the lowest concentration in
b
c
m
m
g/mL that allows no detectable growth).
g/mL that kills the organism).
d
e
NA, no activity at the highest test concentration of 20
“e”, not tested. Amphotericin B: IC50 ¼ 0.25 g/mL, MIC ¼ 0.63
g/mL, MIC ¼ 1.25 g/mL, MFC ¼ 1.25 g/mL (Ck); IC50 ¼ 0.75
mg/mL.
m
m
g/mL, MFC ¼ 1.25
m
g/mL (Ca); IC50 ¼ 0.07
m
g/mL, MIC ¼ 0.31
m
g/mL, MFC ¼ 0.625
mg/mL (Cg);
IC50 ¼ 0.6
m
m
m
m
g/mL, MIC ¼ 1.25 g/mL, MFC ¼ 1.5
m
mg/mL (Cn).

K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
237
ranging between 7 and 12
range of 10e20 g/mL. Analogues 107, 113, 115, and 121 (Series 3)
displayed good activity against C. neoformans with IC50 values
ranging between 3.5 and 4.5 g/mL, and MIC and MFC values in the
m
g/mL, and MIC and MFC values in the
4.2.2. Removal of t-Boc and tert-butyl ester groups
m
A solution of 6 or 8 (0.11 mmol) in 6 N HCl (5 mL) was stirred at
ambient temperature for 5 h. The solvent was evaporated under
reduced pressure to afford product as hygroscopic salt.
m
range of 10e20 mg/mL.
4.2.3. N6-({4-[(6-Methoxyquinolin-8-yl)amino]pentyl}carbamoyl)-
3. Conclusions
D
-lysine$2HCl (9)
Yield: 85%; hygroscopic solid; IR (KBr): 3437, 1728, 1648 cmꢃ1
;
In conclusion, three new series of 8-aminoquinolines modified
at the terminal amino group have been designed and synthesized.
The compounds containing both free amino and carboxyl groups
were less potent than primaquine, possibly due to the presence of
undesirable carboxyl group. The dipeptides having Arg and Lys
residues exhibited promising in vitro and in vivo antimalarial
1H NMR (CD3OD):
d 8.96 (m, 2H), 8.01 (m, 1H), 7.05 (m, 2H), 4.03 (s,
3H), 3.69 (m, 2H), 3.38 (m, 4H), 1.83 (m, 10H), 1.31 (d, 3H,
J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 172.3, 171.6, 162.9, 148.1, 146.2,
141.4, 140.4, 137.5, 134.0, 120.8, 107.1, 97.3, 57.1, 54.2, 42.2, 41.4, 34.2,
29.1, 27.7, 26.8, 26.0, 20.1; APCIMS: m/z 432 (M þ 1); Anal. Calcd for
C22H35Cl2N5O4 (503.2): C, 52.38; H, 6.99; N, 13.88. Found: C, 52.46;
H, 7.08; N, 13.96.
activity. Interestingly, dipeptide analogues containing
D-amino
acids were either inactive or weakly active. The -Lys containing
L
pseudodipeptide 101 has demonstrated most promising anti-
protozoal activities. The synthesized analogues also exhibited
potent inhibition of BH formation underlying their biochemical
mechanism of antimalarial activity. In the in vivo blood-schizo-
ntocidal activity determination against P. berghei infected mice
model, 49 and 101 showed 100% curative activity at a dose of
25 mg/kg, and exhibited suppressive activity at the lowest test
dose of 10 mg/kg. Some analogues exhibited promising antibac-
terial activity against MRSA and M. intracellulare. Majority of the
newly synthesized 8-aminoquinolines were active against
4.2.4. N5-({4-[(6-Methoxyquinolin-8-yl)amino]pentyl}carbamoyl)-
L
-ornithine$2HCl (10)
Yield: 95%; hygroscopic solid; IR (KBr): 3410, 1723, 1637 cmꢃ1
;
1H NMR (CD3OD):
d 8.85 (m, 2H), 7.91 (m, 1H), 6.87 (m, 2H), 4.03 (s,
3H), 3.85 (t, 1H, J ¼ 5.5 Hz), 3.69 (m, 1H), 3.49 (m, 4H), 1.97 (m, 8H),
1.36 (d, 3H, J ¼ 6.5 Hz); 13C NMR (CD3OD):
d 172.0,171.2, 162.9, 161.1,
148.1, 146.2, 141.4, 140.4, 137.5, 134.0, 127.8, 120.8, 107.1, 57.1, 54.2,
42.2, 41.4, 34.2, 29.1, 27.7, 26.8, 26.0, 20.1; APCIMS: m/z 418 (M þ 1);
Anal. Calcd for C21H33Cl2N5O4 (489.1): C, 51.43; H, 6.78; N, 14.28.
Found: C, 51.52; H, 6.85; N, 14.39.
C. neoformans (IC50 ¼ 2.5e15.1
mg/mL). It can be safely concluded
that newly synthesized 8-aminoquinolines exhibit broad spec-
trum of activities against several pathogenic protozoal and
microbial infections, which will be further explored to provide
additional promising compounds with improved biological
activities.
4.2.5. N6-({4-[(2-tert-Butyl-6-methoxyquinolin-8-yl)amino]pentyl}
carbamoyl)-
Yield: 81%; hygroscopic solid; IR (KBr): 3398, 1663 cmꢃ1
NMR (CD3OD):
8.21 (d, 1H, J ¼ 8.3 Hz), 7.69 (d, 1H, J ¼ 8.3 Hz), 7.43
D-lysine$$2HCl (11)
;
1H
d
(s, 1H), 7.07 (s, 1H), 3.96 (m, 4H), 3.31 (m, 5H), 1.84 (m, 10H), 1.48 (s,
9H), 1.38 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 172.0, 169.6, 161.2,
4. Experimental
160.6, 157.8, 138.2, 135.7, 119.3, 97.3, 92.1, 67.3, 60.4, 57.1, 41.7, 38.7,
32.6, 28.1, 27.5, 26.9, 20.8; APCIMS: m/z 488 (M þ 1); Anal. Calcd for
C26H43Cl2N5O4 (559.2): C, 55.71; H, 7.73; N, 12.49. Found: C, 55.82;
H, 7.68; N, 12.57.
4.1. Material and methods
The analogues were checked for their purity on pre-coated silica
gel G254TLC plates (Merck) and the spots were visualized under UV
light and by exposing them to iodine vapors. Column chromato-
graphic purification was carried out on Merck silica gel
(100e200 mesh). Melting points were recorded on a capillary
melting point apparatus and are uncorrected. All solvents used for
synthesis were of analytical grade and used without any further
purification unless otherwise stated. 1H and 13C NMR spectra were
recorded on a 300 MHz Bruker FT-NMR (Avance DPX 300) spec-
trometer using tetramethylsilane as internal standard and the
4.2.6. N5-({4-[(2-tert-Butyl-6-methoxyquinolin-8-yl)amino]pentyl}
carbamoyl)-
Yield: 91%; hygroscopic solid; IR (KBr): 3283, 3030, 1640 cmꢃ1
1H NMR (CD3OD):
L
-ornithine$2HCl (12)
;
d
8.35 (d, 1H, J ¼ 8.7 Hz), 7.82 (d, 1H, J ¼ 8.7 Hz),
7.58 (s, 1H), 7.47 (s, 1H), 4.09 (s, 3H), 4.03 (t, 1H, J ¼ 6.1 Hz), 3.31 (m,
5H), 1.98 (m, 8H), 1.50 (s, 9H), 1.40 (d, 3H, J ¼ 6.3 Hz); 13C NMR
(CD3OD):
d 172.0, 169.6, 161.2, 161.2, 158.4, 138.2, 130.7, 122.3, 98.1,
92.3, 67.3, 60.4, 57.1, 41.7, 39.7, 32.2, 30.8, APCIMS: m/z 474 (M þ 1);
Anal. Calcd for C25H41Cl2N5O4 (545.2): C, 54.94; H, 7.56; N, 12.81.
Found: C, 55.06; H, 7.62; N, 12.91.
chemical shifts are reported in d units. Mass spectra were recorded
on a Finnigan Mat LCQ spectrometer (APCI/ESI). Elemental analyses
were recorded on Elementar Vario EL spectrometer. The elemental
analyses of all final compounds were within ꢂ0.4% of the expected
values, unless otherwise stated. All reagents were purchased from
Aldrich Chemicals Ltd.
4.3. General method for the synthesis of D/L-lysyl/arginyl/ornithyl-
N-{4-[(6-methoxy-2-substituted-quinolin-8-yl)amino]pentyl}-D/L-
lysinamide/argininamide/ornithinamide$4HCl (49e60)
4.2. General method for the synthesis of N5/6-({4-[(6-methoxy-2-
substituted-quinolin-8-yl)amino]pentyl}carbamoyl)-D/L-lysine/
ornithine$2HCl (9e12)
To a mixture of Z group containing conjugates 37e40 and43e46
(0.11 mmol), glacial acetic acid (1 mL) and 10% PdeC (0.04 g) in
CH3OH (5 mL) was bubbled a slow stream of H2 gas for 4 h. The
catalyst was filtered and filtrate was evaporated under reduced
pressure. The resulting residue upon treatment with a solution of
ethereal HCl (2 N) provided the hydrochloride salts of 49e52 and
55e58.
Alternatively, in the cases of conjugates containing Z and t-Boc
groups (42 and 48) and Z and Pmc groups (41 and 47), Z group was
removed first as described above. The resulting residue was stirred
in 6 N HCl in methanol (10 mL) for 45 min (for t-Boc group) or 8 N
4.2.1. Removal of Z and methyl ester groups
A slow stream of H2 gas was bubbled to a mixture of quinoline
conjugates (5 or 7, 0.1 mmol), 10% PdeC (0.04 g), and glacial acetic
acid (1 mL) in CH3OH (20 mL) for 4 h at ambient temperature. The
catalyst was filtered and solvent removed. To the residue was added
6 N HCl (5 mL) and reaction was stirred at ambient temperature for
5 h. The solvent was removed to afford the product.

238
K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
HCl in methanol (5 mL) for 8 h (for Pmc group). The solvent was
removed to afford 53, 54, 59 and 60 as hygroscopic salts.
3H), 2.62 (m, 1H), 2.40 (m, 3H), 1.79 (m, 4H), 0.76 (m, 12H), 0.15 (d,
3H, J ¼ 5.7 Hz); 13C NMR (CD3OD):
d 172.8, 169.1, 161.9, 145.0, 140.3,
139.4, 133.0, 122.5, 106.1, 91.7, 56.0, 53.8, 52.9, 50.8, 39.8, 39.5, 33.5,
29.4, 28.8, 26.2, 24.4, 23.2, 21.1; APCIMS: m/z 488 (M þ 1); Anal.
Calcd for C25H45Cl4N7O3 (631.2): C, 47.40; H, 7.16; N,15.48. Found: C,
47.40; H, 7.16; N, 15.48.
4.3.1.
lysinamide$4HCl (49)
Yield: 84%; hygroscopic solid; IR (KBr): 3368, 1690 cmꢃ1
NMR (CD3OD): 8.86 (m, 2H), 7.92 (m, 1H), 7.04 (s, 1H), 6.91 (s, 1H),
D-Lysyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-D-
;
1H
d
4.10 (t, 1H, J ¼ 5.7 Hz), 3.86 (s, 3H), 3.81 (m, 4H), 2.99 (m, 4H),
4.3.7.
pentyl}-
Yield: 83%; oil; IR (KBr): 3489, 1644 cmꢃ1 1H NMR (CD3OD):
;
D
-Lysyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)amino]
1.98e1.74 (m, 16H), 1.36 (d, 3H, J ¼ 6.1 Hz); 13C NMR (CD3OD):
D-lysinamide$4HCl (55)
d
175.4, 175.2, 162.4, 158.3, 147.6, 146.8, 137.9, 137.8, 133.0, 124.4,
99.8, 94.6, 57.2, 56.2, 41.8, 41.8, 36.5, 35.2, 29.6, 29.5, 28.6, 25.3, 24.5,
22.3; APCIMS: m/z 516 (M þ 1); Anal. Calcd for C27H49Cl4N7O3
(659.2): C, 49.02; H, 7.47; N, 14.82. Found: C, 49.16; H, 7.38; N, 14.97.
d
8.36 (d, 1H, J ¼ 8.5 Hz), 7.82 (d, 1H, J ¼ 8.5 Hz), 7.64 (s, 1H), 7.48 (s,
1H), 4.04 (t, 1H, J ¼ 6.1 Hz), 3.99 (s, 3H), 3.61 (m, 1H), 3.25 (m, 3H),
2.98 (m, 4H), 1.74 (m, 16H), 1.50 (s, 9H), 1.40 (d, 3H, J ¼ 5.8 Hz); 13C
NMR (CD3OD):
d 176.4, 174.2, 169.6, 158.4, 138.1, 136.6, 132.7, 130.3,
4.3.2.
argininamide$4HCl (50)
Yield: 76%; hygroscopic solid; IR (KBr): 3401, 1701 cmꢃ1
NMR (free base, CDCl3): 9.34 (bs, 2H), 9.20 (bs, 2H), 8.49 (d, 1H,
D
-Arginyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
D
-
122.3, 108.4, 97.6, 57.2, 54.3, 40.8, 40.4, 32.3, 30.8, 28.4, 28.2, 25.8,
24.4, 23.3, 22.9; APCIMS: m/z 572 (M þ 1); Anal. Calcd for
C31H57Cl4N7O3 (715.3): C, 51.88; H, 8.01; N, 13.66. Found: C, 51.73;
H, 8.10; N, 13.74.
;
1H
d
J ¼ 4.1 Hz), 8.04 (d, 1H, J ¼ 8.2 Hz), 7.38 (dd, 1H, J ¼ 4.1 and 8.2 Hz),
6.46 (d,1H, J ¼ 2.3 Hz), 6.30 (d,1H, J ¼ 2.3 Hz), 6.27 (bs, 2H), 6.15 (bs,
2H), 5.97 (bs, 2H), 5.34 (bs, 2H), 4.95 (bs, 1H), 4.30 (m, 1H), 3.87 (s,
3H), 3.82e3.73 (m, 4H), 3.31 (m, 4H), 1.68 (m, 12H), 1.29 (d, 3H,
4.3.8.
amino]pentyl}-
Yield: 78%; hygroscopic solid; IR (KBr): 3445, 1662 cmꢃ1
NMR (CD3OD):
D
-Arginyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
D
-argininamide$4HCl (56)
;
1H
J ¼ 5.5 Hz); 13C NMR (free base, CDCl3):
d
170.1, 168.9, 162.0, 145.1,
d
8.36 (d, 1H, J ¼ 8.6 Hz), 8.18 (d, 1H, J ¼ 8.6 Hz), 7.35
140.2, 139.7, 133.1, 126.9, 122.5, 105.8, 96.4, 62.1, 56.0, 44.6, 43.9,
39.9, 33.6, 30.9, 26.3, 22.9, 20.3; APCIMS: m/z 572 (M þ 1); Anal.
Calcd for C27H49Cl4N11O3 (715.2): C, 45.19; H, 6.88; N, 21.47. Found:
C, 45.27; H, 7.01; N, 21.38.
(m, 2H), 4.09 (t, 1H, J ¼ 5.5 Hz), 3.99 (s, 3H), 3.60 (m, 1H), 3.35e3.26
(m, 7H), 1.99e1.76 (m, 12H), 1.50 (s, 9H), 1.41 (d, 3H, J ¼ 6.1 Hz); 13C
NMR (CD3OD):
d 173.0, 169.4, 168.6, 158.1, 137.2, 129.2, 12.1, 118.3,
107.8, 97.6, 56.2, 54.3, 53.2, 41.4, 41.2, 35.6, 31.4, 29.8, 29.0, 25.3,
24.5, 22.3, 21.7; APCIMS: m/z 628 (M þ 1); Anal. Calcd for
C31H57Cl4N11O3 (771.3): C, 48.13; H, 7.43; N, 19.91. Found: C, 48.24;
H, 7.37; N, 19.86.
4.3.3.
D-Ornithyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-D-
ornithinamide$4HCl (51)
Yield: 85%; hygroscopic solid; IR (KBr): 3467, 1640 cmꢃ1 1H
;
NMR (CD3OD):
d
8.49 (s, 1H), 8.01 (s, 1H), 7.38 (s, 1H), 6.46 (s, 1H),
4.3.9.
amino]pentyl}-
Yield: 83%; hygroscopic solid; IR (KBr): 3331, 1691 cmꢃ1
NMR (CD3OD):
D
-Ornithyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
6.31 (s, 1H), 4.34 (m, 1H), 3.87 (s, 3H), 3.61 (m, 1H), 3.31e3.24 (m,
D
-ornithinamide$4HCl (57)
3H), 2.91 (m, 4H), 1.93e1.72 (m, 12H), 1.29 (d, 3H, J ¼ 5.6 Hz); 13C
;
1H
NMR (CD3OD):
d
174.8, 159.8, 144.7, 135.7, 122.3, 97.7, 92.4, 55.0,
d
8.37 (d, 1H, J ¼ 8.0 Hz), 7.82 (d, 1H, J ¼ 8.0 Hz), 7.64
53.5, 39.5, 34.4, 30.9, 29.6, 26.4, 24.4, 23.9, 22.4, 20.1; APCIMS: m/z
488 (M þ 1); Anal. Calcd for C25H45Cl4N7O3 (631.2): C, 47.40; H, 7.16;
N, 15.48. Found: C, 47.32; H, 7.28; N, 15.61.
(s, 1H), 7.47 (s, 1H), 4.40 (t, 1H, J ¼ 5.9 Hz), 4.00 (s, 3H), 3.69 (m, 1H),
3.36 (m, 3H), 3.03 (m, 4H), 1.88 (m, 12H), 1.51 (s, 9H), 1.42 (d, 3H,
J ¼ 5.1 Hz); 13C NMR (CD3OD):
d 174.7, 173.8, 169.5, 158.4, 138.1,
136.6, 133.6, 129.0, 121.8, 118.3, 108.0, 57.2, 54.9, 53.9, 40.6, 40.5,
32.5, 30.8, 27.0, 25.4, 24.3; APCIMS: m/z 544 (M þ 1); Anal. Calcd for
C29H53Cl4N7O3 (687.3): C, 50.51; H, 7.75; N, 14.22. Found: C, 50.58;
H, 7.84; N, 14.31.
4.3.4.
lysinamide$4HCl(52)
Yield: 82%; hygroscopic solid; IR (KBr): 3497, 1652 cmꢃ1
NMR (CD3OD): 8.37 (s, 1H), 7.92 (s, 1H), 7.25 (m, 1H), 6.34 (s, 1H),
L-Lysyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-L-
;
1H
d
6.19 (s, 1H), 4.19 (m, 1H), 3.76 (s, 3H), 3.51 (m, 1H), 3.19 (m, 3H), 2.79
4.3.10.
pentyl}-
Yield: 81%; hygroscopic solid; IR (KBr): 3401, 1692 cmꢃ1
NMR (CD3OD):
L
-Lysyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)amino]
(m, 4H), 1.83 (m, 8H), 1.55 (m, 8H), 1.27 (d, 3H, J ¼ 6.6 Hz); 13C NMR
L
-lysinamide$4HCl (58)
(CD3OD):
d
176.9, 173.3, 160.3, 158.0, 145.5, 144.8, 135.8, 131.0, 122.4,
;
1H
97.8, 92.5, 64.0, 57.7, 55.1, 39.8, 39.6, 34.4, 31.7, 27.2, 26.5, 23.5, 21.9;
APCIMS: m/z 516 (M þ 1); Anal. Calcd for C27H49Cl4N7O3 (659.2): C,
49.02; H, 7.47; N, 14.82. Found: C, 48.94; H, 7.60; N, 14.71.
d
8.07 (d, 1H, J ¼ 8.2 Hz), 7.52 (d, 1H, J ¼ 8.2 Hz), 7.37
(s, 1H), 7.19 (s, 1H), 4.03 (m, 1H), 3.76 (s, 3H), 3.69 (m, 1H), 3.05 (m,
3H), 2.69 (m, 4H), 1.66 (m, 16H), 1.21 (s, 9H), 1.11 (d, 3H, J ¼ 5.7 Hz);
13C NMR (CD3OD):
d 171.0, 167.8, 166.9, 155.7, 138.6, 137.9, 127.6,
4.3.5.
argininamide$4HCl (53)
Yield: 74%; hygroscopic solid; IR (KBr): 3392, 1639 cmꢃ1
NMR (CD3OD): 8.80 (m, 2H), 7.92 (m, 1H), 7.04 (s, 1H), 6.88 (s, 1H),
L
-Arginyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
L
-
119.6, 108.1, 97.3, 57.2, 54.5, 52.8, 51.6, 43.0, 38.2, 38.0, 37.8, 37.0,
30.3, 29.7, 29.6, 28.1, 25.7, 25.5, 21.7; APCIMS: m/z 572 (M þ 1);
Anal. Calcd for C31H57Cl4N7O3 (715.3): C, 51.88; H, 8.01; N, 13.66.
Found: C, 52.01; H, 8.10; N, 13.54.
;
1H
d
4.01 (t, 1H, J ¼ 5.8 Hz), 3.99 (s, 3H), 3.32 (m, 4H), 2.13 (m, 4H), 1.80
(m, 12H), 1.36 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
d
174.0, 170.4,
4.3.11.
amino]pentyl}-
Yield: 75%; hygroscopic solid; IR (KBr): 3445, 1683 cmꢃ1
NMR (CD3OD):
L
-Arginyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
159.0, 146.3, 141.2, 140.4, 134.0, 123.6, 117.8, 98.2, 91.3, 57.2, 55.3,
51.8, 42.4, 42.2, 30.6, 30.0, 27.5, 27.4, 26.8, 25.5, 20.02; MALDIMS:
m/z 573 (Mþ2); Anal. Calcd for C27H49Cl4N11O3 (715.3): C, 45.19; H,
6.88; N, 21.47. Found: C, 45.25; H, 6.96; N, 21.32.
L
-argininamide$4HCl (59)
;
1H
d
7.81 (d, 1H, J ¼ 8.2 Hz), 7.10 (d, 1H, J ¼ 8.2 Hz), 6.50
(s, 1H), 6.48 (s, 1H), 4.13 (t, 1H, J ¼ 6.3 Hz), 3.87 (s, 3H), 3.56 (m, 4H),
2.65 (m, 4H), 1.55 (m, 12H), 1.40 (s, 9H), 1.26 (d, 3H, J ¼ 6.1 Hz); 13C
4.3.6.
L
-Ornithyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
L
-
NMR (CD3OD): d 174.7, 169.0, 163.0, 157.7, 144.1, 134.1, 134.0, 128.3,
ornithinamide$4HCl (54)
118.0, 105.4, 96.1, 56.0, 55.7, 43.1, 39.8, 35.8, 31.5, 25.9, 21.6;
APCIMS: m/z 628 (M þ 1); Anal. Calcd for C31H57Cl4N11O3 (771.3): C,
48.13; H, 7.43; N, 19.91. Found: C, 48.06; H, 7.51; N, 20.11.
Yield: 85%; hygroscopic solid; IR (KBr): 3415, 1653 cmꢃ1
;
1H
NMR (CD3OD):
d 7.61 (m, 3H), 6.72 (m, 2H), 2.89 (m, 1H), 2.77 (s,

K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
239
4.3.12.
amino]pentyl}-
Yield: 84%; hygroscopic solid; IR (KBr): 3362, 1678 cmꢃ1
NMR (CD3OD):
L
-Ornithyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
4.4.6.
glutamine$3HBr (104)
Yield: 91%; hygroscopic solid; IR (KBr): 3430, 1726, 1639 cmꢃ1
1H NMR (CD3dOD):
8.87 (m, 2H), 7.93 (m, 1H), 7.09 (s, 1H), 6.95 (s,
L-Lysyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-D-
L
-ornithinamide$4HCl (60)
;
1H
;
d
7.53 (d, 1H, J ¼ 8.2 Hz), 7.16 (d, 1H, J ¼ 8.2 Hz),
d
6.62 (s, 1H), 6.47 (s, 1H), 3.21 (t, 1H, J ¼ 6.0 Hz), 2.92 (s, 3H), 2.68
(m, 2H), 2.31 (t, 2H, J ¼ 6.4 Hz), 2.17 (m, 4H), 0.80 (m, 12H), 0.32 (s,
1H), 4.12 (t, 1H, J ¼ 6.3 Hz), 3.98 (s, 3H), 3.83 (m, 2H), 3.31 (t, 2H,
J ¼ 6.2 Hz), 3.02 (t, 2H, H ¼ 6.0 Hz), 2.44 (t, 2H, J ¼ 6.2 Hz), 2.23 (m,
2H), 1.98 (m, 12H), 1.36 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
9H), 0.22 (d, 3H, J ¼ 6.2 Hz); 13C NMR (CD3OD):
d 171.6, 167.3,
158.4, 143.9, 143.7, 134.2, 128.9, 120.9, 95.9, 90.7, 59.0, 58.7, 54.2,
49.4, 48.1, 46.7, 38.4, 32.8, 28.9, 25.1, 23.7, 22.8; APCIMS: m/z 544
(M þ 1); Anal. Calcd for C29H53Cl4N7O3 (687.3): C, 50.51; H, 7.75; N,
14.22. Found: C, 50.66; H, 7.67; N, 14.23.
d 176.5, 176.3, 173.3, 165.4, 148.3, 144.6, 142.6, 136.6, 126.3, 97.4,
92.3, 59.7, 57.1, 56.4, 43.4. 43.3, 37.0, 36.2, 35.0, 31.4, 31.1, 29.9, 25.6,
22.7; APCIMS: m/z 517 (M þ 1); Anal. Calcd for C26H43Br3N6O5
(756.0): C, 41.12; H, 5.71; N, 11.07. Found: C, 41.24; H, 5.86; N, 11.13.
4.4. General method for the synthesis of
N-{4-[(6-methoxy-2-substituted-quinolin-8-yl)amino]pentyl}-D/L-
asparagine/glutamine (101e124)
D
/
L
-lysyl/arginyl/ornithyl-
4.4.7.
glutamine$3HCl (105)
Yield: 79%; hygroscopic solid; IR (KBr): 3435, 1729, 1630 cmꢃ1
1H NMR (CD3OD):
8.79 (m, 2H), 7.88 (m, 1H), 6.99 (s, 1H), 6.83 (s,
L-Arginyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-D-
;
d
4.4.1. Removal of Z group
1H), 4.04 (t, 1H, J ¼ 5.3 Hz), 3.98 (s, 3H), 3.82 (m, 2H), 3.28 (m, 4H),
To a solution of protected conjugates (0.12 mmol) and 10% PdeC
(0.04 g) in glacial acetic acid (1 mL) and CH3OH (20 mL) was
bubbled a slow stream of H2 gas for 4 h. The catalyst filtered and
solvent removed to afford product.
2.82 (t, 2H, J ¼ 5.7 Hz), 2.00 (m, 2H), 1.84 (m, 8H), 1.36 (d, 3H,
J ¼ 6.0 Hz); 13C NMR (CD3OD):
d 173.9, 162.4, 158.8, 145.6, 135.3,
133.8, 141.5, 123.2, 97.3, 91.4, 56.6, 54.0, 42.8, 41.9, 40.4, 37.9, 34.1,
34.0, 29.6, 26.9, 25.0, 19.8; MALDIMS: m/z 545 (M þ 1); Anal. Calcd
for C26H43Cl3N8O5 (652.2): C, 47.75; H, 6.63; N, 17.13. Found: C,
47.84; H, 6.52; N, 17.27.
4.4.2. Removal of t-Boc and tert-butyl ester groups
A solution of protected conjugates (0.7 mmol) in 4 N HCl
(10 mL) was stirred at ambient temperature for 5 h. In
some cases, a solution of protected derivatives and 33% HBr
in AcOH (5 mL) was stirred for 30 min. The solvent was
evaporated under reduced pressure to afford product as hygro-
scopic salt.
4.4.8.
glutamine$3HBr (106)
Yield: 88%; hygroscopic solid; IR (KBr): 3435, 1728, 1633 cmꢃ1
1H NMR (CD3OD):
8.75 (m, 2H), 7.84 (m, 1H), 7.00 (s, 1H), 6.86 (s,
L-Ornithyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-D-
;
d
1H), 4.37 (t, 1H, J ¼ 5.4 Hz), 4.05 (t, 1H, J ¼ 6.1 Hz), 3.89 (s, 3H), 3.74
(m, 1H), 3.22 (t, 2H, J ¼ 5.9 Hz), 2.97 (t, 2H, J ¼ 7.1 Hz), 2.35 (t, 2H,
J ¼ 7.4 Hz), 1.95 (m, 10H), 1.27 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
4.4.3.
asparagine$3HBr (101)
Yield: 92%; hygroscopic solid; IR (KBr): 3385, 1726, 1659 cmꢃ1
1H NMR (CD3OD):
8.86 (m, 2H), 7.93 (m, 1H), 7.08 (s, 1H), 6.95 (s,
L-Lysyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-D-
d
173.2, 172.2, 171.9, 162.7, 145.5, 142.0, 139.9, 133.9, 130.9, 123.6,
;
113.6, 96.4, 57.0, 53.9, 40.7, 38.1, 36.3, 34.3, 29.9, 27.3, 25.7, 24.2,
19.9; APCIMS: m/z 503 (M þ 1); Anal. Calcd for C25H41Br3N6O5
(742.0): C, 40.29; H, 5.54; N, 11.28. Found: C, 40.17; H, 5.49; N, 11.39.
d
1H), 3.98 (m, 4H), 3.86 (t, 1H, J ¼ 6.9 Hz), 3.31 (m, 1H), 2.99 (t, 2H,
J ¼ 7.3 Hz), 2.82 (t, 2H, J ¼ 5.0 Hz), 1.98 (d, 2H, J ¼ 6.6 Hz), 1.75 (m,
10H), 1.37 (d, 3H, J ¼ 6.2 Hz); 13C NMR (CD3OD):
d
173.1, 172.0, 170.3,
4.4.9.
asparagine$3HBr (107)
Yield: 84%; hygroscopic solid; IR (KBr): 3435, 1638 cmꢃ1
NMR (CD3OD): 8.88 (m, 2H), 7.94 (m, 1H), 7.08 (s, 1H), 6.94 (s, 1H),
L-Lysyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-L-
159.2, 145.7, 141.8, 133.9, 123.6, 98.3, 92.7, 67.2, 57.0, 54.3, 40.7, 38.2,
28.4, 27.2, 22.9, 20.0; MALDIMS: m/z 503 (M þ 1); Anal. Calcd for
C25H41Br3N6O5 (742.0): C, 40.29; H, 5.54; N, 11.28. Found: C, 40.19;
H, 5.61; N, 11.35.
;
1H
d
4.05 (m, 1H), 3.98 (s, 3H), 3.83 (m, 1H, N-CH), 3.26 (t, 1H, J ¼ 5.8 Hz),
3.03 (m, 4H), 2.84 (m, 2H), 1.79 (m, 10H), 1.37 (d, 3H, J ¼ 6.3 Hz); 13C
4.4.4.
asparagine$3HCl (102)
Yield: 76%; hygroscopic solid; IR (KBr): 3433, 1730, 1658 cmꢃ1
1H NMR (CD3OD):
8.77 (m, 2H), 7.82 (m, 1H), 7.19 (s, 1H), 6.95 (s,
L
-Arginyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
D-
NMR (CD3OD): d 173.1, 172.0, 170.3, 162.8, 145.8, 141.7, 140.0, 133.9,
123.6, 98.1, 92.3, 67.2, 57.1, 48.6, 40.8, 38.2, 34.3, 32.3, 28.4, 27.3,
22.9, 20.1; APCIMS: m/z 503 (M þ 1); Anal. Calcd for C25H41Br3N6O5
(742.0): C, 40.29; H, 5.54; N, 11.28. Found: C, 40.35; H, 5.38; N, 11.42.
;
d
1H), 3.94 (m, 4H), 3.82 (t, 1H, J ¼ 6.3 Hz), 3.42 (m, 3H), 2.70 (t, 2H,
J ¼ 6.0 Hz), 1.88 (m, 2H), 1.63 (m, 8H), 1.27 (d, 3H, J ¼ 5.7 Hz); 13C
4.4.10.
asparagine$3HBr (108)
Yield: 76%; hygroscopic solid; IR (KBr): 3421, 1721, 1665 cmꢃ1
1H NMR (CD3OD):
8.83 (m, 2H), 7.93 (m, 1H), 6.96 (s, 1H), 6.78 (s,
D-Arginyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-L-
NMR (CD3OD):
d 173.1, 172.0, 170.2, 162.9, 159.3, 159.0, 146.0, 141.5,
140.3, 134.0, 123.6, 67.3, 57.0, 54.2, 45.1, 42.3, 38.2, 30.0, 27.3, 25.4,
23.2, 20.1; MALDIMS: m/z 531 (M þ 1); Anal. Calcd for
C25H41Cl3N8O5 (638.2): C, 46.92; H, 6.46; N, 17.51. Found: C, 47.01;
H, 6.53; N, 17.44.
;
d
1H), 4.01 (m, 4H), 3.83 (m, 2H), 3.31 (m, 4H, J ¼ 5.4 Hz), 2.84 (m,
2H), 1.80 (m, 8H), 1.37 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 172.2,
168.1, 154.3, 145.8, 133.2, 123.9, 96.4, 91.8, 67.2, 57.5, 54.6, 49.5, 48.3,
46.8, 41.5, 38.6, 32.3, 28.9, 26.3, 23.2, 21.1; APCIMS: m/z 531
(M þ 1); Anal. Calcd for C25H43Br3N8O5 (772.0): C, 38.73; H, 5.59; N,
14.45. Found: C, 38.65; H, 5.73; N, 14.28.
4.4.5.
L
-Ornithyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
D
-
asparagine$3HBr (103)
Yield: 94%; hygroscopic solid; IR (KBr): 3400, 1630 cmꢃ1
;
1H
NMR (CD3OD): d 8.88 (m, 2H), 7.94 (m, 1H), 7.12 (s, 1H), 6.97 (s, 1H),
4.12 (m, 1H), 3.98 (s, 3H), 3.78 (m, 2H), 3.27 (t, 2H, J ¼ 6.2 Hz), 3.07
4.4.11.
D
-Ornithyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
L
-
(t, 2H, J ¼ 6.1 Hz), 2.84 (m, 2H), 1.98 (m, 8H), 1.37 (d, 3H, J ¼ 6.2 Hz);
asparagine$3HBr (109)
13C NMR (CD3OD):
d
172.8, 172.2, 170.9, 169.0, 161.7, 155.3, 144.8,
Yield: 89%; hygroscopic solid; IR (KBr): 3435, 1637 cmꢃ1
;
1H
140.8, 132.8, 122.6, 97.4, 91.2, 66.2, 56.0, 52.9, 49.5, 48.4, 47.8, 37.2,
33.3, 28.9, 26.3, 23.2, 19.9; APCIMS: m/z 488.9 (M þ 1); Anal. Calcd
for C24H39Br3N6O5 (728.0): C, 39.42; H, 5.38; N, 11.49. Found: C,
39.59; H, 5.21; N, 11.65.
NMR (CD3OD): d 8.85 (m, 2H), 7.92 (m, 1H), 7.08 (s, 1H), 6.96 (s, 1H),
4.92 (m, 1H), 4.08 (s, 3H), 3.98 (m, 1H), 3.29 (t, 1H, J ¼ 5.4 Hz), 3.02
(m, 4H), 2.84 (m, 2H), 1.95 (m, 8H), 1.37 (d, 3H, J ¼ 6.3 Hz); 13C NMR
(CD3OD):
d 173.2, 169.1, 155.3, 145.2, 133.9, 123.6, 97.4, 90.8, 66.2,

240
K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
57.0, 53.9, 49.5, 48.4, 47.8, 41.5, 38.9, 34.3, 29.9, 27.3, 24.2, 19.9;
APCIMS: m/z 489 (M þ 1); Anal. Calcd for C24H39Br3N6O5 (728.0): C,
39.42; H, 5.38; N, 11.49. Found: C, 39.37; H, 5.28; N, 11.57.
4.4.17.
amino]pentyl}-
Yield: 96%; hygroscopic solid; IR (KBr): 3425, 1658 cmꢃ1
NMR (CD3OD):
L
-Ornithyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
D
-asparagine$3HBr (115)
;
1H
d
8.37 (d, 1H, J ¼ 8.7 Hz), 7.82 (d, 1H, J ¼ 8.7 Hz), 7.61
4.4.12.
glutamine$3HCl (110)
Yield: 85%; hygroscopic solid; IR (KBr): 3430, 1730, 1629 cmꢃ1
1H NMR (CD3OD):
8.86 (m, 2H), 7.91 (m, 1H), 7.18 (s, 1H), 6.91 (s,
L
-Lysyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
L
-
(s, 1H), 7.49 (s, 1H), 4.11 (m, 1H), 3.99 (s, 3H), 3.73 (t, 1H, J ¼ 5.7 Hz),
3.35 (m, 1H), 3.22 (t, 2H, J ¼ 6.0 Hz), 3.05 (t, 2H, J ¼ 5.7 Hz), 2.82 (m,
2H), 2.02 (m, 8H), 1.50 (s, 9H), 1.42 (d, 3H, J ¼ 6.5 Hz); 13C NMR
;
d
(CD3OD): d 172.4, 172.1, 170.8, 159.4, 156.2, 144.9, 144.2, 135.3, 134.7,
1H), 4.47 (t, 1H, J ¼ 5.1 Hz), 4.04 (t, 1H, J ¼ 5.7 Hz), 3.98 (s, 3H), 3.87
129.9, 121.8, 96.7, 91.6, 55.2, 54.7, 52.3, 47.8, 39.8, 39.5, 34.0, 32.4,
31.8, 29.6, 28.4, 28.2, 27.9, 26.2, 22.4, 20.5; APCIMS: m/z 545
(M þ 1); Anal. Calcd for C28H47Br3N6O5 (784.1): C, 42.71; H, 6.02; N,
10.67. Found: C, 42.65; H, 6.20; N, 10.54.
(m, 1H), 3.25 (t, 2H, J ¼ 5.6 Hz), 2.41 (t, 2H, J ¼ 6.1 Hz), 1.96 (m, 4H),
1.73 (m, 8H), 1.36 (d, 3H, J ¼ 5.7 Hz); 13C NMR (CD3OD):
d 173.9,
172.2, 169.2, 140.1, 132.6, 122.1, 98.7, 96.1, 65.9, 39.3, 31.9, 30.9, 27.4,
27.0, 25.7, 21.5; APCIMS: m/z 517 (M þ 1); Anal. Calcd for
C26H43Cl4N6O5 (659.2): C, 47.21; H, 6.55; N,12.71. Found: C, 47.14; H,
6.48; N, 12.63.
4.4.18.
pentyl}-
Yield: 91%; hygroscopic solid; IR (KBr): 3421, 1712, 1667 cmꢃ1
1H NMR (CD3OD):
L
-Lysyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)amino]
-glutamine$3HCl (116)
D
;
4.4.13.
D-Arginyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
L
-
d
8.35 (d, 1H, J ¼ 8.7 Hz), 7.81 (d, 1H, J ¼ 8.7 Hz),
glutamine$3HCl (111)
7.56 (s,1H), 7.47 (s,1H), 4.47 (t,1H, J ¼ 6.4 Hz), 4.02 (m, 4H), 3.31 (m,
1H), 3.23 (t, 2H, J ¼ 6.5 Hz), 3.00 (t, 2H, J ¼ 7.3 Hz), 2.38 (t, 2H,
J ¼ 6.8 Hz), 1.97 (m, 2H), 1.75 (m, 10H), 1.50 (s, 9H), 1.39 (d, 3H,
Yield: 92%; hygroscopic solid; IR (KBr): 3408, 1645 cmꢃ1
;
1H
NMR (CD3OD): d 8.83 (m, 2H), 7.91 (m, 1H), 7.17 (s, 1H), 6.91 (s, 1H),
4.45 (t, 1H, J ¼ 6.0 Hz), 3.98 (s, 3H), 3.92 (t, 1H, J ¼ 6.8 Hz), 3.31 (m,
J ¼ 6.5 Hz); 13C NMR (CD3OD):
d 170.6, 169.6, 161.3, 146.1, 144.5,
5H), 2.42 (t, 2H, J ¼ 5.3 Hz), 2.01 (m, 2H), 1.75 (m, 8H), 1.28 (d, 3H,
135.6, 122.3, 98.4, 92.3, 67.3, 57.1, 54.3, 40.7, 40.3, 32.3, 30.8, 28.7,
28.4, 26.9, 22.9, 21.3; APCIMS: m/z 573 (M þ 1); Anal. Calcd for
C30H51Cl3N6O5 (680.3): C, 52.82; H, 7.54; N, 12.32. Found: C, 52.88;
H, 7.61; N, 12.41.
J ¼ 6.1 Hz); 13C NMR (CD3OD):
d 175.6, 174.5, 170.5, 159.0, 145.9,
142.7, 141.6, 134.0, 123.1, 107.6, 93.8, 67.3, 57.1, 54.3, 53.5, 45.5, 42.3,
33.4, 30.0, 29.0, 27.1, 25.5, 23.1, 20.1; ESIMS: m/z 545 (M þ 1); Anal.
Calcd for C26H43Cl3N8O5 (652.2): C, 47.75; H, 6.63; N, 17.13. Found:
C, 47.64; H, 6.54; N, 17.21.
4.4.19.
amino]pentyl}-
Yield: 86%; hygroscopic solid; IR (KBr): 3398, 1731, 1683 cmꢃ1
1H NMR (CD3OD):
L
-Arginyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
D
-glutamine$3HCl (117)
4.4.14.
-glutamine$3HBr (112)
Yield: 92%; hygroscopic solid; IR (KBr): 3430, 1730, 1629 cmꢃ1
1H NMR (CD3OD):
8.79 (m, 2H), 7.85 (m, 1H), 6.99 (s, 1H), 6.85 (s,
D-Ornithyl-N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-
;
L
d
8.74 (d, 1H, J ¼ 8.5 Hz), 8.36 (d, 1H, J ¼ 8.5 Hz),
;
7.85 (m, 2H), 4.45 (t, 1H, J ¼ 6.8 Hz), 4.05 (t, 1H, J ¼ 5.4 Hz), 3.99 (s,
d
3H), 3.34 (m, 5H), 2.37 (t, 2H, J ¼ 6.1 Hz), 2.23 (m, 2H), 1.97 (m, 8H),
1H), 4.39 (t, 1H, J ¼ 7.1 Hz), 4.09 (t, 1H, J ¼ 5.4 Hz), 3.89 (s, 3H), 3.74
(m, 1H), 3.22 (t, 2H, J ¼ 5.9 Hz), 2.98 (t, 2H, J ¼ 7.1 Hz), 2.37 (t, 2H,
J ¼ 7.3 Hz), 2.14 (m, 2H), 1.80 (m, 8H), 1.27 (d, 3H, J ¼ 6.3 Hz); 13C
1.50 (s, 9H),1.33 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 173.5,170.5,
169.6, 159.2, 159.0, 155.4, 136.7, 135.5, 131.2, 129.0, 126.0, 121.9, 98.4,
67.3, 62.5, 57.9, 54.2, 45.4, 42.2, 40.4, 30.8, 30.7, 28.7, 26.9, 23.1, 21.7;
APCIMS: m/z 601 (M þ 1); Anal. Calcd for C30H51Cl3N8O5 (708.3): C,
50.74; H, 7.24; N, 15.78. Found: C, 50.81; H, 7.32; N, 15.69.
NMR (CD3OD):
d 175.2, 173.8, 173.6, 170.2, 162.7, 145.7, 141.8, 140.0,
133.9, 123.6, 67.3, 57.1, 54.0, 45.1, 40.7, 34.3, 33.5, 29.9, 28.7, 27.2,
24.3, 22.9, 20.9; APCIMS: m/z 503 (M þ 1); Anal. Calcd for
C25H41Br3N6O5 (742.0): C, 40.29; H, 5.54; N, 11.28. Found: C, 40.24;
H, 5.42; N, 11.16.
4.4.20.
amino]pentyl}-
Yield: 95%; hygroscopic solid; IR (KBr): 3392, 3078, 1729, 1677,
1641 cmꢃ1; 1H NMR (CD3OD):
L
-Ornithyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
D
-glutamine$3HCl (118)
4.4.15.
pentyl}-
Yield: 93%; hygroscopic solid; IR (KBr): 3435, 1635 cmꢃ1
NMR (CD3OD):
L
-Lysyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)amino]
d
8.37 (d, 1H, J ¼ 8.4 Hz), 7.83 (d, 1H,
D
-asparagine$3HBr (113)
J ¼ 8.4 Hz), 7.62 (s, 1H), 7.49 (s, 1H), 4.47 (t, 1H, J ¼ 6.3 Hz), 4.10 (t,
1H, J ¼ 6.9 Hz), 4.00 (s, 3H), 3.32 (m,1H), 3.24 (t, 2H, J ¼ 5.4 Hz), 3.04
(t, 2H, J ¼ 6.0 Hz), 2.41 (t, 2H, J ¼ 7.1 Hz), 2.01e1.76 (m, 10H), 1.51 (s,
;
1H
d
8.35 (d, 1H, J ¼ 8.7 Hz), 7.82 (d, 1H, J ¼ 8.7 Hz), 7.57
(s, 1H), 7.48 (s, 1H), 4.09 (m, 4H), 3.31 (m, 2H), 3.01 (t, 2H,
9H), 1.41 (d, 3H, J ¼ 5.9 Hz); 13C NMR (CD3OD):
d 173.8, 172.9, 168.6,
J ¼ 5.7 Hz), 2.79 (t, 2H, J ¼ 6.4 Hz), 1.96 (m, 2H, J ¼ 6.1 Hz), 1.78 (m,
156.7, 136.5, 134.9, 130.9, 128.6, 120.6, 117.0, 93.4, 65.6, 58.8, 55.5,
52.0, 38.8, 30.6, 29.1, 28.2, 25.2, 22.5, 21.4; APCIMS: m/z 559
(M þ 1); Anal. Calcd for C29H49Cl3N6O5 (666.2): C, 52.13; H, 7.39; N,
12.58. Found: C, 52.25; H, 7.44; N, 12.45.
10H), 1.50 (s, 9H), 1.41 (d, 3H, J ¼ 6.5 Hz); 13C NMR (CD3OD):
d 173.1,
171.9, 162.1, 156.7, 145.6, 143.8, 138.1, 122.4, 97.6, 91.3, 67.2, 57.1,
54.3, 40.7, 40.4, 39.7, 38.2, 32.3, 30.8, 28.4, 26.9, 23.2, 22.9, 21.4;
MALDIMS: m/z 559 (M þ 1); Anal. Calcd for C29H49Br3N6O5 (798.1):
C, 43.46; H, 6.16; N, 10.49. Found: C, 43.56; H, 6.25; N, 10.58.
4.4.21.
pentyl}-
Yield: 81%; hygroscopic solid; IR (KBr): 3415, 1710, 1672 cmꢃ1
1H NMR (CD3OD):
L
-Lysyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)amino]
-asparagine$3HCl (119)
L
4.4.16.
amino]pentyl}-
Yield: 79%; hygroscopic solid; IR (KBr): 3445, 1622 cmꢃ1
NMR (CD3OD):
L
-Arginyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
;
D-asparagine$3HCl (114)
d
8.25 (d, 1H, J ¼ 8.5 Hz), 7.73 (d, 1H,
;
1H
J ¼ 8.5 Hz), 7.45 (s, 1H), 7.39 (s, 1H), 4.68 (t, 1H, J ¼ 6.1 Hz), 3.99 (s,
3H), 3.82 (t, 1H, J ¼ 5.8 Hz), 3.35 (m, 3H), 3.00 (t, 2H, J ¼ 5.6 Hz),
2.73 (d, 2H, J ¼ 6.1 Hz), 1.98 (m, 10H), 1.51 (s, 9H), 1.38 (d, 3H,
d
8.75 (d, 1H, J ¼ 8.4 Hz), 8.50 (d, 1H, J ¼ 8.4 Hz), 7.85
(m, 2H), 4.01 (t, 1H, J ¼ 7.3 Hz), 3.88 (m, 4H), 3.57 (m, 1H), 3.21 (m,
2H), 2.76 (t, 2H, J ¼ 5.8 Hz), 2.67 (d, 2H, J ¼ 7.3 Hz), 1.97 (m, 8H), 1.49
J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 172.4, 170.5, 168.6, 166.7, 157.1,
(s, 9H), 1.38 (d, 3H, J ¼ 6.2 Hz); 13C NMR (CD3OD):
d
172.1, 169.7,
155.0, 148.9, 138.3, 136.0, 134.5, 133.9, 130.1, 128.2, 119.6, 96.3,
56.0, 55.5, 43.3, 41.3, 39.0, 38.7, 37.6, 36.9, 35.8, 34.1, 31.3, 30.7,
29.2, 28.7, 26.5, 22.2; APCIMS: m/z 559 (M þ 1); Anal. Calcd for
C29H49Cl3N6O5 (666.2): C, 52.13; H, 7.39; N, 12.58. Found: C,
52.24; H, 7.46; N, 12.51.
159.3, 146.4, 144.9, 135.6, 129.0, 118.6, 97.5, 91.3, 67.3, 62.5, 57.8,
54.4, 45.0, 42.2, 39.6, 30.7, 25.3, 23.2, 21.8; APCIMS: m/z 587
(M þ 1); Anal. Calcd for C29H49Cl3N8O5 (694.2): C, 50.04; H, 7.10; N,
16.10. Found: C, 50.10; H, 7.23; N, 16.05.

K. Kaur et al. / European Journal of Medicinal Chemistry 52 (2012) 230e241
241
4.4.22.
amino]pentyl}-
Yield: 77%; hygroscopic solid; IR (KBr): 3415, 1723, 1648 cmꢃ1
1H NMR (CD3OD):
D
-Arginyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
NIAID, Division of AIDS, grant no. AI 27094. Support from the USDA
Agricultural Research Service Specific Cooperative Agreement No.
58-6408-2-0009 is also acknowledged in the in vitro screening of
antimicrobial, antiprotozoal, and cytotoxic activity at NCNPR,
University of Mississippi.
L
-asparagine$3HCl (120)
;
d
8.35 (d, 1H, J ¼ 8.8 Hz), 7.89 (d, 1H, J ¼ 8.8 Hz),
7.55 (m, 2H), 4.43 (m, 1H), 4.02 (t, 1H, J ¼ 6.7 Hz), 3.99 (s, 3H), 3.52
(m, 1H), 3.31 (m, 2H), 2.82 (t, 2H, J ¼ 5.8 Hz), 2.67 (m, 2H), 1.96 (m,
Appendix 1. Supplementary material
8H), 1.49 (s, 9H), 1.38 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 172.7,
171.6, 169.2, 159.2, 158.7, 155.1, 136.3, 135.2, 130.9, 128.6, 120.5, 97.4,
92.1, 60.6, 57.6, 53.8, 44.7, 41.9, 40.0, 39.4, 39.3, 38.2, 31.9, 30.5, 29.6,
28.1, 26.5, 25.3, 23.0, 22.1, 20.9; APCIMS: m/z 587 (M þ 1); Anal.
Calcd for C29H49Cl3N8O5 (694.2): C, 50.04; H, 7.10; N, 16.10. Found:
C, 50.14; H, 7.15; N, 16.18.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2012.03.019.
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702e709.
4.4.23.
amino]pentyl}-
Yield: 98%; hygroscopic solid; IR (KBr): 3397,1725,1661 cmꢃ1; 1H
NMR (CD3OD):
D
-Ornithyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
L
-asparagine$3HCl (121)
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d
8.39 (d, 1H, J ¼ 8.3 Hz), 7.82 (d, 1H, J ¼ 8.3 Hz), 7.66
(s,1H), 7.49 (s,1H), 4.87 (t,1H, J ¼ 5.7 Hz), 4.12 (t,1H, J ¼ 6.8 Hz), 4.00
(s, 3H), 3.56 (m, 1H), 3.24 (m, 4H), 2.83 (d, 2H, J ¼ 5.7 Hz), 2.06 (m,
8H), 1.51 (s, 9H), 1.35 (d, 3H, J ¼ 6.3 Hz); 13C NMR (CD3OD):
d 176.3,
171.4, 168.7, 156.6, 136.5, 134.8, 131.0, 128.5, 120.5, 116.8, 58.6, 55.5,
43.3, 42.3, 38.9, 38.0, 36.5, 35.7, 34.6, 30.6, 29.1, 28.1, 25.1, 23.4, 22.6,
21.9; APCIMS: m/z 545 (M þ 1); Anal. Calcd for C28H47Cl3N6O5
(652.2): C, 51.42; H, 7.24; N, 12.85. Found: C, 51.36; H, 7.32; N, 12.93.
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K. Kamei, Biol. Pharm. Bull. 31 (2008) 1483e1488.
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1030e1034.
4.4.24.
pentyl}-
Yield: 83%; hygroscopic solid;IR (KBr): 3409,1724,1663 cmꢃ1; 1H
NMR (CD3OD):
L
-Lysyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)amino]
-glutamine$3HCl (122)
L
d
8.25 (d, 1H, J ¼ 8.7 Hz), 7.71 (d, 1H, J ¼ 8.7 Hz), 7.51
(s, 1H), 7.43 (s, 1H), 4.38 (m, 1H), 3.95 (t, 1H, J ¼ 6.2 Hz), 3.89 (s, 3H),
3.64 (m,1H), 3.12 (t, 2H, J ¼ 6.6 Hz), 2.90 (t, 2H, J ¼ 7.5 Hz), 2.26 (t, 2H,
J ¼ 7.1 Hz),1.90 (m,12H),1.40 (s, 9H),1.29 (d, 3H, J ¼ 6.5 Hz); 13C NMR
(CD3OD): d 173.2, 171.9, 161.3, 156.8, 146.4, 144.3, 135.3, 128.5, 120.5,
98.6, 91.7, 55.4, 52.5, 38.9, 38.5, 37.9, 31.6, 30.5, 29.0, 26.9, 26.6, 25.2,
21.9, 21.1; APCIMS: m/z 573 (M þ 1); Anal. Calcd for C30H51Cl3N6O5
(680.3): C, 52.82; H, 7.54; N,12.32. Found: C, 52.93; H, 7.47; N,12.26.
4.4.25.
amino]pentyl}-
Yield: 78%; hygroscopic solid; IR (KBr): 3435, 1726, 1662 cmꢃ1
1H NMR (CD3OD):
D
-Arginyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
L
-glutamine$3HCl (123)
;
d
8.45 (d, 1H, J ¼ 8.3 Hz), 7.81 (d, 1H, J ¼ 8.3 Hz),
7.17 (m, 2H), 4.46 (m, 1H), 4.05 (t, 1H, J ¼ 6.3 Hz), 3.99 (s, 3H), 3.85
(m, 1H), 3.34 (m, 4H), 2.36 (t, 2H, J ¼ 7.1 Hz), 1.97 (m, 10H), 1.50 (s,
9H), 1.38 (d, 3H, J ¼ 6.5 Hz); 13C NMR (CD3OD):
d 172.1, 168.1, 161.3,
157.2, 144.9, 143.7, 136.1, 122.4, 98.1, 92.3, 65.5, 52.5, 42.9, 40.5, 29.0,
28.3, 21.6; APCIMS: m/z 601 (M þ 1); Anal. Calcd for C30H51Cl3N8O5
(708.3): C, 50.74; H, 7.24; N, 15.78. Found: C, 50.82; H, 7.15; N, 15.89.
4.4.26.
amino]pentyl}-
Yield: 95%; hygroscopic solid; IR (KBr): 3390, 1728, 1663 cmꢃ1
1H NMR (CD3OD):
D
-Ornithyl-N-{4-[(2-tert-butyl-6-methoxyquinolin-8-yl)
[26] J. Mustafa, S.I. Khan, G. Ma, L.A. Walker, I.A. Khan, Lipids 39 (2004) 167e172.
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Biochem. 349 (2006) 292e296.
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[29] J. Mikus, D. Steverding, Parasitol. Int. 48 (2000) 265e269.
[30] G. Ma, S.I. Khan, M.R. Jacob, B.L. Tekwani, Z. Li, D.S. Pasco, L.A. Walker,
I.A. Khan, Antimicrob. Agents Chemother. 48 (2004) 4450e4452.
[31] NCCLS, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria
that Grow Aerobically M7-A5, vol. 20, National Committee on Clinical Labo-
ratory Standards, 2000.
[32] NCCLS, Reference Method for Broth Dilution Antifungal Susceptibility Testing
of Yeasts; Approved Standard M27-A2, vol. 22, National Committee on Clinical
Laboratory Standards, 2002.
[33] NCCLS, Reference Method for Broth Dilution Antifungal Susceptibility Testing
of Filamentous Fungi; Approved Standard, M38-A, vol. 22, National
Committee on Clinical Laboratory Standards, 2002.
L
-glutamine$3HCl (124)
;
d
8.34 (d, 1H, J ¼ 8.5 Hz), 7.81 (d, 1H, J ¼ 8.5 Hz),
7.69 (s, 1H), 7.46 (s, 1H), 4.46 (m, 1H), 4.08 (m, 4H), 3.22 (m, 3H),
3.02 (t, 2H, J ¼ 6.4 Hz), 2.36 (t, 2H, J ¼ 6.9 Hz), 1.99 (m, 10H), 1.51 (s,
9H), 1.30 (d, 3H, J ¼ 6.2 Hz); 13C NMR (CD3OD):
d 173.4, 172.9, 163.4,
144.1, 143.8, 133.6, 120.5, 118.1, 95.4, 65.4, 55.3, 43.2, 38.7, 38.4, 37.9,
31.8, 30.5, 28.9, 28.0, 27.1, 25.1, 22.4, 21.7; APCIMS: m/z 559 (M þ 1);
Anal. Calcd for C29H49Cl3N6O5 (666.2): C, 52.13; H, 7.39; N, 12.58.
Found: C, 52.20; H, 7.26; N, 12.52.
Acknowledgements
[34] NCCLS, Susceptibility Testing of Mycobacteria, Nocardia, and Other Aerobic
Actinomycetes; Tentative StandarddSecond Edition, M24-T2, vol. 20,
National Committee on Clinical Laboratory Standards, 2000.
[35] S.G. Franzblau, R.S. Witzig, J.C. McLaughlin, P. Torres, G.G. Madico,
A. Hernandez, M.T. Degnan, M.B. Cook, V.K. Quenzer, R.M. Ferguson,
R.H. Gilman, J. Clin. Microbiol. 36 (1998) 362e366.
Kirandeep Kaur thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for the award of Senior Research
Fellowship. The antimicrobial testing was supported by the NIH,