2-[2-Substituted-3-(3,4-dichlorobenzylamino)propylamino]-1H-quinolin-4-ones as Staphylococcus aureus methionyl-tRNA synthetase inhibitors

Article abstract of DOI:10.1016/j.ejmech.2008.02.021

New analogues of 2-[2-substituted-3-(3,4-dichlorobenzylamino)propylamino]quinolin-4-ones, 26a, 26b, 31a-e, 34, 35, 38 and 40, have been synthesized and evaluated against Staphylococcus aureus methionyl-tRNA synthetase. All of the synthesized compounds were less active than the reference compound 2. The compounds were also screened against various strains of S. aureus and Enterococci for their antibacterial activities. Among the compounds, 26b, 31c and 31e displayed significant inhibitory properties against various strains of Enterococci compared to compound 2.

Full text of DOI:10.1016/j.ejmech.2008.02.021

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 44 (2009) 239e250
http://www.elsevier.com/locate/ejmech
Original article
2-[2-Substituted-3-(3,4-dichlorobenzylamino)propylamino]-
1H-quinolin-4-ones as Staphylococcus aureus
methionyl-tRNA synthetase inhibitors
Farhanullah a, Taehee Kang b, Eun-Jung Yoon b, Eun-Chil Choi b,
Sunghoon Kim b, Jeewoo Lee a,
*
a Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University,
Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea
b Laboratory of Microbiology, Center for Medicinal Protein Network and Systems Biology, College of Pharmacy,
Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea
Received 11 December 2007; received in revised form 8 February 2008; accepted 8 February 2008
Available online 6 March 2008
Abstract
New analogues of 2-[2-substituted-3-(3,4-dichlorobenzylamino)propylamino]quinolin-4-ones, 26a, 26b, 31aee, 34, 35, 38 and 40, have been
synthesized and evaluated against Staphylococcus aureus methionyl-tRNA synthetase. All of the synthesized compounds were less active than
the reference compound 2. The compounds were also screened against various strains of S. aureus and Enterococci for their antibacterial
activities. Among the compounds, 26b, 31c and 31e displayed significant inhibitory properties against various strains of Enterococci compared
to compound 2.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Antibiotic; Aminoacyl-tRNA synthetase; Methionyl-tRNA synthetase inhibitors
1. Introduction
aa-AMP intermediate and forms an ester bond with the amino-
acyl moiety. The aaRSs have a proof-reading mechanism to
check the amino acids attached to their cognate tRNAs, which
ensures their functional accuracy [2] of attaching the correct
amino acids. The topology of the ATP binding domain and
the functions of the human aaRSs differ from those of bacteria,
thus providing an opportunity to inhibit them selectively in
bacteria. Therefore, the aaRSs have the potential to be ex-
ploited as antibacterial drug targets by the synthesis of aaRS
inhibitors to treat bacterial infections, including antibiotic
resistant strains such as methicillin resistant Staphylococcus
aureus (MRSA) and vancomycin resistant Enterococci
(VRE) [3e5].
Aminoacyl-tRNA synthetases (aaRSs) have been identified
as promising antibacterial drug targets, since the emergence of
drug resistance against the existing antibiotics. The amino-
acyl-tRNA synthetases are a family of 20 enzymes that are
essential for the translation of the genetic code into proteins.
The aaRSs transfer amino acids from the cellular pool to their
cognate [1] tRNAs during protein synthesis. The transfer of
amino acids to the tRNAs by the aaRSs occurs in two steps.
The first step is the formation of an enzyme-bound amino-
acyl-adenylate (aa-AMP) active intermediate, by the reaction
of the amino acid and ATP. In the second step, either the 20-
OH or 30-OH of the ribose of the cognate tRNA attacks the
Previously, several approaches have been reported for the
synthesis of aaRS inhibitors, particularly methionyl-tRNA
synthetase inhibitors. Among them, the substitution of the hy-
drolytically unstable acylphosphate and ribose moieties pres-
ent in methionyl adenylate (Met-AMP, 1) by their isosteres
* Corresponding author. Tel.: þ82 2 880 7846; fax: þ82 2 888 0649.
E-mail address: jeewoo@snu.ac.kr (J. Lee).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.02.021

240
Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
NH2
N
precursor 23 was prepared from aniline according to the
published procedure [16,17].
N
N
O
O
O P O
O-
The diamines 6a and b were obtained in five steps from
commercially available (hydroxymethyl) propane-1,3-diol.
Initially, the two hydroxyl groups of the (hydroxymethyl)-
1,3-diol were protected as acetonide 1, followed by either
benzylation or methylation with NaH and a suitable halide
at room temperature to provide 2. The acetonide group of 2
was removed by stirring with a catalytic amount of
PTSA$H2O in methanol. The dihydroxy compound 3 thus
obtained was converted into the corresponding diamine 6, as
shown in Scheme 5. The 2-alkoxy-1,3-diamines 10aed re-
quired for the preparation of 29aed were synthesized from
commercially available 1,3-diaminopropane-2-ol (7), as
shown in Scheme 6. The two amino groups of compound 7
were initially protected as carbamates by the reaction of di-
tert-butyldicarbonyldicarbonate in presence of triethlyamine
and DMAP, to yield the biscarbamate 8. Compound 8, upon
alkylation in a biphasic medium (H2O:Toluene) in the pres-
ence of the phase transfer catalyst Bu4NHSO4, provided
9aed, which upon hydrolysis with 4M HCl in THF yielded
10aed.
S
N
+
O
NH3
OH OH
O
1
Cl
Cl
N
N
H
N
H
H
R
2 R=H
3 R=OCH3
Compound 7 was again protected as bisbenzylcarbamate
11, followed by azide (13) substitution and SnCl2 mediated re-
duction to provide the corresponding amine 14. Compound 14
was dimethylated with an equimolar mixture of formaldehyde
and formic acid in water under reflux conditions to yield 15.
The BOC-protected compound 16 was also synthesized from
14 and di-tert-butyldicarbonyldicabonate at room temperature.
Compounds 15 and 16 were both debenzylated with 10% Pde
C in methanol under a hydrogen atmosphere to give 17 and 18,
respectively, as shown in Scheme 7.
Our effort to synthesize 2-allyloxypropane-1,3-diamine
(22) from the allylation of 8, through Scheme 6, provided
a very poor yield. This was then synthesized through an alter-
native route from commercially available 1,3-dibromopro-
pane-2-ol (19) in good yield, as shown in Scheme 8.
Compound 19 was transformed into the corresponding diazide
20, which upon allylation with allyl iodide in presence of
Fig. 1. Molecular superimposition of 1 and 2.
has provided interesting inhibitors of methionyl-tRNA
synthetase. In this respect, alkylphosphate, ester, amide,
hydroxamate, sulfamate, sulfamide, N-alkoxysulfamide, and
N-hydroxysulfamide were prepared as stable surrogates to
the linear chain acylphosphate [6], and deoxyribosyl surro-
gates of Met-AMP were also investigated [7]. In addition,
a high throughput screening followed by SAR studies provided
the quinoline derivative (2, IC50 ¼ 16 nM) as a competitive
inhibitor of S. aureus methionyl-tRNA synthetase [8e11]. A
very potent analogue of 2 has been reported and is in clinical
trials [12e14]. Recently, ethanolamine derivatives, a new class
of inhibitors of bacterial phenylalanyl-tRNA synthetase [15],
have been discovered by high throughput screening. Herein,
we report the synthesis and the methionyl-tRNA synthetase
inhibitory and antibacterial activities of a new series of 2-
substituted-4-quinolones (26a, b, 39aee, 32, 33, 36, 38).
The synthesized compounds were evaluated against strains
of S. aureus, Enterococcus faecium, and Enterococcus faecalis
for their antibacterial activities. The present work is an exten-
sion of our previous report [16] on the study of 3D pharmaco-
phoric superimposition and the synthesis of 1, 2, and 3
(IC50 ¼ 2.48 nM), [16] Fig. 1.
˚
CsOH$H2O, tetra n-butyl iodide and 4 A molecular sieves,
gave 21. The diazide groups of 21 were selectively reduced
to yield the diamine 22, Scheme 8, according to the procedure
for compound 13.
3. Results and discussion
3.1. Methionyl-tRNA synthetase enzyme assay
2. Chemistry
All of the synthesized compounds, 2, 26a, b, 29aee, 32,
33, 36, and 38, were evaluated for their in vitro inhibitory
activity against the S. aureus methionyl-tRNA synthetase
enzyme. The inhibitory properties of the compounds were de-
termined by measuring the decrease in the generation of the
aminoacyl product [35S]methionyl S. aureus-tRNAMet in the
presence of different chemical concentrations, as reported [7].
All of the synthesized compounds were less active than the
reference compound 2. A substitution of the hydroxymethyl
The target compounds 26a, b, 29aee, 32, 33, 36, 37 were
synthesized in two steps by amination of 2-chloro-4-(4-me-
thoxybenzyloxy)quinoline 23 with the 2-substituted 1,3-
diamines 6a, b, 10aed, 17, 18, 22 in the presence of K2CO3,
followed by the removal of the 4-methoxybenzyl group and
reductive alkylation of the resulting intermediates 25, 28, 31,
34, 35 with 3,4-dichlorobenzaldehyde (Schemes 1e4). The

Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
241
Scheme 1. Reagents and conditions: (i) 6a or 6b, K2CO3, DMSO, 100 ꢀC, 48 h, 24a, 44%, 24b, 45%; (ii) 20% TFAeDCM, 2 h, rt; (iii) 3,4-Cl2PhCHO, NaCNBH3,
MeONa, MeOH, 50 ꢀC, 26a, 52%, 26b, 54%.
Scheme 2. Reagents and conditions: (i) 10aed, or 22, K2CO3, DMSO, 100 ꢀC, 48 h (27a, R ¼ C2H5, 51%: 27b, R ¼ CHMe2, 47%: 27c, R ¼ Bn, 45%: 27d,
R ¼ COPh, 70%: 27e, R ¼ allyl, 53%); (ii) 20% TFAeDCM, 2 h, rt; (iii) 3,4-Cl2PhCHO, NaCNBH3, MeONa, MeOH, 6 h, 50 ꢀC (29a, R ¼ C2H5 50%: 29b,
R ¼ CHMe2, 52%: 29c, R ¼ Bn, 48%: 29d, R ¼ COPh, 47%: 29e, R ¼ allyl, 55%).
Scheme 3. Reagents and conditions: (i) 17, K2CO3, DMSO, 100 ꢀC, 44%; (ii) 20% TFAeDCM, 2 h, rt; (iii) 3,4-Cl2PhCHO, NaCNBH3, MeONa, MeOH, 52%; (iv)
3,4-Cl2PhCHO, NaCNBH3, AcOH, MeOH, 55%.
Scheme 4. Reagents and conditions: (i) 18, K2CO3, DMSO, 100 ꢀC, 46%; (ii) 10% PdeC, H2 (1 atm), MeOH, 1 h, rt; 100%; (iii) 3,4-Cl2PhCHO, NaCNBH3,
MeONa, MeOH, 54%; (iv) 20% TFAeDCM, 2h.

242
Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
Scheme 5. Reagents and conditions: (i) RX, NaH, THF, 6 h, rt, 2a, 90%; 2b, 92% (ii) PTSA.H2O, MeOH, 1 h, rt, 3a, 97%, 3b, 96%; (iii) MeSO2Cl, TEA, DCM,
1.5 h, 0ert, 4a, 94%, 4b, 94%; (iv) NaN3, DMF, 20 h, 80ꢀC, 5a, 98%, 5b, 98%;(v) Pd(OH)2, H2 (1 atm), MeOH, overnight, rt, 100%.
Scheme 6. Reagents and conditions: (i) (BOC)2O, TEA, DMAP, H2OeTHF (1:1), 14 h, rt, 94%; (ii) 9aec, RX, NaOH, Bu4NHSO4, PhCH3eH2O, 18 h, 100 ꢀC,
9d, C6H5COCl, pyridine: DCM (1:1), 6 h, rt (9a, R ¼ C2H5, 51%: 9b, R ¼ CHMe2, 47%: 9c, R ¼ Bn, 45%: 9d, R ¼ COPh, 70%); (iii) 4M HCleTHF, 4 h, rt
(9a, R ¼ C2H5 95%: 9b, R ¼ CHMe2, 94%: 9c, R ¼ Bn, 95%: 9d, R ¼ COPh, 93%).
Scheme 7. Reagents and conditions: (i) C6H5CH2OCOCl (CbzCl), NaOH, 12 h, 0ert, 80%; (ii) MeSO2Cl, TEA, DCM, 0ert, 90%; (iii) NaN3, DMF, 20 h, 100 ꢀC,
95% (iv) SnCl2, PhSH, TEA, 1 h, rt, 62%; (v) HCO2H, HCHO, H2O, 8 h, reflux, 80% (vi) (BOC)2O, C2H5OH, 6 h, rt, 96%; (vii) 10% PdeC, H2 (1 atm), MeOH,
2 h, rt, 17, 100%, 18, 100%.
ꢀ
˚
Scheme 8. Reagents and conditions: (i) NaN3, DMF, 24 h, 80 C, 90%; (ii) Allyl iodide, CsOH$H2O, TBAI, 4 A MS, CH3CN, 48 h, rt, 80%; (iii) SnCl2/PhSH/
TEA/1 h/rt, 66%.
group at the C-2 position of the linear chain yielded the w4-
fold less potent compound 26a. Its methyl derivative, 26b, was
slightly more active than 26a and around five times less potent
than compound 2. Thus, hydrogen bond donor and acceptor
substitutions at C-2 of the linear chain in 2 do not favor me-
thionyl-tRNA synthetase enzyme inhibitory activity.
Displacement of the oxygen atom while keeping the chain
length of the substituent the same as that of compound 26b re-
sulted in compound 29a, with a 2-fold decrease in activity as
compared to 26b and 10 times less potency than compound 2.
The isopropyl derivative 29b displayed a further decrease in
inhibitory properties. It was around 30-fold less potent than
compound 2. The allyloxy derivative 29e also showed less po-
tency, but was more active than the isopropoxy derivative. A
change of the alkyl substitution to an aryl group, such as in
29c, d, decreased the potency. Among these, 29c, an ether de-
rivative, displayed better activity than 29d, an ester derivative.
The difference in the inhibitory activity may be due to the
greater hydrophobicity of compound 29c. The synthesis of
more polar and basic derivatives, such as the amino and
substituted amino analogues 32, 33, 36 and 38, resulted in
a large decrease in the activity. Thus, oxygen analogues with

Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
243
small carbon chain lengths are favorable for the activity, and
amino or substituted amino group substitutions at the C-2
position in the linear chain of 2 are detrimental for the activity.
4. Conclusion
The S. aureus methionyl-tRNA enzyme inhibitory activity
data (Table 1) of the synthesized compounds suggest that substi-
tutions of the hydroxymethyl, alkoxy or aryloxy group at the C-2
position of compound 2 are not favorable for the activity. How-
ever, the antibacterial data presented in Table 2 indicate that the
alkoxy substitution at the C-2 position in the linear chain of the
parent compound 2 is not detrimental for the activity.
3.2. Antibacterial assay
Minimum inhibitory concentrations (MIC) of the synthe-
sized compounds shown in Table 2 were determined by the
microdilution method with MuellereHinton Broth (MH, Difco
Laboratories, Detroit, MI) for Staphylococci and Brain Heart
Infusion Broth (BHI, Difco) for Enterococci, according to
the Clinical and Laboratory Standards Institute (CLSI) [18].
Seven strains of S. aureus (ATCC25923, ATCC6538P,
ATCC10537, GIORGIO, Smith, SP-N2, and a methicillin re-
sistant clinical isolate MRSA K2007-6), one Staphylococcus
epidermidis strain (ATCC12228), two E. faecalis strains
(ATCC29212, ATCC19433), and one E. faecium strain
(ATCC10541) were used to determine the MICs of the com-
pounds, as shown in Table 2. The stock solutions of the test
compounds were diluted to give a serial, 2-fold series yielding
final chemical concentrations ranging from 64 to 0.06 mg/mL.
The MIC was defined as the lowest concentration of chemicals
that inhibited the development of visible bacterial growth after
an incubation for 16e18 h at 36 ꢀC. Mupirocin and amoxicil-
lin antibiotics were used as the reference compounds.
The synthesized molecules 2, 26a, b, 29aee, 32, 33, 36, 38
were screened against various strains of S. aureus and Entero-
cocci, as shown in Table 2. All of the tested compounds were
less potent than both mupirocin and amoxicillin in various
strains of S. aureus, but displayed significant inhibitory prop-
erties in strains of Enterococci. Compound 26a, a hydroxy
derivative, displayed low inhibitory activity in all strains of
S. aureus than both the references and compound 2, but was
more active against E. faecium than amoxicillin. Compound
26b, a methylated derivative of 26a, displayed interesting
inhibitory activity against the Enterococci strains and was
more potent than both the references and compound 2. It
showed 8-fold more inhibition in E. faecium (ATCC10541),
4-fold more in E. faecalis (ATCC19433) and 2-fold more in
E. faecalis (ATCC29212) than amoxicillin. Compound 26b
also displayed 128 times more inhibition against a strain of
E. faecalis (ATCC19433) and 64 times more against E. fae-
cium (ATCC10541) and E. faecalis (ATCC29212) than mupir-
ocin, but only 4-fold more inhibition than 2 in all of the strains
of Enterococci. The oxygen analogues of the synthesized com-
pounds 29aee showed interesting inhibition against Entero-
cocci. They displayed either similar or better activities
against the strains of E. faecium, but were less potent in
S. aureus. Among these compounds, benzyloxy and allyloxy
derivatives displayed the best inhibitory activities against the
strains of Enterococci. Thus, compounds with hydrophobic
substituents, such as methoxy (26b), benzyloxy (29c) and
allyloxy (29e), are favorable for antibacterial activity, while
molecules with polar, hydrophilic substituents, such as 26a,
32, 36 and 38, are not suitable for the inhibitory activity. A
certain level of lipophilicity may be required for the antibacte-
rial activities, for permeability of the bacterial membrane.
Table 1
In vitro inhibitory activity data of the synthesized compounds against Staphy-
lococcus aureus methionyl-tRNA synthetase
Compound Structure
IC50a(nM)
O
2
3.4 (ꢁ0.4)
Cl
Cl
N
H
N
H
N
H
O
26a
26b
29a
11.9(ꢁ1.6)
15.0(ꢁ1.3)
30.3(ꢁ3.8)
Cl
Cl
N
H
N
H
N
H
OH
O
Cl
Cl
N
H
N
H
N
H
OMe
O
Cl
Cl
N
H
N
H
N
H
OEt
O
29b
91.0(ꢁ7.8)
Cl
Cl
N
H
N
H
N
H
OCH(CH3)2
O
29c
29d
29e
24.7(ꢁ0.8)
69.4(ꢁ5.8)
29.4(ꢁ1.6)
Cl
Cl
N
H
N
H
N
H
OBn
O
Cl
Cl
N
H
N
H
N
H
OCOPh
O
Cl
Cl
N
H
N
H
N
H
O
(continued on next page)

244
Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
Table 1 (continued)
a PerkineElmer 1710 Series FTIR. Mass spectra were re-
corded on a VG Trio-2 GCeMS.
Compound Structure
IC50a(nM)
O
5.1.1. (2,2-Dimethyl-[1,3]-dioxan-5-yl)methanol (1)
2,2-Dimethoxypropane (3.25 mL, 26.45 mmol) was added
to a stirred suspension of 2-(hydroxymethyl)propane-1,3-diol
(2.5 g, 22.8 mmol) and p-toluenesulfonic acid monohydrate
(140 mg, 0.73 mmol) in THF (30 mL). The resultant mixture
was stirred for 2.5 h at room temperature. The reaction mix-
ture was neutralized with NaHCO3 and evaporated under
reduced pressure. The crude product thus obtained was puri-
fied by silica gel column chromatography using CH2Cl2/
MeOH (20:1) as an eluent. Colorless oil; MS (FAB) 147
32
33
39.6(ꢁ4.8)
Cl
Cl
N
H
N
H
N
H
NMe2
O
131.2(ꢁ15.2)
Cl
N
H
N
H
N
NMe2
Cl 2
1
(MHþ); H NMR (CDCl3, 300 MHz) d 1.40 (s, 3H, CH3),
O
1.45 (s, 3H, CH3), 1.73 (s, 1H, OH), 1.79e1.90 (m, 1H,
CH), 3.74e3.81 (m, 4H, CH2), 4.0e4.05 (m, 2H, CH2).
36
102.8(ꢁ5.6)
136.9(ꢁ2.2)
N
H
N
H
N
H
NHBOC
Cl
5.1.2. 5-Benzyloxymethyl-2,2-dimethyl-[1,3]dioxane (2a)
To a mixture of 1 (1.46 g, 100 mmol) and NaH (0.36 g,
150 mmol) in THF was added benzyl bromide (3.42 g,
200 mmol) dropwise at room temperature, and the solution
was stirred for 6 h. The reaction mixture was poured into water
and extracted with ethyl acetate (20 mL ꢂ 3). The ethyl ace-
tate layers were washed with water, dried over Na2SO4 and
evaporated under reduced pressure. The crude product was pu-
rified by silica gel column chromatography using CH2Cl2/
MeOH (100:1) as an eluent. Colorless oil; MS (FAB) 237
Cl
O
38
Cl
N
H
N
H
N
H
.2TFA
NH2
Cl
a
Values represent means of the three experiments.
5. Experimental
1
(MHþ); H NMR (CDCl3, 300 MHz) d 1.40 (s, 3H, CH3),
1.43 (s, 3H, CH3), 1.96e2.07 (m, 1H, CH), 3.52 (d,
J ¼ 6.7 Hz, 2H, CH2), 3.72e3.80 (m, 2H, CH2), 3.95e4.05
(m, 2H, CH2), 4.5 (s, 2H, CH2), 7.28e7.37 (m, 5H, ArH).
5.1. Chemistry
All of the chemical reagents used were either synthesized
or commercially available. Melting points were determined
on a Melting Point Buchi B-540 apparatus, and are uncor-
¨
5.1.3. 5-Methoxymethyl-2,2-dimethyl-[1,3]dioxane (2b)
rected. Silica gel column chromatography was performed
with 230e400 nm mesh, from Merck. Proton NMR spectra
were recorded on a JEOL JNM-LA 300 at 300 MHz. Chemical
shifts are reported in ppm units with Me4Si as an internal
reference standard. Infrared spectra were recorded on
To a mixture of 1 (1.46 g, 100 mmol) and NaH (0.36 g,
150 mmol) in THF was added methyl iodide (4.26 g,
300 mmol) dropwise at room temperature, and the solution
was stirred for 6 h. The workup and purification of the reaction
mixture were the same as those for compound 2a. Colorless
Table 2
In vitro minimum inhibitory concentration (MIC)a,b of the synthesized compounds against the strain of Staphylococcus aureus, Enterococcus faecium, Enterococ-
cus faecalis
Strains
Mup/amox
2
26a
26b
29a
29b
29c
29d
29e
32
33
36
38
S. aureus ATCC25923
S. aureus ATCC6538P
S. aureus ATCC10537
S. aureus GIORGIO
S. aureus Smith
S. aureus SP-N2
0.25/0.25
0.125/0.5
0.125/0.25
0.125/0.25
0.125/0.25
0.25/>64
0.125/2
0.25/>64
8/1
16
4
64
16
32
64
32
16
16
16
2
16
4
16
8
16
16
16
32
16
16
16
8
4
64
32
64
32
32
32
16
32
8
8
8
>64
>64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
32
32
32
32
32
32
32
32
8
64
64
64
64
64
64
32
64
16
64
64
4
16
32
16
8
8
16
16
16
16
8
4
16
16
8
16
8
4
>64
64
4
8
4
8
64
32
Staphylococcus epidermidis ATCC12228
MRSA KS2007-6
E. faecium ATCC10541
E. faecalis ATCC19433
E. faecalis ATCC29212
8
4
2
4
8
0.5
4
0.125
8
2
4
64
1
2
0.5
2
1
8
16
64/1
64/2
2
2
8
0.5
0.5
4
4
16
16
2
32
32
8
4
4
2
2
16
Mup ¼ Mupirocin; amox ¼ Amoxicillin.
a
Indicates MIC values in mM/mL.
Values represent are means of the three experiments.
b

Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
245
1
oil; MS (FAB) 161 (MHþ); 1H NMR (CDCl3, 300 MHz)
d 1.31 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.81e1.93 (m, 1H,
CH), 3.24 (s, 3H, OCH3), 3.33 (d, J ¼ 6.7 Hz, 2H, CH2),
3.62e3.68 (m, 2H, CH2), 3.83e3.89 (m, 2H, CH2).
an eluent. Colorless viscous oil; MS (FAB) 247 (MHþ); H
NMR (CDCl3, 300 MHz) d 2.04e2.15 (m, 1H, CH), 3.37e
3.48 (m, 6H, CH2), 4.50 (s, 2H, CH2), 7.29e7.39 (m, 5H, PhH).
5.1.7.1. 1,3-Diazido-2-methoxymethylpropane (5b). A mixture
of 4b (2.0 g, 7.24 mmol) and sodium azide (2.95 g,
57.97 mmol) was stirred in dry DMF at 80 ꢀC for 20 h. The re-
action mixture was cooled to room temperature, diluted with
water and extracted with ethyl acetate (20 mL ꢂ 2). The ethyl
acetate layer was washed with water, dried over Na2SO4 and
evaporated under vacuum. The oily product was purified by
silica gel column chromatography using hexane/CH2Cl2
(9:1) as an eluent. Colorless viscous oil; MS (FAB) 171
5.1.4. 2-Benzyloxymethylpropane-1,3-diol (3a)
Compound 3awas obtained by stirring a mixture of 2a (2.8 g,
11.86 mmol) and p-toluenesulfonic acid monohydrate (0.22 g,
1.17 mmol) in methanol (15 mL) for 1 h at room temperature.
The reaction mixture was neutralized with triethylamine, evap-
orated and purified by silica gel column chromatography using
CH2Cl2/MeOH (9:1) as an eluent. Colorless oil; IR (Neat) n
1
3390 cmꢃ1 (OH); MS (FAB) 197 (MHþ); H NMR (CDCl3,
1
300 MHz) d 1.98e2.02 (m, 1H, CH), 2.52 (br s, 2H, OH),
3.62 (d, J ¼ 5.6 Hz, 2H, CH2), 3.80 (d, J ¼ 5.6 Hz, 4H, CH2),
4.5 (s, 2H, CH2), 7.26e7.37 (m, 5H, PhH).
(MHþ); H NMR (CDCl3, 300 MHz) d 2.00e2.12 (m, 1H,
CH), 3.34 (s, 3H, OCH3), 3.37e3.46 (m, 6H, CH2).
5.1.8. 3-Amino-2-aminomethylpropan-1-ol (6a)
5.1.5. 2-Methoxymethylpropane-1,3-diol (3b)
This was obtained by stirring a mixture of 5a (0.8 g mmol)
and 10% Pd(OH)2 (80 mg), under a hydrogen atmosphere in
methanol at room temperature for 20 h. The reaction mixture
was filtered through celite powder and evaporated under vac-
uum. The product thus obtained was directly used for the
next reaction without purification.
A mixture of 2b (2.5 g, 15.62 mmol) and i-toluenesulfonic
acid monohydrate (0.3 g, 1.56 mmol) was stirred in methanol
for 1 h at room temperature. The product was isolated as com-
pound 3a. Colorless oil; IR (Neat) n 3400 cmꢃ1 (OH); MS
1
(FAB) 121 (MHþ); H NMR (CD3OD, 300 MHz) d 1.83e
1.95 (m, 1H, CH), 2.36 (s, 2H, OH), 3.32 (s, 3H, OCH3),
3.43 (d, J ¼ 5.6 Hz, 2H, CH2), 3.63 (d, J ¼ 5.6 Hz, 4H, CH2).
5.1.8.1. 2-Methoxymethylpropane-1,3-diamine (6b). This was
obtained from the reduction of the diazide 5b, using the pro-
cedure for compound 6a. Compound 6b was used as such
without purification.
5.1.6. Methanesulfonic acid 2-benzyloxymethyl-3-
methanesulfonyloxypropyl ester (4a)
To a mixture of 3a (2.0 g, 10.20 mmol) and triethylamine
(6.0 mL, 42.85 mmol) in dichloromethane (15 mL) was added
methanesulfonic acid (2.56 g, 22.44 mmol) dropwise at 0 ꢀC.
The reaction mixture was allowed to warm to room tempera-
ture and was stirred for 1.5 h, poured into water and extracted
with dichloromethane (20 mL ꢂ 2). The dichloromethane
layer was washed with water, dried over Na2SO4 and evapo-
rated under reduced pressure. The crude product was purified
by silica gel column chromatography using CH2Cl2/MeOH
5.1.9. (3-tert-Butoxycarbonylamino-2-
hydroxypropyl)-carbamic acid tert-butyl ester (8)
Di-tert-butyldicarbonate (45.92 g, 210.64 mmol) was added
in portions to a stirred solution of 7 (8.0 g, 88.89 mmol), trie-
thylamine (25 mL, 177.8 mmol) and DMAP (2.4 g, 20 mmol)
in THF/H2O (1:1300 mL). The resulting reaction mixture was
stirred at room temperature overnight, acidified with 1 M HCl
to pH 2 and extracted with ethyl acetate. The ethyl acetate ex-
tract was dried over Na2SO4 and evaporated under reduced
pressure to yield the desired product. White solid; H NMR
(CDCl3, 300 MHz) d 1.44 (s, 18H, BOC), 3.11e3.28 (m,
4H, CH2), 3.70e3.78 (m, 1H, CH), 5.14 (br s, 2H, NH).
1
(99:1) as an eluent. Colorless oil; MS (FAB) 353 (MHþ); H
1
NMR (CDCl3, 300 MHz) d 2.41e2.58 (m, 1H, CH), 3.01 (s,
6H, SO2Me), 3.56 (d, J ¼ 5.8 Hz, 2H, CH2), 4.27e4.38 (m,
4H, CH2), 4.51 (s, 2H, CH2), 7.24e7.39 (m, 5H, PhH).
5.1.6.1. Methanesulfonic acid 3-methanesulfonyloxy-2-methox-
5.1.10. (3-tert-Butoxycarbonylamino-2-O-
ymethylpropyl ester (4b). Compound 4b was prepared exactly
substituted propyl)-carbamic acid tert-butyl ester (9aed):
general procedure
1
as compound 4a. Colorless oil; MS (FAB) 277 (MHþ); H
NMR (CDCl3, 300 MHz) d 2.43e2.55 (m, 1H, CH), 3.05 (s,
6H, SO2Me), 3.35 (s, 3H, OCH3), 3.46 (d, J ¼ 6.0 Hz, 2H,
CH2), 4.25e4.37 (m, 4H, CH2).
To a stirred solution of 8 (4.0 g, 13.8 mmol) and ethyl io-
dide (3.34 mL, 41.4 mmol) in toluene (15 mL) was added
NaOH (50% aq, 15 mL) followed by Bu4NHSO4 (0.88 g,
2.6 mmol) at room temperature. The reaction mixture was
stirred at 100 ꢀC for 18 h, diluted with water and extracted
with ethyl acetate. The organic extract was washed with brine
and with water, and was evaporated under vacuum. The resi-
due thus obtained was purified by silica gel column chroma-
tography using hexane/EtOAc (4:1) as an eluent.
5.1.7. 1,3-Diazido-2-benzyloxymethylpropane (5a)
A mixture of 4a (2.0 g, 5.68 mmol) and sodium azide (2.95 g,
45.45 mmol) was stirred in dry DMF at 80 ꢀC for 20 h. The re-
action mixture was cooled to room temperature, diluted with
water and extracted with ethyl acetate (20 mL ꢂ 2). The ethyl
acetate layer was washed with water, dried over Na2SO4 and
evaporated under vacuum. The oily product was purified by sil-
ica gel column chromatography using hexane/CH2Cl2 (9:1) as
5.1.10.1. (3-tert-Butoxycarbonylamino-2-ethoxypropyl)-carba-
mic acid tert-butyl ester (9a). White solid; MS (FAB) 319

246
Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
(MHþ); 1H NMR (CDCl3, 300 MHz) d 1.19 (t, J ¼ 6.7 Hz, 3H,
CH3), 1.44 (s, 18H, BOC), 3.04e3.08 (m, 2H, CH2), 3.34e
3.42 (m, 3H, CH, CH2), 3.56 (q, J ¼ 6.7 Hz, 2H, CH2), 5.02
(br s, 2H, NH).
(Na2SO4) and evaporated under reduced pressure to yield the
desired product in pure form. White solid; MS (FAB) 437
1
(MHþ); H NMR (CDCl3, 300 MHz) d 3.03 (s, 3H, SO2Me),
3.37e3.52 (m, 4H, CH2), 4.58e4.68 (m, 1H, CH), 5.09 (s,
4H, CH2), 5.52 (br s, 2H, NH), 7.30e7.33 (m, 10H, PhH).
5.1.10.2. (3-tert-Butoxycarbonylamino-2-isopropoxypropyl)-
carbamic acid tert-butyl ester (9b). White solid; MS (FAB)
334 (MHþ); 1H NMR (CDCl3, 300 MHz) d 1.15 (d,
J ¼ 6.0 Hz, 6H, CH3), 1.44 (s, 18H, BOC), 2.99e3.04 (m,
2H, CH2), 3.29e3.40 (m, 2H, CH2), 3.47e3.50 (m, 1H,
CH), 3.70e3.74 (m, 1H, CH), 5.02 (br s, 2H, NH).
5.1.14. (2-Azido-3-benzyloxycarbonyl-
aminopropyl)-carbamic acid benzyl ester (13)
A mixture of 12 (4.0 g, 9.17 mmol) and sodium azide
(2.38 g, 36.7 mmol) in DMF (30 mL) was stirred at 100 ꢀC
for 20 h. The reaction mixture was cooled to room temperature,
diluted with water and extracted with ethyl acetate
(20 mL ꢂ 2). The ethyl acetate layer was washed with water,
dried (Na2SO4) and evaporated under reduced pressure to
give the desired compound. White solid; MS (FAB) 384
5.1.10.3. (2-Benzyloxy-3-tert-butoxycarbonylaminopropyl)-
carbamic acid tert-butyl ester (9c). White solid; MS (FAB)
381 (MHþ); 1H NMR (CDCl3, 300 MHz) d 1.43 (s, 18H,
BOC), 3.10e3.15 (m, 2H, CH2), 3.39e3.50 (m, 2H, CH2),
3.53e3.55 (m, 1H, CH), 4.59 (s, 2H, CH2), 5.01 (br s, 2H,
NH), 7.29e7.34 (m, 5H, PhH).
1
(MHþ); H NMR (CDCl3, 300 MHz) d 3.15e3.24 (m, 2H,
CH2), 3.36e3.42 (m, 2H, CH2), 3.64e3.66 (m, 1H, CH), 5.09
(s, 4H, CH2), 5.42 (br s, 2H, NH), 7.33e7.34 (m, 10H, PhH).
5.1.15. (2-Amino-3-benzyloxycarbonyl-
5.1.10.4. Benzoic acid 2-tert-butoxycarbonylamino-1-(tert-bu-
aminopropyl)-carbamic acid benzyl ester (14)
toxycarbonylaminomethyl)-ethyl ester (9d). White solid; MS
1
(FAB) 395 (MHþ); H NMR (CDCl3, 300 MHz) d 1.37 (s,
To a suspension of SnCl2 (1.11 g, 5.87 mmol) in acetoni-
trile (10 mL) at room temperature was added thiophenol
(2.4 mL, 23.49 mmol) followed by triethylamine (2.47 mL,
17.62 mmol). To the reaction mixture, a solution of 13
(1.5 g, 3.91 mmol) in acetonitrile (10 mL) was added slowly
at room temperature, and the mixture was stirred for 1 h and
evaporated under reduced pressure. The residue was purified
by basic alumina column chromatography using a CH2Cl2/
MeOH/NH3 solution (90:10:1) as an eluent. White solid; MS
18H, BOC), 3.40e3.43 (m, 4H, CH2), 5.01e5.02 (m, 1H,
CH), 5.01 (br s, 2H, NH), 7.35e7.40 (m, 2H, PhH), 7.49e
7.53 (m, 1H, PhH), 7.94e8.01 (m, 2H, PhH).
5.1.11. 2-Alkoxy-, 2-benzyloxypropane-1,
3-diamine (10aed)
Compound 9a (800 mg) was stirred in 4 M HCl (30 mL) in
THF at room temperature for 4 h. The precipitate thus formed
was filtered and washed with ether to give compound 10a as
a white solid. Similarly, compounds 10bed were obtained
from their corresponding protected derivatives 9bed. The
compounds 10aed were used as such for the next stage of
reactions.
1
(FAB) 358 (MHþ); H NMR (CD3OD, 300 MHz) d 2.84e
2.93 (m, 1H, CH), 3.03e3.19 (m, 4H, CH2), 5.06 (s, 4H,
CH2), 7.33e7.34 (m, 10H, PhH).
5.1.16. (3-Benzyloxycarbonylamino-2-dimethyl-
aminopropyl)-carbamic acid benzyl ester (15)
To an ice-cold suspension of 14 (1.6 g, 4.48 mmol) in water
(5 mL), formaldehyde (0.67 mL, 8.96 mmol, 40% aq solution)
followed by formic acid (0.41 g, 8.96 mmol) were added with
stirring. The reaction mixture was heated under reflux for 8 h,
neutralized with a 2 M NaOH solution and extracted with di-
chloromethane (20 mL ꢂ 2). The dichloromethane extract was
dried under vacuum and the residue was purified by silica gel
column chromatography using CH2Cl2/MeOH (19:1) as an el-
5.1.12. (3-Benzyloxycarbonylamino-2-
hydroxypropyl)-carbamic acid benzyl ester (11)
Benzyl chloroformate (75 g, 440 mmol) was added to
a stirred solution of 7 (18.0 g, 200 mmol) in 1 N NaOH
(300 mL) at 0 ꢀC, and the mixture was stirred for 12 h at
room temperature. The solid product thus formed was filtered,
washed with water and crystallized from a mixture of hexane/
EtOA (1:1). White solid; MS (FAB) 358 (MHþ); H NMR
1
1
uent. White solid; MS (FAB) 386 (MHþ); H NMR (CD3OD,
(CDCl3, 300 MHz) d 3.25e3.27 (m, 4H, CH2), 3.80e3.81
(m, 1H, CH), 5.10 (s, 4H, CH2), 5.52 (br s, 2H, NH), 7.30e
7.31 (m, 10H, PhH).
300 MHz) d 2.31 (s, 6H, CH3), 2.61e2.67 (m, 1H, CH), 3.11e
3.29 (m, 4H, CH2), 5.06 (s, 4H, CH2), 7.24e7.33 (m, 10H,
PhH).
5.1.13. Methanesulfonic acid 2-benzyloxycarbonylamino-1-
(benzyloxycarbonylaminomethyl)-ethyl ester (12)
5.1.17. [2-Benzyloxycarbonylamino-1-(benzyloxycarbonyl-
aminomethyl)-ethyl]-carbamic acid i-butyl ester (16)
Methanesulfonyl choride (3.7 g, 32.4 mmol) was added
dropwise to a suspension of 11 (10.5 g, 29.3 mmol) and trie-
thylamine (6.9 mL, 48.9 mmol) in dichloromethane (200 mL)
at 0 ꢀC. The resultant reaction mixture was allowed to warm
to room temperature and was stirred for 1 h. Water was added
and the organic phase was separated, washed with water, dried
A mixture of 14 (2.34 g, 6.55 mmol) and di-tert-butyldicar-
bonate (1.70 g, 7.8 mmol) in ethanol (20 mL) was stirred at
room temperature for 6 h. The solvent was evaporated and
the residue was purified by silica gel column chromatography,
using CH2Cl2/MeOH (99:1) as an eluent. White solid; MS
1
(FAB) 458 (MHþ); H NMR (CD3OD, 300 MHz) d 1.40 (s,

Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
247
9H, BOC), 2.96e3.26 (m, 4H, CH), 3.68e3.72 (m, 1H, CH),
5.06 (s, 4H, CH2), 7.23e7.32 (m, 10H, PhH).
5.1.22. 4-Aryl-2-substituted aminoquinoline (24a, b, 27aee,
30, 34): general procedure
A mixture of 23 (228 mg, 0.76 mmol) and 6a (400 mg,
3.84 mmol) in DMSO (15 mL) was stirred in the presence
of K2CO3 (210 mg, 1.52 mmol) at 100e110 ꢀC for 48 h.
The reaction mixture was diluted with water at room temper-
ature and extracted with ethyl acetate (20 mL ꢂ 2). The ethyl
acetate extract was washed with water, dried over Na2SO4
and evaporated under reduced pressure. The residue was pu-
rified by silica gel column chromatography with a CH2Cl2/
MeOH/NH3 solution (90:10:1) as an eluent. Similarly, com-
pounds 24b, 27aee, 30 and 34 were prepared from the reac-
tions of diamines 6b, 10aed & 22, 17 and 18 with 23,
respectively.
5.1.18. N,N-Dimethylpropane-1,2,3-triamine (17)
This was obtained by stirring 15 (1.0 g) with 10% PdeC
(100 mg) under a hydrogen atmosphere in methanol at room
temperature for 2 h. The reaction mixture was filtered through
celite powder and evaporated under reduced pressure to give
the desired product in a quantitative yield. Similarly, com-
pound 18 was obtained from debenzylation of 16. Both com-
pounds 17 and 18 were used directly for the next reaction
without purification.
5.1.19. 1,3-Diazidopropan-2-ol (20)
5.1.22.1. 2-Aminomethyl-3-[4-(4-methoxybenzyloxy)-quinolin-
A mixture of 19 (10.85 g, 50.0 mmol) and sodium azide
(9.75 g, 150.0 mmol) in DMF was heated at 80 ꢀC for 24 h.
The reaction mixture was allowed to cool to room tempera-
ture, diluted with water and extracted with ethyl acetate
(25 mL ꢂ 3). The organic layer was collected, washed with
water and dried under vacuum. The residue thus obtained
was purified by silica gel column chromatography using hex-
ane/EtOAc (9:1) as an eluent. Colorless oil; MS (FAB) 143
2-ylamino]-propan-1-ol (24a). White solid; MS (FAB) 368
1
(MHþ); H NMR (CD3OD, 300 MHz) d 1.81e1.89 (m, 1H,
CH), 2.64e2.78 (m, 2H, CH2), 3.49e3.64 (m, 4H, CH2),
3.80 (s, 3H, OCH3), 5.14 (s, 2H, CH2), 6.23 (s, 1H, ArH),
6.95 (d, J ¼ 8.76 Hz, 2H, ArH), 7.09e7.16 (m, 1H,
ArH), 7.41 (d, J ¼ 8.76 Hz, 2H, ArH), 7.46e7.49 (m, 2H,
ArH), 7.90 (d, J ¼ 8.10 Hz, 1H, ArH).
1
(MHþ); H NMR (CDCl3, 300 MHz) d 3.36e3.37 (m, 4H,
5.1.22.2. N1-[4-(4-Methoxybenzyloxy)-quinolin-2-yl]-2-meth-
CH), 3.66e3.68 (m, 1H, CH).
oxymethylpropane-1,3-diamine (24b). White solid; MS
1
(FAB) 382 (MHþ); H NMR (CD3OD, 300 MHz) d 1.99e
2.07 (m, 1H, CH), 2.65e2.78 (m, 2H, CH2), 3.36 (s, 3H,
OCH3), 3.42e3.63 (m, 4H, CH2), 3.80 (s, 3H, OCH3), 5.15
(s, 2H, CH2), 6.26 (s, 1H, ArH), 6.95 (d, J ¼ 8.76 Hz, 2H,
ArH), 7.09e7.14 (m, 1H, ArH), 7.42 (d, J ¼ 8.76 Hz, 2H,
ArH), 7.46e7.49 (m, 2H, ArH), 7.90 (d, J ¼ 8.10 Hz, 1H,
ArH).
5.1.20. 3-(2-Azido-1-azidomethylethoxy)-propene (21)
˚
A mixture of 20 (5.0 g, 35.2 mmol), 4 A molecular sieves
(20 g) and CsOH$H2O (11.8 g, 70.4 mmol) in acetonitrile
(30 mL) was stirred at room temperature for 20 min under a ni-
trogen atmosphere. Tetra-n-butylammonium iodide (12.98 g,
35.2 mmol) and allyl iodide (9.58 mL, 105.6 mmol) were
added sequentially, and the resultant mixture was stirred for
48 h at room temperature. The molecular sieves were filtered
and the solvent was evaporated under reduced pressure. The
crude product was purified by silica gel column chromatogra-
phy using hexane/EtOAc (19:1) as an eluent. Colorless oil;
MS (FAB) 183 (MHþ); 1H NMR (CDCl3, 300 MHz)
d 3.37e3.39 (m, 4H, CH), 3.68e3.69 (m, 1H, CH), 4.13e
4.15 (m, 2H, allyl), 5.21e5.36 (m, 2H, allyl), 5.87e6.00 (m,
1H, allyl).
5.1.23. 2-Ethoxy-N1-[4-(4-methoxybenzyloxy)-
quinolin-2yl]-propane-1,3-diamine (27a)
White solid; MS (FAB) 382 (MHþ); 1H NMR (CDCl3,
300 MHz) d 1.21 (t, J ¼ 6.9 Hz, 3H, CH3), 2.78e2.94 (m,
2H, CH2), 3.45e3.74 (m, 4H, CH2), 3.80 (s, 3H, OCH3),
4.03e4.12 (m, 1H, CH), 5.15 (s, 2H, CH2), 6.29 (s, 1H,
ArH), 6.95 (d, J ¼ 8.76 Hz, 2H, ArH), 7.11e7.17 (m, 1H,
ArH), 7.42 (d, J ¼ 8.76 Hz, 2H, ArH), 7.47e7.53 (m,
2H, ArH), 7.92 (d, J ¼ 8.10 Hz, 1H, ArH).
5.1.21. 2-Allyloxypropane-1,3-diamine (22)
5.1.23.1. 2-Isopropoxy-N1-[4-(4-methoxybenzyloxy)-quinolin-
To a suspension of SnCl2 (5.67 g, 30.0 mmol) in acetoni-
trile (30 mL) at room temperature was added thiophenol
(12.3 mL, 120 mmol) followed by triethylamine (12.6 mL,
90.12 mmol). To the reaction mixture, a solution of 21
(1.82 g, 10.0 mmol) in acetonitrile (20 mL) was added slowly
at room temperature. The mixture was stirred for 1 h and evap-
orated under reduced pressure. The residue was purified by ba-
sic alumina column chromatography using a CH2Cl2/MeOH/
2yl]-propane-1,3-diamine (27b). White solid; MS (FAB) 396
1
(MHþ); H NMR (CD3OD, 300 MHz) d 1.18 (d, J ¼ 6.0 Hz,
6H, CH3), 2.72e2.80 (m, 2H, CH2), 3.42e3.75 (m, 3H, CH,
CH2), 3.80 (s, 3H, OCH3), 3.84e3.88 (m, 1H, CH), 5.14 (s,
2H, CH2), 6.26 (s, 1H, ArH), 6.95 (d, J ¼ 8.76 Hz, 2H,
ArH), 7.09e7.15 (m, 1H, ArH), 7.41 (d, J ¼ 8.76 Hz,
2H, ArH), 7.45e7.51 (m, 2H, ArH), 7.93 (d, J ¼ 8.10 Hz,
1H, ArH).
1
NH3 solution (90:10:1) as an eluent. White solid; H NMR
(CD3OD, 300 MHz) d 2.73e2.88 (m, 4H, CH2), 3.40e3.47
(m, 1H, CH), 4.02e4.10 (m, 2H, allyl), 5.13e5.34 (m, 2H,
allyl), 5.89e6.01 (m, 1H, allyl).
5.1.23.2. 2-Benzyloxy-N1-[4-(4-methoxybenzyloxy)-quinolin-
2yl]-propane-1,3-diamine (27c). White solid; MS (FAB) 444
1
(MHþ); H NMR (CD3OD, 300 MHz) d 2.68e2.80 (m, 2H,

248
Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
CH2), 3.60e3.61 (m, 3H, CH2), 3.76 (s, 3H, OCH3), 4.58e
4.68 (m, 2H, CH2), 5.07 (s, 2H, CH2), 6.21 (s, 1H, ArH),
6.92 (d, J ¼ 8.76 Hz, 2H, ArH), 7.20e7.38 (m, 8H, ArH),
7.42e7.46 (m, 1H, ArH), 7.50e7.51 (m, 1H, ArH), 7.87 (d,
J ¼ 8.10 Hz, 1H, ArH).
5.1.25. 2-[3-(3,4-Dichlorobenzylamino)-2-
substituted-propylamino]-1H-quinolin-4-one
(26a, 26b, 29aee, 32, 32, 36, 37): general procedure
To a stirred solution of 25a (100 mg, 0.40 mmol) in meth-
anol (5 mL) was added a 0.5 M methanolic solution of
MeONa (1 mL, 0.43 mmol). Additional amounts of the
0.5 M MeONa solution were added to maintain a pH of 12
for the reaction mixture, which was stirred for 10 min
at room temperature. 3,4-Dichlorobenzaldehyde (70 mg,
0.40 mmol) was added, and the resultant reaction mixture
was stirred at 50 ꢀC for 1 h. To this NaCNBH3 (38 mg,
0.60 mmol) in methanol (2 mL) was added dropwise, and
the stirring was continued for an additional 6 h. The solvent
was evaporated under reduced pressure, and the residue thus
obtained was purified by silica gel column chromatography us-
ing a CH2Cl2/MeOH/NH3 solution (95:5:1) as an eluent.
5.1.23.3. Benzoic acid 1-aminomethyl-2-[4-(4-methoxybenzy-
loxy)-quinolin-2ylamino]-ethyl ester (29d). White solid; MS
(FAB) 458 (MHþ); 1H NMR (CDCl3, 300 MHz) d 3.45e
3.64 (m, 2H, CH2), 3.75e3.80 (m, 2H, CH2), 3.82 (s, 3H,
OCH3), 4.00e4.01 (m, 1H, CH), 5.01 (s, 2H, CH2), 6.05 (s,
1H, ArH), 6.92 (d, J ¼ 6.2 Hz, 2H, ArH), 7.15e7.22 (m, 1H,
ArH), 7.33e7.56 (m, 7H, ArH), 7.78 (d, J ¼ 6.2 Hz, 2H,
ArH), 7.87 (d, J ¼ 8.10 Hz, 1H, ArH).
5.1.23.4.
2-Allyloxy-N1-[4-(4-methoxybenzyloxy)-quinolin-
2yl]-propane-1,3-diamine (27e). White solid; MS (FAB) 394
1
(MHþ); H NMR (CDCl3, 300 MHz) d 2.80e2.87 (m, 2H,
5.1.25.1.
2-[3-(3,4-Dichlorobenzylamino)-2-hydroxymethyl-
CH2), 3.42e3.73 (m, 3H, CH, CH2), 3.80 (s, 3H, OCH3),
4.12e4.14 (m, 2H, allyl), 5.12 (s, 2H, CH2), 5.18e5.34 (m,
2H, CH2, allyl), 5.89e6.00 (m, 1H, CH, allyl), 6.02 (s, 1H,
ArH), 6.95 (d, J ¼ 8.76 Hz, 2H, ArH), 7.13e7.20 (m, 1H,
ArH), 7.40 (d, J ¼ 8.76 Hz, 2H, ArH), 7.47e7.53 (m,
1H, ArH), 7.58e7.61 (m, 1H, ArH), 7.92 (d, J ¼ 8.10 Hz,
1H, ArH).
propylamino]-1H-quinolin-4-one (26a). White solid; mp
222e224 ꢀC; IR (KBr) n 3560 cme1 (OH); MS (FAB) 407
1
(MHþ); H NMR (CD3OD, 300 MHz) d 2.26e2.33 (m, 1H,
CH), 3.02e3.12 (m, 2H, CH2), 3.33e3.45 (m, 2H, CH2),
3.67e3.80 (m, 2H, CH2), 4.06e4.19 (m, 2H, CH2), 5.67 (s,
1H, ArH), 7.24e7.28 (m, 1H, ArH), 7.34e7.39 (m, 2H,
ArH), 7.52e7.56 (m, 2H, ArH), 7.63e7.65 (m, 1H, ArH),
8.06 (d, J ¼ 8.10 Hz, 1H, ArH).
5.1.23.5. N1-[4-(4-Methoxybenzyloxy)-quinolin-2-yl]-N2,N2-di-
methylpropane-1,2,3-triamine (30). White solid; MS (FAB)
381 (MHþ); 1H NMR (CD3OD, 300 MHz) d 2.40 (s, 6H,
NCH3), 2.68e2.81 (m, 2H, CH2), 3.44e3.53 (m, 2H,
CH2), 3.80 (s, 3H, OCH3), 4.08e4.12 (m, 1H, CH), 5.16
(s, 2H, CH2), 6.26 (s, 1H, ArH), 6.95 (d, J ¼ 8.76 Hz, 2H,
ArH), 7.09e7.14 (m, 1H, ArH), 7.42 (d, J ¼ 8.76 Hz, 2H,
ArH), 7.47e7.54 (m, 2H, ArH), 7.92 (d, J ¼ 8.10 Hz, 1H,
ArH).
5.1.25.2. 2-[3-(3,4-Dichlorobenzylamino)-2-methoxymethyl-
propylamino]-1H-quinolin-4-one (26b). White solid; mp
168e170 ꢀC; MS (FAB) 421 (MHþ); 1H NMR (CD3OD,
300 MHz) d 2.05e2.13 (m, 1H, CH), 2.51e2.69 (m, 2H,
CH2), 3.35 (s, 3H, OCH3), 3.38e3.45 (m, 4H, CH2), 3.75 (s,
2H, CH2), 5.66 (s, 1H, ArH), 7.21e7.27 (m, 3H, ArH),
7.40e7.43 (m, 1H, ArH), 7.46e7.53 (m, 2H, ArH), 8.06 (d,
J ¼ 8.10 Hz, 1H, ArH).
5.1.23.6. {1-Aminomethyl-2-[4-(4-methoxybenzyloxy)-quino-
5.1.25.3.
2-[3-(3,4-Dichlorobenzylamino)-2-ethoxypropyla-
lin-2-ylamino]ethyl}-carbamic
acid
tert-butyl
ester
mino]-1H-quinolin-4-one (29a). White solid; mp 110e
112 ꢀC; MS (FAB) 421 (MHþ); 1H NMR (CD3OD,
300 MHz) d 1.19 (t, J ¼ 6.9 Hz, 3H, CH3), 2.74 (d,
J ¼ 5.50 Hz, 2H, CH2), 3.39e3.66 (m, 5H, CH, CH2), 3.77e
3.88 (m, 2H, CH2), 5.68 (s, 1H, ArH), 7.23e7.32 (m, 3H,
ArH), 7.43e7.46 (m, 1H, ArH), 7.50e7.56 (m, 2H, ArH),
8.06 (d, J ¼ 8.10 Hz, 1H, ArH).
(34). White solid; MS (FAB) 453 (MHþ); 1H NMR
(CD3OD, 300 MHz) d 1.40 (s, 9H, BOC), 2.64e2.78 (m,
2H, CH2), 3.56e3.58 (m, 2H, CH2), 3.69e3.76 (m, 1H,
CH), 3.80 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 6.29 (s, 1H,
ArH), 6.95 (d, J ¼ 8.76 Hz, 2H, ArH), 7.09e7.14 (m, 1H,
ArH), 7.42 (d, J ¼ 8.76 Hz, 2H, ArH), 7.47e7.54 (m, 2H,
ArH), 7.92 (d, J ¼ 8.10 Hz, 1H, ArH).
5.1.25.4. 2-[3-(3,4-Dichlorobenzylamino)-2-isopropoxy-propy-
lamino]-1H-quinolin-4-one (29b). White solid; mp 120e
122 ꢀC; MS (FAB) 435 (MHþ); 1H NMR (CD3OD,
300 MHz) d 1.18 (d, J ¼ 6.0 Hz, 6H, CH3), 2.72 (d,
J ¼ 5.3 Hz, 2H, CH2), 3.39e3.56 (m, 2H, CH), 3.75e3.89
(m, 4H, CH2), 5.72 (s, 1H, ArH), 7.27e7.36 (m, 3H, ArH),
7.46e7.49 (m, 1H, ArH), 7.54e7.59 (m, 2H, ArH), 8.13 (d,
J ¼ 8.10 Hz, 1H, ArH).
5.1.24. 3-(4-Oxo-1,4-dihydroquinolin-2-ylamino)-
2-substituted-propylammonium trifluoroacetate
(25a, b, 28aee, 31, 35): general procedure
The compounds 25a, b, 28aee, 31 were prepared from
TFA-catalyzed hydrolysis of their 4-methoxybenzyl-protected
derivatives, 24a, b, 27aee, and 30. Compound 35 was
obtained upon stirring with 10% PdeC in methanol under a hy-
drogen atmosphere at room temperature for 2 h. These com-
pounds were directly used for the next stage of the reaction
without purification or isolation.
5.1.25.5. 2-[2-Benzyloxy-3-(3,4-dichlorobenzylamino)-propy-
lamino]-1H-quinolin-4-one (29c). White solid; mp 138e
140 ꢀC; MS (FAB) 483 (MHþ); 1H NMR (CD3OD,

Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
249
300 MHz) d 2.72 (d, J ¼ 5.3 Hz, 2H, CH2), 3.42e3.55 (m, 2H,
CH), 3.69e3.76 (m, 3H, CH, CH2), 4.57 (s, 2H, CH2), 5.65 (s,
1H, ArH), 7.13e7.30 (m, 8H, ArH), 7.37e7.47 (m, 3H, ArH),
8.06 (d, J ¼ 8.10 Hz, 1H, ArH).
ArH), 7.27e7.62 (m, 8H, ArH), 8.02 (d, J ¼ 8.10 Hz, 1H,
ArH).
5.1.25.12. 2-[2-Amino-3-(3,4-dichlorobenzylamino)-propyla-
mino]-1H-quinolin-4-one tri(trifluoroacetic acid) (38). This
compound was obtained by incubating 37 (100 mg) in 20%
TFAeDCM at room temperature for 2 h. The settled precipi-
tate was filtered and washed with plain dichloromethane.
White solid; mp 158e160 ꢀC; MS (FAB) 392 (MHþ); 1H
NMR (CD3OD, 300 MHz) d 3.33e3.34 (m, 2H, CH2),
3.88e3.93 (m, 3H, CH, CH2), 4.20e4.22 (m, 2H, CH2),
6.48 (s, 1H, ArH), 7.41e7.56 (m, 3H, ArH), 7.70e7.76 (m,
3H, ArH), 8.02 (d, J ¼ 8.10 Hz, 1H, ArH).
5.1.25.6. Benzoic acid 1-[(3,4-dichlorobenzylamino)-methyl]-
2-(4-oxo-1,4-dihydroquinolin-2ylamino)-ethyl ester (29d).
White solid; mp 122e124 ꢀC; MS (FAB) 497 (MHþ); 1H
NMR (CD3OD, 300 MHz) d 3.31e3.33 (m, 2H, CH2),
3.51e3.53 (m, 2H, CH2), 3.80e3.89 (m, 2H, CH2),
4.20e4.25 (m, 1H, CH), 5.69 (s, 1H, ArH), 7.21e7.26
(m, 1H, ArH), 7.32e7.35 (m, 1H, ArH), 7.42e7.55 (m,
6H, ArH), 7.83e7.86 (m, 3H, ArH), 8.06 (d, J ¼ 8.10 Hz,
1H, ArH).
6. Biology
5.1.25.7. 2-[2-Allyloxy-3-(3,4-dichlorobenzylamino)-propyla-
mino]-1H-quinolin-4-one (29e). White solid; mp 33e135 ꢀC;
MS (FAB) 433 (MHþ); 1H NMR (CDCl3, 300 MHz)
d 2.55e2.68 (m, 2H, CH2), 3.25e3.40 (m, 2H, CH2), 3.48e
3.60 (m, 3H, CH, CH2), 3.85e4.05 (m, 2H, allyl), 4.97e
5.13 (m, 2H, CH2, allyl), 5.65 (s, 1H, ArH), 5.66e5.79 (m,
1H, CH, allyl), 6.93e6.98 (m, 2H, ArH), 7.05e7.10 (m, 1H,
ArH), 7.17e7.23 (m, 2H, ArH), 7.31e7.37 (m, 1H, ArH),
8.13 (d, J ¼ 8.10 Hz, 1H, ArH).
MICs were determined by a microdilution method with
MuellereHinton Broth (MH, Difco Laboratories, Detroit,
MI) for staphylococci and Brain Heart Infusion Broth (BHI,
Difco) for Enterococci, following the National Committee
for Clinical Laboratory Standards (NCCLS) (now called the
Clinical Laboratory Standards Institute [CLSI]) [18] Six S. au-
reus strains (ATCC25923, ATCC6538P, ATCC10537, GIOR-
GIO, SP-N2 and SMITH), one S. epidermidis strain
(ATCC12228), two E. faecalis strains (ATCC29212 and
ATCC19433) and one E. faecium strain (ATCC10541) were
used. The stock solutions of test compounds were diluted to
give a serial, 2-fold series, yielding final chemical concentra-
tions that ranged from 64 to 0.03 mg/mL. The MIC was defined
as the lowest concentration of the chemical that inhibited the
development of visible bacterial growth after an incubation
for 16 h at 36 ꢀC. The MICs of standard antibiotics (mupirocin
and amoxicillin) were determined by the same method.
5.1.25.8. 2-[3-(3,4-Dichlorobenzylamino)-2-dimethylamino-
propylamino]-1H-quinolin-4-one (3þ2). White solid; mp
110e112 ꢀC; MS (FAB) 420 (MH ); 1H NMR (CD3OD,
300 MHz) d 2.65 (s, 6H, NCH3), 3.33e3.36 (m, 1H, CH),
3.62e3.87 (m, 4H, CH2), 4.21 (s, 2H, CH2), 6.38 (s, 1H,
ArH), 7.40e7.55 (m, 3H, ArH), 7.70e7.79 (m, 3H, ArH),
8.11 (d, J ¼ 8.10 Hz, 1H, ArH).
5.1.25.9. 2-{3-[Bis-(3,4-dichlorobenzyl)-amino]-2-dimethyla-
mino-propylamino}-1H-quinolin-4-one (33). White solid; mp
88e90 ꢀC; MS (FAB) 579 (MHþ); 1H NMR (CD3OD,
300 MHz) d 2.90 (s, 6H, NCH3), 3.66e3.97 (m, 9H, CH),
6.32 (s, 1H, ArH), 7.26e7.29 (m, 2H, ArH), 7.42e7.51 (m,
5H, ArH), 7.74e7.81 (m, 2H, ArH), 8.16 (d, J ¼ 8.10 Hz,
1H, ArH).
Acknowledgement
This work was supported by a Grant (03-PJ2-PG4-BD02-
0001) from the Ministry of Health and Welfare, Republic of
Korea and by the Korea Science and Engineering Foundation
(KOSEF) grant funded by the Korean Government (MOST)
(R17-2007-020-01000-0).
5.1.25.10. [1-[(3,4-Dichlorobenzylamino)-methyl]-2-(4-oxo-
1,4-dihydroquinolin-2-ylamino)ethyl]-carbamic acid tert-butyl
ester (36). White solid; mp 202e204 ꢀC; MS (FAB) 492
References
1
(MHþ); H NMR (CD3OD, 300 MHz) d 1.44 (s, 9H, BOC),
2.63e2.75 (m, 2H, CH2), 3.34e3.42 (m, 2H, CH2), 3.74e
3.77 (m, 3H, CH, CH2), 5.65 (s, 1H, ArH), 7.11e7.27 (m,
2H, ArH), 7.33e7.40 (m, 2H, ArH), 7.48e7.54 (m, 2H,
ArH), 8.13 (d, J ¼ 8.10 Hz, 1H, ArH).
[1] M. Ibba, D. Soll, Annu. Rev. Biochem. 69 (2000) 617e650.
¨
[2] P. Schimmel, E. Schmidt, Trends Biochem. Sci. 20 (1995) 1e2.
[3] U.A. Ochsner, X. Sun, T. Jarvis, I. Critchley, N. Janjic, Expert Opin.
Investig. Drugs 16 (2007) 573e593.
[4] S.F. Ataide, M. Ibba, ACS Chem. Biol. 1 (2006) 285e297.
[5] J.G. Hurdle, A.J. O0Neill, I. Chopra, Antimicrob. Agents Chemother. 49
(2005) 4821e4833.
5.1.25.11. {1-[(3,4-Dichlorobenzylamino)-methyl]-2-[4-(4-me-
thoxybenzyloxy)-quinolin-2ylamino]ethyl}-carbamic acid tert-
butyl ester (37). White solid; mp 80e82 ꢀC; MS (FAB) 611
(MHþ); 1H NMR (CD3OD, 300 MHz) d 1.45 (s, 9H,
BOC), 2.91e2.93 (m, 2H, CH2), 3.59e3.65 (m, 2H, CH2),
3.81 (s, 3H, OCH3), 3.93e4.10 (m, 3H, CH, CH2), 5.28 (s,
2H, CH2), 6.43 (s, 1H, ArH), 6.98 (d, J ¼ 6.6 Hz, 2H,
[6] J. Lee, S.E. Kim, J.Y. Lee, S.Y. Kim, S.U. Kang, S.H. Seo, M.W. Chun,
T. Kang, S.Y. Choi, H.O. Kim, Bioorg. Med. Chem. Lett. 13 (2003)
1087e1092.
[7] S.E. Kim, S.Y. Kim, S. Kim, T. Kang, J. Lee, Bioorg. Med. Chem. Lett.
15 (2005) 3389e3393.
[8] R.L. Jarvest, J.M. Berge, V. Berry, H.F. Boyd, M.J. Brown, J.S. Elder,
A.K. Forrest, A.P. Fosberry, D.R. Gentry, M.J. Hibbs, D.D. Jaworski,

250
Farhanullah et al. / European Journal of Medicinal Chemistry 44 (2009) 239e250
P.J. O0 Hanlon, A.J. Pope, S. Rittenhouse, R.J. Sheppard, C. Slater-
Radosti, A. Worby, J. Med. Chem. 45 (2002) 1959e1962.
[13] U.A. Ochsner, C.L. Young, K.C. Stone, F.B. Dean, Antimicrob. Agents
Chemother. 49 (2005) 4253e4262.
[9] R.L. Jarvest, S.A. Armstrong, J.M. Berge, P. Brown, J.S. Elder,
M.J. Brown, R.C.B. Copley, A.K. Forrest, D.W. Hamprecht, P.J. O0 Han-
lon, D.J. Mitchell, S. Rittenhouse, D.R. Witty, Bioorg. Med. Chem. Lett.
14 (2004) 3937e3941.
[10] R.L. Jarvest, J.M. Berge, P. Brown, C.S.V. Houge- Frydrych, P.J. O0 Han-
lon, D.J. McNair, A.J. Pope, S. Rittenhouse, Bioorg. Med. Chem. Lett. 13
(2003) 1265e1268.
[14] T. Li, M. Froeyen, P. Herdewijn, J. Mol. Graph. Model. 26 (2008)
813e823.
[15] R.L. Jarvest, S.G. Erskine, A.K. Forest, A.P. Fosberry, M.J. Hibbs,
J.J. Jonnes, P.J. O0 Hanlon, R.J. Sheppard, A. Worby, Bioorg. Med.
Chem. Lett. 15 (2005) 2305e2309.
[16] S.Y. Farhanullah, E.-J. Kim, E.-C. Yoon, S. Choi, T. Kim, F. Kang,
S. Samrin, J. PuriLee, Bioorg. Med. Chem. 14 (2006) 7154e7159.
[17] G. Osborne, J.M. Buley, H. Clarke, R.C.H. Dakin, C.I. Price, J. Chem.
Soc., Perkin Trans. 1 (1993) 2747e2755.
[11] R.L. Jarvest, J.M. Berge, J.M. Brown, P. Brown, J.S. Elder, A.K. Forest,
C.S.V. Houge-Frydrych, P.J. O0 Hanlon, D.J. McNair, S. Rittenhouse,
R.J. Sheppard, Bioorg. Med. Chem. Lett. 13 (2003) 665e668.
[12] I.A. Critchley, C.L. Young, K.C. Stone, U.A. Ochsner, J. Guiles, T. Tarasow,
N. Janjic, Antimicrob. Agents Chemother. 49 (2005) 4247e4252.
[18] Clinical and Laboratory Standards Institute (CLSI), Performance
Standards for Antimicrobial Susceptibility Testing; 15th Informational
Supplement Document M100-S15, CLSI, Wayne, PA, 2005.