Design and synthesis of quinolinones as methionyl-tRNA synthetase inhibitors

Article abstract of DOI:10.1016/j.bmc.2006.06.062

Five new structural analogues of substituted-1H-quinolinones (19, 20, 23, 24, and 26) have been synthesized and evaluated for Staphylococcus aureus methionyl-tRNA synthetase enzyme inhibitory activity. These compounds were also tested against pathogens of six S. aureus, two Enterococcus faecalis, and one Enterococcus faecium. Among all the synthesized quinolinones, compound 20 displayed significant inhibitory activities in the strains of E. faecalis and E. faecium.

Full text of DOI:10.1016/j.bmc.2006.06.062

Bioorganic & Medicinal Chemistry 14 (2006) 7154–7159
Design and synthesis of quinolinones as methionyl-tRNA
synthetase inhibitors
Farhanullah,a Su Yeon Kim,a Eun-Jeong Yoon,b Eung-Chil Choi,b Sunghoon Kim,c
Taehee Kang,d Farhana Samrin,a,e Sadhna Purie and Jeewoo Leea,*
aLaboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea
bLaboratory of Microbiology, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku,
Seoul 151-742, Republic of Korea
cCenter for ARS Network, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku,
Seoul 151-742, Republic of Korea
dImagene Co. Ltd., Biotechnology Incubating Center, Seoul National University, Seoul 151-742, Republic of Korea
eDepartment of Chemistry, Dayanand Girls Post Graduate College, Kanpur 208024, India
Received 5 May 2006; revised 26 June 2006; accepted 28 June 2006
Available online 18 July 2006
Abstract—Five new structural analogues of substituted-1H-quinolinones (19, 20, 23, 24, and 26) have been synthesized and evalu-
ated for Staphylococcus aureus methionyl-tRNA synthetase enzyme inhibitory activity. These compounds were also tested against
pathogens of six S. aureus, two Enterococcus faecalis, and one Enterococcus faecium. Among all the synthesized quinolinones,
compound 20 displayed significant inhibitory activities in the strains of E. faecalis and E. faecium.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
to develop antibacterial agents for the treatment of anti-
biotic-resistant bacterial strains such as methicillin,
resistant Staphylococcus aureus (MRSA) and Vancomy-
cin resistant enterococci (VRE).2–4
Aminoacyl-tRNA synthetases (aaRSs) are a group of
enzymes that precisely transfer amino acids from cellu-
lar pool to their corresponding tRNA cognates to form
aminoacyl-tRNAs which serve as substrates for protein
synthesis.1 The transfer of a particular amino acid to
tRNA under influence of aaRS occurs through forma-
tion of an active intermediate aminoacyladenylate
(aa-AMP) by the reaction of the amino acid and ATP.
The aa-AMP thus formed is attacked by either 20-OH
or 30-OH of adenosine of tRNA to form ester with ami-
noacyl moiety. The catalytic activity of aaRSs is organ-
ism specific and it is different in pathogens and human
beings. This difference in catalytic activity of aaRSs
provides an opportunity to inhibit pathogens’ aaRSs
selectively without perturbing host aaRSs. Thus, amino-
acyl-tRNA synthetases make an alternative drug target
Aminoacyladenylate (aa-AMP) being highly active and
susceptible to hydrolysis makes the possibility of synthe-
sizing its stabilized analogues having potential inhibito-
ry properties. In this respect various isosteres of linear
chain attached to aa-AMP, such as alkylphosphate,
ester, amide, hydroxamate, sulfamate,5 sulfamide,
N-alkoxysulfamide, and N-hydroxysulfamide have been
prepared as replacement of the hydrolytically labile
acylphosphate of the aminoacyladenylate. Inhibitors of
aminoacyladenylate have been also synthesized by
modifying hydroxyl groups of ribose present in
aminoacyladenylate.6
Recently, a quinoline derivative7 has been identified by
high throughput screening of a library of compounds
as a competitive inhibitor of methionyl-tRNA synthe-
tase (MRS). Structure–activity relationship7–10 study of
the derivative led to the synthesis of 2 with IC50 value
16 nM against MRSA.
Keywords: Methionyl-tRNA synthetase inhibitor; Antibacterial agent;
Quinolone.
*
Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 888 0649;
e-mail: jeewoo@snu.ac.kr
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.06.062

Farhanullah et al. / Bioorg. Med. Chem. 14 (2006) 7154–7159
7155
and 4-methoxybenzylalcohol in presence of sodium
hydride and catalyst 15-crown-5.
2-Methoxypropane-1,3-diamine (10) required for
the synthesis of 20 was prepared in three steps from
epichlorohydrin (7). A reaction of 7 and excess of diben-
zylamine afforded 2-hydroxy-tetrabenzylpropane-1,3-di-
amine (8) which on methylation with sodium hydride
and MeI furnished 9. The compound 9 was debenzylat-
ed by stirring a mixture of 9 and Pd(OH)2 in methanol at
rt to produce 10. The compound 10 was used as such
without purification (Scheme 2).
2,4-Diaminobutanol-1 (14) essential for synthesis of tar-
get compounds (23, 24) was delineated from 2,4-diamin-
obutyric acid dihydrochloride (11) by different
procedure as shown in Scheme 3. A reaction of 11 and
benzylbromide in 1:1 mixture of NaOH and K2CO3 in
aqueous methanol at reflux temperature provided 12 in
good yield. Reduction of the ester 12 into corresponding
alcohol 13 by LiAlH4 in THF under reflux condition
and subsequent debenzylation with Pd(OH)2 yielded
14 which was used as such without purification. Synthe-
sis of 23 and 24 relied on efficient isolation and charac-
terization of their respective intermediates 21 and 22 in
different yields. Stirring a mixture of 5 and 14 in 1:5
molar ratios in presence of K2CO3/DMSO at 80 ꢁC for
48 h provided 21 in 41% and 22 in 8% yields.
Figure 1. Pharmacophoric superimposition of compounds 1 and 2.
Our presumption that quinolone (2) inhibits catalytic
activity of 1 by occupying binding site of methionylade-
nylate (1) led us to perform molecular modeling study of
1 and 2. In the modeling principal pharmacophores of 2
were identified and compared with methionyladenylate
(1). Positions of all five pharmacophoric groups of 2
were matched with those of methionyladenylate 1 in
an energy-minimized conformation (Fig. 1).11
3. Results and discussion
3.1. Methionyl-tRNA synthetase enzyme assay
Carbonyl group, nitrogen atom of quinolone ring, and
exocyclic nitrogen atom were superimposed with
N6-amino, N3, and N9-atoms of adenine ring of 1,
respectively. The other nitrogen atom of the linker and
a chloro group of 2 superimposed with an oxygen and
sulfur atoms of 1. The RMS superposition of the phar-
macophoric groups verified perfect correlation between
1 and 2. Further, it is evident from Figure 1 that linear
chain of compound 2 provides appropriate separation
between quinolone and 3,4-dichlorobenzene ring but
does not fully superimpose with ribose ring of 1. The
linker with a hydrophilic functionality such as hydroxy,
methoxy, or hydroxymethyl might provide a better sur-
rogate for ribose. This notion led us to design and
synthesize 19, 20, 23, 24, and 26.
All the synthesized compounds 2, 19, 20, 23, 24, and 26
were evaluated for in vitro inhibitory activity against S.
aureus methionyl-tRNA synthetase. The inhibitory activ-
ities of the compounds shown in Table 1 have been deter-
mined by measuring decrease in the generation of the
aminoacyl product [35S]methionyl S. aureus-tRNA,Met
in presence of different chemical concentrations as
described.6
The reference compound 2 was found most active
with IC50 value 1.09 nM under this condition. Intro-
duction of a hydroxyl and methoxy group at C-2
in the linear chain of 2 provided relatively less potent
compounds 19 and 20 by ca. 2-fold, respectively.
Thus, C-2 position does not tolerate either H-bond
donor or acceptor substituents. A compound 23 was
then synthesized to explore C-3 position of the linker
of compound 2 but this displayed almost same level
of activity (IC50 = 2.85 nM). C-1 position of the line-
ar chain of 2 was investigated by preparing com-
pound 24 which showed around 9-fold decrease in
2. Chemistry
The designed compounds 2, 19, 20, 23, 24, and 26 have
been synthesized by nucleophilic substitution reaction of
aryloxyquinoline 5 with excess of either 1,3-diaminopro-
pane or suitably substituted 1,3-diaminopropanes (10,
14) followed by TFA-catalyzed hydrolysis of 4-meth-
oxybenzyl group and reductive alkylation with
3,4-dichlorobenzaldehyde (Schemes 4–6). The quinoline
5 was previously prepared in two steps from aniline
using literature procedure12 (Scheme 1). Quinolone 6
has been isolated as minor product during the synthesis
of 5 by the reaction of 2,4-dichloroquinoline (Scheme 1)
Scheme 1. Reagents and conditions: (a) Malonic acid, POCl3, reflux,
55%; (b) (4-OMe)BnOH, 15-crown-5 ether, NaH, rt, 5:82%, 6:6%.

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Farhanullah et al. / Bioorg. Med. Chem. 14 (2006) 7154–7159
Scheme 2. Reagents and conditions: (a) Bn2NH, 130 ꢁC, 20 h, 85%; (b) MeI, NaH, rt, 6 h, 52%; (c) Pd(OH)2, MeOH, rt, 24 h.
Scheme 3. Reagents and conditions: (a) BnBr, NaOH, K2CO3, MeOH–H2O, reflux, 5 h, 88%; (b) LiAlH4ÆTHF, reflux, 6 h, 92%; (c) Pd(OH)2,
MeOH, rt, 24 h.
Table 1. In vitro inhibitory activities of the synthesized compounds
against S. aureus methionyl-tRNA synthetase enzyme
3.2. Antibacterial assay
a
IC50 (nM)
Minimum inhibitory concentration (MIC) of the synthe-
sized compounds shown in Table 2 was determined by a
microdilution method with Mueller–Hinton Broth (MH,
Difco Laboratories, Detroit, MI) for staphylococci and
Brain Heart Infusion Broth (BHI, Difco) for Enterococci
following the National Committee for Clinical Labora-
tory Standards (NCCLS).13 Six bacterial strains of S.
aureus (ATCC25923, ATCC6538P, ATCC10537,
GIORGIO, SP-N2, and SMITH), one Staphylococcus
epidermidis (ATCC12228), two Enterococcus faecalis
(ATCC29212, ATCC19433), and one Enterococcus
faecium (ATCC10541) were used for the assay. The
stock solutions of test compounds were diluted to give
a serial, 2-fold series yielding final chemical concentra-
tions ranging from 64 to 0.03 lg/mL. The MIC was
defined as the lowest concentration of the chemical that
inhibited the development of visible bacterial growth
after incubation for 16 h at 36 ꢁC. Mupirocin and
amoxicillin antibiotics were used as standard drug.
Compound
Structure
2
1.09
19
20
23
24
26
2.32
2.48
2.85
18.6
All the tested compounds were found less potent than
both the standard antibiotic mupirocin and amoxicillin
in all the strains of S. aureus. However, compounds 2,
19, and 20 displayed significant inhibitory activities
against strains of E. faecalis and E. faecium but are less
active than amoxicillin (Table 2). The compound 2
showed 64 times more inhibition against both the strains
of E. faecalis, while 32-fold more inhibition against E.
faecium strain than mupirocin. The compound 19 was
found 4- and 8-fold more potent against strains of E.
faecalis ATCC29212 and ATCC19433, respectively but
only two times more active against E. faecium strain
4946
a Values represent means of three experiments.
potency. Replacement of 4-quinolone of
2-quinolone resulted a compound 26 with 5000 times
2
by
less activity.
Table 2. In vitro minimum inhibitory concentration (MIC) of compounds against strains of S. aureus, E. faecalis, and E. faecium
Strains
STD1/STD2
2
19
20
23
24
26
S. aureus ATCC25923
S. aureus ATCC6538P
S. aureus ATCC10537
S. aureus GIORGIO
S. aureus SP-N2
0.12/0.25
0.06/0.25
0.12/0.12
0.06/0.12
0.25/>64
0.12/0.25
0.12/8
32
8
>64
32
64
64
32
64
64
16
8
>64
16
32
32
32
32
32
8
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
>64
64
32
32
32
32
32
32
32
64
32
64
32
32
16
16
16
1
S. aureus Smith
S. epidermidis ATCC12228
E. faecalis ATCC29212
E. faecalis ATCC19433
E. faecium ATCC10541
64/0.5
64/0.5
16/2
1
0.5
4
32
32
64
64
8
2
STD1, Mupirocin; STD2, Amoxicillin.

Farhanullah et al. / Bioorg. Med. Chem. 14 (2006) 7154–7159
7157
Scheme 4. Reagents and conditions: (a) NH2CH2CH(OH)CH2NH2 or 10, K2CO3, DMSO, 80 ꢁC, 48 h, 15, 55%, 16, 51%; (b) 20% TFA–DCM, rt,
2 h; (c) 3,4-Cl2PhCHO, AcOH, MeONa, NaCNBH3, MeOH, 50 ꢁC, 6 h, 19, 48%, 20, 52%.
Scheme 5. Reagents and conditions: (a) 14, K2CO3, DMSO, 80 ꢁC, 48 h, 21, 41%, 22, 8%; (b) 20% TFA–DCM, rt, 2 h; (c) 3,4-Cl2PhCHO, AcOH,
MeONa, NaCNBH3, MeOH, 50 ꢁC, 6 h, 23, 55%, 24, 48%.
on a Melting Point Buchi B-540 apparatus and are
¨
uncorrected. Silica gel column chromatography was per-
formed on silica gel 230–400 mesh, 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 a Perkin-Elmer 1710 Series
FTIR. Mass spectra were recorded on a VG Trio-2
GC–MS.
Scheme 6. Reagents and conditions: (a) NH2(CH2)3NH2, 110 ꢁC, 48 h,
62%; (b) 3,4-Cl2PhCHO, AcOH, MeONa, NaCNBH3, MeOH, 50 ꢁC,
6 h, 60%.
ATCC10541 than the standard mupirocin. Compound
20, a methylated analogue of 19, showed similar pattern
of antibacterial properties but found 2-fold more active
against E. faecalis and 4-fold more active against E. fae-
cium than 19. The increased inhibitory activity of com-
pound 20 was probably due to less polarity and better
bioavailability than 19. The compounds 23 and 26 dis-
played similar antibacterial activity in all pathogens of
S. aureus and E. faecium, while 2-fold more activity in
E. faecalis ATCC19433 than mupirocin. Compound 24
did not show any significant activity.
5.2. 1,3-Bis-dibenzylaminopropan-2-ol (8)
A mixture of 7 (1.0 mL) and dibenzylamine (10 mL) was
stirred at 130 ꢁC for 20 h. Excess of dibenzylamine
was removed under vacuum and residue thus obtained
was purified on silica gel using hexane/CH2Cl2 (9:1) as
eluent. Colorless oil; yield 85%; IR (Neat) m 3457 cmꢀ1
(OH); MS(FAB) m/z 451 (MH+, 100%). 1H NMR
(CDCl3, 300 MHz) d 2.41 (d, J = 6.21 Hz, 4H, CH2),
3.44–3.65 (m, 8H, CH2), 3.74–3.84 (m, 1H, CH),
7.20–7.31 (m, 20 H, ArH).
5.3. N,N,N0,N0-Tetrabenzyl-2-methoxypropane-1,3-di-
amine (9)
4. Conclusion
The present study suggests that linear carbon chain pres-
ent in the compound 2 seems to be appropriate and sub-
stitution of hydroxyl or hydroxymethyl group at any
position in the chain is detrimental for the methionyl-
tRNA synthetase inhibitory activity. However, non-
polar substitution at C-2 position favors antibacterial
activity. Further optimization of linear chain of 2 is
under progress.
To a solution of 8 (2.0 g, 4.45 mmol) in dry DMF
(10 mL), sodium hydride (0.12 g, 4.88 mmol) was added
in portions and resulting suspension stirred at rt for
15 min. Methyl iodide (0.41 mL, 6.67 mmol) was added
dropwise and stirred for 4 h at rt. The reaction mixture
was poured into water (30 mL) and extracted with dieth-
yl ether (15· 3 mL). Ether layers were combined, dried
over MgSO4, and evaporated under vacuum. Residue
obtained was purified on silica gel column using hex-
ane/CH2Cl2 (1:1) as eluent. White solid; mp 64–65 ꢁC;
5. Experimental
5.1. Chemistry
1
yield 52%; MS(FAB) m/z 465 (MH+, 100%). H NMR
(CDCl3, 300 MHz) d 2.36 (dd, J = 13.38, 5.90 Hz, 2H,
CH2), 2.54 (dd, J = 13.38, 5.90 Hz, 2H, CH2), 3.32
(s, 3H, OCH3), 3.38–3.67 (m, 9H, CH and CH2),
7.22–7.31 (m, 20H, ArH).
All the chemical reagents used were either synthesized or
commercially available. Melting points were determined

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Farhanullah et al. / Bioorg. Med. Chem. 14 (2006) 7154–7159
5.4. 2-Methoxypropane-1,3-diamine (10)
silica gel column using CH2Cl2/MeOH/NH3 sol
(90:10:0.5) as eluent. Similarly, 16, 21, and 22 were pre-
pared by the reaction of 5 with 10 and 14, respectively.
A mixture of 3 (2.0 g) and Pd(OH)2 (2.0 g, 20%) in meth-
anol (15 mL) was stirred under H2 balloon for 24 h at rt.
Pd(OH)2 was filtered over a Celite pad, evaporated
under reduced pressure to yield 10 which, used as such
for next stage.
5.8.1. 1-Amino-3-[4-(4-methoxybenzyloxy)-quinolin-2-yl-
amino]-propan-2-ol (15). White solid; mp 133–135 ꢁC;
yield 55%; IR (KBr) m 3336 cmꢀ1 (OH); MS(FAB) m/z
1
354 (MH+, 30%). H NMR (CDCl3, 300 MHz) d 3.48–
5.5. 2,4-Bis-dibenzylaminobutyric acid benzyl ester (12)
3.59 (m, 2H, NCH2), 3.64–3.69 (m, 2H, NCH2), 3.73–
3.76 (m, 1H, CH), 3.88 (s, 3H, OCH3), 5.09 (s, 2H,
OCH2), 6.37 (s, 1H, ArH), 9.94 (d, J = 8.70 Hz, 2H,
ArH), 7.15–7.20 (m, 1H, ArH), 7.38 (d, J = 8.70 Hz,
2H, ArH), 7.48–7.53 (m, 1H, ArH), 7.58–7.61 (m, 1H,
ArH), 7.96–7.99 (m, 1H, ArH).
Benzyl bromide (6.8 mL, 57.59 mmol) was added to a
solution of 2,4-diaminobutyric acid dihydrochloride 11
(2.0 g, 10.47 mmol) in a mixture of sodium hydroxide
(1.24 g, 31.32 mmol) and K2CO3 (4.32 g, 31.32 mmol)
in MeOH/H2O (15 mL/15 mL). The reaction mixture
was refluxed for 6 h, cooled to rt, extracted with dichlo-
romethane (20· 3 mL), evaporated, and purified on
silica gel column using hexane/CH2Cl2 (1:1). Colorless
oil; yield: 88%; IR (neat) m 1727 cmꢀ1 (CO); MS(EI)
5.8.2. 2-Methoxy-N0-[4-(4-methoxybenzyloxy)-quinolin-
2-yl]propane-1,3-diamine (16). White solid; mp 125–
127 ꢁC; yield 51%; MS(FAB) m/z 368 (MH+, 100%).
1H NMR (CDCl3, 300 MHz) d 2.85–2.90 (m, 1H,
CH), 3.46–3.48 (m, 2H, NCH2), 3.45 (s, 3H, OCH3),
3.70–3.75 (m, 2H, NCH2), 3.84 (s, 3H, OCH3), 5.13 (s,
2H, CH2), 6.11 (s, 1H, ArH), 6.95 (d, J = 8.58 Hz, 2H,
ArH), 7.15–7.20 (m, 1H, ArH), 7.40 (d, J = 8.58 Hz,
2H, ArH), 7.48–7.54 (m, 1H, ArH), 7.58–7.61 (m, 1H,
ArH), 7.97–7.99 (m, 1H, ArH).
1
m/z 568 (M+, 100%). H NMR (CDCl3, 300 MHz) d
1.82–2.05 (m, 2H, CH2), 2.22–2.30 (m, 1H, NCH2),
2.56–2.66 (m, 1H, NCH2), 3.28 (d, J = 13.53 Hz, 2H,
NCH2), 3.39 (d, J = 13.53 Hz, 2H, NCH2), 3.42 (d,
J = 13.53 Hz, 2H, NCH2), 3.46 (t, J = 7.14 Hz, 1H,
CH), 3.79 (d, J = 13.53 Hz, 2H, CH2), 4.98 (d,
J = 12.27 Hz, 1H, OCH2), 5.15 (d, J = 12.27 Hz, 1H,
OCH2), 7.16–7.39 (m, 25H, ArH).
5.8.3. 2-Amino-4-[4-(4-methoxybenzyloxy)quinolin-2-yl-
amino]butan-1-ol (21). White solid; mp 134–135 ꢁC;
yield 41%; IR (KBr) m 3340 cmꢀ1 (OH); MS(EI): m/z
367 (M+, 100%). 1H NMR (CDCl3, 300 MHz) d
1.62–1.83 (m, 2H, CH2), 2.95–2.99 (m, 1H, CH),
3.48–3.63 (m, 2H, OCH2), 3.73–3.80 (m, 2H, CH2),
3.84 (s, 3H, OCH3), 5.12 (s, 2H, OCH2), 5.98 (s,
1H, ArH), 6.96 (d, J = 8.60 Hz, 2H, ArH), 7.13–7.18
(m, 1H, ArH), 7.40 (d, J = 8.60 Hz, 2H, ArH), 7.43–7.53
(m, 1H, ArH), 7.61–7.64 (m, 1H, ArH), 7.98 (m,
1H, ArH).
5.6. 2,4-Bis-dibenzylaminobutan-1-ol (13)
A solution of 12 (3.0 g, 5.28 mmol) in THF (10 mL) was
added slowly to a stirred suspension of LiAlH4 in THF
(20 mL). The reaction mixture was refluxed overnight,
cooled, and added NaOH (15% aq) to quench the
LiAlH4, again refluxed for 30 min, cooled to rt, and fil-
tered the solid precipitate. The filtrate was dried over
MgSO4, evaporated under vacuum, and purified on
silica gel column using CH2Cl2/MeOH (49:1) as eluent.
Colorless oil; yield 92%; IR (neat) m 3430 cmꢀ1 (OH);
MS(FAB) m/z 465 (MH+, 100%); 1H NMR (CDCl3,
300 MHz) d 1.36–1.46 (m, 1H, CH2), 1.89–2.0 (m, 1H,
CH2), 2.30–2.47 (m, 2H, NCH2). 2.71–2.74 (m, 1H,
CH), 3.27 (d, J = 5.67 Hz, 2H, CH2OH), 3.34 (d,
J = 13.38 Hz, 2H, NCH2), 3.48 (d, J = 13.38 Hz, 2H,
NCH2), 3.62 (d, J = 13.38 Hz, 2H, NCH2), 3.72 (d,
J = 13.38 Hz, 2H, NCH2), 7.17–7.37 (m, 20H, ArH).
5.8.4. 4-Amino-2-[4-(4-methoxybenzyloxy)quinolin-2-yl-
amino] butan-1-ol (22). White solid; mp 155–156 ꢁC;
yield 8%; IR(KBr) m 3337 cmꢀ1 (OH); MS(EI): m/z 367
1
(M+, 100%). H NMR (CDCl3, 300 MHz) d 1.65–1.66
(m, 2H, CH2), 2.97–2.99 (m, 2H, NCH2), 3.72–3.79
(m, 3H, CH and OCH2), 3.83 (s, 3H, OCH3), 5.09 (s,
2H, OCH2), 6.10 (s, 1H, ArH), 6.94 (d, J = 8.60 Hz,
2H, ArH), 7.11–7.16 (m, 1H, ArH), 7.38 (d,
J = 8.60 Hz, 2H, ArH), 7.44–7.49 (m, 1H, ArH), 7.53–
7.56 (m, 1H, ArH), 7.94 (m,1H, ArH).
5.7. 2,4-Diaminobutan-1-ol (14)
A mixture of 13, (2.0 g) and Pd(OH)2 (2.0 g, 20%) was
stirred in methanol for 24 h at rt. Pd(OH)2 was filtered,
methanol evaporated, and used as such for next stage.
5.9. 4-(3-Aminopropylamino)-1H-quinolin-2-one (25)
A mixture of 6 (150 mg, 0.837 mmol) and 1,3-diamino-
propane (2 mL, 23.9 mmol) was stirred at 110 ꢁC for
48 h under nitrogen atmosphere. 1,3-Diaminopropane
was evaporated under vacuum, the crude product was
purified on silica gel column using CH2Cl2/MeOH/
NH3 soln (9:1:0.5) as eluent. Colorless oil; yield 62%;
5.8. General procedure for preparation of 4-Aryl-2-
substituted aminoquinoline (15, 16, 21, 22)
A mixture of 9 (150 mg, 0.50 mmol) and 2-hydroxy-1,3-
diaminopropane (225 mg, 2.5 mmol) was stirred in
DMSO (15 mL) at 80 ꢁC in presence of potassium car-
bonate (83 mg, 0.6 mmol) for 48 h. The reaction mixture
was poured into distilled water (50 mL) and extracted
with ethyl acetate (25· 3 mL), dried over sodium sulfate,
and evaporated. The solid obtained was purified on
1
MS(FAB) m/z 218 (MH+, 100%). H NMR (CD3OD,
300 MHz)
d 1.84–1.94 (m, 2H, CH2), 2.79 (t,
J = 7.2 Hz, 2H, NCH2), 3.35 (t, J = 6.9 Hz, 2H,
NCH2), 5.54 (s, 1H, ArH), 7.19–7.24 (m, 1H, ArH),
7.31 (dd, J = 8.1, 0.6 Hz, 1H, ArH), 7.48–7.54 (m, 1H,
ArH), 7.88 (dd, J = 8.4, 0.9 Hz, 1H, ArH).

Farhanullah et al. / Bioorg. Med. Chem. 14 (2006) 7154–7159
7159
5.10. 3-(4-Oxo-1,4-dihydroquinolin-2-ylamino)-substitut-
ed-propylammonium (17,18)
7.21–7.28 (m, 3H, ArH),7.37 (d, 1H, J = 8.20 Hz, ArH),
7.46–7.54 (m, 2H, ArH), 8.06 (dd, 1H, J = 8.1, 1.2 Hz,
ArH).
These compounds were obtained by TFA-catalyzed
hydrolysis of their corresponding 4-methoxybenzyl-
oxybenzyloxy derivatives 15 and 16, respectively. The
compounds 17, 18 were subjected to reductive alkylation
with 3,4-dichlorobenzaldehyde without purification.
Similarly 21 and 22 were hydrolyzed and used to synthe-
size target compounds 23 and 24, respectively.
5.11.5. 4-[3-(3,4-Dichlorobenzylamino)propylamino]-1H-
quinolin-2-one (26). White Solid; mp 197–199 ꢁC; yield
60%; MS(FAB) m/z 376 (MH+, 100%). 1H NMR
(CD3OD, 300 MHz) 1.89–2.00 (m, 2H, CH2), 2.73 (t,
J = 6.9 Hz, 2H, NCH2), 3.34 (t, J = 7.2 Hz, 2H,
NCH2), 3.74 (s, 2H, CH2), 5.51 (s, 1H, ArH), 7.12–
7.7.18 (m, 1H, ArH), 7.24 (dd, J = 8.2, 2.0 Hz, 1H,
ArH), 7.30 (dd, J = 8.4, 0.9 Hz, 1H, ArH), 7.41 (d,
J = 8.1, 0.9 Hz, 1H, ArH), 7.47–7.52 (m, 2H, ArH),
7.76 (dd, J = 8.1, 0.9 Hz, 1H, ArH).
5.11. 2-[3-(3,4-Dichlorobenzylamino)-substituted pro-
pylamino]1H-quinolin-4-one (19, 20, 23, 24, 26)
General procedure
Acknowledgment
To a solution of 17 (100 mg, 0.43 mmol) in methanol
(5 mL), acetic acid was added (0.1 mL) followed by
0.5 M MeONa (1 mL, 0.43 mmol) at rt (20 ꢁC). The
reaction mixture was stirred for 15 min at rt (20 ꢁC) then
3,4-dichlorobenzaldehyde (75 mg, 0.43 mmol) added
and stirred at 50 ꢁC for 1 h. NaCNBH3 (40 mg,
0.64 mmol) solution in MeOH (5 mL) was added, again
stirred for 6 h at 50 ꢁC. Methanol was evaporated and
crude product purified by Silica gel column using
CH2Cl2/MeOH/NH3 sol (95:5:0.5) as eluent.
This work was supported by a Grant (03-PJ2-PG4-
BD02-0001) from the Ministry of Health and Welfare,
R.O.K.
References and notes
1. Ibba, M.; So¨ll, D. Annu. Rev. Biochem. 2000, 69, 617.
2. van der Haar, F.; Gabius, H. J.; Cramer, F. Angew.
Chem., Int. Ed. Engl. 1981, 20, 217.
3. Schimmel, P.; Tao, J.; Hill, J. FASEB J. 1998, 12, 1599.
4. De Pouplana, L. R.; Schimmel, P. Cell. Mol. Life Sci.
2000, 57, 865.
5.11.1. 2-[3-(3,4-Dichlorobenzylamino)-2-hydroxypropyl-
amino]-1H-quinolin-4-one (19). White solid; mp 220–
1
222 ꢁC; yield 48%; MS(FAB) m/z 393 (MH+, 100%). H
NMR (CD3OD, 300 MHz) d 2.67–2.80 (m, 2H, NCH2),
3.33–3.57 (m, 2H, NCH2), 3.85 (s, 2H, CH2), 3.92–3.99
(m, 1H, CHOH), 5.67 (s, 1H, ArH), 7.21–7.31 (m, 3H,
ArH), 7.44 (d, J = 8.4 Hz, 1H, ArH), 7.49–7.56 (m, 2H,
ArH), 8.06 (dd, J = 8.1, 1.2 Hz, 1H, ArH).
5. Lee, J.; Kim, S. E.; Lee, J. Y.; Kim, S. Y.; Kang, S. U.;
Seo, S. H.; Chun, M. W.; Kang, T.; Choi, S. Y.; Kim, H.
O. Bioorg. Med. Chem. Lett. 2003, 13, 1087.
6. Kim, S. E.; Kim, S. Y.; Kim, S.; Kang, T.; Lee, J. Bioorg.
Med. Chem. Lett. 2005, 15, 3389.
7. Jarvest, R. L.; Berge, J. M.; Berry, V.; Boyd, H. F.;
Brown, M. J.; Elder, J. S.; Forrest, A. K.; Fosberry, A. P.;
Gentry, D. R.; Hibbs, M. J.; Jaworski, D. D.; O’Hanlon,
P. J.; Pope, A. J.; Rittenhouse, S.; Sheppard, R. J.; Slater-
Radosti, C.; Worby, A. J. Med. Chem. 2002, 45, 1959.
8. Jarvest, R. L.; Armstrong, S. A.; Berge, J. M.; Brown, P.;
Elder, J. S.; Brown, M. J.; Copley, R. C. B.; Forrest, A.
K.; Hamprecht, D. W.; O’Hanlon, P. J.; Mitchell, D. J.;
Rittenhouse, S.; Witty, D. R. Bioorg. Med. Chem. Lett.
2004, 14, 3937.
9. Jarvest, R. L.; Berge, J. M.; Brown, P.; Houge-Frydrych,
C. S. V.; O’Hanlon, P. J.; McNair, D. J.; Pope, A. J.;
Rittenhouse, S. Bioorg. Med. Chem. Lett. 2003, 13, 1265.
10. Jarvest, R. L.; Berge, J. M.; Brown, M. J.; Brown, P.;
Elder, J. S.; Forrest, A. K.; Houge-Frydrych, C. S. V.;
O’Hanlon, P. J.; McNair, D. J.; Rittenhouse, S.; Shepp-
ard, R. J. Bioorg. Med. Chem. Lett. 2003, 13, 665.
11. The structure was built using the Sybyl molecular mod-
eling program (Tripos Inc.), and then the geometry was
fully optimized by energy minimization using the Tripos
5.11.2. 2-[3-(3,4-Dichlorobenzylamino)-2-methoxypropyl-
amino]-1H-quinolin-4-one (20). White Solid; mp 180–
182 ꢁC; yield 52%; MS(FAB) m/z 407 (MH+, 100%).
1H NMR (CD3OD, 300 MHz) d 2.72 (d, J = 5.13 Hz,
2H, NCH2), 3.43 (s, 3H, OCH3); 3.49–3.61 (m, 3H,
CH), 3.74–3.84 (m, 2H, CH2), 5.68 (s, 1H, ArH), 7.22–
7.32 (m, 3H, ArH), 7.43 (d, J = 8.22 Hz, 1H, ArH),
7.49–7.54 (m, 2H, ArH), 8.06 (dd, J = 8.22, 1.2 Hz,
1H, ArH).
5.11.3. 2-[3-(3,4-Dichlorobenzylamino)-4-hydroxybutyl-
amino]-1H-quinolin-4-one (23). White solid; mp 223–
224 ꢁC; yield 55%; IR (KBr) m 3427 cmꢀ1 (OH); MS(FAB)
1
m/z 407 (MH+, 100%). H NMR (CD3OD, 300 MHz) d
1.77–1.83 (m, 2H, CH2), 2.69–277 (m, 1H, CH), 3.34–
3.46 (m, 2H, OCH2), 3.54–3.69 (m, 2H, NCH2), 3.74–
3.85 (m, 2H, CH2), 5.62 (s, 1H, ArH), 7.21–7.28 (m, 3H,
ArH),7.37 (d, 1H, J = 8.20 Hz, ArH), 7.46–7.54 (m, 2H,
ArH), 8.06 (dd, 1H, J = 8.1, 1.2 Hz, ArH).
force field and Gasteiger–Huckel partial atomic charges
¨
with the following non-default options (method: conjugate
˚
gradient, termination: gradient 0.01 kcal/mol A, and max
iterations: 10,000). All computational work was done on a
Silicon Graphics O2 R10000 workstation.
5.11.4. 2-[3-(3,4-Dichlorobenzylamino)-1-hydroxymethyl-
propylamino]-1H-quinolin-4-one (24). White solid; mp
210–212 ꢁC; yield 48%; IR (KBr) m 3430 cmꢀ1 (OH);
12. Osborne, A. G.; Buley, J. M.; Clarke, H.; Dakin, R. C. H.;
Price, P. I. J. Chem. Soc. Perkin Trans. 1993, 2747.
13. National Committee for Clinical Laboratory Standards.
2002. Performance standards for antimicrobial susceptibil-
ity testing; twelfth informational supplement, NCCLS,
Wayne, PA 2002, 22, M100–S12.
1
MS(FAB) m/z 407 (MH+, 100%). H NMR (CD3OD,
300 MHz) d 1.77–1.83 (m, 2H, CH2), 2.69–2.77 (m, 1H,
CH), 3.34–3.46 (m, 2H, OCH2), 3.54–3.69 (m, 2H,
NCH2), 3.74–3.85 (m, 2H, CH2), 5.62 (s, 1H, ArH),