Synthesis and antibacterial activity of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones

Article abstract of DOI:10.1016/j.bmcl.2007.01.038

Synthesis and antibacterial activity of a number of substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones is reported. The antibacterial activities were evaluated in standard in vitro MIC assay method. Some of the compounds showed in vitro (MIC) antibacterial activity comparable to those of Gatifloxacin, Ciprofloxacin, and Sparfloxacin.

Full text of DOI:10.1016/j.bmcl.2007.01.038

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1924–1929
Synthesis and antibacterial activity of
4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones
Brijesh Kumar Srivastava,* Manish Solanki, Bhupendra Mishra,
Rina Soni, Sanjaya Jayadev, Darshan Valani, Mukul Jain and Pankaj R. Patel
Zydus Research Centre , Sarkhej-Bavla N.H. 8A, Moraiya, Ahmedabad, Gujarat 382210, India
Received 7 November 2006; revised 5 January 2007; accepted 10 January 2007
Available online 24 January 2007
Dedicated to Late Shri Ramanbhai Patel, the founder of Zydus Research Centre, Ahmedabad.
Abstract—Synthesis and antibacterial activity of a number of substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones is
reported. The antibacterial activities were evaluated in standard in vitro MIC assay method. Some of the compounds showed in vitro
(MIC) antibacterial activity comparable to those of Gatifloxacin, Ciprofloxacin, and Sparfloxacin.
Ó 2007 Elsevier Ltd. All rights reserved.
Fluoroquinoloneshave been the landmark discovery in
the treatment of bacterial infections.1 Ciprofloxacin
introduced in the year 1986 by Bayer is one of the most
potent and widely used antibacterial agents.2
laboratory6 wherein, the substitution is linked through
the carbon atom. Although good antibacterial activities
have been reported against several strains such as
Staphylococcus aureus, Enterococcus faecalis, Moraxella
catarrahalis, Escherichia coli, Haemophilius influenzae,
and Streptococcus pneumoniae, no compound is in devel-
opment from this class of molecules. Interestingly, none
of the quinolones having C-7 linkage through C-atom
have succeeded to reach the market due to various kinds
of toxicity, although some of them showed very potent
antibacterial profile in preclinical evaluation.5 Thus,
we believed that safer and superior antibacterial com-
pounds can be developed by attaching tetrahydrothie-
no[3,2-c]pyridine moiety through N-atom of the
substituent at C-7 position, which would result in com-
pounds 7–20. Earlier, we have reported tetrahydrothie-
no[3,2-c]pyridine incorporated oxazolidinones, wherein
compounds showed significant antibacterial activities
in MIC assay.7 In this communication we are reporting
the synthesis, characterization,8 and antibacterial
activity of compounds 7–20 (Fig. 2), which bear the
4,5,6,7- tetrahydrothieno[3,2-c]pyridine moiety attached
through N-atom at the C-7 position of the quinolone.
Despite a large number of fluoroquinolones approved
for the treatment of bacterial infection, there have
been unabated efforts for the discovery of new quino-
lones3 with specific properties and most importantly to
overcome the problem of growing bacterial resistance.
The major concern has been the growing incidence of
resistance especially to Staphylococci and Enterococci.4
Some of the side effects of quinolone antibacterials are
unacceptable, for example, Grepafloxacin was with-
drawn from market, due to increased cases of heart
problems in clinical findings.5 Similarly, Trovafloxacin
was removed from the market due to liver toxicity5
(Fig. 1).
Several drugs belonging to fluoroquinolone class having
a substitution at the C-7 position attached through the
N-atom are in clinical use. Recently, fluoroquinolones
6 having 4,5,6,7-tetrahydrothieno [3,2-c] pyridine moiety
at C-7 position (Fig. 2) have been reported from Abbott
Interestingly, quinolones 7–20 displayed significant in vi-
tro antibacterial activities for most of the Gram-positive
strains (Tables 1 and 2).
Keywords: 4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine; Quinolone anti-
bacterial agent; In vitro MIC assay; Gram-positive organism; Linezo-
lid resistant staphylococcus aureus.
The minimum inhibitory concentration (MIC) for 90%
bacterial growth inhibition was determined by micro-
broth dilution technique using the National Committee
*
Corresponding author. Tel.: +91 2717 250801; fax: +91 2717
250606; e-mail: brijeshsrivastava@zyduscadila.com
ZRC communication # 177.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.038

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1924–1929
1925
O
O
Me
O
N
O
F
F
OH
OH
Me
HN
H
N
N
N
N
F
H2N
H
F
1
2
Grepafloxacin
Trovafloxacin
O
N
O
NH2
O
N
O
O
O
F
F
F
OH
OH
OH
N
N
N
N
HN
OMe
HN
F
HN
Me
Me
3
4
5
Ciprofloxacin
Gatifloxacin
Sparfloxacin
Figure 1.
R3
5
O
N
O
O
N
O
4
1
F
OH
OH
6
3
2
4'
5'
N
3'
7
R1
8
R2
S
OMe
HN
2'
6'
S
1' 7'
6
7-20
Figure 2.
for Clinical and Laboratory Standards (NCCLS) meth-
od,9 now known as Clinical and Laboratory Standards
Institute Guidelines.
sponding carboxylic acid derivatives 7–11, 14–17, 19,
and 20 by refluxing in an 80% solution of ethanol in
water and triethylamine as depicted in Scheme 1. The
formyl derivative 10 was oxidized to compound 12 by
silver oxide and methyl alcohol derivative 11 was con-
verted to –OCOMe derivative 13 by reacting with acetic
anhydride. The aniline derivative 17 was converted to
–NHCOMe derivative 18 in a similar manner (Scheme 2).
Compounds, which showed in vitro MIC values in the
range of 0.25–1.0 lg/mL for most of the strains men-
tioned in Table 1, were further evaluated against a
broader panel of susceptible and resistant Gram-positive
strains (Table 2).
The results of in vitro antibacterial activities (MIC) of
compounds 7–20 against various bacterial strains are
summarized in Tables 1 and 2. The quinolones substitut-
ed by 8-methoxy have shown better antibacterial activity
than their corresponding 8-unsubstituted analogs.12 The
8-methoxy template is present in Gatifloxacin (4), there-
fore we introduced tetrahydrothienopyridine moiety at
C-7 to obtain 7. It has been observed that introduction
of tetrahydrothienopyridine led to significant loss of
antibacterial activity against susceptible Staphylococcus
epidermis and Pseudomonas aeruginosa (Table 1) com-
pared to Gatifloxacin for compound 7. However, in
most of the Staphylococcus aureus and Enterococcus fae-
cium strains, good antibacterial activity was observed
and compound 7 is more potent than Gatifloxacin in
MIC assay (Table 2). The corresponding 8-unsubstitut-
ed analog 15 showed inferior antibacterial activity
(Tables 1 and 2) indicating the importance of –OMe
The syntheses of compounds have been outlined in
Schemes 1 and 2. 4,5,6,7-Tetrahydro-thieno[3,2-c]pyri-
dine and its derivatives 21–25 were synthesized by meth-
od described in the literature.10 The difluoro derivatives
26–30 were synthesized conveniently using the methods
described in the literature.11 Conventional method to
introduce 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 21 or
its derivatives in quinolone scaffold of 26–30 failed to af-
ford the desired compounds 36–46. Thus, we decided to
activate the C-7 position by converting compounds
26–30 to fluoroborate derivatives 31–35 through transe-
sterification reaction using 40% aqueous solution of tet-
rafluoroboric acid. The nucleophilic substitution at 7th
position of fluoroborate derivatives 31–35 with tetrahy-
drothienopyridine derivatives 21–25 was achieved using
triethylamine in dimethylsulfoxide to afford compounds
36–46. Compounds 36–46 were hydrolyzed to the corre-

1926
B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1924–1929
Table 1. In vitro MIC values of novel quinolones 7–20 in various Gram-positive and Gram-negative bacteriaa
R3
O
N
O
F
OH
N
R1
R2
S
7-20
Compound
R1
R2
R3
Gram-positive
Gram-negative
K.p.
B.s.
S.e.
>16
S.a.
E.f.
P.a.
E.c.
7
8
–H
–Br
–OMe
–OMe
–OMe
–OMe
–OMe
–OMe
–OMe
–OMe
–H
–H
–H
60.12
60.12
60.12
60.12
60.12
0.5
60.12
1
2
0.5
>16
>16
1
0.25
4
60.12
2
0.5
60.12
4
9
–NO2
–CHO
–CH2OH
–COOH
–CH2OAc
–H
–H
–H
60.12
60.12
60.12
0.5
0.25
60.12
60.12
2
10
11
12
13
14
15
16
17
18
19
20
3
60.12
>16
1
60.12
8
16
0.25
0.25
8
–H
–H
2
2
8
0.5
>16
>16
>16
>16
>16
>16
>16
>16
>16
0.25
1.0
–H
60.12
0.25
60.12
2.0
0.25
8
2
0.5
16
–NO2
–H
–H
ND
ND
ND
>16
>16
>16
>16
2
ND
60.12
2
–H
–Br
60.12
60.12
60.12
1
8
0.5
4
0.25
1
–H
–F
4
–H
–H
–NH2
–NHAc
–F
16
4
4
0.25
>16
0.5
–F
–F
>16
2
>16
4
>16
8
–H
–Br
0.25
>16
–F
NH2
>16
60.12
0.25
0.25
ND
1
>16
60.12
60.12
60.12
>16
60.12
60.12
ND
60.12
60.12
60.12
4
0.5
16
0.5
ND
5
0.25
a MIC were determined by microbroth dilution technique and values reported in the table represent the values obtained in triplicate. B.s., Bacillus
subtilis ATCC 6633; S.e., Staphylococcus epidermidis ATCC 12228; S.a., Staphylococcus aureus ATCC 33591; E.f., Enterococcus faecalis ATCC
29212; P.a., Pseudomonas aeruginosa ATCC 27853; K.p., Klebsiella pneumoniae ATCC 10031; E.c., Escherichia coli ATCC 25922.
Table 2. In vitro (MIC values in lg/mL) antibacterial activity for selected quinolone compounds against broader panel susceptible and resistant
Gram-positive strainsa
Compound
S.a.1
S.a.2
S.a.3
S.a.4
S.a.5
E.f.1
E.f.2
E.f.3
S.p
7
8
60.125
60.125
0.25
2
2
>16
>16
>16
60.12
0.5
0.25
>16
>16
2
60.125
>16
16
16
60.125
8
0.5
2
4
>16
16
>16
>16
>16
ND
>16
ND
>16
ND
>16
>16
>16
>16
16
9
4
4
8
10
11
12
13
15
16
17
19
3
60.125
2
60.125
2
60.125
ND
0.5
2
0.25
0.25
16
60.12
60.12
1
ND
>16
ND
16
2
2
0.5
2
>16
4
>16
2
1
4
1
60.12
0.25
2
1
0.5
4
1
>16
>16
>16
>16
>16
8
>16
>16
>16
>16
>16
4
4
4
4
>16
>16
>16
1
>16
16
4
8
4
2
2
4
2
0.5
16
1
2
0.25
60.125
60.125
1
0.25
0.25
60.125
60.125
4
4
0.5
>16
0.5
1
5
60.125
60.125
8
16
a MIC were determined by microbroth dilution technique and values reported in the table represent the values obtained in triplicate. S.a.1,
Staphylococcus aureus ATCC 25923; S.a.2, Staphylococcus aureus ATCC 29213; S.a.3, Staphylococcus aureus ATCC 33592; S.a.4, methicillin
resistant Staphylococcus aureus ATCC 700699; S.a.5, linezolid resistant Staphylococcus aureus NRS 119; E.f.1, Enterococcus faecalisATCC 14506;
E.f.2, vancomycin resistant Enterococcus faecalis ATCC 700802; E.f.3, vancomycin resistant Enterococcus faecium ATCC 700221; S.p., penicillin
resistant Streptococcus pneumoniae ATCC 700904.
group at C-8. Compound 14, where a nitro group is
present at C-5 reduced the activity compared to 7. Fur-
thermore, we synthesized few tetrahydrothienopyridine
analogues 17, 18, and 20, having Sparfloxacin 5
(Fig. 1) template. However, compounds 17, 18, and 20
showed inferior in vitro activity than Sparfloxacin
(Tables 1 and 2). When fluoro was substituted at C-5
(19), moderate antibacterial activity is obtained. Fur-
ther, we studied the effect of a few substituents on the
tetrahydrothienopyridine moiety, which subsequently
furnished quinolones 8–13. Quinolone containing bro-
mo substituted tetrahydrothienopyridine as in com-
pound
8
showed antibacterial activities against
sensitive Bacillus subtilis and Staphylococcus epidermi-
dis, Staphylococcus aureus, Klebsiella pneumoniae, and
Escherichia coli. (Tables 1 and 2). However, 8 did not

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1924–1929
1927
R3
O
N
O
R3
O
N
O
R3
O
N
O
F
F
F
F
F
OBF2
OEt
(ii)
OBF2
R1
(i)
N
R1
NH
R2
R2
R2
S
S
26-30
31-35
21-25
36-46
(iii)
26: R2 = -OMe, R3 = -H
27: R2 = -OMe, R3 = -NO2
28: R2 = -H, R3 = -H
29: R2 = -F, R3 = -F
30: R2 = -F, R3 = -NH2
21: R1 = -H
31: R2 = -OMe, R3 = -H
32: R2 = -OMe, R3 = -NO2
33: R2 = -H, R3 = -H
34: R2 = -F, R3 = -F
35: R2 = -F, R3 = -NH2
22: R1 = -Br
23: R1 = -NO2
24: R1 = -CHO
R3
O
O
F
OH
25: R1 = -COOH
N
N
R1
R2
36: R1 = -H, R2 = -OMe, R3 = -H
37: R1 = -Br, R2 = -OMe, R3 = -H
38: R1 = -NO2, R2 = -OMe, R3 = -H
39: R1 = -CHO, R2 = -OMe, R3 = -H
40: R1 = -CH2OH, R2 = -OMe, R3 = -H
41: R1 = -H, R2 = -OMe, R3 = -NO2
42: R1 = -H, R2 = -H, R3 = -H
S
7-11, 14-17, 19 & 20
43: R1 = -Br, R2 = -H, R3 = -H
44: R1 = -H, R2 = -F, R3 = -NH2
45: R1 = -H, R 2= -F, R3 = -F
46: R1 = -Br, R2 = -F, R3 = -NH2
Scheme 1. Reagents and conditions: (i) 40% HBF4, 90–100 °C, 3.5 h; (ii) thienopyridine, DMSO, 40 °C, 1 h; (iii) 80% EtOH, TEA, 78–80 °C, 1 h.
R3
O
N
O
R3
O
N
O
R3
O
N
O
F
(i)
(ii)
F
F
OH
OH
OH
N
N
R1
N
R1
R1
R2
R2
R2
S
S
S
13
10 & 11, 17
12
(iii)
10: R1 = -CHO, R2 = -OMe, R3 = -H
12: R1 = -CO2H, R2 = -OMe, R3 = -H
R3
O
N
O
(i)
F
OH
11: R1 = -CH2OH, R2= -OMe, R3= -H
13: R1 = -CH2OAc, R2 =-OMe, R3 = -H
17: R1 =-H, R2 = -F, R3 = -NH2
(ii)
N
R1
R2
S
18
(iii)
18: R1 =-H, R2 = -F, R3 = -NHAc
Scheme 2. Reagents and conditions: (i) NaOH, AgNO3, H2O, 27–28 °C, 16 h; (ii) Ac2O, C5H5N, 0–5 °C, 1.5 h; (iii) AcOH, Ac2O, 110 °C, 30 min.
show activity against resistant strains (Table 2) as well as
against Pseudomonas aeruginosa (Table 1). The corre-
sponding C-8 unsubstituted analog 16 did not apprecia-
bly alter the antibacterial activities. Compound 9 with
an electron withdrawing –NO2 group on the tetrahydro-
thienopyridine exhibited comparable antibacterial activ-
ities with that of Gatifloxacin against the strains of
Table 1, but the same trend was not observed against
the strains mentioned in Table 2. When the –CHO
group was introduced in the thienopyridine system, the
quinolone 10 showed excellent in vitro antibacterial
activity against all the bacteria strains (Table 1). In view
of emerging resistance to linezolid, we wanted to test a
few selected quinolone derivatives against linezolid resis-
tant strains, which has G 2576-U mutations in the 23S
rRNA and these mutations have been reported to devel-
op microorganism having linezolid resistance.13 Thus,
we tested these compounds in linezolid resistant Staphy-

1928
B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1924–1929
Mahmoudi, N.; Santillana-Hayat, M.; Gozalbes, R.;
Farhati, K.; Derouin, F.; Aubry, A.; Cambu, E.; Vierling,
P. Eur. J. Med. Chem 2006 (article in press); (d) Forou-
madi, A.; Ghodsi, S.; Emami, S.; Najjari, S.; Samadi, N.;
Faramarzi, M. A.; Beikmohammadi, L.; Shirazi, F. H.;
Shafiee, A. Bioorg. Med. Chem. Lett. 2006, 16, 3499; (e)
Sriram, D.; Aubry, A.; Yogeeswari, P.; Fisher, L. M.
Bioorg. Med. Chem. Lett. 2006, 16, 2982; (f) Foroumadi,
A.; Oboudiat, M.; Emami, S.; Karimollah, A.; Saghee, L.;
Moshafi, M. H.; Shafiee, A. Bioorg. Med. Chem. 2006, 14,
3421; (g) Jarak, I.; Kralj, M.; Piantanida, I.; Suman, L.;
Zinic, M.; Pavelic, K.; Karminski-Zamola, G. Bioorg.
Med. Chem. 2006, 14, 2859; (h) Liu, B.; Yang, C. H.; Xu,
G. Y.; Zhu, Y. H.; Cui, J. R.; Wu, X. H.; Xie, Y. Y.
Bioorg. Med. Chem. 2005, 13, 2451; (i) Lohray, B. B.;
Lohray, V. B.; Srivastava, B. K. WO 05019224, 2005;
Chem. Abstr. 2005, 142, 280194; (j) Inagaki, H.; Miyauchi,
S.; Miyauchi, R. N.; Kawata, H. C.; Ohki, H.; Matsuh-
ashi, N.; Kawakami, K.; Takahashi, H.; Takemura, M.
J. Med. Chem. 2003, 46, 1005; (k) Foroumadi, A.;
Mansouri, S.; Kiani, Z.; Rahmani, A. Eur. J. Med. Chem.
2003, 38, 851; (l) Hubschwerlen, C.; Specklin, J. L.;
Baeschlin, D. K.; Borer, Y.; Haefeli, S.; Sigwalt, C.;
Schroeder, S.; Locher, H. H. Bioorg. Med. Chem. Lett.
2003, 13, 4229; (m) Kerns, R. J.; Rybak, M. J.; Kaatz, G.
W.; Vaka, F.; Cha, R.; Grucz, R. G.; Diwadkar, V. U.
Bioorg. Med. Chem. Lett. 2003, 13, 2109; (n) Jefferson, E.
A.; Swayze, E. E.; Osgood, S. A.; Miyaji, A.; Risen, L. M.;
Blyn, L. B. Bioorg. Med. Chem. Lett. 2003, 13, 1635; (o)
Chen, Y. L.; Fang, K. C.; Sheu, J. Y.; Hsu, S. L.; Tzeng,
C. C. J. Med. Chem. 2001, 44, 2374.
lococcus aureus strains NRS 119 from NARSA, USA.
(We are registered user of Network on Antimicrobial
Resistance in Staphylococcus aureus, www.narsa.net).
The compound 10 was found to be active against the
resistant strains such as methicillin resistant staphylococ-
cus aureus, vancomycin resistant enterococcus faecalis,
penicillin resistant streptococcus pneumoniae as well as
against linezolid resistant staphylococcus aureus (Table
2). A hydroxymethyl analog 11 in general has been
found to be less potent than its –CHO derivative 10.
On the other hand, the corresponding carboxylic acid
derivative 12 showed moderate antibacterial activity in
some of the strains. When the –OH group of hydroxy-
methyl group in 11 is protected by acetyl group, the –
OCOCH3 derivative 13 showed comparable in vitro
activities to its parent alcohol 11.
In summary, tetrahydrothienopyridine substitution at
the 7th position of quinolone moiety 7 showed in vitro
antibacterial activities against both susceptible and resis-
tant strains of bacteria. The bromo derivative 8 has infe-
rior potency than its desbromo derivative 7. The nitro
derivative 9 displayed similar in vitro MIC values as that
of bromo derivative 8. However, formyl derivative 10
emerged as the best compound as indicated by low
MIC values and among some of the resistant strains
tested. The compound 10 exhibited 4–8 times superior
antibacterial activity than Gatifloxacin, Ciprofloxacin,
and Sparfloxacin. The hydroxymethyl derivative 11
exhibited deterioration in antibacterial activities than
its precursor formyl derivative 10 and the corresponding
carboxylic acid derivative 12 did not show activities for
resistant strains. The –OCOCH3 derivative 13 is as good
as its hydroxy counterpart 11. The modifications in
quinolone nucleus, which resulted compounds 14–20,
showed significant loss of antibacterial activity. The
unsubstituted and substituted thienopyridine incorpo-
rated quinolones have shown a remarkable influence
on the antibacterial activities.
4. (a) Noguchi, N.; Okihara, T.; Namiki, Y.; Kumaki, Y.;
Yamanaka, Y.; Koyama, M.; Wakasugi, K.; Sasatsu, M.
Int. J. Antimicrob. Agents 2005, 25, 374; (b) Olliver, A.;
Valle, M.; Chaslus-Dancla, E.; Cloeckaert, A. FEMS
Microb. Lett. 2004, 238, 267; (c) Brown, P. D.; Izundu, A.
Rev. Panam. salud publica 2004, 16, 125; (d) Oh, H.;
Stenhoff, J.; Jalal, S.; Wretlind, B. Microb. Drug Resist.
2003, 9, 323; (e) Jang, C. H.; Park, S. Y. Int. J. Pediatric
Otrohinolaryngology 2003, 67, 313; (f) Raherison, S.;
Gonzalez, P.; Renaudin, H.; Charron, A.; Bebear, C.;
Bebear, C. M. Antimicrob. Agents Chemother. 2002, 46,
672; (g) Nakaya, H.; Yasuhara, A.; Yoshimura, K.;
Oshihoi, Y.; Izumiya, H.; Watanabe, H. Kansenshogaku
Zasshi 2001, 75, 815; (h) Ruiz, J.; Sierra, J. M.; De Anta,
M. T.; Vila, J. Int. J. Antimicrob. Agents 2001, 18, 107; (i)
Tanaka, M.; Wang, T.; Onodera, Y.; Uchida, Y.; Sato, K.
J. Infect. Chemother. 2000, 6, 131; (j) Liu, J.; Takiff, H. E.;
Nikkaido, H. J. Bacteriol. 1996, 178, 3791; (k) Fiuza de
Melo, F.; Affiune, J. B.; Ide Neto, J.; Seiscento, M.;
Castelo, A. Tubecle and Lung Disease 1995, 76, 89.
Acknowledgments
Authors are thankful to NARSA, USA, for providing
linezolid resistant strains. We are grateful to Dr. B. B.
Lohray, Dr. V. B. Lohray for valuable suggestions,
management of Zydus Group for encouragement, and
the analytical department for support.
5. Graul, A.; Rabasseda, X.; Castaner, J. Drugs Fut. 1999,
24, 1324.
6. Elmore, S. W.; Cooper, C. S.; Schultz, C. C.; Hutchinson,
D. K.; Donner, P. L.; Green, B. E.; Anderson, D. D.; Xie,
Q. WO 01/ 32655 A2, 2001, Chem. Abstr. 2001, 134, 34037.
7. Lohray, B. B.; Lohray, V. B.; Srivastava, B. K.; Kapadnis,
P.; Pandya, P. Bioorg. Med. Chem. 2004, 12, 4557.
References and notes
1. (a) Ray, S.; Pathak, S. R.; Chaturvedi, D. Drugs Fut. 2005,
30, 161, and references cited therein; (b) Ball, P.; Tillotson,
G.; Fernald, A. Exp. Opin. Invest. Drugs 1998, 7, 761; (c)
Bryskier, A. Exp. Opin. Invest. Drugs 1997, 6, 1227.
2. Rudolph, J.; Theis, H.; Hanke, R.; Endermann, R.;
Johansen, L.; Geschke, F. U. . J. Med. Chem 2001, 44,
619, and references cited therein.
3. (a) Farahanullah; Kim, S. Y.; Yoon, E. J.; Xu, G. Y.;
Choi, E. C.; Kim, S.; Kang, T.; Samrin, F.; Puri, S.; Lee, J.
Bioorg. Med. Chem. 2006, 14, 7154; (b) Zhao, G.; Miller,
M. J.; Franzblau, S.; Wan, B.; Mo¨llmann, U. Bioorg. Med.
Chem. Lett. 2006, 16, 5534; (c) Anquetin, G.; Greiner, J.;
8. 7. 99% purity by HPLC; mp 175 °C; IR (KBr): 3429, 1732,
1622 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 14.98 (s,
;
1H), 8.70 (s, 1H), 7.77 (d, J = 10.95 Hz, 1H), 7.35 (d,
J = 5.13 Hz, 1H), 6.91 (d, J = 5.13 Hz, 1H), 4.42 (s, 2H),
4.17 (m, 1H), 3.70 (s, 3H), 3.65 (t, J = 4.65 Hz, 2H), 2.98
(br s, 2H), 1.14–1.07 (m, 4H); ESI-MS: 415 (M+H)+.
Compound 8. 95.41% purity by HPLC; mp 180 °C (with
dec); IR (KBr): 3431, 1730, 1620 cmÀ1
;
1H NMR
(300 MHz, DMSO-d6): d 14.90 (s, 1H), 8.70 (s, 1H), 7.78
(d, J = 12.13 Hz, 1H), 7.05 (s, 1H), 4.36 (s, 2H), 4.18 (m,
1H), 3.70 (s, 3H), 3.63 (t, J = 4.92 Hz, 2H), 2.91 (br s, 2H),

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1924–1929
1929
1.14–1.04 (m, 4H); ESI-MS: 494 (M+H)+. Compound 9.
94.35% purity by HPLC; mp 220 °C (with dec); IR (KBr):
DMSO-d6): d 15.23 (s, 1H), 8.64 (s, 1H), 7.92 (d,
J = 13.32 Hz, 1H), 7.57 (d, J = 7.56 Hz, 1H), 7.09 (s,
1H), 4.45 (s, 2H), 3.79 (m, 1H), 3.73 (t, J = 5.43 Hz, 2H),
2.71 (br s, 2H), 1.14–1.12 (m, 4H); ESI-MS: 463.0
(M+H)+. Compound 17. 97.58% purity by HPLC; mp
3398, 1732, 1624 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
14.64 (s, 1H), 8.85 (s, 1H), 7.95(d, J = 12.0 Hz, 1H), 7.70
(s, 1H), 4.45 (s, 2H), 4.05 (m, 1H), 3.74 (t,J = 5.28 Hz,
2H), 3.71 (s, 3H), 3.12 (t, J = 5.46 Hz, 2H), 1.27 (m, 4H);
ESI-MS: 459.7 (M+H)+. Compound 10. 95.39% purity by
HPLC; mp 230–232 °C (with dec); IR (KBr): 3459, 1676,
277–280 °C (with dec); IR (KBr): 3338, 1683 cmÀ1
;
1H
NMR (300 MHz, CDCl3): d 14.68 (s, 1H), 8.66 (s, 1H),
7.16 (d, J = 5.13 Hz, 1H), 6.81 (d, J = 5.16 Hz, 1H), 6.51
(br s, 2H), 4.52 (s, 2H), 3.97 (m, 1H), 3.68 (t, J = 5.44 Hz,
2H), 3.05 (t, J = 5.32 Hz, 2H), 1.22 (m, 2H), 1.09 (m, 2H);
ESI-MS: 418.0 (M+H)+. Compound 18. 94.47% purity by
HPLC; mp above 275 °C (with dec); IR (KBr): 3325, 1629,
1624 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 14.93 (s,
;
1H), 9.85 (s, 1H), 8.71 (s, 1H), 7.85 (s, 1H), 7.77 (d,
J = 12.09 Hz, 1H), 4.48 (s, 2H), 4.17 (m, 1H), 3.71 (s, 3H),
3.67 (t, J = 5.23 Hz, 2H), 3.10 (t, J = 5.04 Hz, 2H), 1.14–
1.05 (m, 4H); ESI-MS: 443 (M+H)+. Compound 11.
94.95% purity by HPLC; mp 172–174 °C; IR (KBr): 3354,
1706, 1618 cmÀ1; 1H NMR (300 MHz, CDCl3 + few drops
of CD3OD): d 14.89 (s, 1H), 8.83 (s, 1H), 7.88(d,
J = 12.13 Hz, 1H), 6.73 (s, 1H), 5.33 (s, 1H), 4.74 (s,
2H), 4.42 (s, 2H), 4.0 (m, 1H), 3.75 (s, 3H), 3.72 (br s, 2H),
3.04 (br s, 2H), 1.15–1.05 (m, 4H); ESI-MS: 445 (M+H)+.
Compound 12. 98.52% purity by HPLC; mp 235–240 °C
1517 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 14.85 (s,
;
1H), 10.09 (s, 1H), 8.65 (s, 1H), 7.35 (d, J = 5.13 Hz, 1H),
6.90 (d, J = 5.16 Hz, 1H), 4.49 (s, 2H), 4.13 (m, 1H), 3.64
(br s, 2H), 2.97 (br s, 2H), 2.10 (s, 3H), 1.18–1.13 (m, 4H);
ESI-MS: 460.0 (M+H)+. Compound 19. 97.57% purity by
HPLC; mp 250–253 °C; IR (KBr): 3431, 1732,
1633 cmÀ1;1H NMR (300 MHz, DMSO-d6): d 14.74 (s,
1H), 8.64 (s, 1H), 7.36 (d, J = 5.16 Hz, 1H), 6.90 (d,
J = 5.16 Hz, 1H), 4.54 (s, 2H), 4.11 (m, 1H), 3.69 (t,
J = 5.04 Hz, 2H), 2.98 (br s, 2H), 1.16–1.14 (m, 4H); ESI-
MS: 421 (M+H)+. Compound 20. 97.5% purity by HPLC;
mp 265–268 °C (with dec); IR (KBr): 3446, 1645,
(with dec); IR (KBr): 3435, 1730, 1670 cmÀ1 1H NMR
;
(300 MHz, CDCl3 + few drops of CD3OD): d 8.84 (s, 1H),
7.91 (d, J = 12.09 Hz, 1H), 7.54 (s, 1H), 4.47 (s, 2H), 4.15
(m, 1H), 3.75 (s, 3H), 3.74 (t, J = 5.58 Hz, 2H), 3.09 (t,
J = 5.70 Hz, 2H), 1.26 (m, 2H), 1.05 (br s, 2H); ESI-MS:
459.0 (M+H)+. Compound 13. 95.28% purity by HPLC;
mp 202-204 °C (with dec); IR (KBr): 3435,
1587 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 14.68 (s,
;
1H), 8.51 (s, 1H), 7.30 (br s, 2H), 7.03 (s, 1H), 4.38 (s, 2H),
4.02 (m, 1H), 3.59 (br s, 2H), 2.86 (br s, 2H), 1.16–1.09 (m,
4H); ESI-MS: 498.0 (M+H)+.
1624,1512 cmÀ1 1H NMR (300 MHz, CDCl3): d 14.50
;
(s, 1H), 8.82 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 6.81 (s, 1H),
5.18 (s, 2H), 4.40 (s, 2H), 4.03 (m, 1H), 3.75 (s, 3H), 3.69
(t, J = 5.43 Hz, 2H), 3.03 (t, J = 5.33 Hz, 2H), 2.08 (s, 3H),
1.13 (m, 2H), 1.02 (m, 2H); ESI-MS: 487.0 (M+H)+.
Compound 14. 94.03% purity by HPLC; mp 180 °C (with
9. National Committee for Clinical Laboratory Standards.
Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically, 4th ed. (Approved
Standard); NCCLS Document M7-A4; NCCLS: Wayne,
Pa. 1997.
10. (a) Yamamoto, T.; Miura, T.; Isomura, Y.; Tadauchi, K.;
Iida, H.; Ouchi, S.; Katano, K. WO 97/ 36887, 1997,
Chem. Abstr. 1997, 127, 307400; (b) Halczenko, W.;
Stump, C. A. WO 99/ 27929, 1999, Chem. Abstr. 1999,
131, 19011; (c) Koike, H.; Asai, F.; Sugidachi, A.; Kimura,
T.; Inoue, T.; Nishino, S.; Tsuzuki, Y. CA 2077695, 1994,
Chem. Abstr. 1994, 120, 8583.
dec); IR (KBr): 3431, 1620, 1544 cmÀ1
;
1H NMR
(300 MHz, DMSO-d6): d 13.8 (s, 1H), 8.74 (s, 1H), 7.36
(d, J = 5.13 Hz, 1H), 6.91 (d, J = 5.16 Hz, 1H), 4.48 (s,
2H), 4.17 (m, 1H), 3.71 (s, 3H), 3.70 (br s, 2H), 2.99 (br s,
2H), 1.14–1.03 (m, 4H); ESI-MS: 460.0 (M+H)+. Com-
pound 15. 95% purity by HPLC; mp 230 °C (with dec); IR
(KBr): 3421, 1629, 1490 cmÀ1 1H NMR (300 MHz,
;
DMSO-d6): d 15.26 (s, 1H), 8.64 (s, 1H), 7.93 (d,
J = 13.35 Hz, 1H), 7.60 (d, J = 7.59 Hz, 1H), 7.39 (d,
J = 5.07 Hz, 1H), 6.97 (d, J = 5.10 Hz, 1H), 4.51 (s, 2H),
3.78 (m, 1H), 3.74 (t,J = 5.41 Hz, 2H), 2.98 (br s, 2H), 1.24
(m, 2H), 1.14 (m, 2H); ESI-MS: 385 (M+H)+. Compound
16. 95.11% purity by HPLC; mp 235–238 °C (with dec); IR
11. Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.;
Gracheck, S. J.; Huband, M. D.; Sesnie, J. A.; Cohen,
M. A.; Shapiro, M. A. J. Med. Chem. 1995, 38, 4478.
12. Kishii, R.; Takei, M.; Fukuda, H.; Hayashi, K.; Hosaka,
M. Antimicrob. Agents Chemother. 2003, 47, 77.
13. Bozdogan, B.; Appelbaum, P. C. Int. J. Antimicrob.
Agents 2004, 23, 113, and references cited therein.
(KBr): 3404, 1624, 1585 cmÀ1 1H NMR (300 MHz,
;