Construction and functionalization of fused pyridine ring leading to novel compounds as potential antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2012.05.096

A series of fused and functionalized pyridine derivatives were designed, synthesized and tested for their potential antitubercular properties. All these novel compounds were prepared by using multistep methods involving the construction of pyridine ring as a key synthetic step. Some of these compounds were found to be interesting when tested for their antitubercular properties in vitro and one of them appeared as an attractive and potential antitubercular agent.

Full text of DOI:10.1016/j.bmcl.2012.05.096

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4629–4635
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Construction and functionalization of fused pyridine ring leading to novel
compounds as potential antitubercular agents
Balakrishna Dulla a,b, Baojie Wan c, Scott G. Franzblau c, Ravikumar Kapavarapu b, Oliver Reiser a,
,
⇑
b,
Javed Iqbal b, , Manojit Pal
⇑
⇑
a Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
b Department of Medicinal Chemistry, Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India
c Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-723, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of fused and functionalized pyridine derivatives were designed, synthesized and tested for their
potential antitubercular properties. All these novel compounds were prepared by using multistep meth-
ods involving the construction of pyridine ring as a key synthetic step. Some of these compounds were
found to be interesting when tested for their antitubercular properties in vitro and one of them appeared
as an attractive and potential antitubercular agent.
Received 17 March 2012
Revised 15 May 2012
Accepted 28 May 2012
Available online 5 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Quinoline
X-ray
In vitro
Tuberculosis
Tuberculosis (TB),
a
major global health problem causes
The shikimate pathway constitutes the biosynthesis of aromatic
rings from carbohydrate precursors in microorganisms and plants
involving a range of chemical transformations. Through the seven
enzymatic steps, phosphoenol pyruvate (PEP) and D-erythrose
4-phosphate (E4P) are condensed to a branching point compound
called chorismate (the end product), which leads to several addi-
tional terminal pathways.8 Shikimate dehydrogenase (EC
1.1.1.25) plays an important role in catalyzing the fourth step in
the shikimate pathway (Fig. 1), involving the reversible conversion
of 3-dehydro shikimate (DHS) and NADPH to yield shikimate, a
3,4,5-trihydroxycyclohexene-1-carboxylic acid and NADP+.9–11
The absence of shikimate pathway in humans and its indispensible
morbidity and mortality in developing countries.1 It is estimated
that one-third of the entire human population is infected with
this disease.2–4 Complicated by the human immunodeficiency
virus (HIV), TB turns out to be most opportunistic co-infection
posing twin trouble which is growing at an alarming rate with
the increase of world human population.5,6 Additionally, with
the recent emergence of multidrug-resistant (MDR) and exten-
sively drug resistant (XDR)-TB, the disease poses a major threat
to the human life and hence, requires an immediate attention
for the identification and development of new and novel antitu-
bercular drugs.7
COO
COO
OH
OOC
shikimate
O
P O
O
O
P O
O
O
dehydrogenase
O
H2C
Chorismate
+
O
HO
OH
HO
O
OH
OH
OH
Erythrose
Phosphoenol
pyruvate
4-phosphate
3-dehydro shikimate
Shikimate
Figure 1. The role of shikimate dehydrogenase in the shikimate pathway.
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: Oliver.Reiser@chemie.uni-regensburg.de (O. Reiser), JIqbal@ilsresearch.org (J. Iqbal), manojitpal@rediffmail.com (M. Pal).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.096

4630
B. Dulla et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4629–4635
CO2H
COY
COY
X = Cl, OR3
R1
R2
R1
R2
Y = OH, OR3, NHNH2
Z = OH, O-
O
N
OH
O
N
Z
X
N
OH
A
B
C
Figure 2. Design of new and potential antitubercular agents from a known DHS analog A.
COOCH3
COOC2H5
n
COOH
O
1. POCl3
1) NaOEt
rt, 12 h
NC
O
HCl or H2SO4
Reflux, 18 h
n
n
n
24 h, reflux
75-91%
2. MeOH
rt, 24 h
Cl
N
2) 2-cyanoacetamide
80 °C; 6h
N
H
O
N
H
68-75%
65-75%
n = 0, 1a
1b
2a
n = 0,
3a
n = 0,
n = 0, a
2,
3, 1c
1d
2, 2b
2, 3b
b
2,
3, c
2c
2d
3,
5,
3c
3d
3,
5,
5,
d
5,
COOPr-n
N
DMF, 0 °C,
Cs2CO3, 1h, rt
O
n-PrI, 60 °C, 12 h
60 %
H
3e
COOH
COOH
COOCH3
Na
COOCH3
n
mCPBA
CH2Cl2
6N HCl
Reflux
MeOH
n
n
or EtOH
and
O
N
OH
EtO
N
O
48 h, rt
60-75%
O
N
OH
Cl
N
O
100 °C, 2 h
57-60%
COOH
0 °C, HCl,1 h
60-72%
7a
n = 2
n = 2, 5b
5a
3 7b
5c
3,
4a
n = 0,
2, 4b
LiOH.H2O
4c
4d
3,
5,
O
N
OH
THF + H2O (1:3)
63%
6
Scheme 1. Synthesis of 2-oxo-1,2-dihydropyridine-4-carboxylic acid derivatives (B).
COOCH3
COOH
6N HCl,
Reflux
12 h
COOH
COOCH3
Dry CH3CN,
Na2CO3.1.5H2O2
Na, EtOH
100°C, 2 h
Cl
N
O
Cl
EtO
N
O
OEt
65%
Tf2O, 0 °C 1h
rt, 16 h
81%
O
N
OH
OH
Cl
N
Cl
0 °C, HCl,1h
66%
8
9
11
10
Scheme 2. Synthesis of 1,6-dihydroxy-2-oxoisonicotinic acid A (11).13
importance in algae, higher plants, bacteria, and fungi makes the
pathway a potential target for the development of novel antituber-
cular agents.12
Accordingly, a novel DHS analog that is, 1,6-dihydroxy-2-oxoi-
sonicotinic acid (A, Fig. 2) was reported as a potential herbicide
based on the results obtained in the enzyme assay of shikimate
dehydrogenase.13 Indeed, the compound A has been reported as
evaluating a series of pyridine-4-carboxylic acid derivatives (B
and C, Fig. 2) for their potential antitubercular properties. The
structures of all target compounds were attained by introducing
a fused ring with or without substituents into the 2-pyridone moi-
ety of A and/or converting the carboxylate group into an ester or
hydrazide moiety (Fig. 2). The newly introduced fused ring was ex-
pected to provide additional hydrophobicity into the molecule
which was thought to be beneficial for the potential and enhanced
pharmacological properties of the resulting molecules.
a
powerful inhibitor of shikimate dehydrogenase from pea
(Ki = 0.12 mM) but was found to be less effective against couch en-
zyme (Ki = 0.32 mM).13 Prompted by these observations and due to
our continuing interest in the identification of novel small mole-
cules as potential antitubercular agents we became interested in
The synthesis14 of our target molecules based on B and C are
shown in the following Schemes. The 3-cyano-2-pyridone deriva-
tives (1a–d) prepared by treating appropriate ketones with cyano-

B. Dulla et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4629–4635
4631
Na2CO3,
1.5 H2O2
CH3CN
COOR1
1.POCl3
Reflux
3 h
COOH
O
CH2(CO2H)2
AcOH
R
R
R
O
N
2.SOCl2
Reflux
12 h
Tf2O, 0°C, 1h
rt, 16 h
Cl
N
O
N
H
H
Reflux, 2 h
R = H,
13a
ROH, Et3N
Reflux, 2 h
65-70%
R = H,
a
68-80%
R = H,
12a
70-75%
13b
13c
13d
CH3,
CH3, b
12b
12c
12d
CH3,
F,
F,
c
F,
NO2,
NO2, d
NO2,
R1= CH3, C2H5
COOR1
COOH
Na, R1OH
R
R
100°C;2 h
Cl
N
O
O
N
OH
0 °C, HCl,1 h
60-68%
R = H,
15a
R = H,
CH3,
F,
14a
15b
15c
CH3,
14b
14c
F,
R1= CH3, C2H5
Scheme 3. Synthesis of 2-oxo-1,2-dihydropyridine-4-carboxylic acid derivatives (B).
COOH
acetamide in the presence of NaOEt were converted to 2-pyridone
carboxylic acids (2a–d) and subsequently to 2-chloro ester deriva-
tives (3a–d) (Scheme 1). The acid 2a was also converted to the cor-
responding ester 3e as shown in Scheme 1. Treating the
compounds 3a–d with m-CPBA provided the corresponding N-oxi-
des (4a–d) that were converted to 1-hydroxy 2-pyridone deriva-
tive (5a) or 2-ethoxy pyridine N-oxides (5b–c) depending on the
reaction conditions employed. Finally, the ester 5a was hydrolyzed
to the corresponding acid 6 or the acids 5b–c were transformed
into the corresponding 1-hydroxy 2-pyridone derivatives (7a–b).
The DHS analog A (or 11) was prepared according to a known
method as shown in Scheme 2.13 The synthesis of our other target
molecules based on B is shown in Scheme 3. The 2-oxo-1,2-dihy-
droquinoline-4-carboxylic acid derivatives (12a–d) prepared from
appropriate indoline-2,3-diones were converted to the correspond-
ing 2-chloro ester derivatives (13a–d). Treating these compounds
with H2O2 provided the corresponding N-oxides (14a–c) that were
4a
4b
4c
4d
16a
n = 0,
LiOH.H2O
n
2, 16b
16c
16d
3,
5,
THF, H2O
0°C 2 h
60-80%
Cl
N
O
Scheme 4. Synthesis of 2-chloro acid derivatives (16).
COOH
LiOH
14a
14b
14c
17a
R = H
R
CH3 17b
THF, H2O
0°C 2 h
70-80%
Cl
N
O
17c
F
Scheme 5. Synthesis of 2-chloro acid derivatives (17a–c).
COOH
CONHNH2
COOC2H5
EtOH,AcCl
NH2NH2.H2O
12 h Reflux
EtOH,
N
H
O
O
N
H
n
n
n
O
N
H
85°C 4 h
74-82%
60-75%
n = 2, 19a
19b
n = 2, 2b
18a
n = 2,
2c
2d
3,
3,
5,
3, 18b
5 18c
Scheme 6. Synthesis of 2-oxo-1,2-dihydropyridine-4-carbohydrazide derivatives I.
COOC2H5
CONHNH2
COOH
EtOH,AcCl
NH2NH2.H2O
R
R
R
O
N
H
O
N
H
12 h Reflux
70-80%
EtOH,
O
N
H
85°C 4 h
66-75%
12a
12b
12c
12d
R = H,
R = H,
CH3, 21b
21c
NO2 21d
21a
R = H,
20a
CH3,
20b
20c
20d
CH3,
F,
F,
F,
NO2
NO2
Scheme 7. Synthesis of 2-oxo-1,2-dihydropyridine-4-carbohydrazide derivatives I.

4632
B. Dulla et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4629–4635
O
N
COOR1
COOH
O
N
O
N
COOCH3
O
N
R
O
a) POCl3
Reflux,18 h
DMAD
MeOH
R
O
R
O
N
R
O
N
N
1N NaOH
N
N
Cl
b) MeOH
rt, 24 h
65-75%
N
H
O
NH2
N
H
O
Reflux
2 h
Reflux
1-2 h
60-70%
50-60%
22d
23d
22e
R = H,
R = H,
22c
R = H,
= n-propyl 23a
22a
R = H,
22b
= n-propyl
R = R1= H,
= n-propyl 23c
= n-propyl 23b
Scheme 8. Synthesis of 7-chloro-2,4-dioxo-1-propyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine derivatives.
HN
O
COOC3H7
Figure 3. ORTEP representation of the 3e (C10H13NO3). (Thermal ellipsoids are drawn at 50% probability level).
HO
N
O
O
O
Figure 4. ORTEP representation of the 5a (C8H9NO4). (Thermal ellipsoids are drawn at 50% probability level).
converted to the desired 1-hydroxy-2-oxo-1, 2-dihydroquinoline-
4-carboxylic acid derivatives (15a–c).
The synthesis of target molecules based on C is shown in
Schemes 6 and 7. The ethyl-2-oxo-1,2-dihydropyridine-4-carbox-
ylate derivatives (18a–c and 20a–d) were prepared from the
appropriate 2-oxo-1,2-dihydroquinoline-4-carboxylic acid deriva-
tives (2b–d and 12a–d). The resulting ethyl esters were treated
with hydrazine hydrate to afford 2-oxo-1,2-dihydropyridine-4-car-
bohydrazide derivatives (19a–b and 21a–d).
Synthesis of 2-chloro acid derivatives (16a–d) from
4 is
shown in Scheme 4 whereas preparation of other 2-chloro acid
derivatives (17a–c) from 14a–c is shown in Scheme 5. The reac-
tions were carried out carefully in the presence of LiOH in these
cases.

B. Dulla et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4629–4635
4633
O
N
O
COOH
Figure 5. ORTEP representation of the 5b (C11H13NO4.H2O). (Thermal ellipsoids are drawn at 50% probability level).
Table 1
In vitro assay results of selected compounds
Table 2
Dock scores obtained after docking the molecules into the SDHmt protein
Compound
Structure
MIC (
l
g/mL)
IC50
mL)
Vero cell
(
l
g/
Molecules
MOE Dock score (K cal/mol)
14a
14b
14c
11
À10.03
À12.84
À10.93
À8.87
MABA LORA
CO2Et
14a
9.2
7.3
n.d.
Cl
Cl
Cl
O
N
O
CO2Et
The 4-methylcarboxylate-2-pyridone derivatives ( 22b, 23b)
were prepared by treating appropriate uracil derivatives (22a,
23a) with dimethyl acetylenedicarboxylate in MeOH. These com-
pounds were converted to 2-pyridone carboxylic acids (22c, 23c)
and subsequently to 2-chloro ester derivatives (22d, 23d) (Scheme
8). Treating the compounds 22d, 23d with several per acids did not
provide the corresponding N-oxides. Saponification of 22d with
LiOHÁH2O provided the compound 22e.
Me
F
14b
14c
11
4.33
10.9
>100
>50
3.65
13.1
n.d.
n.d.
<8.0 (96%)
N
O
CO2Et
While all the compounds synthesized were characterized by
spectral (NMR, IR and MS) data the molecular structure of few rep-
resentative compounds for example, 3e, 5a, and 5b were confirmed
unambiguously by single crystal X-ray diffraction (Figs. 3–5).15
All the compounds synthesized initially were tested for their
activity against Mycobacterium tuberculosis H37Rv that was deter-
mined by using fluorescence readout in the Microplate Alamar
Blue Assay (MABA).16 The MIC value obtained through this assay
was defined as the minimum concentration inhibiting fluorescence
by 90% relative to bacteria-only controls. The compounds found
promising in this assay were then tested for their activity against
non-replicating M. tuberculosis that was determined by using the
Low-Oxygen Recovery Assay (LORA).17 Like earlier case, MIC value
obtained was defined as the lowest concentration inhibiting
recovery of luciferase signal, greater or equal to 90% relative to
bacteria-only controls. The well-known agents such as rifampicin
(a semisynthetic bactericidal antibiotic drug), isoniazide (or ison-
icotinylhydrazine, an antitubercular agent) and moxifloxacin (a
fluoroquinolone antibacterial agent) were used as reference
compounds in these assays. Finally, the cytotoxicity assay18 of
the best compound was carried out using Vero cells. Among all
n.d.
N
O
COOH
n.d.
N
OH
COOH
OH
Citrazinic
acid
n.d.
O
N
H
OH
Rifampicin
Isoniazide
0.05
0.33
1.47
n.d.
n.d.
>128
(84%)
15.93
Moxifloxacin
0.39
n.d.
n.d. = not determined.

4634
B. Dulla et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4629–4635
Figure 7. The ligand interaction and binding pose of compound 14b with SDHmt
protein.
Figure 6. The ligand interaction and binding pose of compound 14a with SDHmt
protein.
summarized in Table 2. It is evident from Table 2 that in compared
to compound 11 these molecules (14a–c) bind better with SDHmt
the compound 14b being the best among them. The ligand interac-
tion and binding pose of compound 14a–c with SDHmt protein is
shown in Figs. 6–8. All these molecules were found to interact with
the SDHmt protein through H-bonding. For example, compound
14a with Arg 29 or 14b with Lys69 or 14c with Arg29 residue of
the protein used. Additionally, the fused ring (introduced by drug
design approach, see Fig. 2) that is, the benzene ring fused with
the pyridine moiety participated well in hydrophobic interactions
in all these cases. The compound 11 showed H-bonding interac-
tions with the Pro57 and Glu58 residues of SDHmt protein (see
ESI). Overall, the docking studies indicated that the present N-oxi-
des19 14a–c could be potential inhibitors of shikimate dehydroge-
nase and are of further interest.
In summary, based on the reported assay results of a novel DHS
analog that is, 1,6-dihydroxy-2-oxoisonicotinic acid against shi-
kimate dehydrogenase a series of fused and functionalized pyri-
dine derivatives were designed, synthesized and tested for their
potential antitubercular properties. All these pyridine based com-
pounds were prepared by using multistep methods involving the
construction of pyridine ring as a key synthetic step followed by
further functionalization reactions. Few of these compounds were
found to be interesting when tested in vitro. Based on overall re-
sults the compound 14b appeared as an attractive and potential
antitubarcular agent.
the compounds tested quinoline-1-oxides that is, 14a, 14b, and 14c
were found to be promising in MABA (Table 1). Indeed, compound
14b showed the lowest MIC that is, 4.33
compound also showed the lowest MIC that is, 3.65
(Table 1). Finally, this compound showed IC50 value <8.0
the cytotoxicity assay in Vero cells. Among the other compounds
2a–d, 4d, 6, 12a–d and 16b showed MIC >50 g/mL whereas the
rest of the compounds showed MIC >100 g/mL when tested in
l
g/mL among them. This
g/mL in LORA
g/mL in
l
l
l
l
MABA (see ESI). Notably, MIC of the known inhibitor of shikimate
dehydrogenase13 11 and citrazinic acid were found to be >50 and
100 lg/mL, respectively, in the same assay (Table 1). Nevertheless,
the compound 14b though found to be slightly less effective than
the reference compounds employed in MABA but was comparable
or better than rifampicin, isoniazide and moxifloxacin in LORA.
Overall, the compound 14b appeared as attractive new chemical
entity due to its interesting and novel structural features.
To understand the nature of interactions of these molecules
with the shikimate dehydrogenase protein of Mycobacterium
tuberculosis (SDHmt) in silico docking studies were performed
using compounds 14a–c along with the known inhibitor of shikim-
ate dehydrogenase13 11. An SDHmt protein homology model was
developed and used for this purpose (see ESI). The dock scores ob-
tained after docking these molecules into the SDHmt protein are

B. Dulla et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4629–4635
2. LoBue, P. Curr. Opin. Infect. Dis. 2009, 22, 167.
4635
3. Jain, A.; Dixit, P. J. Biosci. 2008, 33, 605.
4. Rattan, A.; Kalita, A.; Ahmed, N. Emerg. Infect. Dis. 1998, 4, 195.
5. (a) Global Tuberculosis Control: epidemiology, strategy, financing. WHO Report
2009, Geneva, World Health, Organization, 2009 (WHO/HTM/TB/2009.411).;
(b) WHO Report. http://www.who.int/tb/publications/globalreport/2009/
update/en/index.html.
6. WHO
Report.
http://www.who.int/tb/publications/globalreport/2009/
summary/en/index.html.
7. Mandavilli, A. Nat. Med. 2007, 13, 271.
8. Stokstad, E. Science 2000, 287, 2391.
9. Anton, I. A.; Coggins, J. R. Biochem. J. 1988, 249, 319.
10. Bentley, R. Crit. Rev. Biochem. Mol. Biol. 1990, 25, 307.
11. Yaniv, H.; Gilvarg, C. J. Biol. Chem. 1955, 213, 787.
12. Baillie, A. C.; Corbett, J. R.; Dowsett, J. R.; McCloskey, P. Biochem. J. 1972, 126,
21P.
13. Baillie, A. C.; Corbett, J. R.; Dowsett, J. R.; McCloskey, P. Pestic. Sci. 1972, 3, 113.
14. (a) Havas, F.; Leygue, N.; Danel, M.; Mestre, B.; Picard, C. G. C. Tetrahedron 2009,
65, 7673; (b) Hundscheid, A. F. J.; Engberts, J. B. F. N. J. Org. Chem. 1984, 49,
3088; (c) Lowe, J. A.; Ewinga, F. E.; Drozda, S. E. Synth. Commun. 1989, 19, 3027;
(d) Isler, O.; Gutmann, H.; Straub, O.; Fust, B.; Bohni, E.; Studer, A. Helv. Chim.
Acta. 1955, 1033, 38; (e) Hirota, K.; Kitade, Y.; Senda, S.; Halat, J. M.; Watanabe,
A. K.; Fox, J. J. J. Org. Chem. 1981, 46, 846; (f) Zhu, X.; Kreutter, K. D.; Hu, H.;
Player, M. R.; Gaul, M. D. Tetrahedron Lett. 2008, 49, 832; (g) Markley, L. D.;
Soper, J. M. US Patent application US4,474,602, 1984.; (h) Mello, J. V.; Finney, N.
S. J. Am. Chem. Soc. 2005, 127, 10124; (i) Brian, A.; Stephanos, I.; Paul, L.;
Timothy, P. World patent application WO 2006003378, 2006.; (j) El Ashrya, E.
S. H.; Ramadan, E. S.; Hamida, H. A.; Hagara, M. Synth. Commun. 2005, 35, 2243;
(k) Feldman, K. S.; Coca, A. Tetrahedron Lett. 2008, 49, 2136; (l) Zhuravleva, A.
Y.; Zimichev, A. V.; Zemtsova, M. N.; Klimochkin, Yu. N. Russ. J. Org. Chem. 2009,
45, 609; (m) Biichi, J.; Hurni, H.; Lieberherr, R. Helv. Chim. Acta 1950, 114, 858;
(n) Cappelli, A.; Gallelli, A.; Manini, M.; Anzini, M.; Mennuni, M.; Mennuni, L.;
Makovec, F.; Menziani, M. C.; Alcaro, S.; Ortuso, F.; Vomero, S. J. Med. Chem.
2005, 48, 3564; (o) Movrin, M.; Majsinger, D. Eur. J. Med. Chem. 1974, 9, 615; (p)
Anderson, G. L.; Shim, J. L.; Broom, A. D. J. Org. Chem. 1976, 1095, 41; (q) Muller,
C. E.; Sandoval-Ramirez, J. Synthesis 1995, 1295; (r) Isaac, M.; Slassi, A.;
Edwards, L.; Dove, P.; Xin, T.; Stefanac, T. World patent application WO
2008041075, 2008.; (s) Mei, F.; Wu, S.-Y.; Wang, Y.-Y.; Kao, I.-S. Yaoxue Xuebao
1959, 7, 311; (t) Li, J.; Zhang, J.; Chen, J.; Luo, X.; Zhu, W.; Shen, J.; Liu, H.; Xu,
Shen; Jiang, H. J. Comb. Chem. 2006, 8, 326.
15. (a) Crystal data of 3e: Molecular formula = C10H13NO3, formula weight = 195.21,
crystal system = monoclinic, space group = P2(1)/n, a = 8.918 (11) Å, b = 7.969
(7) Å, c = 14.721 (18) Å, V = 1009.73 (2) Å3, T = 296 K, Z = 4, Dc = 1.284 Mg mÀ3
,
l
(Mo
K
a
) = 0.79 mmÀ1
,
5081 reflections measured, 1808 independent
(I)], R1_obs = 0.009, goodness
reflections, 1612 observed reflections [I >2.0
r
of fit = 1.081. Crystallographic data (excluding structure factors) for 3e have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication number CCDC 871206. (b) Crystal data of 5a:
Molecular
system = orthorhombic, space group = Pna21, a = 23.033 (6) Å, b = 4.038
(10) Å, c = 18.018 (5) Å, V = 1676.2 (8) Å3, T = 296 K, Z = 8, Dc = 1.456 Mg mÀ3
(Mo 5768 reflections measured, 2506 independent
) = 1.01 mmÀ1
reflections, 2371 observed reflections [I >2.0 (I)], R1_obs = 0.026, goodness
formula = C8H9NO4,
formula
weight = 183.16,
crystal
Figure 8. Ligand interaction and binding pose of compound 14c with SDHmt
protein.
,
l
K
a
,
r
Acknowledgements
of fit = 1.05. Crystallographic data (excluding structure factors) for 5a have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication number CCDC 871207. (c) Crystal data of 5b:
Molecular formula = C11H13NO4,H2O, formula weight = 241.24, crystal
system = monoclinic, space group = P2(1)/n, a = 10.413 (19) Å, b = 19.895
The authors thank the management of ILS for encouragement
and support, Dr. M. Zabel and S. Stempfhuber for single crystal
X-ray structure analyses and Dr. G. Gopikrishna for literature help.
B.D. thanks A.K. Reiser, University of Regensburg, Germany and
DAAD (Indigo) for providing a fellowship. B.D. also thanks Dr. T.
D. Neelima for support and DST for providing a fellowship.
(3) Å, c = 11.164 (2) Å, V = 2256.54 (7) Å3, T = 296 K, Z = 8, Dc = 1.387 Mg mÀ3
,
l
(Mo
K
a
) = 0.95 mmÀ1
,
17064 reflections measured, 4439 independent
(I)], R1_obs = 0.031, goodness
reflections, 3792 observed reflections [I >2.0
r
of fit = 1.05. Crystallographic data (excluding structure factors) for 5b have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication number CCDC 871209.
16. Collins, L. A.; Franzblau, S. G. Antimicrob. Agents Chemother. 1997, 1004, 41.
17. Cho, S. H.; Warit, S.; Wan, B.; Hwang, C. H.; Pauli, G. F.; Franzblau, S. G.
Antimicrob. Agents Chemother. 2007, 51, 1380.
Supplementary data
18. Macabeo, A. P. G.; Vidar, W. S.; Chen, X.; Decker, M.; Heilmann, J.; Wan, B.;
Franzblau, S. G.; Galvez, E. V.; Aguinaldo, M. A. M.; Cordell, G. A. Eur. J. Med.
Chem. 2011, 46, 3118.
19. Pyridine N-oxides are well known in the literature and found to be beneficial in
terms of their pharmacological properties. For example, pyridine N-oxide
showed protective effects against 3-chloropyridine-induced cytotoxicity and
clastogenicity (see: Anuszewska, E. L.; Koziorowska, J. H. Toxicol. In Vitro 1995,
9, 91).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
05.096.
References and notes
1. Bloom, B. R.; Murray, C. J. Science 1992, 1055, 257.