Synthesis and biological evaluation of indole core-based derivatives with potent antibacterial activity against resistant bacterial pathogens

Article abstract of DOI:10.1038/ja.2017.55

The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-spectrum anti-infective agents.

Full text of DOI:10.1038/ja.2017.55

The Journal of Antibiotics (2017), 1–13
2017 Japan Antibiotics Research Association All rights reserved 0021-8820/17
www.nature.com/ja
&
ORIGINAL ARTICLE
Synthesis and biological evaluation of indole
core-based derivatives with potent antibacterial activity
against resistant bacterial pathogens
1
2
3
3
3
3
4
5
Wei Hong , Jingyang Li , Zhe Chang , Xiaoli Tan , Hao Yang , Yifan Ouyang , Yanhui Yang , Sargit Kaur ,
6
5
3,7
Ian C Paterson , Yun Fong Ngeow and Hao Wang
The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient
management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target
extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel
indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of
these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus
aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum
beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter
baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-
spectrum anti-infective agents.
The Journal of Antibiotics advance online publication, 3 May 2017; doi:10.1038/ja.2017.55
INTRODUCTION
and transpeptidase (TP) enzymes have a major role together in the
Antibiotic resistance in bacterial pathogens has become a global public synthesis of peptidoglycan. These enzymes are suitable targets for
health threat associated with grave human and economic loss. This antibacterial drugs because they are not present in mammalian cells,
problem, previously characteristic of nosocomial infections, is now and hence, drugs inhibiting them will not affect normal mammalian
increasingly seen in community-acquired infections as well. Notable cells.8
,9
examples include the Gram-positive pathogens, such as methicillin-
TP enzymes, also called penicillin-binding proteins, are well-known
resistant Staphylococcus aureus, vancomycin-resistant enterococci and targets of β-lactam antibiotics. GT inhibitors, on the other hand, have
drug-resistant Streptococcus pneumoniae, as well as multiply resistant been less studied for their antibacterial activity. The best known
Gram-negative bacilli, such as Klebsiella pneumoniae, Acinetobacter peptidoglycan GT inhibitors are moenomycins, which are a family of
baumanii, Pseudomonas aeruginosa, Enterobacter cloacae and Escher- phosphoglycolipids produced by the Streptomyces genus. These inhi-
ichia coli. These bacteria are common nosocomiants, but the bitors have been used as growth promoters in animal feed but have
emergence of multidrug resistance via multiple resistance mechanisms not been developed as antibiotics for human infections.10 Their
has made them deadly pathogens in a wide range of infections.1–7 activity against multidrug-resistant bacteria has not been reported.
With the escalation of multidrug resistance, the need for new
Indoles are natural organic compounds with an aromatic hetero-
antibiotics is urgent. Unfortunately, very few antibiotics currently cyclic structure that are widely used in the synthesis of pharmaceutical
available can combat multidrug resistance and also very few are in the agents. Many synthesized derivatives have potent activity against fungi,
pipeline for future development.
viruses and Leishmania parasites as well as Gram-positive and Gram-
Peptidoglycan is an essential component to keep the bacterial cell negative bacteria and mycobacterial species.11–14 This wide-spectrum
wall’s strength and shape. The peptidoglycan glycosyltransferase (GT) activity makes them suitable candidates for the development of novel
1
3
2
School of Chemistry and Chemical Engineering, Beifang University of Nationalities, Yinchuan, PR China; Logistics University of the China Armed Police Force, Tianjin, PR China;
4
5
School of Pharmacy, Ningxia Medical University, Yinchuan, PR China; School of Basic Medicine, Ningxia Medical University, Yinchuan, PR China; Department of Pre-Clinical
6
Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia; Department of Oral Biology and Biomedical Sciences and Oral Cancer
Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia and Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of
7
Education, Ningxia Medical University, Yinchuan, PR China
Correspondence: Dr W Hong, School of Chemistry and Chemical Engineering, Beifang University of Nationalities, Yinchuan, Ningxia 750021, PR China.
E-mail: hongwei136@hotmail.com
or Professor YF Ngeow, Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sungai Long Campus, Selangor 43000,
Malaysia.
E-mail: yunngeow@yahoo.com
or Professor H Wang, School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China.
E-mail: paxhw@yahoo.co.uk
Received 6 December 2016; revised 12 March 2017; accepted 20 March 2017

Indole core-based derivatives
W Hong et al
2
Figure 1 The design of the glycosyltransferase inhibitors. (a) The binding site of moenomycin. The moenomycin is represented as a balls–sticks model, and
the protein is representad as a ribbon; (b) the pharmacophore designed to fit the binding site; (c) the detailed interactions between the template compound
and the GT-binding site; (d) combining bioactive molecules to generate target compounds. A full color version of this figure is available at The Journal of
Antibiotics journal online.
anti-infectives so urgently needed to overcome the current global added to form same interactions with Phe158. Recently,
problem of multidrug resistance.
much attention has been paid to indole core derivatives due to their
Here we describe the discovery of new indole core derivatives diverse biological activities, for instance, the inhibition of bacteria,12
showing activity against bacterial pathogens commonly isolated viruses,13 leishmania parasites14 and cancerous cells.16 More recently,
from clinical specimens. We synthesized indole compounds with
substituted side-chains to act as potential GT inhibitors. In the
bacterial cell wall, TP and GT work as bifunctional proteins, in which
the TP domain is located in the C-terminal and the GT domain in the
N-terminal, with a small linker region separating the two domains.
The crystal structure of the GT-binding site of S. aureus complexed
with moenomycin (PDB 2OLV) has been reported.15 The
moenomycin-binding site is a relatively big site. As Figure 1a
shows, from studies on the crystal structure and drug-like properties
of moenomycin, it appears unnecessary to design inhibitors to occupy
the whole binding site. Hence, we chose the segment of the binding
site composed by Asp156, Glu114, Pro231, Tyr196 and Phe158
it has been discovered that aminoguanidine or 2-hydrazino-2-
imidazoline derivatives display antitumor activities17 and aminogua-
nidine derivatives show antibacterial activities.18,19 Using this informa-
tion, we designed a template compound (Figure 1c), which contains
the indole core to form π–π interactions with Tyr196 (area 2),
the aminoguanidine to form static electricity interactions with
Asp156 and Glu114 and the N-1 substituted benzyl to form a potential
π–π interaction with Phe158 (area 3). Based on the template
compound, we noticed by the molecular docking results that
aminoguanidine may form additional hydrogen bonds with Pro231
and Tyr191, and by adding methoxycarbonyl group on the indole
core, hydrogen bonds may be formed with Asn235 (area 4). By further
considering Pro231, which contains five-membered aromatic ring, it
was thought an aromatic ring close by should increase the binding
affinity. Therefore, in our second series, we used 2-(4,5-dihydro-1H-
(area in the red circle) as the target for our new indole derivatives.
Based on the structure of the GT binding site (Figure 1b), it was
noticed that Asp156, Glu114 and Pro231 form a hydrophilic
pocket, which should be occupied by the positive-charged group to
form strong static electricity interaction with the negative-charged imidazol-2-yl)hydrazone to form an extra π–π interaction with
residues (Asp156 and Glu114). Considering the Tyr196 in the Pro231. Subsequently, we prepared indole core derivatives by combin-
binding site, it was believed that an aromatic ring around it should ing 3-acylindoles with either aminoguanidine or 2-hydrazino-2-
form strong π–π interactions, and another aromatic ring should be imidazoline (Figure 1d).
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
3
NH2
NH
O
O
H
Br
HN
N
HCl
R2
H
a
c
R1
R1
R1
R1
N
N
H
b
N
R2
N
R2
H
1a-b
2a-b
3
a-l
4
a-l
1
1
a, 2a, R1 = 5-COOCH3;
b, 2b, R1 = 6-COOCH3
d
3
3
a, 4a, 5a, R1 = 5-COOCH3; R2 = p-Cl;
b, 4b, 5b, R1 = 5-COOCH3; R2 = p-F;
N
HBr
3c, 4c, 5c, R1 = 5-COOCH3; R2 = p-COOCH3;
d, 4d, 5d, R1 = 5-COOCH3; R2 = m-COOCH3;
3e, 4e, 5e, R1 = 5-COOCH3; R2 = p-NO2;
HN
N
3
N
H
3
3
3
3
3
f, 4f, 5f, R1 = 5-COOCH3; R2 = m-NO2;
g, 4g, 5g, R1 = 6-COOCH3; R2 = p-Cl;
h, 4h, 5h, R1 = 6-COOCH3; R2 = p-F;
i, 4i, 5i, R1 = 6-COOCH3; R2 = p-COOCH3;
j, 4j, 5j, R1 = 6-COOCH3; R2 = m-COOCH3;
R1
N
R2
5a-l
3k, 4k, 5k, R1 = 6-COOCH3; R2 = p-NO2;
l, 4l, 5l, R1 = 6-COOCH3; R2 = m-NO2;
3
Scheme 1 (a) POCl3 dry DMF; (b) substituted benzyl bromide, NaH, dry DMSO; (c) aminoguanidine hydrochloride, dry CH3OH; (d) 2-hydrazino-2-imidazoline
hydrobromide, dry CH3OH.
NH2
NH
O
O
HN
N
HCl
H
H
a
b
R1
R1
R1
N
N
O
N
H
O
2a-b
6
a-b
7
a-b
c
N
HBr
HN
N
N
H
R1
N
O
2
2
a, 6a, 7a, 8a, R1 = 5-COOCH3;
b, 6b, 7b, 8b, R1 = 6-COOCH3;
8
a-b
Scheme 2 (a) benzoyl chloride, NaH, dry DMF; (b) aminoguanidine hydrochloride, dry CH3OH; (c) 2-hydrazino-2-imidazoline hydrobromide, dry CH3OH.
RESULTS AND DISCUSSION
Chemistry
hydrobromide in dry methanol under reflux, followed by purification
by tutrition with ethyl ether in 82–96% yields.
We synthesized a series of aminoguanidine derivatives of 3-acylindoles
In Scheme 2, treatment of compounds 2a-b with benzoyl chloride
4a-l, 7a-b, 13a-f and 2-(4,5-dihydro-1H-imidazol-2-yl)hydrazone in the presence of sodium hydride in dry DMF generated 6a-b in
derivatives of 3-acylindoles 5a-l, 8a-b and 14a-f as illustrated in 66–71% yields. Then target compounds 7a-b and 8a-b were obtained
Schemes 1,2,3. In Scheme 1, the substituted indoles 2a-b were by the reaction of 6a-b separately with aminoguanidine hydrochloride
generated in the presence of phosphorus oxychloride and dry under pH 3–4 and 2-hydrazino-2-imidazoline hydrobromide under
dimethylformamide (DMF) by Vilsmeier–Haack reaction.20 Treatment reflux, followed by the purification by tutrition with ethyl ether in
of 2a-b with substituted benzyl bromide in the presence of sodium 70–92% yields.
hydride in dry dimethyl sulfoxide (DMSO) generated 3a-l in
In Scheme 3, compound 10 was generated from 9 in the presence of
moderate-to-good yields (51–96%). Finally, target compounds 4a-l phosphorus oxychloride and dry DMF by Vilsmeier–Haack reaction.20
were obtained by the reaction of 3a-l with aminoguanidine hydro- Treatment of 10 with benzenesulfonyl chloride in the presence of
chloride under pH 3–4 in dry methanol in 76–97% yields, which were sodium hydride in dry DMF generated 11, which was reacted with
purified by tutrition with ethyl ether. Target compounds 5a-l were substituted phenylboronic acid in the presence of PdCl (dtbpf) and
2
generated by the reaction of 3a-l with 2-hydrazino-2-imidazoline potassium carbonate in tetrahydrofuran/H O by Suzuki reaction21 to
2
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
4
O
N
O
H
H
O
Br
Br
a
Br
b
c
HO
HO
N
N
H
H
S
B
O
R1
9
1
0
11
NH2
NH
HN
N
HCl
R
O
N
N
O
d
H
O
S
R
O
13a-f
S
e
O
N
HN
HBr
N
HN
R
1
2a-f
1
2a, 13a, 14a, R = p-COOCH3;
N
O
12b, 13b, 14b, R = m-COOCH3;
12c, 13c, 14c, R = p-OCF3;
S
O
12d, 13d, 14d, R = m-OCF3;
12e, 13e, 14e, R = p-CF3;
12f, 13f, 14f, R = p-F-m-Cl
1
4a-f
Scheme 3 (a) POCl3, dry DMF; (b) benzenesulfonyl chloride, NaH, dry DMF; (c) substituted phenylboronic acid, K2CO3, Pd(dbpf)Cl2, tetrahydrofuran/H2O;
d) aminoguanidine hydrochloride, dry CH3OH; (e) 2-hydrazino-2-imidazoline hydrobromide, dry CH3OH.
(
give 12a-f in moderate-to-good yields (53–89%). Finally, the target tested, including reference and clinical strains of methicillin-
compounds 13a-f and 14a-f were obtained by the reaction of 12a-f susceptible and -resistant S. aureus, Streptococcus pyogenes and S.
separately with aminoguanidine hydrochloride under pH 3–4 and pneumoniae from respiratory tract infections, a strain of vancomycin-
2-hydrazino-2-imidazoline hydrobromide under reflux, followed by resistant enterococcus from a urinary tract infection, a coagulase-
the purification by tutrition with ethyl ether in 53–98% yields. All of negative Staphylococcus, a Corynebacterium sp. and M. tuberculosis
1
the novel target compounds were characterized by H-NMR, MS, H37Ra. Against Gram-negative bacilli, all four compounds inhibited
HRMS and m.p.
A. baumanii strains, which were resistant to multiple antibiotics,
including carbapenem and imipenem, and were susceptible to only
colistin, the ‘last-resort’ antibiotic for many multidrug-resistant
Determination of in vitro antibacterial activity
In the preliminary screen where all 40 compounds were tested for bacteria. 4a and 4g inhibited E. coli and Klebsiella pneumoniae strains
antibacterial activity against S. aureus, 20 compounds showed in vitro that were producers of extended-spectrum beta-lactamases. None of
growth inhibition with minimum inhibitory concentrations (MICs) the compounds, however, showed activity against P. aeruginosa at
ranging from 3.13 to 100 μg ml− and a median MIC of 12.5 μg ml
data not shown).
Subsequent MIC and minimum bactericidal concentration (MBC) Molecular docking
1
− 1
concentrations o100 μg ml− 1
.
(
studies on these 20 compounds showed the inhibition of both The molecular docking research showed that all the molecules were
methicillin-susceptible and methicillin-resistant S. aureus with median docked into a relative small area, although the binding site indicated
MICs of 12.5 and 6.25 μg ml− , respectively (Table 1). These six by Moenomycin A is much larger than the synthesized molecules
compounds (4a, 13a, 13c, 13d, 13e, 13f) showed antimethicillin- (Figure 2). By comparing with the literature, it was observed that the
resistant Staphylococcus aureus MICs that were almost the same as that binding site of the current study is similar to that published before,19
of vancomycin, the standard antibiotic for the treatment of which is a site composed by Glu 114, TYR191, Gln 152, Asp 156, Ile
methicillin-resistant Staphylococcus aureus infections. Eleven (58%) 195, Phe 158, Gln 161, Tyr 196, Asn 235, Gln 232 and Pro234.
1
of the MICs and MBCs were within one doubling dilution difference,
suggesting bactericidal activity from the majority of the compounds Glu114 and Gln232 form a hydrophilic and negative charged site,
tested.
which is a perfect binding site for some positive charged groups to
It was observed that, in the binding site, Asp156, Gln152, Tyr191,
Four compounds, 4a, 4g, 5a and 5h, showed an MIC and MBC bind. For compound 4a (Figure 3), it was observed that the
o100 μg ml− against a strain of multidrug-resistant A. baumanii, and aminoguanidine forms strong electric effects with Glu114 and
two of them, 4a and 4g, also inhibited a strain of multidrug-resistant Asp156 and hydrogen bonds with Gln152 and Pro231. Tyr196,
K. pneumoniae that carried the NDM-1 beta-lactamase gene.22 With Ile195, Gln161 and Phe158 contribute large Vdw interactions for the
these encouraging preliminary results, we expanded our MIC deter- binding of 4a, and Asn235 can form a potential link with the ester
mination to a larger set of both Gram-positive and -negative bacteria group. Chloride (Cl) on compound 4a has polar effects with Gln161
along with Mycobacterium tuberculosis H37Ra. The results (Table 2) and some other polar groups. The binding pose of compound 4g is
showed all four compounds inhibiting all Gram-positive bacteria very similar to that of compound 4a, but the difference is on the
1
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
5
Table 1 In vitro MIC and MBC values (μg ml− 1) of novel aminoguanidine and 2-hydrazone derivatives against multidrug-resistant nosocomiants
MDR Klebsiella
MDR Acinetobacter
Staphylococcus aureus ATCC 29213
MRSA
pneumoniae
baumanii
Compound R1
R2
MIC
MIC MBC
MIC
MBC
MIC
MBC
4
4
4
4
5
5
5
5
1
1
1
1
1
1
1
1
1
1
1
1
a
5-COOCH3
5-COOCH3
6-COOCH3
6-COOCH3
5-COOCH3
5-COOCH3
6-COOCH3
6-COOCH3
4-Chloro benzyl
3.13
12.5
50
3.13 3.13
50 100
12.5 12.5
12.5
4
25
4
4
4
−
12.5
4
25
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
−
50
4
25
4
25
4
50
4
4
4
4
4
4
4
4
4
4
4
4
4
−
100
4
25
4
100
4
100
4
4
4
4
4
4
4
4
4
4
4
4
4
−
c
4-(methoxycarbonyl) benzyl
4-Chloro benzyl
g
k
4-nitro benzyl
12.5
12.5
6.25
6.25
25
4
4
a
4-Chloro benzyl
6.25 6.25
c
4-(methoxycarbonyl) benzyl
4-Fluoro benzyl
4
4
h
12.5 25
l
3-Nitro benzyl
4
−
4
4
4
4
4
4
4
4
4
4
4
4
4
−
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
4-(methoxycarbonyl) phenyl Benzenesulfonyl
3-(methoxycarbonyl) phenyl Benzenesulfonyl
4-(trifluoromethoxy) phenyl Benzenesulfonyl
3-(trifluoromethoxy) phenyl Benzenesulfonyl
4
3.13 25
6.25 6.25
3.13 12.5
3.13 3.13
3.13 100
3.13 50
12.5 12.5
50 100
6.25 12.5
6.25 25
6.25 12.5
12.5 50
6.25
25
6.25
25
4-(trifluoromethyl) phenyl
Benzenesulfonyl
Benzenesulfonyl
4-Fluoro-3-chloro phenyl
4
4-(methoxycarbonyl) phenyl Benzenesulfonyl
3-(methoxycarbonyl) phenyl Benzenesulfonyl
4-(trifluoromethoxy) phenyl Benzenesulfonyl
3-(trifluoromethoxy) phenyl Benzenesulfonyl
12.5
4
12.5
25
4-(trifluoromethyl) phenyl
Benzenesulfonyl
Benzenesulfonyl
25
4-Fluoro-3-chloro phenyl
4
Levofloxacin
0.25
−
−
−
−
Vancomycin
2
−
−
−
−
Abbreviations: MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus aureus; 4, 4100 μg ml 1;
−
−
, not done.
Table 2 In vitro activity (MIC μg ml− 1) of four novel indole derivatives against common bacterial pathogens
Compound
4a
4g
5a
5h
MRSA ATCC-S-6007
3.13
6.25–12.5 (6.25)
3.13
12.5
6.25–12.5 (12.5)
12.5
6.25
25
25 (25)
25
MRSA (clinical strains) (n = 8)
MSSA ATCC-25923
12.5–25 (12.5)
12.5
12.5
MSSA (clinical strain)
12.5
12.5
25
Staphylococcus saprophyticus
Streptococcus pyogenes
12.5
6.25
6.25
6.25
3.13
1.56
6.25
25
3.13
6.25
3.13
Streptococcus pneumoniae
VRE
1.56
6.25
6.25
6.25
6.25
12.5
Corynebacterium urealyticum
ESBL+ve Escherichia coli (n = 10)
ESBL+ve Klebsiella pneumoniae (n = 11)
MDR Acinetobacter baumanii (n = 11)
Pseudomonas aeruginosa
M. tuberculosis H37Ra
6.25
12.5
6.25
50–100 (100)
12.5–100 (100)
6.25–100 (25)
4
12.5–25 (25)
12.5–100 (50)
12.5–25 (12.5)
100
4
4
4
4
12.5–100 (25)
4
25–100 (50)
4
12.5
12.5
3.13
6.25
Abbreviations: ESBL, extended-spectrum beta-lactamase; MDR, multidrug resistant; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible
−
1
S. aureus; VRE, vancomycin-resistant Enterococcus; (value), (median MIC); +ve, positive; 4, 4100 μg ml
.
position of ester group. When the ester group is located at the indole of compounds 5a and 5h shows binding poses similar to those of
-position, the distance between the ester group and Asn235 is compounds 4a and 4g (Figure 3). They also form interactions similar
increased so that a hydrogen bond cannot be formed. The docking to those of compounds 4a and 4g, but because of the 2-(4,5-dihydro-
6
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
6
1H-imidazol-2-yl)hydrazone group, they can form π–π interactions
with Pro231. For compound 5h, same as compound 4g, as the ester
group is located on the indole 6-position, it cannot form hydrogen
bond with Asn235.
CONLUSIONS
Based on the crystal structure of GT, 40 novel indole core derivatives
were designed and synthesized. Among these 40 compounds,
20 compounds showed anti-staphylococcal effects, of which 4 compounds
can potentially be further developed into broad-spectrum anti-infective
agents against common and multidrug-resistant bacterial and mycobac-
terial pathogens. Based on molecular modeling, we predicted that these
compounds may target at GT, but further experiments are required for
confirming this assumption, which is beyond our current research.
Although β-lactam antibiotics inhibit the cross-linking of peptidoglycan
chains by binding to the active site of the TP enzyme, GT inhibitors are
Figure 2 The compound 4a (represented by balls and sticks model with N
atoms colored in blue, O atoms in red, C atoms in yellow and C1 atom in
green) occupies the Moenomycin A-binding site (represented by blue mesh
surface). A full color version of this figure is available at The Journal of expected to prevent the transfer of disaccharide peptides onto the
Antibiotics journal online.
growing glycan chains before the cross-linking step. Thus GT inhibitors
Figure 3 The binding poses of compounds 4a (a), 4g (b), 5a (c) and 5h (d). A full color version of this figure is available at The Journal of Antibiotics journal
online.
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
7
are likely to act synergistically with β-lactam antibiotics to inhibit the 7.06 (t, J = 8.8, 2H, Ar-H), 5.36 (s, 2H, CH2), 3.94 (s, 3H, CH3); ES-MS
+
polymerization and cross-linking of cell wall peptidoglycan.
312.1 (M+H) .
Methyl 3-formyl-1-(4-(methoxycarbonyl)benzyl)-1H-indole-5-carboxylate (3c). 3c
METHODS
Chemistry
was obtained by reaction of 2a as previously described for 3a as a white solid
− 1
(
767 mg, 92%), m.p. 203.6–204.0 °C; IR (KBr): υ max cm
2360 (CH2),
All chemicals were purchased from commercial sources and used as supplied
unless stated. Dry CH Cl2 was distilled over calcium hydride and dry
tetrahydrofuran was distilled over sodium benzophenone. TLC was carried
out using silica gel 60 precoated aluminium plates (0.20 mm thickness) from
Macherey-Nagel (Damstadt, Germany) with visualization by UV light
1
716 (C= O), 1661 (C= O), 1615 (C= C), 1534 (C= C), 1436 (C = C), 1278
2
1
(
C-O-C); H-NMR (400 MHz, CDCl3): δ 10.06 (s, 1H, CHO), 9.03 (d, J = 1.2,
1H, Ar-H), 8.03 (d, J = 8.4, 2H, Ar-H), 8.00 (dd, J1 = 8.8, J2 =1.6, 1H, Ar-H),
7
.81 (s, 1H, Ar-H), 7.30 (d, J = 8.8, 1H, Ar-H), 7.21 (d, J = 8.4, 2H, Ar-H), 5.46
+
(
s, 2H, CH2), 3.94 (s, 3H, CH3), 3.91 (s, 3H, CH3); ES-MS 352.1 (M+H) .
(254 nm). Flash chromatography was performed on silica gel (particle size
4
0–63 μm). 1H-NMR spectra were obtained from Bruker AVANCE III 400 Methyl 3-formyl-1-(3-(methoxycarbonyl)benzyl)-1H-indole-5-carboxylate (3d). 3d
spectrometers (Fällanden, Switzerland). The chemical shifts, given as δ values, was obtained by reaction of 2a as previously described for 3a as a white solid
were quoted in p.p.m.; 1H-NMR chemical shifts were measured relative to (787 mg, 91%), m.p. 148.6–149.3 °C; IR (KBr): υ max cm 2360 (CH ), 1718
− 1
2
internal tetramethylsilane; apparent coupling constants (absolute values), J, (C= O), 1667 (C= O), 1617 (C= C), 1532 (C= C), 1438 (C = C), 1292
1
were measured in Hertz and multiplicities quoted as singlet (s), doublet (d), (C-O-C); H-NMR (400 MHz, CDCl3):
δ 10.06 (s, 1H, CHO), 9.03
triplet (t), quartet (q) or combinations thereof as appropriate. Mass spectra (d, J = 1.2, 1H, Ar-H), 8.02 (dd, J = 8.8, J =1.2, 2H, Ar-H), 7.94 (s, 1H,
1
2
were obtained from Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS Ar-H), 7.80 (s, 1H, Ar-H), 7.44 (t, J = 8.0, 1H, Ar-H), 7.34 (d, J = 8.8, 1H,
Agilent Technologies Inc., CA, USA). IR spectra were obtained from the solid Ar-H), 7.31 (d, J =8.0, 1H, Ar-H), 5.44 (s, 2H, CH ), 3.94 (s, 3H, CH ), 3.91
(
2
3
+
phase using Bruker Tensor 27 spectrometer (Germany). Melting points were (s, 3H, CH ); ES-MS 352.1 (M+H) .
3
determined using WRS-1B melting point measurement (Shanghai, China) and
were uncorrected.
Methyl 3-formyl-1-(4-nitrobenzyl)-1H-indole-5-carboxylate (3e). 3e was
obtained by reaction of 2a as previously described for 3a as an yellow solid
−
1
Methyl 3-formyl-1H-indole-5-carboxylate (2a). To a solution of 1a (5.00 g, (355 mg, 86%), m.p. 219.2–219.6 °C; IR (KBr): υ max cm 2360 (CH ), 1715
2
2
0
8.57 mmol) in dry DMF (20 ml) was added POCl3 (3.62 ml, 38.86 mol) at (C= O), 1671 (C=O), 1636 (C = C), 1540 (C= C), 1521 (NO ), 1458 (C= C),
2
1
°C under N2 and then stirred at room temperature for 2 h. The reaction was 1339 (NO ), 1282 (C-O-C); H-NMR (400 MHz, DMSO): δ 10.01 (s, 1H,
2
quenched with H O (60 ml) at 0 °C and adjusted the pH to 7–8 with 2 M
CHO), 8.80 (d, J = 1.2, 1H, Ar-H), 8.66 (s, 1H, Ar-H), 8.21 (d, J = 8.8, 2H,
NaOH. The resulting solution was heated to 70 °C and stirred for 30 min. After Ar-H), 7.88 (dd, J = 8.4, J = 1.6, 1H, Ar-H), 7.69 (d, J = 8.4, 1H, Ar-H),
2
1
2
cooling to room temperature, the precipitate was filtered and washed with 7.51 (d, J = 8.8, 2H, Ar-H), 5.79 (s, 2H, CH ), 3.87 (s, 3H, CH ); ES-MS
2
3
+
MeOH to give 2a as a light pink solid (5.22 g, 90%), m.p. 231.4–233.0 °C; IR 339.1 (M+H) .
−
1
(
1
KBr): υ max cm 3232 (NH), 1712 (C= O), 1649 (C= O), 1622 (C=C),
531 (C = C), 1448 (C= C), 1281 (C-O-C); 1H-NMR (400 MHz, DMSO):
Methyl 3-formyl-1-(3-nitrobenzyl)-1H-indole-5-carboxylate (3f). 3f was
obtained by reaction of 2a as previously described for 3a as an yellow solid
δ 12.44 (brs, 1H, NH), 9.98 (s, 1H, CHO), 8.77 (d, J = 1.2, 1H, Ar-H), 8.44
s, 1H, Ar-H), 7.88 (dd, J1 = 8.4, J2 = 1.6, 1H, Ar-H), 7.61 (d, J = 8.8, 1H,
−
1
(
588 mg, 71%), m.p. 190.9–193.9 °C; IR (KBr): υ max cm 2361 (CH ), 1712
2
(
+
(C= O), 1668 (C=O), 1617 (C = C), 1537 (C= C), 1521 (NO ), 1459 (C= C),
Ar-H), 3.87 (s, 3H, CH ); ES-MS 204.1 (M+H) .
2
3
1
1
351 (NO2), 1280 (C-O-C); H-NMR (400 MHz, CDCl3): δ 10.09 (s, 1H,
Methyl 3-formyl-1H-indole-6-carboxylate (2b). 2b was obtained by reaction CHO), 9.04(s, 1H, Ar-H), 8.21 (d, J = 8.4, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 8.03
of 1b as previously described for 1a as a white solid (0.875 g, 76%), m.p.
(
7
3
dd, J1 = 8.8, J2 = 1.6, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.55 (t, J = 8.0, 1H, Ar-H),
−
1
221.4–221.7 °C; IR (KBr): υ max cm
3218 (NH), 1707 (C = O), 1639
.41 (d, J = 8.0, 1H, Ar-H), 7.30 (d, J = 8.8 Hz, 1H, Ar-H), 5.52 (s, 2H, CH2),
1
(C = O), 1572 (C = C), 1501 (C= C), 1430 (C = C), 1304 (C-O-C); H-NMR
+
.95 (s, 3H, CH3); ES-MS 339.1 (M+H) .
(400 MHz, DMSO): δ 12.43 (brs, 1H, NH), 9.98 (s, 1H, CHO), 8.51 (s, 1H,
Ar-H), 8.18 (d, J = 8.4, 1H, Ar-H), 8.14 (s, 1H, Ar-H), 7.83 (dd, J = 8.4, Methyl 1-(4-chlorobenzyl)-3-formyl-1H-indole-6-carboxylate (3g). 3g was
1
+
obtained by reaction of 2b as previously described for 3a as a white solid
J2 = 1.6, 1H, Ar-H), 3.87 (s, 3H, CH3); ES-MS 204.1 (M+H) .
−
1
(
515 mg, 64%), m.p. 153.1–154.2 °C; IR (KBr): υ max cm
2924 (CH2),
Methyl 1-(4-chlorobenzyl)-3-formyl-1H-indole-5-carboxylate (3a). To
a
1
714 (C= O), 1666 (C= O), 1617 (C= C), 1529 (C= C), 1456 (C = C), 1273
solution of 2a (500 mg, 2.46 mmol) in dry DMSO (8 ml) was added NaH
60%, 108 mg, 2.71 mmol) and stirred at room temperature for 1 h.
-Chlorobenzyl bromide (557 mg, 2.71 mmol) was added and stirred at room
1
(
(
C-O-C), 748 (C-Cl); H-NMR (400 MHz, CDCl3): δ 10.03 (s, 1H, CHO), 8.36
d, J = 8.0, 1H, Ar-H), 8.09 (s, 1H, Ar-H), 8.02 (dd, J1 = 8.4, J2 =1.6, 1H,
(
4
Ar-H), 7.82 (s, 1H, Ar-H), 7.35 (d, J = 8.4, 2H, Ar-H), 7.12–7.14 (d, J = 8.4,
2
temperature for 10 h. The reaction solution was quenched with saturated
NH Cl and extracted with CH Cl (150 ml× 3), and the combined organic
+
H, Ar-H), 5.40 (s, 2H, CH2), 3.94 (s, 3H, CH3); ES-MS 328.1 (M+H) .
4
2
2
layers dried with Na2SO4, filtered and concentrated. The residue was purified Methyl 1-(4-fluorobenzyl)-3-formyl-1H-indole-6-carboxylate (3h). 3h was
by column chromatography on silica gel using CH Cl as elunt to give 3a as a
obtained by reaction of 2b as previously described for 3a as a white solid
2
2
−
1
− 1
white solid (417 mg, 52%), m.p. 160.2–160.7 °C; IR (KBr): υ max cm 2360 (170 mg, 56%), m.p. 155.6–155.7 °C; IR (KBr): υ max cm
2926 (CH2),
(
CH2), 1700 (C= O), 1656 (C = O), 1616 (C= C), 1534 (C= C), 1433 (C =C), 1713 (C= O), 1662 (C= O), 1618 (C= C), 1531 (C= C), 1439 (C = C), 1272
1
1
1
278 (C-O-C), 744 (C-Cl); H-NMR (400 MHz, CDCl ): δ 10.06 (s, 1H, (C-O-C), 1095 (C-F); H-NMR (400 MHz, CDCl3): δ 10.03 (s, 1H, CHO), 8.35
3
CHO), 9.03 (s, 1H, Ar-H), 8.02 (dd, J1 = 8.4, J2 = 1.6, 1H, Ar-H), 7.78 (s, 1H,
(d, J = 8.4, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 8.01 (dd, J1 = 8.4, J2 =1.6, 1H,
Ar-H), 7.35 (d, J = 8.4, 2H, Ar-H), 7.33 (d, J = 8.4, 1H, Ar-H), 7.10–7.12 Ar-H), 7.81 (s, 1H, Ar-H), 7.20 (dd, J1 = 8.8, J2 = 5.2, 2H, Ar-H), 7.07
(
3
d, J = 8.4, 2H, Ar-H), 5.37 (s, 2H, CH ), 3.95 (s, 3H, CH ); ES-MS
28.1 (M+H) .
(t, J = 8.4, 2H, Ar-H), 5.40 (s, 2H, CH2), 3.94 (s, 3H, CH3); ES-MS
312.1 (M+H) .
2
3
+
+
Methyl 1-(4-fluorobenzyl)-3-formyl-1H-indole-5-carboxylate (3b). 3b was Methyl 3-formyl-1-(4-(methoxycarbonyl)benzyl)-1H-indole-6-carboxylate (3i). 3i
obtained by reaction of 2a as previously described for 3a as a white solid was obtained by reaction of 2b as previously described for 3a as a white solid
−
1
− 1
(
(
(
736 mg, 96%), m.p. 153.3–153.9 °C; IR (KBr): υ max cm 2360 (CH2), 1717 (0.367 g, 58%), m.p. 169.9–171.1 °C; IR (KBr): υ max cm
3102 (CH2),
C = O), 1658 (C = O), 1618 (C = C), 1532 (C = C), 1510 (C= C), 1273 1714 (C= O), 1663 (C= O), 1616 (C= C), 1535 (C= C), 1437 (C = C), 1280
C-O-C), 1088 (C-F); H-NMR (400 MHz, CDCl ): δ 10.05 (s, 1H, CHO), (C-O-C); H-NMR (400 MHz, CDCl3): δ 10.05 (s, 1H, CHO), 8.37 (d, J = 8.0,
1
1
3
9
7
.02 (s, 1H, Ar-H), 8.03 (dd, J1 = 8.8, J2 = 1.6, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 1H, Ar-H), 8.07 (s, 1H, Ar-H), 8.03 (d, J = 8.4, 2H, Ar-H), 8.01–8.03
.35 (d, J = 8.4, 1H, Ar-H), 7.17 (dd, J1 = 8.8, J2 = 5.2, 2H, Ar-H), (dd, J1 =8.4, J2 =1.2, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.23 (d, J = 8.4 Hz, 2H,
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
8
Ar-H), 5.50 (s, 2H, CH2), 3.93 (s, 3H, CH3), 3.91 (s, 3H, CH3); ES-MS
3
1H, Ar-H), 7.56 (s, 3H, NH), 7.34 (d, J = 8.0, 2H, Ar-H), 5.65 (s, 2H, CH2),
3.85 (s, 3H, CH3), 3.82 (s, 3H, CH3); ES-MS 408.2 (M+H) ; HRMS calcd for
C21H22N5O4+ 408.1672, found 408.1663.
52.1 (M+H)+.
+
Methyl 3-formyl-1-(3-(methoxycarbonyl)benzyl)-1H-indole-6-carboxylate (3j). 3j
was obtained by reaction of 2b as previously described for 3a as a white solid Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(3-(methoxycarbonyl)benz
−
1
(
465 mg, 56%), m.p. 141.2–141.7 °C; IR (KBr): υ max cm
2953 (CH2),
yl)-1H-indole-5-carboxylate hydrochloride (4d). 4d was obtained by reaction
1
(
719 (C= O), 1659 (C= O), 1619 (C = C), 1531 (C= C), 1432 (C = C), 1279 of 3d as previously described for 4a as an yellow solid (198 mg, 79%), m.p.
1
− 1
C-O-C); H-NMR (400 MHz, CDCl ): δ 10.03 (s, 1H, CHO), 8.36 (d, J = 8.0,
137.3–138.7 °C; IR (KBr): υ max cm 3365 (NH), 3155 (NH), 2949 (NH),
3
1
H, Ar-H), 8.10 (s, 1H, Ar-H), 8.02 (d, J = 8.0, 1H, Ar-H), 8.01 (dd, J = 8.0,
2361 (CH2), 1715 (C = O), 1672 (C= O), 1617 (C = C), 1536 (C = C), 1433
(C = C), 1281 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.70 (s, 1H, NH),
1
1
J2 = 1.6, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.45 (t, J = 7.6, 1H,
Ar-H), 7.34 (d, J =7.6, 1H, Ar-H), 5.47 (s, 2H, CH2), 3.93 (s, 3H, CH3), 3.91 8.76 (d, J = 1.2, 1H, Ar-H), 8.44 (s, 1H, Ar-H), 8.24 (s, 1H, CH), 7.86–7.88
+
(
s, 3H, CH3); ES-MS 352.1 (M+H) .
(m, 2H, Ar-H), 7.83 (dd, J1 = 8.8, J2 = 1.6, 1H), 7.68 (d, J = 8.8, 1H, Ar-H), 7.56
(
3
4
s, 3H, NH), 7.50–7.52 (m, 2H, Ar-H), 5.64 (s, 2H, CH2), 3.85 (s, 3H, CH3),
Methyl 3-formyl-1-(4-nitrobenzyl)-1H-indole-6-carboxylate (3k). 3k was
obtained by reaction of 2b as previously described for 3a as an yellow solid
+
.81 (s, 3H, CH3); ES-MS 408.2 (M+H) ; HRMS calcd for C21H22N5O4+
08.1672, found 408.1663.
−
1
(
(
0.138 g, 80%), m.p. 184.5–184.9 °C; IR (KBr): υ max cm 2945 (CH2), 1711
C= O), 1663 (C=O), 1616 (C = C), 1516 (NO2), 1436 (C= C), 1392 (C = C),
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-nitrobenzyl)-1H-indole-
5-carboxylate hydrochloride (4e). 4e was obtained by reaction of 3e
1
1
344 (NO ), 1278 (C-O-C); H-NMR (400 MHz, CDCl ): δ 10.08 (s, 1H,
2
3
CHO), 8.39 (d, J = 8.0, 1H, Ar-H), 8.22 (d, J = 8.8, 2H, Ar-H), 8.02–8.04 as previously described for 4a as an yellow solid (210 mg, 88%), m.p.
−
1
(
m, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.30 (d, J = 8.8, 2H, Ar-H), 5.56
229.6–229.9 °C; IR (KBr): υ max cm 3363 (NH), 3113 (NH), 2950 (NH),
+
(
s, 2H, CH2), 3.93 (s, 3H, CH3); ES-MS 339.1 (M+H) .
2361 (CH2), 1701 (C= O), 1674 (C= O), 1620 (C= C), 1520 (NO2), 1435
C = C), 1392 (C = C), 1345 (NO ), 1281 (C-O-C); H-NMR (400 MHz,
DMSO): δ 11.74 (s, 1H, NH), 8.77 (d, J = 1.6, 1H, Ar-H), 8.44 (s, 1H, Ar-H),
.25 (s, 1H, CH), 8.21 (d, J = 8.8, 2H, Ar-H), 7.84 (dd, J = 8.8, J = 1.6, 1H,
Ar-H), 7.64 (d, J = 8.8, 1H, Ar-H), 7.56 (s, 3H, NH), 7.45 (d, J = 8.4, 2H,
1
(
2
Methyl 3-formyl-1-(3-nitrobenzyl)-1H-indole-6-carboxylate (3l). 3l was
obtained by reaction of 2b as previously described for 3a as an yellow solid
(
(
8
1
2
−
1
580 mg, 70%), m.p. 153.8–155.3 °C; IR (KBr): υ max cm 3089 (CH2), 1701
C= O), 1669 (C=O), 1618 (C = C), 1571 (C= C), 1523 (NO2), 1435 (C = C),
+
Ar-H), 5.73 (s, 2H, CH ), 3.85 (s, 3H, CH ); ES-MS 395.1 (M+H) ; HRMS
calcd for C H N O 395.1468, found 395.1460.
2
3
1
1
348 (NO2), 1280 (C-O-C); H-NMR (400 MHz, CDCl3): δ 10.07 (s, 1H,
+
19 19 6 4
CHO), 8.38 (d, J = 8.4, 1H, Ar-H), 8.21 (dd, J = 8.4, J = 1.2, 1H, Ar-H), 8.10
1
2
(
(
(
s, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 8.03 (dd, J = 8.4, J = 1.2, 1H, Ar-H), 7.89 Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(3-nitrobenzyl)-1H-indole-
1 2
s, 1H, Ar-H), 7.55 (t, J = 8.0, 1H, Ar-H), 7.42–7.44 (d, J = 8.0, 1H, Ar-H), 5.55 5-carboxylate hydrochloride (4f). 4f was obtained by reaction of 3f
+
s, 2H, CH2), 3.93 (s, 3H, CH3); ES-MS 339.1 (M+H) .
as previously described for 4a as an yellow solid (223 mg, 88%), m.p.
−
1
227.3–230.2 °C; IR (KBr): υ max cm
3368 (NH), 2361 (CH ), 1699
2
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-chlorobenzyl)-1H-indole-
-carboxylate hydrochloride (4a). To a solution of 3a (200 mg, 0.61 mmol) in
(
C = O), 1639 (C = O), 1517 (NO ), 1435 (C= C), 1392 (C = C), 1355
2
5
1
(NO ), 1278 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.72 (s, 1H, NH),
2
dry MeOH was added aminoguanidine hydrochloride (260 mg, 0.61 mmol)
and then the reaction solution was adjusted pH to 3–4 and stirred at room
temperature for 1.5 h. After the completion of the reaction, the solvent was
removed under reduced pressure, and then the residue was tutrited in Et O and
filtered to give 4a as a white solid (223 mg, 87%), m.p. 241.1–242.1 °C; IR
8.77 (d, J = 1.2, 1H, Ar-H), 8.44 (s, 1H, Ar-H), 8.27 (s, 1H, CH), 8.15 (m, 2H,
Ar-H), 7.84 (dd, J = 8.8, J = 1.6, 1H, Ar-H), 7.62–7.73 (m, 3H, Ar-H), 7.57
1
2
+
(
s, 3H, NH), 5.71 (s, 2H, CH ), 3.85 (s, 3H, CH ); ES-MS 395.1 (M+H) ;
2
3
2
+
HRMS calcd for C H N O 395.1468, found 395.1460.
1
9 19 6 4
−
1
(
KBr): υ max cm
3337 (NH), 3272 (NH), 3099 (NH), 2361 (CH2),
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-chlorobenzyl)-1H-indole-
1
(
(
709 (C= O), 1676 (C= O), 1641 (C = C), 1533 (C= C), 1433 (C = C), 1282 6-carboxylate hydrochloride (4g). 4g was obtained by reaction of 3g as previously
1
C-O-C), 749 (C-Cl); H-NMR (400 MHz,DMSO): δ11.75 (s, 1H, NH), 8.75 described for 4a as a white solid (223 mg, 87%), m.p. 249.6–250.9 °C;
−
1
d, J =1.2, 1H, Ar-H), 8.43 (s, 1H, Ar-H), 8.21 (s, 1H, CH), 7.84 (dd, J = 8.8,
IR (KBr): υ max cm 3470 (NH), 3326 (NH), 3088 (NH), 1718 (C =O),
1
J2 = 1.6, 1H, Ar-H), 7.66 (d, J = 8.4, 1H, Ar-H), 7.57 (s, 3H, NH), 7.40 1645 (C =O), 1622 (C =C), 1513 (C =C), 1438 (C =C), 1287 (C-O-C), 741
1
(
(
d, J = 8.4, 2H, Ar-H), 7.27 (d, J =8.4, 2H, Ar-H), 5.54 (s, 2H, CH2), 3.85 (C-Cl); H-NMR (400 MHz, DMSO): δ 11.71 (s, 1H, NH), 8.43–8.45
s, 3H, CH3); ES-MS 384.1 (M+H) ; HRMS calcd for C19H19ClN5O2
+
+
(d, J=8.4, 1H, Ar-H), 8.37 (s, 1H, Ar-H), 8.27 (s, 1H, CH), 8.17 (s, 1H,
Ar-H), 7.76 (d, J=8.4, 1H, Ar-H), 7.57 (s, 3H, NH), 7.28 (dd, J1 =8.4, J2 =5.6,
3
84.1227, found 384.1221.
2
H, Ar-H), 7.18 (t, J=8.8, 2H, Ar-H), 5.59 (s, 2H, CH2), 3.86 (s, 3H, CH3);
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-fluorobenzyl)-1H-indole-
-carboxylate hydrochloride (4b). 4b was obtained by reaction of 3b as
previously described for 4a as white solid (195 mg, 76%), m.p.
ES-MS 384.1 (M+H) ; HRMS calcd for C19H19ClN5O2+ 384.1227,
+
5
found 384.1217.
a
−
1
2
2
(
37.6–238.4 °C; IR (KBr): υ max cm 3479 (NH), 3275 (NH), 3096 (NH),
Methyl
(E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-fluorobenzyl)-1H-
362 (CH ), 1707 (C= O), 1674 (C = O), 1645 (C= C), 1533 (C= C), 1435 indole-6-carboxylate hydrochloride (4h). 4h was obtained by reaction of 3h
C= C), 1280 (C-O-C), 1092 (C-F); H-NMR (400 MHz, DMSO): δ 11.72 as previously described for 4a as a white solid (251 mg, 97%), m.p.
2
1
−
1
(
s, 1H, NH), 8.75 (d, J = 1.6, 1H, Ar-H), 8.42 (s, 1H, Ar-H), 8.21 (s, 1H, CH),
.83 (dd, J1 = 8.8, J2 = 1.6, 1H, Ar-H), 7.69 (d, J = 8.8, 1H, Ar-H), 7.56 (s, 3H,
NH), 7.33 (dd, J =8.8, J =5.2, 2H, Ar-H), 7.15–7.20 (t, J = 8.8, 2H, Ar-H),
261.4–261.9 °C; IR (KBr): υ max cm 3376 (NH), 3225 (NH), 3177 (NH),
1712 (C = O), 1668 (C= O), 1633 (C= C), 1459 (C = C), 1394 (C= C), 1269
(C-O-C), 1100 (C-F); H-NMR (400 MHz, DMSO): δ 11.70 (s, 1H, NH), 8.45
(d, J = 8.4 Hz, 1H, Ar-H), 8.38 (s, 1H, Ar-H), 8.28 (s, 1H, CH), 8.14 (s, 1H,
Ar-H), 7.76 (dd, J1 = 8.4, J2 = 1.2, 1H, Ar-H), 7.57 (s, 3H, NH), 7.41 (d, J = 8.4,
7
1
1
2
+
5
.52 (s, 2H, CH2), 3.85 (s, 3H, CH3); ES-MS 368.2 (M+H) ; HRMS calcd for
C19H19FN5O2+ 368.1523, found 368.1514.
2
H, Ar-H), 7.23 (d, J = 8.4, 2H, Ar-H), 5.61 (s, 2H, CH2), 3.85 (s, 3H, CH3);
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-(methoxycarbonyl)benz
yl)-1H-indole-5-carboxylate hydrochloride (4c). 4c was obtained by reaction
of 3c as previously described for 4a as an yellow solid (207 mg, 82%), m.p.
+
+
ES-MS 368.2 (M+H) ; HRMS calcd for C19H19FN5O2 368.1523, found
68.1513.
3
−
1
2
25.7–228.6 °C; IR (KBr): υ max cm 3465 (NH), 3344 (NH), 2949 (NH),
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-(methoxycarbonyl)ben-
2
361 (CH2), 1719 (C= O), 1672 (C = O), 1615 (C= C), 1537 (C= C), 1433 zyl)-1H-indole-6-carboxylate hydrochloride (4i). 4i was obtained by reaction
1
(
C= C), 1281 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.72 (s, 1H, NH),
of 3i as previously described for 4a as a white solid (223 mg, 88%), m.p.
−
1
8
.76 (d, J = 1.2, 1H, Ar-H), 8.44 (s, 1H, Ar-H), 8.23 (s, 1H, CH), 7.92 238.8–240.0 °C; IR (KBr): υ max cm 3471 (NH), 3334 (NH), 3159 (NH),
1715 (C = O), 1673 (C= O), 1616 (C= C), 1534 (C = C), 1438 (C= C), 1279
(
d, J = 8.4, 2H, Ar-H), 7.82 (dd, J1 = 8.4, J2 = 1.6, 1H, Ar-H), 7.63 (d, J = 8.8,
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
9
1
+
(
1
C-O-C); H-NMR (400 MHz, DMSO): δ 11.70 (s, 1H, NH), 8.45 (d, J = 8.4, CH2), 3.86 (s, 3H, CH3), 3.73 (s, 4H, CH2); ES-MS 394.2 (M+H) ; HRMS
+
H, Ar-H), 8.39 (s, 1H, Ar-H), 8.30 (s, 1H, CH), 8.10 (s, 1H, Ar-H), 7.92 calcd for C H FN O 394.1679, found 394.1670.
21 21 5 2
(
7
d, J = 8.0, 2H, Ar-H), 7.77 (dd, J1 = 8.4, J2 = 1.2, 1H, Ar-H), 7.52 (s, 3H, NH),
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(4-(meth-
oxycarbonyl)benzyl)-1H-indole-5-carboxylate hydrobromide (5c). 5c was
obtained by reaction of 3c as previously described for 5a as a white solid
.30 (d, J = 8.0, 2H, Ar-H), 5.72 (s, 2H, CH2), 3.84 (s, 3H, CH3), 3.82 (s, 3H,
+
+
CH ); ES-MS 408.2 (M+H) ; HRMS calcd for C H N O 408.1672, found
4
3
21 22 5 4
08.1665.
−
1
(
264 mg, 90%), m.p. 238.7 °C (dec); IR (KBr): υ max cm 3184 (NH), 2950
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(3-(methoxycarbonyl)ben- (NH), 1721 (C = O), 1666 (C = O), 1603 (C = C), 1538 (C= C), 1453 (C = C),
1
zyl)-1H-indole-6-carboxylate hydrochloride (4j). 4j was obtained by reaction 1281 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.99 (s, 1H, NH), 8.80
of 3j as previously described for 4a as a white solid (225 mg, 89%), m.p. (d, J =0.8, 1H, Ar-H), 8.42 (s, 2H, CH, NH), 8.21 (s, 1H, Ar-H), 7.93
−
1
2
28.8–230.9 °C; IR (KBr): υ max cm 3470 (NH), 2956 (NH), 2359 (CH2), (d, J = 8.0, 2H, Ar-H), 7.83 (dd, J = 8.4, J = 1.2, 1H, Ar-H), 7.64 (d, J = 8.4,
1 2
1
717 (C = O), 1667 (C = O), 1640 (C=C), 1535 (C = C), 1435 (C= C), 1284 1H, Ar-H), 7.35 (d, J = 8.4, 2H, Ar-H), 5.65 (s, 2H, CH ), 3.86 (s, 3H, CH ),
2
3
1
+
(C-O-C); H-NMR (400 MHz, DMSO): δ 11.70 (s, 1H, NH), 8.45 (d, J = 8.4, 3.82 (s, 3H, CH ), 3.74 (s, 4H, CH ); ES-MS 434.2 (M+H) ; HRMS calcd for
3
2
+
1H, Ar-H), 8.39 (s, 1H, Ar-H), 8.31 (s, 1H, CH), 8.16 (s, 1H, Ar-H), 7.86–7.88 C H N O 434.1828, found 434.1817.
23 24 5 4
(
d, J = 6.8,1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.77 (d, J = 8.0, 1H, Ar-H), 7.65
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(3-(meth-
oxycarbonyl)benzyl)-1H-indole-5-carboxylate hydrobromide (5d). 5d was
(s, 3H, NH), 7.49–7.51 (m, 2H, Ar-H), 5.71 (s, 2H, CH2), 3.85 (s, 3H, CH3),
+
+
3
4
.82 (s, 3H, CH ); ES-MS 408.2 (M+H) ; HRMS calcd for C H N O
3
21 22
5
4
obtained by reaction of 3d as previously described for 5a as a white solid
08.1672, found 408.1666.
−
(
271 mg, 93%), m.p. 243.4–246.0 °C; IR (KBr): υ max cm 1 3192 (NH), 3086
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(4-nitrobenzyl)-1H-indole- (NH), 2951 (NH), 1704 (C = O), 1666 (C= O), 1601 (C= C), 1539 (C = C),
1
6
-carboxylate hydrochloride (4k). 4k was obtained by reaction of 3k 1449 (C=C), 1291 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.98 (s, 1H,
as previously described for 4a as an yellow solid (230 mg, 96%), m.p. NH), 8.80 (d, J = 1.2, 1H, Ar-H), 8.42 (s, 2H, CH, NH), 8.23 (s, 1H, Ar-H),
−
1
259.8–260.8 °C; IR (KBr): υ max cm
3469 (NH), 2363 (CH2), 1711 7.83–7.89 (m, 3H, Ar-H), 7.69 (d, J = 8.4, 1H, Ar-H), 7.51–7.53 (m, 2H, Ar-H),
(
(
(
C = O), 1673 (C = O), 1644 (C = C), 1519 (NO ), 1436 (C = C), 1395 5.64 (s, 2H, CH ), 3.86 (s, 3H, CH ), 3.81 (s, 3H, CH ), 3.74 (s, 4H, CH );
2
2
3
3
2
C = C), 1349 (NO2), 1277 (C-O-C); 1H-NMR (400 MHz, DMSO): δ 11.71 ES-MS 434.2 (M+H) ; HRMS calcd for C H N O 434.1828, found
+
+
23 24 5 4
s, 1H, NH), 8.47 (d, J = 8.4, 1H, Ar-H), 8.39 (s, 1H, Ar-H), 8.31 (s, 1H, CH), 434.1820.
.21 (d, J = 8.8, 2H, Ar-H), 8.13 (s, 1H, Ar-H), 7.79 (dd, J1 = 8.4, J2 = 1.2, 1H,
Ar-H), 7. 57 (s, 3H, NH), 7.41 (d, J = 8.8, 2H, Ar-H), 5.80 (s, 2H, CH2), 3.84
8
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(4-nitro-
benzyl)-1H-indole-5-carboxylate hydrobromide (5e). 5e was obtained by
reaction of 3e as previously described for 5a as an yellow solid (271 mg,
+
+
(s, 3H, CH ); ES-MS 395.1 (M+H) ; HRMS calcd for C H N O 395.1468,
3 19 19 6 4
found 395.1462.
−
1
93%), m.p. 247.3–247.7 °C; IR (KBr): υ max cm 3463 (NH), 3268 (NH),
Methyl (E)-3-((2-carbamimidoylhydrazono)methyl)-1-(3-nitrobenzyl)-1H-indole- 3107 (NH), 2362 (CH ), 1692 (C= O), 1661 (C= O), 1613 (C = C), 1539
2
6
-carboxylate hydrochloride (4l). 4l was obtained by reaction of 3l as (C= C), 1514 (NO ), 1435 (C= C), 1347 (NO ), 1248 (C-O-C); 1H-NMR
2
2
previously described for 4a as an yellow solid (199 mg, 79%), m.p. 248.9–
(
400 MHz, DMSO): δ 11.99 (s, 1H, NH), 8.81 (s, 1H, Ar-H), 8.44 (s, 2H, CH,
−
1
2
49.3 °C; IR (KBr): υ max cm 3479 (NH), 3402 (NH), 3274 (NH), 2361
NH), 8.23 (s, 1H, Ar-H), 8.21 (d, J = 8.8, 2H, Ar-H), 7.84 (dd, J =8.8, J = 1.2,
1H, Ar-H), 7.65 (d, J = 8.8, 1H, Ar-H), 7.46 (d, J = 8.4, 2H, Ar-H), 5.73 (s, 2H,
CH ), 3.86 (s, 3H, CH ), 3.74 (s, 4H, CH ); ES-MS 421.2 (M+H) ; HRMS
1
2
(
CH ), 1707 (C = O), 1676 (C = O), 1643 (C = C), 1531 (NO ), 1439 (C=C),
393 (C =C), 1348 (NO2), 1271 (C-O-C); 1H-NMR (400 MHz, DMSO):
2
2
1
+
2
3
2
δ 11.68 (s, 1H, NH), 8.47 (d, J = 8.4, 1H, Ar-H), 8.39 (s, 1H, Ar-H), 8.33 (s, 1H,
CH), 8.21 (s, 1H, Ar-H), 8.15 (dd, J1 = 5.6, J2 = 2.0, 1H, Ar-H), 8.12 (s, 1H,
+
calcd for C H N O 421.1624, found 421.1617.
2
1 21 6 4
Ar-H), 7.78 (d, J = 8.4, 1H, Ar-H), 7.64–7.67 (m, 2H, Ar-H), 7. 50 (s, 3H, NH), Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(3-nitro-
+
benzyl)-1H-indole-5-carboxylate hydrobromide (5f). 5f was obtained by
reaction of 3f as previously described for 5a as an yellow solid (265 mg,
5
.79 (s, 2H, CH ), 3.85 (s, 3H, CH ); ES-MS 395.1 (M+H) ; HRMS calcd for
2 3
C19H19N6O4+ 395.1468, found 395.1458.
−
1
9
2
(
0%), m.p. 246.9–250.9 °C; IR (KBr): υ max cm 3424 (NH), 3198 (NH),
Methyl (E)-1-(4-chlorobenzyl)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)
methyl)-1H-indole-5-carboxylate hydrobromide (5a). To a solution of 3a
50 mg, 0.15 mmol) in dry MeOH (2 ml) was added 2-hydrazino-2-
361 (CH2), 1703 (C= O), 1665 (C= O), 1604 (C= C), 1532 (NO2), 1452
C= C), 1395 (C= C), 1346 (NO2), 1248 (C-O-C); H-NMR (400 MHz,
1
(
DMSO): δ 11.99 (s, 1H, NH), 8.81 (s, 1H, Ar-H), 8.43 (s, 2H, CH, NH), 8.27
imidazoline hydrobromide (28 mg, 0.15 mmol), and then the reaction solution
was stirred at 75 °C. After the completion of the reaction, the solvent was
removed under reduced pressure, and then the residue was washed by Et2O and
filtered to give 4a as a white solid (65 mg, 87%), m.p. 243.6–244.3 °C; IR (KBr):
(
s, 1H, Ar-H), 8.15 (m, 2H, Ar-H), 7.85 (d, J = 8.4, 1H, Ar-H), 7.74–7.63
(
m, 3H, Ar-H), 5.72 (s, 2H, CH2), 3.86 (s, 3H, CH3), 3.74 (s, 4H, CH2); ES-MS
+
+
4
21.2 (M+H) ; HRMS calcd for C21H21N6O4 421.1624, found 421.1615.
−
1
υ max cm 3426 (NH), 3185 (NH), 2950 (NH), 2361 (CH2), 1708 (C= O), Methyl (E)-1-(4-chlorobenzyl)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)
1
(
669 (C = O), 1603 (C= C), 1539 (C= C), 1453 (C= C), 1246 (C-O-C), 745 methyl)-1H-indole-6-carboxylate hydrobromide (5g). 5g was obtained by
1
C-Cl); H-NMR (400 MHz, DMSO): δ 11.95 (s, 1H, NH), 8.79 (d, J = 1.2, 1H, reaction of 3g as previously described for 5a as a white solid (281 mg, 94%),
−
1
Ar-H), 8.41 (s, 2H, CH, NH), 8.19 (s, 1H, Ar-H), 7.84 (dd, J1 = 8.8, J2 = 1.6, m.p. 176.7–179.6 °C; IR (KBr): υ max cm 3408 (NH), 2951 (NH), 2361
1
(
H, Ar-H), 7.68 (d, J = 8.8, 1H, Ar-H), 7.41 (d, J = 8.4, 2H, Ar-H), 7.29 (CH2), 1713 (C = O), 1667 (C= O), 1617 (C= C), 1511 (C = C), 1437 (C= C),
1
d, J = 8.4, 2H, Ar-H), 5.54 (s, 2H, CH2), 3.86 (s, 3H, CH3), 3.73 (s, 4H, CH2); 1277 (C-O-C), 748 (C-Cl); H-NMR (400 MHz, DMSO): δ 12.00 (s, 1H, NH),
+
+
ES-MS 410.1 (M+H) ; HRMS calcd for C21H21ClN5O2 410.1384, found 8.58 (brs, 1H, NH), 8.48 (d, J = 8.4, 1H, Ar-H), 8.38 (s, 1H, Ar-H), 8.28 (s, 1H,
10.1374.
CH), 8.18 (s, 1H, Ar-H), 7.77 (dd, J1 = 8.4, J2 = 1.2, 1H, Ar-H), 7.30
dd, J1 = 8.4, J2 = 1.6, 2H, Ar-H), 7.19 (t, J = 8.8, 2H, Ar-H), 5.59 (s, 2H,
4
(
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(4-fluoro-
benzyl)-1H-indole-5-carboxylate hydrobromide (5b). 5b was obtained by reac-
tion of 3b as previously described for 5a as a white solid (279 mg, 92%), m.p.
2
2
+
CH2), 3.86 (s, 3H, CH3), 3.74 (s, 4H, CH2); ES-MS 410.1 (M+H) ; HRMS
calcd for C21H21ClN5O2+ 410.1384, found 410.1374.
−
1
41.5–243.7 °C; IR (KBr): υ max cm 3175 (NH), 3051 (NH), 2952 (NH), Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(4-fluoro-
361 (CH2), 1706 (C = O), 1668 (C= O), 1602 (C = C), 1510 (C= C), 1451 benzyl)-1H-indole-6-carboxylate hydrobromide (5h). 5h was obtained by
C = C), 1246 (C-O-C), 1096 (C-F); 1H-NMR (400 MHz, DMSO): δ 12.00 reaction of 3h as previously described for 5a as a white solid (257 mg, 85%),
s, 1H, NH), 8.79 (s, 1H, Ar-H), 8.41 (s, 2H, CH, NH), 8.19 (s, 1H, Ar-H), m.p. 213.4–214.6 °C; IR (KBr): υ max cm 3403 (NH), 3168 (NH), 2948
.84 (dd, J1 = 8.8, J2 = 1.2, 1H, Ar-H), 7.71 (d, J = 8.4, 1H, Ar-H), 7.33–7.36 (NH), 2361 (CH2), 1709 (C= O), 1665 (C = O), 1617 (C= C), 1511 (C= C),
dd, J =8.4, J = 1.6, 2H, Ar-H), 7.16–7.20 (t, J = 8.8, 2H, Ar-H), 5.52 (s, 2H, 1437 (C=C), 1277 (C-O-C), 1097 (C-F); 1H-NMR (400 MHz, DMSO):
(
(
−
1
7
(
1
2
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
1
0
δ 11.98 (s, 1H, NH), 8.58 (brs, 1H, NH), 8.48 (d, J = 8.4, 1H, Ar-H), 8.38 (s,
Methyl 1-benzoyl-3-formyl-1H-indole-6-carboxylate (6b). 6b was obtained by
reaction of 2b as previously described for 6a as a white solid (99 mg, 66%),
1
H, Ar-H), 8.28 (s, 1H, CH), 8.18 (s, 1H, Ar-H), 7.78 (dd, J = 8.4, J = 1.2, 1H,
1 2
−
1
Ar-H), 7.30 (dd, J1 = 8.4, J2 = 5.6, 2H, Ar-H), 7.19 (t, J = 8.8, 2H, Ar-H), 5.59 m.p. 176.1–176.4 °C; IR (KBr): υ max cm 1718 (C= O), 1672 (C= O), 1612
+
1
(
s, 2H, CH ), 3.86 (s, 3H, CH ), 3.75 (s, 4H, CH ); ES-MS 394.2 (M+H) ;
(C = C), 1547 (C = C), 1431 (C = C), 1283 (C-O-C); H-NMR (400 MHz,
2
3
2
HRMS calcd for C21H21FN5O2+ 394.1679, found 394.1670.
CDCl ): δ 10.09 (s, 1H, CHO), 9.00 (s, 1H, Ar-H), 8.38 (d, J = 8.0, 1H, Ar-H),
3
8
.15 (dd, J = 8.4, J = 1.2, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.81–7.79 (m, 2H,
1 2
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(4-(meth-
oxycarbonyl)benzyl)-1H-indole-6-carboxylate hydrobromide (5i). 5i was
obtained by reaction of 3i as previously described for 5a as a white solid
Ar-H), 7.73 (t, J = 7.6, 1H, Ar-H), 7.62 (t, J =7.6, 2H, Ar-H), 3.97 (s, 3H, CH3);
ES-MS 308.1 (M+H) .
+
−
1
(
(
1
280 mg, 96%), m.p. 239.1 °C (dec); IR (KBr): υ max cm 3416 (NH), 2951 Methyl
(E)-1-benzoyl-3-((2-carbamimidoylhydrazono)methyl)-1H-indole-5-
NH), 2361 (CH ), 1718 (C= O), 1670 (C = O), 1617 (C= C), 1459 (C= C),
436 (C=C), 1281 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.99 (s, 1H,
carboxylate hydrochloride (7a). 7a was obtained by reaction of 6a as previously
described for 4a as a white solid (245 mg, 94%), m.p. 204.6–206.0 °C; IR (KBr):
υ max cm
(C = C), 1371 (C= C), 1298 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.92
(s, 1H, NH), 8.82 (s, 1H, Ar-H), 8.43 (s, 1H, Ar-H), 8.0 (d, J = 8.8, 1H, Ar-H),
2
1
−
1
NH), 8.49 (d, J = 8.4, 2H, Ar-H, NH), 8.39 (s, 1H, Ar-H), 8.30 (s, 1H, CH),
.12 (s, 1H, Ar-H), 7.93 (d, J = 8.4, 2H, Ar-H), 7.78 (dd, J1 = 8.4, J2 = 1.2, 1H,
Ar-H), 7.31 (d, J = 8.0, 2H, Ar-H), 5.72 (s, 2H, CH2), 3.84 (s, 3H, CH3),
3446 (NH), 1685 (C = O), 1627 (C = O), 1551 (C= C), 1451
1
8
+
3
.82 (s, 3H, CH ), 3.75 (s, 4H, CH ); ES-MS 434.2 (M+H) ; HRMS calcd for 8.20 (s, 1H, CH), 8.07 (d, J = 8.4, 1H, Ar-H), 7.85 (d, J = 7.6, 2H, Ar-H),
3 2
C23H24N5O4+ 434.1828, found 434.1816.
+
7.63–7.77 (m, 6H, Ar-H, NH), 3.90 (s, 3H, CH ); ES-MS 364.1 (M+H) ;
HRMS calcd for C19H18N5O3+ 364.1410, found 364.1403.
3
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(3-(meth-
oxycarbonyl)benzyl)-1H-indole-6-carboxylate hydrobromide (5j). 5j was
Methyl
(E)-1-benzoyl-3-((2-carbamimidoylhydrazono)methyl)-1H-indole-6-
obtained by reaction of 3j as previously described for 5a as a white solid carboxylate hydrochloride (7b). 7b was obtained by reaction of 6b as previously
−
1
(
(
1
240 mg, 82%), m.p. 203.7–206.2 °C; IR (KBr): υ max cm 3405 (NH), 2950 described for 4a as a white solid (239 mg, 92%), m.p. 229.0 °C (dec); IR (KBr):
−
1
NH), 2361 (CH2), 1716 (C= O), 1665 (C = O), 1618 (C= C), 1536 (C= C),
457 (C=C), 1287 (C-O-C); H-NMR (400 MHz, DMSO): δ 11.98 (s, 1H,
NH), 8.49 (d, J = 8.4, 2H, Ar-H, NH), 8.40 (s, 1H, Ar-H), 8.31 (s, 1H, CH),
υ max cm
3423 (NH), 2361 (CH ), 1680 (C =O), 1632 (C= O), 1545
2
1
1
(C = C), 1432 (C = C), 1372 (C = C), 1242 (C-O-C); H-NMR (400 MHz,
DMSO): δ 11.93 (s, 1H, NH), 8.94 (d, J = 1.2, 1H, Ar-H), 8.59 (d, J = 8.4, 1H,
8
.17 (s, 1H, Ar-H), 7.89–7.87 (m, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.78 Ar-H), 8.38 (s, 1H, Ar-H), 8.28 (s, 1H, CH), 7.99 (dd, J = 8.4, J = 1.6, 1H,
1 2
(
3
dd, J = 8.4, J = 1.6, 1H, Ar-H), 7.52–7.50 (m, 2H, Ar-H), 5.71 (s, 2H, CH ),
Ar-H), 7.83–7.85(m, 2H, Ar-H), 7.63–7.77 (m, 6H, Ar-H, NH), 3.92 (s, 3H,
1
2
2
+
.85 (s, 3H, CH3), 3.82 (s, 3H, CH3), 3.75 (s, 4H, CH2); ES-MS 434.2 (M+H) ;
CH ); ES-MS 364.1 (M+H) ; HRMS calcd for C H N O 364.1410, found
+
+
3
19 18 5 3
+
HRMS calcd for C H N O 434.1828, found 434.1821.
364.1404.
23 24 5 4
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(4-nitro- Methyl (E)-1-benzoyl-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-
benzyl)-1H-indole-6-carboxylate hydrobromide (5k). 5k was obtained by 1H-indole-5-carboxylate hydrobromide (8a). 8a was obtained by reaction
reaction of 3k as previously described for 5a as an yellow solid (260 mg,
of 6a as previously described for 5a as a white solid (212 mg, 70%), m.p.
215.7–216.7 °C; IR (KBr): υ max cm 3407 (NH), 3291(NH), 2950 (NH),
−
1
− 1
8
2
8%), m.p. 253.6–255.6 °C; IR (KBr): υ max cm 3404 (NH), 3108 (NH),
910 (NH), 2361 (CH2), 1712 (C= O), 1662 (C= O), 1615 (C = C), 1522
1
699 (C = O), 1664 (C= O), 1615 (C= C), 1447 (C = C), 1369 (C= C), 1272
1
(
(
NO ), 1490 (C = C), 1391 (C= C), 1350 (NO ), 1276 (C-O-C); H-NMR
1
2
2
(C-O-C); H-NMR (400 MHz, DMSO): δ 12.24 (s, 1H, NH), 8.86 (d, J = 0.8,
H, Ar-H), 8.42–8.39 (m, 2H, Ar-H, CH), 8.18 (s, 1H, Ar-H), 8.07 (dd, J = 8.8,
400 MHz, DMSO): δ 12.01 (d, J = 3.6, 1H, NH), 8.51 (d, J = 8.4, 2H, Ar-H,
1
1
NH), 8.40 (s, 1H, CH), 8.32 (s, 1H, Ar-H), 8.22 (d, J = 8.8, 2H, Ar-H), 8.14
s, 1H, Ar-H), 7.79 (dd, J1 = 8.4, J2 = 1.6, 1H, Ar-H), 7.42 (d, J =8.8, 2H,
Ar-H), 5.81 (s, 2H, CH2), 3.84 (s, 3H, CH3), 3.75 (s, 4H, CH2); ES-MS 421.2
J2 = 1.6, 1H, Ar-H), 7.85 (d, J = 7.2, 2H, Ar-H), 7.76 (t, J = 7.2, 1H, Ar-H), 7.65
(
(
t, J = 7.6, 2H, Ar-H), 3.91 (s, 3H, CH ), 3.75 (s, 4H, CH ); ES-MS 390.2
3 2
+
+
(
M+H) ; HRMS calcd for C H N O 390.1566, found 390.1562.
2
1 20 5 3
+
+
(
M+H) ; HRMS calcd for C H N O 421.1624, found 421.1618.
21 21 6 4
Methyl (E)-1-benzoyl-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-
H-indole-6-carboxylate hydrobromide (8b). 8b was obtained by reaction
of 6b as previously described for 5a as a white solid (217 mg, 80%), m.p.
Methyl (E)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(3-nitro-
benzyl)-1H-indole-6-carboxylate hydrobromide (5l). 5l was obtained by
reaction of 3l as previously described for 5a as an yellow solid (278 mg,
1
− 1
2
1
18.6–219.6 °C; IR (KBr): υ max cm 3428 (NH), 3366(NH), 2360 (CH2),
712 (C = O), 1661 (C= O), 1613 (C= C), 1432 (C = C), 1380 (C= C), 1230
−
1
9
2
4%), m.p. 252.0–253.8 °C; IR (KBr): υ max cm 3422 (NH), 3234 (NH),
361 (CH ), 1708 (C= O), 1661 (C= O), 1619 (C= C), 1531 (NO ), 1462
1
2
2
(C-O-C); H-NMR (400 MHz, DMSO): δ 12.28 (s, 1H, NH), 8.95 (d, J = 0.8,
1
(
C= C), 1438 (C= C), 1351 (NO2), 1286 (C-O-C); H-NMR (400 MHz,
1
7
1
H, Ar-H), 8.61 (d, J = 8.4, 1H, Ar-H), 8.37 (s, 1H, CH), 8.27 (s, 1H, Ar-H),
.99 (dd, J1 = 8.4, J2 = 1.6, 1H, Ar-H), 7.86–7.84 (m, 2H, Ar-H), 7.76 (t, J = 7.6,
H, Ar-H), 7.65 (t, J = 7.4, 2H, Ar-H), 3.92 (s, 3H, CH3), 3.77 (s, 4H, CH2);
DMSO): δ 12.01 (s, 1H, NH), 8.51 (d, J =8.4, 2H, Ar-H, NH), 8.40 (s, 1H,
Ar-H), 8.34 (s, 1H, CH), 8.22 (s, 1H, Ar-H), 8.15–8.17 (m, 1H, Ar-H), 8.12
(
s, 1H, Ar-H), 7.79 (dd, J1 = 8.4, J2 = 1.2, 1H, Ar-H), 7.67–7.65 (m, 2H, Ar-H),
+
+
ES-MS 390.2 (M+H) ; HRMS calcd for C21H20N5O3 390.1566, found
390.1599.
+
5
.79 (s, 2H, CH ), 3.85 (s, 3H, CH ), 3.75 (s, 4H, CH ); ES-MS 421.2 (M+H) ;
2 3 2
HRMS calcd for C21H21N6O4+ 421.1624, found 421.1618.
5
2
0
-Bromo-1H-indole-3-carbaldehyde (10). To a solution of 9 (5.00 g,
5.5 mmol) in dry DMF (20 ml) was added POCl3 (3.22 ml, 34.68 mol) at
Methyl 1-benzoyl-3-formyl-1H-indole-5-carboxylate (6a). To a solution of 2a
(
100 mg, 0.49 mmol) in dry DMF (2 ml) was added NaH (60%, 22 mg,
.54 mmol) at 0 °C under argon and then stirred at room temperature for 1 h.
The reaction solution was cooled to 0 °C, benzoyl chloride (0.07 ml,
.54 mmol) was added and then stirred at room temperature overnight. The
°C under N and then stirred at room temperature for 2 h. The reaction was
2
0
quenched with H O (60 ml) at 0 °C and adjusted the pH to 7–8 with 2 M
NaOH. The resulting solution was heated to 70 °C and stirred 30 min. After
cooling to room temperature, the precipitate was filtered and washed with
2
0
reaction solution was poured into H2O (20 ml), and the precipitate was filtered.
The crude product was purified by column chromatography on silica gel using
EtOAc/PE (1/8, V/V) as elute to give 6a as a white solid (107 mg, 71%), m.p.
MeOH to give 10 as a white solid (5.19 g, 99%), m.p. 203.5–204.3 °C; IR (KBr):
− 1
υ max cm
3217 (NH), 2361 (C-N), 1645 (C= O), 1523 (C= C), 1437
1
(C = C), 1395 (C= C); H-NMR (400 MHz, DMSO): δ 12.28 (s, 1H, NH), 9.93
s, 1H, CHO), 8.35 (s, 1H, Ar-H), 8.21 (d, J = 2.0, 1H, Ar-H), 7.49 (d, J = 8.4,
−
1
1
72.7–173.3 °C; IR (KBr): υ max cm
C= C), 1552 (C = C), 1452 (C = C), 1267 (C-O-C); H-NMR (400 MHz,
CDCl ): δ 10.10 (s, 1H, CHO), 9.00 (d, J =1.2, 1H, Ar-H), 8.35 (d, J = 8.8, 1H,
1721 (C= O), 1675 (C= O), 1611
(
1
(
+
1H, Ar-H), 7.43 (dd, J1 = 8.8, J2 = 2.0, 1H, Ar-H); ES-MS 225.1 (M+H) .
3
Ar-H), 8.18 (dd, J1 = 8.8, J2 = 1.6, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 7.81–7.79 5-Bromo-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (11). To a solution of
(
(
m, 2H, Ar-H), 7.71 (t, J = 7.6, 1H, Ar-H), 7.61 (t, J = 7.6, 2H, Ar-H), 3.98 10 (2 g, 8.88 mmol) in dry DMSO (15 ml) was added NaH (60%, 0.392 g,
+
s, 3H, CH3); ES-MS 308.1 (M+H) .
9.77 mmol) and stirred at room temperature for 1 h. After the reaction solution
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
1
1
was cooled to 0 °C, benzenesulfonyl chloride (1.36 ml, 10.66 mmol) was added (s, 1H, Ar-H), 8.03–7.99 (m, 3H, Ar-H), 7.67–7.62 (m, 2H, Ar-H), 7.58–7.53
and then stirred at room temperature overnight. The reaction solution was (m, 3H, Ar-H), 7.46 (ddd, J1 = 8.6, J2 = 4.4, J3 = 2.4, 1H, Ar-H), 7.21 (t, J = 8.6,
+
quenched with sat. NH Cl and extracted with CH Cl (200 ml x 3), and the
1H, Ar-H); ES-MS 414.9 (M+H) .
4
2
2
combined organic layers were dried with Na SO , filtered and concentrated.
2
4
Methyl (E)-4-(3-((2-carbamimidoylhydrazono)methyl)-1-(phenylsulfonyl)-1H-indol-
5-yl)benzoate hydrochloride (13a). To a solution of 12a (100 mg, 0.22 mmol) in
dry MeOH was added aminoguanidine hydrochloride (24 mg, 0.22 mmol), and
then the reaction solution was adjusted pH to 3–4 and stirred at room
temperature for 1.5 h. After completion of the reaction, the solvent was
removed under reduced pressure and then the residue was tutrited in EtOAc
and filtered to give 13a as a white solid (100 mg, 89%), m.p. 229.4–232.4 °C; IR
The residue was recrystallized by acetone/hexane to give 11 as a white solid
−
1
(
(
2.67 g, 83%), m.p. 235.2–239.3 °C; IR (KBr): υ max cm 2361 (C-N), 1677
C = O), 1539 (C = C), 1441 (C= C), 1376 (C = C); 1H-NMR (400 MHz,
DMSO): δ 10.06 (s, 1H, CHO), 8.96 (s, 1H, Ar-H), 8.22 (d, J = 2.0, 1H, Ar-H),
8
7
.14–8.12 (m, 2H, Ar-H), 7.95 (d, J = 8.8, 1H, Ar-H), 7.81–7.77 (m, 1H, Ar-H),
.69–7.65 (m, 2H, Ar-H), 7.62 (dd, J = 8.8, J = 2.0, 1H, Ar-H); ES-MS 365.2
1
2
+
(M+H) .
−
1
(
KBr): υ max cm 3736 (NH), 3420 (NH), 3276 (NH), 2361 (C-N), 1677
(C= O), 1540 (C= C), 1452 (C = C), 1379 (C= C); 1H NMR (400 MHz,
4-(3-Formyl-1-(phenylsulfonyl)-1H-indol-5-yl)phenyl acetate (12a). To
a
solution of 11 (0.5 g, 1.37 mmol) in a solution of tetrahydrofuran/H2O DMSO): δ 11.90 (s, 1H, NH), 8.56 (s, 1H, Ar-H), 8.49 (d, J = 1.5, 1H, Ar-H),
20 ml, 1/1, v/v) was added K2CO3 (0.28 g, 2.05 mmol), 4-(methoxycarbo- 8.42 (s, 1H, CH), 8.02–8.09 (m, 5H, Ar-H), 7.89 (d, J = 8.5, 2H, Ar-H),
(
+
nyl)benzeneboronic acid (0.24 g, 1.64 mmol) and Pd(dbpf)Cl2 (8.9 mg, 7.61–7.82 (m, 7H, Ar-H and NH), 3.88 (s, 3H, CH3); ES-MS 476.1 (M+H) ;
0
.0137 mmol) and then stirred at 60 °C for 8 h. The reaction solution was
HRMS calcd for C24H22N5O4S+ 476.1393, found 476.1383.
extracted with EtOAc (100 ml× 3), and the combined organic layers were dried
with Na2SO4, filtered and concentrated. The residue was purified by column
chromatography on silica gel using EtOAc/PE (1/7, v/v) as elunt to give 12a as a
Methyl (E)-3-(3-((2-carbamimidoylhydrazono)methyl)-1-(phenylsulfonyl)-1H-indol-
5-yl)benzoate hydrochloride (13b). 13b was obtained by reaction of 12b as
−
1
previously described for 13a as a white solid (56 mg, 73%), m.p. 206.6–208.6 °
C; IR (KBr): υ max cm 1 3735 (NH), 3396 (NH), 3275 (NH), 2361 (C-N),
white solid (620 mg, 86%), m.p. 166.5–166.8 °C; IR (KBr): υ max cm
361 (C-N), 1720 (C= O), 1678 (C= O), 1541 (C=C), 1455 (C= C), 1378
−
2
1
1
1673 (C= O), 1539 (C=C), 1453 (C= C), 1377 (C = C); H-NMR (400 MHz,
(C = C); H-NMR (400 MHz, CDCl3): δ 10.13 (s, 1H, CHO), 8.52 (d, J = 2.0,
DMSO): δ 12.08 (s, 1H, NH), 8.55 (s, 1H, Ar-H), 8.47 (s, 1H, Ar-H), 8.44
1
H, Ar-H), 8.27 (s, 1H, Ar-H), 8.11 (d, J = 8.4, 2H, Ar-H), 8.04 (d, J = 8.8,
H, Ar-H), 8.02–7.99 (m, 2H, Ar-H), 7.70–7.63 (m, 4H, Ar-H), 7.57–7.53
(
s, 1H, CH), 8.23 (s, 1H, Ar-H),7.99–8.10 (m, 4H, Ar-H), 7.95 (d, J = 7.7, 1H,
1
m, 2H, Ar-H), 3.94 (s, 3H, OCH3); ES-MS 420.5 (M+H)+.
Ar-H), 7.67–7.87 (m, 5H, Ar-H and NH), 7.60–7.66 (m, 3H, Ar-H), 3.89
(
+
+
(
s, 3H, CH ); ES-MS 476.1 (M+H) ; HRMS calcd for C H N O S 476.1393,
3 24 22 5 4
Methyl 3-(3-formyl-1-(phenylsulfonyl)-1H-indol-5-yl)benzoate (12b). 12b was found 476.1388.
obtained by reaction of 11 as previously described for 12a as a white solid
−
1
(E)-2-((1-(Phenylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)-1H-indol-3-yl)methy-
lene)hydrazine-1-carboximidamide hydrochloride (13c). 13c was obtained by
reaction of 12c as previously described for 13a as a white solid (134 mg, 83%),
(
(
(
8
7
328 mg, 53%), m.p. 186.8–187.1 °C; IR (KBr): υ max cm 2361 (C-N), 1714
C = O), 1681 (C=O), 1542 (C= C), 1453 (C=C), 1379 (C = C); 1H NMR
400 MHz, CDCl ): δ 10.13 (s, 1H, CHO), 8.50 (d, J = 1.6, 1H, Ar-H),
.28–8.27 (m, 2H, Ar-H), 8.05–7.99 (m, 4H, Ar-H), 7.83–7.80 (m, 1H, Ar-H),
.69 (dd, J1 = 8.8, J2 =2.0, 1H, Ar-H), 7.66–7.63 (m, 1H, Ar-H), 7.57–7.50
3
−
1
m.p. 268.9–269.4 °C; IR (KBr): υ max cm 3735 (NH), 3488 (NH), 3255
(
NH), 2361 (C-N), 1674 (C= O), 1540 (C= C), 1455 (C=C), 1380 (C= C);
1
+
H-NMR (400 MHz, DMSO): δ 11.93 (s, 1H, NH), 8.55 (s, 1H, Ar-H), 8.43 (d,
(
m, 3H, Ar-H), 3.95 (s, 3H, OCH3); ES-MS 420.5 (M+H) .
J = 1.5, 1H, Ar-H), 8.41 (s, 1H, CH), 8.02–8.10 (m, 3H, Ar-H), 7.81–7.87
(m, 2H, Ar-H), 7.60–7.80 (m, 7H, Ar-H and NH), 7.44 (d, J = 8.0, 2H, Ar-H);
1
(
-(Phenylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)-1H-indole-3-carbaldehyde
12c). 12c was obtained by reaction of 11 as previously described for 12a as a
+
+
ES-MS 502.1 (M+H) ; HRMS calcd for C23H19F3N5O3S 502.1161, found
−
1
white solid (360 mg, 89%), m.p. 180.4–181.3 °C; IR (KBr): υ max cm 2361 502.1152.
(
(
1
C-N), 1678 (C = O), 1542 (C= C), 1457 (C = C), 1380 (C= C); 1H NMR
400 MHz, DMSO): δ 10.12 (s, 1H, CHO), 8.98 (s, 1H, Ar-H), 8.34 (d, J = 1.6,
H, Ar-H), 8.18–8.16 (m, 2H, Ar-H), 8.07 (d, J = 8.8, 1H, Ar-H), 7.80–7.75
(
E)-2-((1-(Phenylsulfonyl)-5-(3-(trifluoromethoxy)phenyl)-1H-indol-3-yl)methy-
lene)hydrazine-1-carboximidamide hydrochloride (13d). 13d was obtained by
reaction of 12d as previously described for 13a as a white solid (170 mg, 65%),
m.p. 218.6–220.8 °C; IR (KBr): υ max cm 3468 (NH), 3255 (NH), 3128
(
(
m, 2H, Ar-H), 7.69–7.65 (m, 3H, Ar-H), 7.61–7.57(m, 2H, Ar-H), 7. 37
−
1
d, J =8.4, 1H, Ar-H); ES-MS 446.4 (M+H)+.
(
NH), 2361 (C-N), 1674 (C= O), 1538 (C= C), 1452 (C=C), 1380 (C= C);
1
1
-(Phenylsulfonyl)-5-(3-(trifluoromethoxy)phenyl)-1H-indole-3-carbaldehyde
H-NMR (400 MHz, DMSO): δ 12.08 (s, 1H, NH), 8.55 (s, 1H, Ar-H), 8.45
(
12d). 12d was obtained by reaction of 11 as previously described for 12a as a
(d, J = 1.5, 1H, Ar-H), 8.43 (s, 1H, CH), 8.05–8.07 (m, 3H, Ar-H), 7.70–7.81
white solid (300 mg, 74%), m.p. 150.4–151.0 °C; IR (KBr): υ max cm 2361 (m, 6H, Ar-H and NH), 7.56–7.70 (m, 4H, Ar-H), 7.36 (d, J = 8.2, 1H, Ar-H);
−
1
+
+
(
(
1
(
C-N), 1677 (C = O), 1541 (C= C), 1450 (C = C), 1379 (C= C); 1H NMR
400 MHz, DMSO): δ 10.12 (s, 1H, CHO), 8.98 (s, 1H, Ar-H), 8.33 (d, J = 1.6, 502.1156.
H, Ar-H), 8.18–8.16 (m, 2H, Ar-H), 8.07 (d, J = 8.8, 1H, Ar-H), 7.78–7.74
m, 4H, Ar-H), 7.70–7.66 (m, 2H, Ar-H), 7.45 (d, J = 8.0, 2H, Ar-H); ES-MS
ES-MS 502.1 (M+H) ; HRMS calcd for C23H19F3N5O3S 502.1161, found
(
E)-2-((1-(Phenylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methy-
lene)hydrazine-1-carboximidamide hydrochloride (13e). 13e was obtained by
reaction of 12e as previously described for 13a as a white solid (55 mg, 89%),
m.p. 249.0–249.3 °C; IR (KBr): υ max cm 3735 (NH), 3396 (NH), 3216
(NH), 2361 (C-N), 1673 (C= O), 1539 (C= C), 1454 (C=C), 1379 (C= C);
H-NMR (400 MHz, DMSO): δ 12.05 (s, 1H, NH), 8.57 (s, 1H, Ar-H), 8.49
+
4
46.4 (M+H) .
−
1
1
-(Phenylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-1H-indole-3-carbaldehyde
(12e). 12e was obtained by reaction of 11 as previously described for 12a as a
−
1
1
white solid (85 mg, 67%), m.p. 216.5–216.8 °C; IR (KBr): υ max cm 2361
(
(
(
(
C-N), 1677 (C = O), 1542 (C= C), 1451 (C = C), 1380 (C= C); 1H NMR (d, J = 1.5, 1H, Ar-H), 8.43 (s, 1H, CH), 8.02–8.13 (m, 3H, Ar-H), 7.95
400 MHz, CDCl3): δ 10.13 (s, 1H, CHO), 8.50 (d, J = 1.6, 1H, Ar-H), 8.28 (d, J = 8.1, 2H, Ar-H), 7.70–7.85 (m, 7H, Ar-H and NH), 7.64 (t, J =7.8, 2H,
+
+
s, 1H, Ar-H), 8.05 (d, J =8.8, 1H, Ar-H), 8.03–8.00 (m, 2H, Ar-H), 7.74–7.68
Ar-H); ES-MS 486.1 (M+H) ; HRMS calcd for C21H19F3N5O2S 486.1212,
m, 4H, Ar-H), 7.68–7.63(m, 2H, Ar-H), 7.58–7.53 (m, 2H, Ar-H); ES-MS found 486.1201.
4
30.4 (M+H)+.
(
E)-2-((5-(3-Chloro-4-fluorophenyl)-1-(phenylsulfonyl)-1H-indol-3-yl)methy-
5-(3-Chloro-4-fluorophenyl)-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde
lene)hydrazine-1-carboximidamide hydrochloride (13f). 13f was obtained by
(
12f). 12f was obtained by reaction of 11 as previously described for 12a as a
reaction of 12f as previously described for 13a as a white solid (110 mg, 98%),
white solid (510 mg, 83%), m.p. 171.1–171.6 °C; IR (KBr): υ max cm 2361 m.p. 234.2–237.3 °C; IR (KBr): υ max cm 3736 (NH), 3462 (NH), 3128
−
1
− 1
(
C-N), 1677 (C = O), 1542 (C= C), 1453 (C = C), 1379 (C= C); 1H NMR (NH), 2361 (C-N), 1672 (C= O), 1539 (C= C), 1455 (C=C), 1379 (C= C);
1
(400 MHz, CDCl ): δ 10.12 (s, 1H, CHO), 8.41 (d, J = 1.6, 1H, Ar-H), 8.27
H-NMR (400 MHz, DMSO): δ 11.91 (s, 1H, NH), 8.55 (s, 1H, Ar-H), 8.41
3
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
1
2
−
1
(
s, 1H, Ar-H), 8.40 (s, 1H, CH), 8.02–8.07 (m, 3H, Ar-H), 7.95 (dd, J = 7.1,
(205 mg, 91%), m.p. 256.3–256.5 °C; IR (KBr): υ max cm 3735 (NH), 3281
1
7
H, Ar-H), 7.70–7.77 (m, 5H, Ar-H and NH), 7.63–7.66 (m, 3H, Ar-H),
(NH), 2925 (NH), 2361 (C-N), 1664 (C = O), 1546 (C = C), 1457 (C= C),
.50 (t, J = 9.1, 1H, Ar-H); ES-MS 470.1 (M+H)+; HRMS calcd for 1373 (C= C); H-NMR (400 MHz, DMSO): δ 12.31 (s, 1H, NH), 8.56 (s, 1H,
1
+
C22H18ClFN5O2S 470.0854, found 470.0849.
Ar-H), 8.42 (d, J =1.6, 1H, Ar-H), 8.41 (s, 1H, CH), 8.03–8.08 (m, 3H, Ar-H),
7
2
.94 (dd, J1 = 7.0, J2 = 2.2, 1H, Ar-H), 7.71–7.77 (m, 3H, Ar-H), 7.65 (t, J = 7.8,
Methyl (E)-4-(3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(phenyl-
sulfonyl)-1H-indol-5-yl)benzoate dihydrobromide (14a). To a solution of 12a
+
H), 7.52 (t, J = 8.8, 1H, Ar-H), 3.74 (s, 4H, CH2); ES-MS 496.1 (M+H) ;
+
HRMS calcd for C24H20ClFN5O2S 496.1010, found 496.1001.
(
50 mg, 0.11 mmol) in dry MeOH (2 ml) was added 2-hydrazino-2-
imidazoline hydrobromide (20 mg, 0.11 mmol), and then the reaction solution
was stirred at 75 °C. After the completion of the reaction, the solvent was
removed under reduced pressure and then the residue was tutrited in EtOAc
and filtered to give 14a as a white solid (48 mg, 88%), m.p. 228.9–230.3 °C; IR
Biology
Bacterial strains. S. aureus strains ATCC 29213, ATCC 25923 and
ATCC-S-6007 were purchased from the American Type Culture Collection
(Manassas, VA, USA). When required for testing, these strains were retrieved
−
1
(
(
KBr): υ max cm 3735 (NH), 3439 (NH), 3174 (NH), 2361 (C-N), 1661
C= O), 1541 (C= C), 1454 (C = C), 1376 (C= C); 1H-NMR (400 MHz,
from storage at − 80 °C and subcultured on Luria-Bertani agar for viability and
purity.
DMSO): δ 12.39 (s, 1H, NH), 8.55 (s, 1H, Ar-H), 8.51 (d, J = 1.6, 1H, Ar-H),
.42 (s, 1H, CH), 8.11–8.01 (m, 5H, Ar-H), 7.88 (d, J = 8.5, 2H, Ar-H), 7.79
dd, J1 = 8.6, J2 = 1.8, 1H, Ar-H), 7.75 (d, J = 7.6, 1H, Ar-H), 7.65 (t, J = 7.8,
The clinical strains used for MIC determinations were isolated from
hospital in-patients as part of their routine investigations for the diagnosis
of various infections. They were identified by standard microbiological methods
and tested for antibiotic susceptibilities by the Kirby Bauer method
well as the semiautomated BD Phoenix system (Becton Dickinson, Franklin
Lakes, NJ, USA).
8
(
+
2
H, Ar-H), 3.88 (s, 3H, CH3), 3.72 (s, 4H, CH2); ES-MS 502.2 (M+H) ; HRMS
23,24
as
calcd for C26H24N5O4S+ 502.1549, found 502.1538.
Methyl (E)-3-(3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(phenyl-
sulfonyl)-1H-indol-5-yl)benzoate hydrobromide (14b). 14b was obtained by
reaction of 12b as previously described for 14a as a white solid (187 mg,
As these strains were archived routine isolates made anonymous by the
removal of all labels that could be traced back to the patient source, ethical
approval for this study was exempted.
−
1
9
7%), m.p. 237.4–240.4 °C; IR (KBr): υ max cm 3736 (NH), 3459 (NH),
3
123 (NH), 2361 (C-N), 1665 (C = O), 1541 (C = C), 1452 (C= C), 1378
Determination of MIC and MBC. All bacterial strains were initially screened
with 100 μg ml−1 of each compound in Trypticase Soy Broth with 1% DMSO.
The compounds showing bactericidal activity at this concentration were then
further tested in two-fold dilutions from 50 to 0.39 μg ml− 1. The inoculum
1
(
C= C); H-NMR (400 MHz, DMSO): δ 12.31 (s, 1H, NH), 8.56 (s, 1H, Ar-H),
8
.49 (s, 1H, Ar-H), 8.43 (s, 1H, CH), 8.25 (s, 1H, Ar-H), 8.07–8.09 (m, 3H,
Ar-H), 8.01 (d, J = 8, 1H, Ar-H), 7.96 (d, J = 7.6, 1H, Ar-H), 7.76 (t, J = 7.6,
H, Ar-H), 7.61–7.67 (m, 3H, Ar-H), 3.89 (s, 3H, OCH ), 3.74 (s, 4H, CH );
2
3
2
used was an overnight culture diluted 1:1000 for Gram-negative bacteria and
+
+
ES-MS 502.2 (M+H) ; HRMS calcd for C H N O S 502.1549, found
5
− 1
26 24 5 4
1
:100 for Gram-positive bacteria, to make approximately 10 cfu ml
.
5
02.1539.
Each well in a sterile 96-well microtiter plate was filled with 150 μl of
compound in Trypticase Soy Broth or Middlebrook broth with 1% DMSO.
Each compound concentration was pipetted into duplicate wells. The wells
were then inoculated with 10 μl of culture, covered with a plate cover
and incubated at 36 °C for 48 h. OD readings (at 600 nm) were taken
at 0, 24 and 48 h. After 48 h of incubation, each well was subcultured onto
a blood agar plate to demonstrate bacterial growth. Viability and 1% DMSO
controls were used in every plate.
(
5
E)-3-((2-(4,5-Dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(phenylsulfonyl)-
-(4-(trifluoromethoxy)phenyl)-1H-indole hydrobromide (14c). 14c was
obtained by reaction of 12c as previously described for 14a as a white solid
−
1
(
(
1
100 mg, 60%), m.p. 254.4–254.5 °C; IR (KBr): υ max cm 3732 (NH), 3445
NH), 3179 (NH), 2361 (C-N), 1667 (C= O), 1541 (C= C), 1455 (C = C),
1
378 (C= C); H NMR (400 MHz, DMSO): δ 12.28 (s, 1H, NH), 8.55 (s, 1H,
Ar-H), 8.44(s, 1H, Ar-H), 8.42 (s, 1H, CH), 8.06–8.09 (m, 3H, Ar-H), 7.83
For the determination of MIC, OD readings for test wells were compared
with those of the control wells; an arrested or at least 50% retarded increase in
OD reading was taken to indicate bacterial growth inhibition. MBC was defined
as the lowest compound concentration to cause complete absence of bacterial
growth on subculture.
(
3
d, J =8.6, 2H, Ar-H), 7.62–7.77 (m, 4H, Ar-H), 7.46 (d, J = 8.1, 2H, Ar-H),
+
.74 (s, 4H, CH2 CH2); ES-MS 528.1 (M+H) ; HRMS calcd for
+
C H F N O S 528.1317, found 528.1306.
25 21 3 5 3
(
5
E)-3-((2-(4,5-Dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(phenylsulfonyl)-
-(3-(trifluoromethoxy)phenyl)-1H-indole hydrobromide (14d). 14d was
For Mycobacterium H37Ra, inoculations were made in Middlebrook 7H9
obtained by reaction of 12d as previously described for 14a as a white solid broth and incubated up to 4 weeks. Subcultures were made onto Middlebrook
−
1
(
3
(
8
7
3
5
183 mg, 53%), m.p. 243.2 °C; IR (KBr): υ max cm 3736 (NH), 3435 (NH),
174 (NH), 2361 (C-N), 1666 (C = O), 1541 (C = C), 1452 (C= C), 1376
7H10 agar at 2 weeks and again at 4 weeks of incubation.
1
C= C); H-NMR (400 MHz, DMSO): δ 12.33 (s, 1H, NH), 8.57 (s, 1H, Ar-H), Molecular docking
.47 (d, J = 1.2, 1H, Ar-H), 8.42 (s, 1H, CH), 8.06–8.09 (m, 3H, Ar-H),
.74–7.78 (m, 4H, Ar-H), 7.58–7.68 (m, 3H, Ar-H), 7.37 (d, J = 8.4, 1H, Ar-H),
.73 (s, 4H, CH2); ES-MS 528.1 (M+H) ; HRMS calcd for C25H21F3N5O3S
In total, 40 compounds were designed and synthesized, and molecular
docking was performed by using GOLD (v 5.2.2 Genetic Optimization for
Ligand Docking, Cambridge, UK). Each ligand was docked 10 times, starting
each time from a different random population of ligand orientations and using
the default automatic genetic algorithm parameter settings. The Moenomycin A
in the crystal structure was used as the reference to indicate the binding site for
the molecular docking. All torsion angles in each compound were allowed
to rotate freely and the results of the different docking runs were ranked
using Gold Score.
+
+
28.1317, found 528.1305.
(
5
E)-3-((2-(4,5-Dihydro-1H-imidazol-2-yl)hydrazono)methyl)-1-(phenylsulfonyl)-
-(4-(trifluoromethyl)phenyl)-1H-indole hydrobromide (14e). 14e was obtained
by reaction of 12e as previously described for 14a as a white solid (204 mg,
−
1
9
3
(
8
7
7
0%), m.p. 249.2–249.7 °C; IR (KBr): υ max cm 3735 (NH), 3449 (NH),
178 (NH), 2361 (C-N), 1666 (C = O), 1542 (C = C), 1451 (C= C), 1379
C= C); H-NMR (400 MHz, DMSO): δ 12.31 (s, 1H, NH), 8.58 (s, 1H, Ar-H),
.49 (d, J = 1.2, 1H, Ar-H), 8.43 (s, 1H, CH), 8.08–8.10 (m, 3H, Ar-H),
.93 (d, J = 8.0, 2H, Ar-H), 7.82 (d, J =8.4, 2H, Ar-H), 7.77 (m, 2H, Ar-H),
.66 (t, J = 7.8, 2H, Ar-H), 3.74 (s, 4H, CH2); ES-MS 512.1 (M+H) ; HRMS
1
CONFLICT OF INTEREST
The authors declare no conflict of interest.
+
+
ACKNOWLEDGEMENTS
calcd for C23H18F3N5O2S 512.1368, found 512.1359.
This work was supported by National Natural Science Foundation of China
(81460538, 81660588) given to WH; IPSR/RMC/UTARRF/2015-C1/NO3
awarded to YFN by Universiti Tunku Abdul Rahman (UTAR), Kuala Lumpur,
(
E)-5-(3-Chloro-4-fluorophenyl)-3-((2-(4,5-dihydro-1H-imidazol-2-yl)hydra-
zono)methyl)-1-(phenylsulfonyl)-1H-indole hydrobromide (14f). 14f was
obtained by reaction of 12f as previously described for 14a as a white solid Malaysia; and University of Malaya-MOHE High Impact Research grant
The Journal of Antibiotics

Indole core-based derivatives
W Hong et al
1
3
(
UM.C/625/1/HIR/MOHE/DENT/22) given to ICP. The authors would like to
12 Zhang, M. Z. et al. Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-
indoles and 3-(1,3,4-oxadiazol-5-yl)methyl-indoles. Eur. J. Med. Chem. 63,
thank Dr Charles Laughton at University of Nottingham, UK for offering the
access to the computing facilities.
22–32 (2013).
1
3 Zhao, F., Liu, N., Zhan, P., Jiang, X. & Liu, X. Discovery of HCV NS5B thumb site I
inhibitors: core-refining from benzimidazole to indole scaffold. Eur. J. Med. Chem. 94,
218–228 (2015).
14 Giraud, F. et al. Design, synthesis and evaluation of 3-(imidazol-1-ylmethyl)indoles
as antileishmanial agents. Part II. J. Enzyme Inhib. Med. Chem. 24,
1
Yang, Z. et al. Proportions of Staphylococcus aureus and methicillin-resistant Staphy-
lococcus aureus in patients with surgical site infections in mainland China: a systematic
review and meta-analysis. PLoS ONE 10, e0116079 (2015).
Kali, A. Antibiotics and bioactive natural products in treatment of methicilln resistant
Staphylococcus aureus: a brief review. Pharmacogn. Rev. 9, 29–34 (2015).
Kumar, A., Verma, N., Agrawal, D. & Sharma, B. S. Endoscopic lavage for antibiotic
unresponsive severe Acinetobacter baumanii ventriculitis: an unexplored
treatment option. Acta Neurochir. (Wien) 157, 1225–1227 (2015).
1
067–1075 (2009).
1
1
5 Andrew, L. L. et al. Structural insight into the transglycosylation step of bacterial
cell-wall biosynthesis. Science 315, 1402–1405 (2007).
6 Penthala, N. R., Yerramreddy, T. R. & Crooks, P. A. Synthesis and in vitro screening of
novel N-benzyl aplysinopsin analogs as potential anticancer agents. Bioorg. Med. Chem.
Lett. 21, 1411–1413 (2011).
7 Andreani, A. et al. Imidazo[2,1-b]thiazole guanidinylhydrazones as RSK2 inhibitors.
Eur. J. Med. Chem. 46, 4311–4323 (2011).
8 Mohammad, H. et al. Synthesis and antibacterial evaluation of a novel series of
synthetic phenylthiazole compounds against methicillin-resistant Staphylococcus
aureus (MRSA). Eur. J. Med. Chem. 94, 306–316 (2015).
2
3
1
4
5
Ahmed, M. U. et al. Sensitive, resistant and multi-drug resistant Acinetobacter
baumanii at Saudi Arabia hospital eastern region. Pak. J. Pharm. Sci. 28,
1
8
25–832 (2015).
Lee, C. Y., Tsai, H. C., Lee, S. S. & Chen, Y. S. Concomitant emphysematous
prostatic and periurethral abscesses due to Klebsiella pneumoniae: a case report and
review of the literature. Southeast Asian J. Trop. Med. Public Health 45,
1
2
2
2
9 Wang, Y. et al. Structure-based design, synthesis, and biological evaluation of isatin
derivatives as potential glycosyltransferase inhibitors. Chem. Biol. Drug Des. 84,
6
85–696 (2014).
0 Xu, H. & Fan, L. Antifungal agents. Synthesis and antifungal activities of novel indole
1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro. Eur. J.
1
099–1106 (2014).
6
7
Huang, C. H. et al. Risk factors for in-hospital mortality in patients with type 2 diabetes
complicated by community-acquired Klebsiella pneumoniae bacteremia. J. Formos
Med. Assoc. 114, 916–922 (2015).
[
Med. Chem. 46, 364–369 (2011).
1 Moseley, J. D., Murray, P. M., Turp, E. R., Tyler, S. N. G. & Burn, R. T. A mild robust
generic protocol for the Suzuki reaction using an air stable catalyst. Tetrahedron 68,
Yaita, K., Komatsu, M., Oshiro, Y.
and epidural abscess due to extended-spectrum β-lactamase-producing Klebsiella
pneumoniae: case report and review of the literature. Intern. Med. 51,
645–2648 (2012).
Wright, G. D.
373–1374 (2007).
& Yamaguchi, Y. Postoperative meningitis
6010–6017 (2012).
a
a
2 Al-Marzooq, F., Ngeow, Y. F. & Tay, S. T. Emergence of Klebsiella pneumoniae
producing dual carbapenemases (NDM-1 and OXA-232) and 16S rRNA methylase
2
8
9
1
1
A
new target for antibiotic development. Science 315,
(armA) isolated from a Malaysian patient returning from India. Int. J. Antimicrob. Agents
1
Halliday, J., McKeveney, D., Muldoon, C., Rajaratnam, P. & Meutermans, W. Targeting
the forgotten transglycosylases. Biochem. Pharmacol. 71, 957–967 (2006).
0 Bohdan, O. B. & Walker, S. Moenomycin family antibiotics: chemical synthesis,
biosynthesis, biological activity. Nat. Prod. Rep. 27, 1594–1617 (2010).
1 Xu, H., Wang, Q. & Yang, W. B. Antifungal activities of some indole derivatives.
Z. Naturforsch C. 65, 437–439 (2010).
45, 445–446 (2015).
23 Clinical and Laboratory Standards Institute. Approved Standard M2-A10. Performance
Standards for Antimicrobial Disk Susceptibility Tests 10th edn. (CLSI, Wayne, PA,
USA, 2009).
24 Clinical and Laboratory Standards Institute. M100-S21 (M2). Disk Diffusion
Supplemental Tables (CLSI, Wayne, PA, USA, 2011).
The Journal of Antibiotics