Synthesis of fluorene and/or benzophenone O-oxime ethers containing amino acid residues and study of their cardiovascular and antibacterial effects

Article abstract of DOI:10.1007/s00044-014-0967-3

The syntheses and biological studies of O -oxime ethers having α-amino acid residues as new analogs of IPS-339 have been described. In this synthesis, the reaction of fluorene and/or benzophenone O-oxime with epichlorohydrin or epibromohydrin afforded the corresponding O-oxime ether adducts. The N-alkylation of amino acid with O-oxime ether adducts led to synthesis of new analogs of IPS-339. The products were examined for their cardiovascular property. It was demonstrated that 2-(3-(9H-fluoren-9- ylideneaminooxy)-2-hydroxypropylamino)-3-methyl-butanoic acid as the most potent compound substantially reduces the heart rate of dogs. Compounds were also evaluated for their in vitro antibacterial activity against some Gram-negative and Gram-positive bacteria. The antibacterial screening proved the considerable antibacterial activity against both groups of bacteria. The docking analysis demonstrated the appropriate fitting of 2-(3-(9H-fluoren-9-ylideneaminooxy)-2- hydroxy-propylamino)-3-methyl-butanoic acid in human β₂- adrenergic receptor active site. Potential drug toxicity for some active compounds has also been predicted. Springer Science+Business Media 2014.

Full text of DOI:10.1007/s00044-014-0967-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0967-3
ORIGINAL RESEARCH
Synthesis of fluorene and/or benzophenone O-oxime ethers
containing amino acid residues and study of their cardiovascular
and antibacterial effects
•
Mohammad Navid Soltani Rad Somayeh Behrouz Elham Zarenezhad
•
•
•
Mohammad Hossein Moslemin Ali Zarenezhad Mehdi Mardkhoshnood
•
•
•
Marzieh Behrouz Saeid Rostami
Received: 23 August 2013 / Accepted: 17 February 2014
ꢀ Springer Science+Business Media New York 2014
Abstract The syntheses and biological studies of
O-oxime ethers having a-amino acid residues as new
analogs of IPS-339 have been described. In this synthesis,
the reaction of fluorene and/or benzophenone O-oxime
with epichlorohydrin or epibromohydrin afforded the cor-
responding O-oxime ether adducts. The N-alkylation of
amino acid with O-oxime ether adducts led to synthesis of
new analogs of IPS-339. The products were examined for
their cardiovascular property. It was demonstrated that
2-(3-(9H-fluoren-9-ylideneaminooxy)-2-hydroxypropylamino)-
3-methyl-butanoic acid as the most potent compound
substantially reduces the heart rate of dogs. Compounds
were also evaluated for their in vitro antibacterial activity
against some Gram-negative and Gram-positive bacteria.
The antibacterial screening proved the considerable anti-
bacterial activity against both groups of bacteria. The
docking analysis demonstrated the appropriate fitting of
2-(3-(9H-fluoren-9-ylideneaminooxy)-2-hydroxy-propylamino)-
3-methyl-butanoic acid in human b2-adrenergic receptor
active site. Potential drug toxicity for some active com-
pounds has also been predicted.
Keywords O-oxime ether ꢀ N-alkyl amino acid ꢀ
IPS-339 ꢀ Cardiovascular ꢀ Antibacterial
Introduction
In recent years, hypertension is known as the silent killer
(WHO, 2013). Hypertension is the most observed cardio-
vascular illness seriously responsible in human mortality.
There is an extensive challenge to explore the novel che-
motherapeutic agents for hypertension remedy in recent
years (Wilson et al., 2004). One way to prevent the
hypertension is antagonizing the b-adrenoceptores espe-
cially b1- and b2-receptores (Brunton et al., 2006). Among
drugs known for inhibiting b-adrenergic receptors, two
well-distinguished classes i.e., (i) arylethanolamine (I) and
(ii) aryloxypropanolamine (II) (Fig. 1) have been exten-
sively investigated. The structural activity relationship
studies have revealed these two classes of compounds are
extremely homogeneous in their scaffolds. However,
aryloxypropanolamine (II) is the most evaluated and used
antagonists for inhibiting b-adrenergic receptors in com-
parison with other related compounds (Patrick, 2001).
Various aryloxypropanol amines have been synthesized so
far and plenty of them are now approved drugs clinically
used as cardiovascular agents (Kleeman et al., 1999). Many
approved drugs with cardiovascular property including
propranolol (III), metoprolol (IV), alprenolol (V), and
carazolol (VI) having aryloxypropanol amine framework
(Fig. 1).
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-0967-3) contains supplementary
material, which is available to authorized users.
M. N. Soltani Rad (&) ꢀ S. Behrouz (&) ꢀ M. Behrouz ꢀ
S. Rostami
Department of Chemistry, Shiraz University of Technology,
71555-313 Shiraz, Iran
e-mail: soltani@sutech.ac.ir; nsoltanirad@gmail.com;
navid_soltani@yahoo.com
S. Behrouz
e-mail: behrouz@sutech.ac.ir
E. Zarenezhad ꢀ M. H. Moslemin
Department of Chemistry, Islamic Azad University, Yazd
Branch, Yazd, Iran
A. Zarenezhad ꢀ M. Mardkhoshnood
Fasa University of Medical Sciences, Fasa, Iran
123

Med Chem Res
Fig. 1 Structure of b-
adrenoceptore blocking agents
OH
OH
O
O
NHR
NHR
R'
R'
(II)
(I)
MeO
Me
Me
O
N
H
Me
N
Me
OH
(III)
H
OH
(IV)
Me
O
N
Me
H
Me
Me
OH
O
N
N
H
OH
H
(VI)
(V)
Me Me
Me
N
O
N
H
OH
(VII)
To develop aryloxypropanol amines drugs, the ring
variations strategy has been applied and in that context,
attempts were mostly carried out to consider diverse a-
ryloxy residues rather than altering the simple amine
moieties. However, the discovery of IPS-339 (VII) as a
potent b2-selective adrenergic blocking agent by Leclerc
and coworkers (Leclerc et al., 1977; Imbs et al., 1977)
demonstrated that the insertion of a C=N–O group
between the propanolamine side chain and the aryl moiety
of b-blockers did not only annihilate the b-adrenoceptors
property but also, in some cases, could lead to potent and
selective ligands (Fig. 1). Thus, the extensive explorations
of other aromatic oxime ethers by different research
groups have emerged into new analogs of IPS-339;
however, the amine residues used in scaffolds of these
compounds have the simple structures. (Tandon et al.,
2004; Saccomanni et al., 2003; Ferrarini et al., 1998,
2000; Schenone et al., 2000; Balsamo et al., 1995, 1996,
1998, 1999; Breschi et al., 1996; Leclerc et al., 1980). El
Hedri and coworkers showed considering a long and
bulky amine substituent moiety linked to the nitrogen of
the lateral propanolamine chain can improve the selec-
tivity of interaction with b-adrenoceptores. Furthermore,
it was also confirmed that considering either mono or
dicarboxyl groups on an alkylamine moiety can lead to
enhancement of the selectivity as well (El Hadri et al.,
2003).
The O-alkylation of oximes is very important in
medicinal chemistry since O-oxime ether derivatives are
prominent structural motifs found in numerous pharma-
ceutically active compounds. Many well-known drugs with
various chemotherapeutic activities contain an oxime ether
moiety in their structures. In our previous researches, we
studied the O-alkylation of structurally diverse oximes with
carbon electrophiles to access various potential bioactive
compounds (Soltani Rad et al., 2009, 2010a, b, 2011a, b).
We also employed the O-oxime ether bond to synthesis of
some novel potentially b-adrenoceptore blocking agent
analogs (Soltani Rad et al., 2008, 2012a).
In this context and in line with our interest in design and
synthesis of new b-adrenoceptore blocking agents (Soltani
Rad et al., 2008, 2012a, b, 2013); hereby, we disclose the
synthesis and biological study of compounds (VIII) and
(X) as new analogs of IPS-339 where a-amino acids have
been surrogated instead of t-butyl amine residue in IPS-339
(Fig. 2).
Results and discussion
Chemistry
The synthesis of new IPS-339 analogs (5) followed the
general pathway illustrated in Scheme 1. As shown in
123

Med Chem Res
Fig. 2 General structure of new
analogs of IPS-339 having a-
amino acid residues
R
R
N
N
O
N
CO2H
O
N
H
CO2H
H
OH
OH
(X)
(VIII)
Scheme 1 Synthetic pathway
for new analogs of IPS-339
OH
O
N
O
(X=Cl, Br)
X
NH2OH.HCl, NaOH
EtOH-H2O, reflux, 12 h
R
KOH, H2O-DMSO,
r.t., 10 h
2
1
O
N
CO2H
R
O
N
O
X
N
H
N
O
OH
OH
H2N
CO2H
+
K2CO3-TEA, TBAB (cat.),
DMF, reflux, 15 h
3
4
5a-j
R
R
O
N
O
CO2H
N
CO2H
N
N
H
H
OH
1
OH
10
6
5
7
13
6
8
8
5
9
9
12
11
1
2
13
4
2
11
4
3
7
5e-j 12
10
3
5a-d
5e
5f
5g
5h
5i
R= CH(Me)2
R= Me
R= H
R= CH2Ph
R= CH2CH(Me)2
R= CH2CH2SMe
5a
R= CH(Me)2
R= Me
R= H
5b
5c
5d
R= CH2Ph
5j
Scheme 1, the first step includes the oximation reaction of
aromatic ketone (1) (i.e., flourene and/or benzophenone).
The oximation of ketones was achieved using hydroxyl
amine hydrochloride in refluxing alkali solution of EtOH–
H2O (10:1, V/V) due to well-known procedure and almost
yielded quantitatively (Soltani Rad et al., 2009). Oxime 2
as a labile nucleophile is able to react with epoxide (Soltani
Rad et al., 2008) especially with that of epichlorohydrin
and/or epibromohydrin to afford the halohydrin 3 and
epoxide 4. Due to our previous experiences in O-alkylation
of oximes, adducts of 3 and 4 were prepared efficiently by
O-alkylation of oxime in H2O–DMSO (1:9, V/V) solution
in the presence of KOH at ambient temperature (Soltani
Rad et al., 2008, 2009, 2010a, 2011a, 2012a). Since epi-
chlorohydrin and/or epibromohydrin are ambident elec-
trophiles; therefore, the O-oximation leads to a mixture of
adducts. While the O-oximation with epichlorohydrin
normally tends to form the chlorohydrin; nevertheless, the
O-oximation with epibromohydrin often leads to epoxide
adduct. In our current synthesis, the O-oximation of both
aromatic ketoximes with epichlorohydrin nearly afforded
the ratio of 40:60 (%) for adducts 4 versus 3, whereas in a
same circumstance, the ratio of 70:30 (%) was nearly
obtained when epibromohydrin was used to synthesis the
respective adducts. These ratios were determined using
GC-analysis. It is not necessary to separate adducts 3 from
4 because their reaction with amino acids leads to a single
product.
The N-alkylation of a-amino acids with mixture of
adducts 3 and 4 can be directly achieved without requiring
the protection of amino acids (Santra and Perez, 2011)
using a combination of K2CO3–triethyl amine (TEA) and a
catalytic amount of tetrabutylammonium bromide (TBAB)
in refluxing anhydrous DMF. Interestingly, using this
protocol, the selective mono-N-alkylation of a-amino acid
is happened, whereas for mono-N-alkylation of a-amino
acid with simple and small alkyl groups i.e., Me, Et… the
presence of protective groups such as CBZ, acyl, etc. is
critically essential (Stodulski and Mlynarski, 2008). The
mono-N-alkylation of amino acid in our reaction is
123

Med Chem Res
attributed to bulky nature of both adducts 3 and 4 in which
preventing the further N-alkylation and forming di-N-
alkylated product.
Table 1 Structure of new IPS-339 analogs
Product
Structurea
Time (h)
12
Yield (%)b
72
5a
Me
Me
Diverse a-amino acids were used to prepare the different
IPS-339 analogs in which the related structures are shown
in Table 1. As can be seen in Table 1, a-amino acids
including, valine (5a and 5e), alanine (5b and 5f), glycine
(5c and 5g), phenylalanine (5d and 5h), leucine (5i), and
methionine (5j) have been incorporated in scaffold of the
new IPS-339 analogs. In general, good to excellent yields
of products were obtained using current synthetic proto-
cols. As expected, the use of amino acids bearing bulkier
residue such as leucine (5i), methionine (5j), and phenyl-
alanine (5d and 5 h) afforded lower yields of product
(Table 1).
N
O
O
N
H
CO2H
OH
OH
Me
CO2H
5b
5c
5d
10
10
12
75
81
63
N
N
N
H
O
N
H
CO2H
OH
Cardiovascular study
N
O
N
H
CO2H
OH
The cardiovascular properties of compounds 5a–j have
been studied. In this regard, twenty four clinically healthy
mongrel dogs of same sex, weight between 15 and 24 kg
were examined. The dogs were fed a commercials diet
once daily and water to drink. They were dewormed,
washed with acaricide solution, and acclimatized for
2 weeks. The dogs were randomly divided into 12 groups
of two members. Ten groups received 2 mg kg-1 body
weight of each compound (5a–j) intravenously, whereas
group 11 and 12 received only DMSO–water (distil.) and
propranolol (Inderal) (2 mg kg-1), respectively.
Me
Me
5e
5f
12
10
11
13
62
68
70
56
N
N
O
O
N
H
CO2H
OH
OH
Me
N
H
CO2H
CO2H
5g
5h
N
Electrocardiograph (ECG) was recorded with lead II,
while each dog was positioned right lateral recumbent and
using the heat sensitive paper at a recording speed of
25 mm s-1 with sensitivity of 10 mm for 0.1 mV on a
Kenz-ECG-103 (Suzuken Co., Japan). The recording was
run successively by 5 min time interval on each dog before,
simultaneously, and after compound infusion. Data after
administration were taken from normal sinus beats that
were closely related to the arrhythmias whenever they
occurred.
The effect on heart rate (beat min-1) was determined for
all compounds at dose of 2 mg kg-1 body weight by using
a standard ECG device, and results are depicted in Table 2.
In general, no detectable arrhythmia was observed in all
ECG records regardless of increasing the heart rate that
likely caused by stress origin from invasive procedure just
after infusion. All of the tested compounds diminished the
heart rate during study especially at 20th minute compared
to propranolol as a reference drug. 5a was the most
effective compound of all with remarkable ability in
O
N
H
OH
N
O
N
H
CO2H
OH
Me
5i
15
15
58
55
Me
N
N
O
O
N
H
CO2H
OH
OH
SMe
CO2H
5j
N
H
All products were characterized by 1H and 13C NMR, IR, CHN, and
MS analysis
a
b
Isolated yield
123

Med Chem Res
Table 2 The effect of compounds 5a–j on dog’s heart rate
Compound
Heart rate (beat/min)a
Normal
0 min
5 min
10 min
20 min
5a
5b
5c
5d
5e
5f
120
123
110
114
123
121
124
115
121
120
2
110
112
107
104
113
109
115
105
109
110
120
130
5
4
2
5
3
3
3
3
3
3
2
3
100
102
100
100
103
100
100
98
3
2
3
2
2
2
4
3
4
4
2
2
103
106
93
3
3
3
3
2
4
2
3
2
5
3
4
90
94
4
5
2
2
5
4
3
4
5
3
4
4
3
3
4
2
3
2
5
2
3
4
2
100
97
95
108
103
104
102
104
97
96
105
99
5g
5h
5i
97
100
101
112
131
100
103
105
129
5j
Propranolol 127
114
129
DMSO
131
a
ECG recording time
declining of the heart rate, and 5f was the least potent agent
in reduction of the heart rate (Table 2).
Figure 3 indicates the electrocardiograph records con-
cerning to infusion of the most potent compound 5a to a
dog. As can be seen, the ECGs have been recorded for
different status of infusion including before and after
infusion. By comparing these ECGs to each other, it is well
demonstrated that compound 5a is capable of reducing
heart rate in considerable value.
Antibacterial study
Compounds 5a–j were also assessed for their in vitro
antibacterial activity against several Gram-negative
(Pseudomonas aeruginosa, and Escherichia coli) and
Gram-positive (Staphylococcus aureus, and Bacillus cer-
eus) bacteria (Table 3). The antibacterial activity of 5a–j
was compared to gentamycin and ampicillin as reference
drugs for Gram-negative and Gram-positive bacteria,
respectively.
Fig. 3 ECG scan showing: a normal sinus rhythm before infusion;
b simultaneously infusion; c 5 min after administration of 5a; d
10 min after administration of 5a; e 20 min after administration of 5a.
(recording lead II, paper speed 25 mm s-1 and sensitivity
1 mm = 0.1 mV)
The minimum inhibitory concentration (MIC) values of
the examined compounds were measured by a serial dilu-
tion assay using the micro-plate dilution method for finding
the MICs values (Table 3) (National Committee for Clin-
ical Laboratory Standards, 2000; Davis et al., 1990).
Compound 5f was found as the most potent compound
against two examined Gram-positives bacteria (MIC
[3.125 lg mL-1), and its antibacterial potency against B.
cereus is comparable with ampicillin (MIC[12.5 lg mL-1).
Other tested compounds were showed varying antibac-
terial activity against the two examined Gram-positive
bacteria. In the case of P. aeroginosa, compounds 5a and
5d (MIC [6.25 lg ml-1) and for E. coli, compounds 5d
and 5g (MIC [12.5 lg ml-1) showed the promising to
good antibacterial activity against these Gram-negative
bacteria. In general, compound 5d was the most potent
agent against both tested Gram-negative and positive
bacteria.
Theoretical aspects
Gaussian 03W program (Frisch et al., 2004) has been used
for calculations, employing DFT method at B3LYP/6-
311?G**level of theory to optimize and compare the
structure of 5a as the most potent compound in reducing
123

Med Chem Res
Table 3 In vitro antibacterial study of compounds 5a–j
Compound
MIC (mg/mL)a
P. aeruginosa
E. coli
B. cereus
S. aureus
5a
[6.25
[50
[50
[50
[25
[12.5
[50
[50
[12.5
[25
[100
[35
–
[25
[25
5b
[50
[50
5c
[12.5
[6.25
[25
[12.5
[12.5
[50
[25
5d
[25
5e
[50
5f
[100
[12.5
[50
[3.125
[3.125
[6.25
[6.25
[6.25
[12.5
–
[3.125
[25
5g
5h
[12.5
[3.125
[25
5i
[50
5j
[100
–
R.D.1b
R.D.2c
a
[3.125
–
[6.25
[6.25
Examined bacteria: Staphylococcus arueus (PTCC 1133), Bacillus
cereus (PTCC 1015), Pseudomonas aeruginosa (PTCC 1077), and
Escherichia coli (PTCC 1330)
b
Reference drug for Gram-positive bacteria (Ampicillin)
c
Reference drug for Gram-negative bacteria (Gentamycin)
dog’s heart rate with IPS-339 as a lead compound. The
optimized geometry of both compounds is shown using
Chem3D Ultra 8.0 software (Fig. 4). Structurally, these
two compounds are similar except in an amine residue
(Fig. 4a, b). While fluorene oxime residue because of its
aromaticity in both molecules are flat; nevertheless, the
conformations of hydroxypropyl residue in both com-
pounds are different. In 5a, the hydroxyl group orients to
carboxyl residue because of its tendency to form internal
hydrogen bonding.
The molecular electrostatic potential (MEP) represents
the attraction or repulsion between a molecule and elec-
trophilic or nucleophilic sites such as proton or lone-pair.
MEP provides insight into which regions of a molecule are
more susceptible to electrophilic or nucleophilic interac-
tion, as an instance, the binding on the surface of receptor
(Patrick, 2001). The 3D isosurface plots of MEP for
compound 5a and IPS-339 have been shown in Fig. 4c, d.
As it is observed, the negative electrostatic potentials are
shown in blue contour maps around the negative atoms like
oxygen and nitrogen of both compounds; while, other
atoms carrying the positive electrostatic potentials are
shown in red contour maps. If the MEP of the lead com-
pound (i.e., IPS-339) is indicated, then by comparing the
MEP of other analogs with that of lead compound, one can
judge and predict about the potential bioactivity of analogs.
As it is shown in Fig. 4c, d, both IPS-339 and 5a have a
considerable resemblance in their MEPs feature and in
conformity with biological data, 5a can be considered as a
promising compound use in cardiovascular chemotherapy.
Fig. 4 Structure of 5a versus IPS-339: a optimized geometry of 5a;
b optimized geometry of IPS-339; c 3D isosurface plots of the
molecular electrostatic potential (MEP) of 5a; and d IPS-339
Molecular docking study
Molecular docking is an extensively used method to predict
interactions of new drug candidates with receptor binding
sites. Inspired by remarkable activity of 5a in reducing the
heart rate of dogs, molecular docking study was carried out
for 5a with crystal structure of the human b2-adrenergic
receptor in complex with alprenolol as a famous b-blocker.
The crystal structure of the selected receptor (PDB code:
3NYA) was retrieved from the Protein Data Bank (http://
www.rcsb.org). The receptor was then modified by
removing all the ligands and water molecules. The
molecular docking study was performed using Molegro
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Med Chem Res
Virtual Docker (MVD) software (Thomsen and Christen-
sen, 2006). As explained, the optimized geometry of 5a
was obtained by employing DFT method at B3LYP/6-
311?G**level of theory (Fig. 4b).
some descriptors including topological factors, fingerprints
of molecular structure or other properties such as molecular
weight, water solubility, and cLogP (Tetko, 2005).
In this current research, the open-source program OSI-
RIS Property Explorer (Organic, 2013) was used to assess
the fragment-based drug-likeness of 5a, 5d, 5f, and IPS-
339 as the most effective agent in lowering dog’s heartbeat,
effective compound against both gram-positive and nega-
tive bacteria, effective compound against gram positive
bacteria, and lead cardiovascular compound, respectively.
OSIRIS program involves the database of traded drugs and
commercially available compounds (Fluka) assumable as
none drug-like dataset to assess the occurrence frequency
of each fragment in the individual structure. The program
estimated the risks of side effects, such as mutagenic,
tumorigenic, irritant, and reproductive effects, as well as
drug-relevant properties including cLogP, LogS (solubility
in water), MW, and drug-likeness. Additionally, the overall
drug score was estimated by combining resulted data from
cLogP, LogS, MW, toxicity risks, and drug-likeness. Drug
score is a measure of compound’s potential to meet the
criteria of a possible drug candidate.
It is well indicated that the binding site of b2-adreno-
receptor is a narrow cleft which is surrounded by few polar
residues at its front and back (Wacker et al., 2010).
Additionally, the binding of oxypropanolamine moiety of
alprenolol to the receptor affords a hydrogen bond network
with Asp113, Tyr316, and Asn312 in the front polar region
of the binding pocket. Furthermore, the aromatic ring of
alprenolol locates between the side chains of Val114 and
Phe290 in the lipophilic region of the pocket. Due to the
detailed analysis, both hydrophobic and hydrogen bonding
are significant stabilizing factors in interaction between
ligand and receptors. Additionally, no electrostatic inter-
action was detected. Interestingly, in same circumstance as
alprenolol, it was observed that 5a is anchored to the same
binding site and showed good interaction with the afore-
mentioned receptor. In the case of 5a, hydrogen bonding of
aliphatic chain with Asp113 is not detected; nevertheless,
hydrogen bonding with Tyr308 and Trp313 was also
observed which stabilizes the ligand in active site of
receptor (Fig. 5). As alprenolol, compound 5a is also
anchored in the hydrophobic residue of the pocket sur-
rounded by Val114 and Phe290 (Fig. 6).
The in silico drug-relevant properties obtained by OSIRIS
Property Explorer are given in Table 4. The toxicity risks
were estimated for studied compounds, and it is demon-
strated that all studied compounds have the low risk of
mutagenic, irritant, and reproductive effect properties;
whereas the except that of compound 5f all studied com-
pounds are predicted to have the high risk of tumorigenic
which potentially attribute to the presence of fluorene core.
However, risk alerts are by no means meant to be a fully
In silico predictions for drug toxicity and property
Recently, several approaches have been developed to pre-
dict the drug-likeness of bioactive compounds based on
Fig. 5 The hydrogen bonding of compound 5a in active site of human b2-adrenergic receptor
123

Med Chem Res
Fig. 6 a The hydrophobic interaction of compound 5a in active site of human b2-adrenergic receptor. b The combination of hydrophobic and
hydrogen bond interactions of compound 5a in active site of human b2-adrenergic receptor
Table 4 Toxicity risks and physicochemical properties of compounds 5a, 5d, 5f, and IPS-339 are predicted by OSIRIS property
Compound Toxicity risks
Physicochemical properties
Mutagenic Tumorigenic Irritant Reproductive effect cLog P Solubility (Log S) MW Drug Likeness Drug Score
5a
LRa
LR
LR
LR
HRb
HR
LR
LR
LR
LR
LR
LR
LR
LR
LR
3.85
4.33
2.61
4.55
-5.33
-6.04
-3.9
368
416
342
324
-4.86
-7.91
6.37
0.17
0.14
0.78
0.29
5d
5f
IPS-339
HR
-5.54
1.58
Explorer
a
Low risk
b
High risk
reliable toxicity prediction. The LogP value of a compound,
which is the logarithm of its partition coefficient between n-
octanol and water Log(coctanol/cwater), is a well-established
measure of the compound’s hydrophobicity. It is well dem-
onstrated that most established drugs have the LogP values
less than 5.0. Accordingly, all studied compounds have the
appropriate LogP values less than 5.0. It is also indicated that
most drugs on the market have the estimated LogS value
greater than -4.0. Except that of compound 5f all studied
compounds have a Log S value smaller than -4.0. In general,
the presence of fluorene residue is main factor in lowering
log S values in compounds 5a, 5d, and IPS-339. Further-
more, the lowest Log S value for 5d is also attributed to the
presence of benzyl residue in phenyl alanine core. From
molecular weight standpoint, it is estimated that most
established drugs have a molecular weight ranged in
200–450 g mol-1. All studied compounds are line in this
range. For most drugs, the potential drug-likeness values are
positive. In the case of studied compounds, 5a and 5d show
the negative drug-likeness, while 5f and IPS-339 show the
positive value. The drug score combines drug-likeness,
cLogP, LogS, molecular weight, and toxicity risks in one
handy value than may be used to judge the compound’s
overall potential to qualify for a drug. In this case, the highest
drug score value was estimated for compound 5f with
remarkable activity against tested gram-negative bacteria.
123

Med Chem Res
General procedure for the synthesis of compounds
Conclusion
3 and 4
In conclusion, we described the synthesis and biological
study of O-oxime ethers having a-amino acid residues as
new analogs of IPS-339. In this synthesis, the reaction of
fluorene and/or benzophenone O-oxime with epichlorohy-
drin or epibromohydrin afforded the corresponding
O-oxime ether adducts. The N-alkylation of amino acid
with O-oxime ether adducts led to synthesis of new analogs
of IPS-339. The products were examined for their cardio-
vascular property. It was demonstrated that 5a as the most
potent compound, remarkably reduces the heart rate of
dogs. Compounds were also evaluated for their in vitro
antibacterial activity against some Gram-negative and
Gram-positive bacteria. The antibacterial tests have shown
the considerable antibacterial activity against both groups
of bacteria for some compounds. The docking analysis has
demonstrated the appropriate fitting of 5a in human b2-
adrenergic receptor active site.
In a round bottomed flask (100 mL), 0.04 mol epichloro-
hydrin (2.70 g) or epibromohydrin (3.90 g) was added to a
solution of the appropriate oxime 2 (0.01 mol), KOH
(0.56 g, 0.01 mol) in H2O/DMSO 1:9 (20 mL). The mix-
ture was stirred for 10 h at room temperature (TLC con-
trol). Then, the crude product was dissolved in CHCl3
(150 mL) and washed with H2O (3 9 200 mL). The
organic layer was dried (10 g of Na2SO4) and concentrated
to afford the crude product, which was used in the next step
without further purification.
General procedure for the synthesis of compound 5
In a double-necked round bottomed flask (100 mL)
equipped with a condenser, a mixture of appropriate amino
acid (0.01 mol), triethylamine (1.31 g, 0.013 mol), and a
catalytic amount of TBAB (0.1 g) was added to a solution
of the crude product of 3 and 4 (0.01 mol) in acetonitrile
(40 mL). The solution was heated to reflux for appropriate
time controlled by TLC (Table 1). Then, the solvent was
evaporated at reduced pressure, and the residue was dis-
solved in CHCl3 (100 mL) and washed with H2O
(2 9 100 mL). The organic layer was dried (Na2SO4, 10 g)
and concentrated to afford the crude product which was
purified by column chromatography eluting with proper
solvents.
Experimental
General
All preliminary chemicals were purchased from either
Fluka or Merck. Solvents were purified by standard pro-
˚
cedures and stored over 3 A molecular sieves. Reactions
were followed by TLC using SILG/UV 254 silica-gel
plates. Column chromatography was performed on silica
gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). IR
Spectra were obtained using a Shimadzu FT-IR-8300
spectrophotometer. 1H- and 13C-NMR Spectra were
obtained using a Bru¨ker Avance-DPX-400 spectrometer
operating at 400/100 MHz, respectively (d in ppm, J in
Hz). GC/MS were performed on a Shimadzu GC/MS-QP
1000-EX apparatus (m/z; rel.%). Elemental analyses were
performed on a Perkin–Elmer 240-B micro-analyzer.
2-(3-(9H-fluoren-9-ylideneaminooxy)-2-
hydroxypropylamino)-3-methylbutanoic acid (5a)
This compound was obtained as a creamy solid using
column chromatography on silica gel (EtOAc–n-hexane,
1:4); Yield: 2.65 g, 72 %; mp 112–113 ꢁC; Rf = 0.17
(EtOAc–n-hexane, 1:2); IR (KBr) mmax: 3600, 3076, 2928,
1690, 1650, 1494, 1232, 1062 cm-1; H NMR (CDCl3,
1
400 MHz): d 0.83 (6H, dd, J = 6.8, 11.2 Hz, 2CH3),
1.18–1.24 (1H, m, CH(CH3)2), 1.51 (1H, s, NH), 2.07 (1H,
s, CHOH), 2.86 (1H, s, CO2H), 3.66 (2H, dd, J = 5.6,
11.2 Hz, NCH2), 3.75 (2H, dd, J = 4.0, 11.6 Hz, OCH2),
4.12-4.17 (1H, m, CHOH), 4.42 (1H, d, J = 5.2 Hz,
CHCO2H), 7.22–7.38 (5H, m, Ar–H), 7.55–7.64 (2H, m,
Ar–H), 8.17 (1H, d, J = 7.6 Hz, Ar–H); 13C NMR (CDCl3,
100 MHz): d 21.6 (2CH3), 32.8 (CH(CH3)2), 61.9 (NCH2),
66.6 (NCH), 70.8 (OCH), 73.6 (OCH2), 118.6 (C-12),
119.4 (C-1), 119.9 (C-10), 121.6 (C-3), 127.4 (C-13), 128.0
(C-6), 129.4 (C-8), 129.9 (C-5), 130.5 (C-11), 134.9 (C-2),
140.5 (C-7), 141.0 (C-4), 151.3 (C=N), 174.1 (C = O); MS
(m/z, %): 368 (21.4, M?); Anal. calcd. for C21H24N2O4: C,
68.46; H, 6.57; N, 7.60. Found: C, 68.40; H, 6.64; N, 7.69.
General procedure for the synthesis of oximes 2
In a round bottomed flask (100 mL), a mixture of the
appropriate ketone 1 (0.01 mol), NaOH (0.6 g, 0.015 mol),
and hydroxylamine hydrochloride (1.03 g, 0.015 mol) was
dissolved in H2O/EtOH 1:10 (33 mL). The solution was
heated to reflux for 12 h (TLC control), and then the
mixture was poured into 20 g ice/10 g H2O. Oxime pre-
cipitate immediately formed which was filtered and washed
with cold H2O and dried. Recrystallization from hot
MeOH/H2O afforded the pure oxime 2 which were used for
the next step.
123

Med Chem Res
2-(3-(9H-fluoren-9-ylideneaminooxy)-2-
3.72 (2H, dd, J = 4.0, 11.6 Hz, OCH2), 3.90 (1H, s,
CO2H), 4.09–4.14 (1H, m, CHOH), 4.38 (1H, d,
J = 5.2 Hz, CHCO2H), 7.11–7.33 (8H, m, Ar–H),
7.48–7.63 (3H, m, Ar–H), 7.88 (1H, br.s, Ar–H), 8.16 (1H,
d, J = 7.6 Hz, Ar–H); 13C NMR (CDCl3, 100 MHz): d
34.1 (PhCH2), 60.8 (NCH2), 65.5 (NCH), 68.5 (OCH), 72.2
(OCH2), 120.2 (C-para, amino acid), 120.5 (2C-ortho,
amino acid), 121.1 (C-12), 126.1 (C-1), 127.2 (C-10),
128.5 (C-3), 128.8 (2C-meta, amino acid), 129.1 (C-13),
129.4 (C-6), 130.5 (C-8), 130.8 (C-5), 131.1 (C-11), 135.5
(C-2), 138.3 (CH2C, amino acid), 140.2 (C-7), 141.3 (C-4),
152.7 (C=N), 178.3 (C=O); MS (m/z, %): 416 (23.1, M?);
Anal. calcd. for C25H24N2O4: C, 72.10; H, 5.81; N, 6.73.
Found: C, 72.23; H, 5.95; N, 6.70.
hydroxypropylamino) propanoic acid (5b)
This compound was obtained as a bright brown solid using
column chromatography on silica gel (EtOAc–n-hexane,
1:2); Yield: 2.55 g, 75 %; mp 110–111 ꢁC; Rf = 0.13
(EtOAc–n-hexane, 1:2); IR (KBr) mmax: 3557, 3053, 2932,
2871, 1692, 1615, 1456, 1134 cm-1; H NMR (CDCl3,
1
400 MHz): d 1.36 (3H, d, J = 7.2 Hz, CH3), 1.55 (1H, s,
NH), 2.16 (1H, s, CHOH), 2.91 (1H, s, CO2H), 3.66 (2H,
dd, J = 5.6, 11.2 Hz, NCH2), 3.74 (2H, dd, J = 4.0,
11.6 Hz, OCH2), 4.11–4.16 (1H, m, CHOH), 4.39–4.44
(1H, m, CHCO2H), 7.18–7.39 (4H, m, Ar–H), 7.53–7.64
(3H, m, Ar–H), 8.16 (1H, d, J = 7.6 Hz, Ar–H); 13C NMR
(CDCl3, 100 MHz): d 18.6 (CH3), 62.2 (NCH2), 66.4
(NCH), 68.9 (OCH), 73.1 (OCH2), 118.0 (C-12), 118.3 (C-
1), 118.9 (C-10), 120.8 (C-3), 126.4 (C-13), 126.9 (C-6),
128.0 (C-8), 128.6 (C-5), 130.5 (C-11), 134.4 (C-2), 139.7
(C-7), 144.4 (C-4), 153.0 (C=N), 173.9 (C=O); MS (m/z,
%): 340 (18.6, M?); Anal. calcd. for C19H20N2O4: C,
67.05; H, 5.92; N, 8.23. Found: C, 67.14; H, 5.80; N, 8.26.
2-(3-(Diphenylmethyleneaminooxy)-2-
hydroxypropylamino)-3-methylbutanoic acid (5e)
This compound was obtained as a brown foam using col-
umn chromatography on silica gel (EtOAc–n-hexane, 1:4);
Yield: 2.29 g, 62 %; Rf = 0.19 (EtOAc–n-hexane, 1:2); IR
(KBr) mmax: 3610, 3076, 2924, 1700, 1645, 1494,
1
1232 cm-1; H NMR (CDCl3, 400 MHz): d 0.88 (6H, dd,
2-(3-(9H-fluoren-9-ylideneaminooxy)-2-
hydroxypropylamino) acetic acid (5c)
J = 7.0, 14.8 Hz, 2CH3), 1.14–1.27 (1H, m, CH(CH3)2),
2.07 (1H, s, NH), 2.19 (1H, s, CHOH), 2.29 (1H, s, CO2H),
3.65 (2H, dd, J = 5.6, 11.6 Hz, NCH2), 3.72 (2H, dd,
J = 4.0, 11.6 Hz, OCH2), 4.08 (1H, d, J = 4.4 Hz,
CHCO2H), 4.26-4.31 (1H, m, CHOH), 7.28-7.48 (10H, m,
Ar–H); 13C NMR (CDCl3, 100 MHz): d = 20.2 (2CH3),
31.4 (CH(CH3)2), 63.7 (NCH2), 67.5 (NCH), 71.4 (OCH),
75.2 (OCH2), 127.9 (C-1, C-3), 128.2 (C-10, C-12), 128.3
(C-4, C-6), 129.0 (C-7, C-13), 129.1 (C-2), 129.7 (C-11),
132.8 (C-5), 135.8 (C-8), 158.2 (C=N), 171.5 (C=O); MS
(m/z, %): 370 (20.7, M?); Anal. calcd. for C21H26N2O4: C,
68.09; H, 7.07; N, 7.56. Found: C, 68.16; H, 7.01; N, 7.52.
This compound was obtained as a brown solid using col-
umn chromatography on silica gel (EtOAc–n-hexane, 1:2);
Yield: 2.64 g, 81 %; mp 105–106 ꢁC; Rf = 0.14 (EtOAc–
n-hexane, 1:2); IR (KBr) mmax: 3600, 3057, 2932, 2875,
1721, 1611, 1448, 1123 cm-1
;
1H NMR (CDCl3,
400 MHz): d 1.19 (1H, s, NH), 2.18 (2H, s, CHOH,
CO2H), 3.66 (2H, dd, J = 5.6, 11.2 Hz, NCH2), 3.74 (2H,
dd, J = 4.0, 11.6 Hz, OCH2), 4.11–4.16 (1H, m, CHOH),
4.43 (2H, s, CH2CO2H), 7.19–7.39 (5H, m, Ar–H),
7.53–7.64 (2H, m, Ar–H), 8.17 (1H, d, J = 7.6 Hz, Ar–H);
13C NMR (CDCl3, 100 MHz): d 60.2 (NCH2CH), 63.0
(NCH2CO2), 66.6 (OCH), 72.5 (OCH2), 119.7 (C-12),
119.9 (C-1), 121.6 (C-10), 127.4 (C-3), 128.2 (C-13), 129.1
(C-6), 129.6 (C-8), 130.2 (C-5), 131.1 (C-11), 135.5 (C-2),
140.8 (C-7), 141.3 (C-4), 152.4 (C=N), 174.3 (C=O); MS
(m/z, %): 326 (15.2, M?); Anal. calcd. for C18H18N2O4: C,
66.25; H, 5.56; N, 8.58. Found: C, 66.18; H, 5.50; N, 8.51.
2-(3-(Diphenylmethyleneaminooxy)-2-
hydroxypropylamino)propanoic acid (5f)
This compound was obtained as a white foam using col-
umn chromatography on silica gel (EtOAc–n-hexane, 1:2);
Yield: 2.32 g, 68 %; Rf = 0.28 (EtOAc–n-hexane, 1:2); IR
(KBr) mmax: 3550, 3050, 2928, 1690, 1620, 1452,
1
1054 cm-1; H NMR (CDCl3, 400 MHz): d 1.87 (3H, d,
2-(3-(9H-fluoren-9-ylideneaminooxy)-2-
hydroxypropylamino)-3-phenylpropanoic acid (5d)
J = 4.4 Hz, CH3), 3.04 (1H, s, NH), 3.34 (2H, dd, J = 6.0,
11.6 Hz, NCH2), 3.46 (2H, dd, J = 3.2, 11.6 Hz, OCH2),
3.59 (1H, s, CHOH), 3.82-3.87 (1H, m, CHOH), 3.91 (1H,
s, CO2H), 4.02–4.05 (1H, m, CHCO2H), 7.12–7.31 (10H,
m, Ar–H); 13C NMR (CDCl3, 100 MHz): d 18.0 (CH3),
58.6 (NCH2), 63.8 (NCH), 71.0 (OCH), 75.2 (OCH2),
127.4 (C-1, C-3), 128.0 (C-10, C-12), 128.2 (C-4, C-6),
128.4 (C-7, C-13), 129.1 (C-2), 129.3 (C-11), 133.1 (C-5),
136.2 (C-8), 157.6 (C=N), 177.7 (C=O); MS (m/z, %): 342
This compound was obtained as a bright brown foam using
column chromatography on silica gel (EtOAc–n-hexane,
1:2); Yield: 2.62 g, 63 %; Rf = 0.14 (EtOAc–n-hexane,
1:2); IR (KBr) mmax: 3600, 3057, 2936, 2875, 1671, 1617,
1
1448, 1319 cm-1; H NMR (CDCl3, 400 MHz): d 2.53
(1H, s, NH), 3.03 (2H, dd, J = 4.0, 14.0 Hz, PhCH2), 3.45
(1H, s, CHOH), 3.63 (2H, dd, J = 6.0, 11.2 Hz, NCH2),
123

Med Chem Res
1
(17.5, M?); Anal. calcd. for C19H22N2O4: C, 66.65; H,
6.48; N, 8.18. Found: C, 66.73; H, 6.57; N, 8.12.
1051 cm-1; H NMR (CDCl3, 400 MHz): d 0.75 (1H, s,
NH), 0.82 (6H, d, J = 6.0 Hz, 2CH3), 1.23 (1H, s, CHOH),
1.34-1.45 (1H, m, CH(CH3)2), 1.85–1.98 (2H, m,
CH2CH(CH3)2), 3.37 (2H, dd, J = 6.0, 11.2 Hz, NCH2),
3.48 (2H, dd, J = 3.0, 11.2 Hz, OCH2), 3.69 (1H, s,
CO2H), 3.85–3.87 (1H, m, CHOH), 4.04 (1H, d, J = 5.2,
CHCO2H), 7.08-7.32 (10H, m, Ar–H); 13C NMR (CDCl3,
2-(3-(Diphenylmethyleneaminooxy)-2-
hydroxypropylamino) acetic acid (5g)
This compound was obtained as a bright brown foam using
column chromatography on silica gel (EtOAc–n-hexane,
1:2); Yield: 2.29 g, 70 %; Rf = 0.14 (EtOAc–n-hexane,
1:2); IR (KBr) mmax: 3600, 3051, 2940, 2870, 1695, 1620,
100 MHz):
d 21.5 (2CH3), 24.1 (CH(CH3)2), 39.1
(NCHCH2), 60.8 (NCH2), 63.8 (NCH), 71.1 (OCH), 75.2
(OCH2), 128.0 (C-1, C-3), 128.2 (C-10, C-12), 128.4 (C-4,
C-6), 129.1 (C-7, C-13), 129.2 (C-2), 129.6 (C-11), 133.0
(C-5), 136.1 (C-8), 157.7 (C = N), 179.1 (C=O); MS (m/z,
%): 384 (21.5, M?); Anal. calcd. for C22H28N2O4: C,
68.73; H, 7.34; N, 7.29. Found: C, 68.70; H, 7.31; N, 7.23.
1
1448, 1077 cm-1; H NMR (CDCl3, 400 MHz): d 1.18
(1H, s, NH), 2.36 (1H, s, CHOH), 3.06 (1H, s, CO2H), 3.51
(2H, dd, J = 5.6, 11.6 Hz, NCH2), 3.59 (2H, dd, J = 4.0,
11.6 Hz, OCH2), 3.92-3.97 (1H, m, CHOH), 4.16 (2H, s,
CH2CO2H), 7.17–7.37 (10H, m, Ar–H); 13C NMR (CDCl3,
100 MHz): d 59.7 (NCH2CH), 63.7 (NCH2CO2), 71.4
(OCH), 75.2 (OCH2), 127.9 (C-1, C-3), 128.2 (C-10,
C-12), 128.3 (C-4, C-6), 129.1 (C-7, C-13), 129.2 (C-2),
129.7 (C-11), 132.8 (C-5), 135.8 (C-8), 158.1 (C=N), 174.1
(C=O); MS (m/z, %): 328 (16.2, M?); Anal. calcd. for
C18H20N2O4: C, 65.84; H, 6.14; N, 8.53; Found: C, 65.80;
H, 6.19; N, 8.57.
2-(3-(Diphenylmethyleneaminooxy)-2-
hydroxypropylamino)-4-(methylthio) butanoic acid (5j)
This compound was obtained as a bright brown foam using
column chromatography on silica gel (EtOAc–n-hexane,
1:4); Yield: 2.21 g, 55 %; Rf = 0.18 (EtOAc–n-hexane,
1:2); IR (KBr) mmax: 3600, 3083, 2932, 1717, 1670, 1490,
1444, 1331, 1058 cm-1; H NMR (CDCl3, 400 MHz): d
1
2-(3-(Diphenylmethyleneaminooxy)-2-
1.86–1.89 (2H, m, SCH2CH2), 2.35 (1H, s, NH), 2.70 (3H, s,
SCH3), 3.03 (2H, t, J = 7.2 Hz, SCH2CH2), 3.32 (1H, s,
CHOH), 3.39 (2H, dd, J = 6.0, 11.6 Hz, NCH2), 3.49 (2H,
dd, J = 3.2, 11.2 Hz, OCH2), 3.69 (1H, s, CO2H),
3.84–3.89 (1H, m, CHOH), 4.05 (1H, d, J = 5.2 Hz,
CHCO2H), 7.13–7.33 (10H, m, Ar–H); 13C NMR (CDCl3,
100 MHz): d 14.2 (SCH3), 29.9 (SCH2), 31.6 (NCHCH2),
61.9 (NCH2), 63.7 (NCH), 71.1 (OCH), 75.2 (OCH2), 128.0
(C-1, C-3), 128.2 (C-10, C-12), 128.3 (C-4, C-6), 129.0 (C-
7, C-13), 129.2 (C-2), 129.6 (C-11), 133.0 (C-5), 136.1 (C-
8), 157.7 (C=N), 175.2 (C=O); MS (m/z, %): 402 (19.3,
M?); Anal. calcd. for C21H26N2O4S: C, 62.66; H, 6.51; N,
6.96; S, 7.97. Found: C, 62.74; H, 6.59; N, 7.02; S, 7.91.
hydroxypropylamino)-3-phenylpropanoic acid (5h)
This compound was obtained as a bright brown foam using
column chromatography on silica gel (EtOAc–n-hexane,
1:2); Yield: 2.34 g, 56 %; Rf = 0.19 (EtOAc–n-hexane,
1:2); IR (KBr) mmax: 3550, 3050, 2915, 1689, 1591, 1492,
1
1048 cm-1; H NMR (CDCl3, 400 MHz): d 1.13 (1H, s,
NH), 1.85 (1H, s, CHOH), 2.92 (2H, dd, J = 4.0, 14.8 Hz,
PhCH2), 3.34 (2H, dd, J = 6.0, 11.6 Hz, NCH2), 3.45 (2H,
dd, J = 3.6, 11.6 Hz, OCH2), 3.63 (1H, s, CO2H),
3.81–3.86 (1H, m, CHOH), 4.02 (1H, d, J = 4.0 Hz,
CHCO2H), 7.10–7.31 (15H, m, Ar–H); 13C NMR (CDCl3,
100 MHz): d 35.9 (PhCH2), 58.0 (NCH2), 63.8 (NCH),
71.1 (OCH), 75.2 (OCH2), 126.1 (C-para, amino acid),
127.0 (2C-ortho, amino acid), 127.7 (2C-meta, amino
acid), 128.1 (C-1, C-3), 128.2 (C-10, C-12), 128.4 (C-4,
C-6), 129.1 (C-7, C-13), 129.3 (C-2), 129.6 (C-11), 133.1
(C-5), 135.7 (C-8), 136.2 (CH2C, amino acid), 157.7
(C=N), 174.9 (C=O); MS (m/z, %): 418 (24.8, M?); Anal.
Calcd. for C25H26N2O4: C, 71.75; H, 6.26; N, 6.69. Found:
C, 71.86; H, 6.34; N, 6.78.
Supporting data
Supplementary data associated with this article including
1H NMR and 13C NMR can be found, in the online version.
Acknowledgments The authors wish to thank Shiraz University of
Technology research council for partial support of this work. Authors
are thankful from Dr. A.R. Nekoei and Dr. H. Fattahi for helpful
discussions.
2-(3-(Diphenylmethyleneaminooxy)-2-
hydroxypropylamino)-4-methylpentanoic acid (5i)
This compound was obtained as a brown foam using col-
umn chromatography on silica gel (EtOAc–n-hexane, 1:2);
Yield: 2.23 g, 58 %; Rf = 0.19 (EtOAc–n-hexane, 1:2); IR
(KBr) mmax: 3600, 3050, 2932, 1695, 1671, 1490,
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123

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