Synthesis and structure-antibacterial activity of triazolyl oxazolidinones containing long chain acyl moiety

Article abstract of DOI:10.1016/j.ejmech.2007.07.006

A series of new piperazinyl 5-triazolylmethyl oxazolidinones containing long chain acyl group at the piperazine N-4-position were synthesized and evaluated against a panel of standard and clinical isolates of Gram-positive and Gram-negative bacteria. Deri

Full text of DOI:10.1016/j.ejmech.2007.07.006

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European Journal of Medicinal Chemistry 43 (2008) 1095e1104
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Short communication
Synthesis and structureeantibacterial activity of triazolyl oxazolidinones
containing long chain acyl moiety
b
a
Oludotun A. Phillips a, , Edet E. Udo , Santhosh M. Samuel
*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
b Department of Microbiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
Received 22 April 2007; received in revised form 9 July 2007; accepted 9 July 2007
Available online 27 July 2007
Abstract
A series of new piperazinyl 5-triazolylmethyl oxazolidinones containing long chain acyl group at the piperazine N-4-position were synthe-
sized and evaluated against a panel of standard and clinical isolates of Gram-positive and Gram-negative bacteria. Derivatives having long chain
acyl groups with nine or more number of carbon atoms showed significant decrease in antibacterial activity. Antibacterial activity correlated
positively with heat of formation of the compounds, but correlated negatively with Clog P values, surface area, ovality and molecular volume.
However, no significant correlation was observed between activity and ELUMO, EHOMO and dipole, respectively.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Antibacterial activity; Heat of formation; Linezolid; Molecular descriptors; Oxazolidinones; Structureeactivity relationships
1. Introduction
the most prevalent bacteria species isolated from inpatient
specimens in USA [5]. These organisms are also reported to
be resistant to at least three classes of antibacterial agents
commonly used for therapy. Oxazolidinones, linezolid and
eperezolid (Fig. 1) exhibit a unique mechanism of action
that involves interference with the binding of mRNA to the
ribosomes at the initiation phase of translation. They explicitly
inhibit the formation of the initiation complex in bacterial
translation system thus preventing formation of the
N-formylmethionyl-tRNA-ribosome-mRNA ternary complex
(tRNAfMet-mRNA) [6e8]. Although linezolid has demon-
strated clinical success, recent reports on emerging linezolid-
resistant S. aureus [9] and Enterococcus spp. [10e12] in
hospital isolates suggest an increasing need for new, more
effective and safer antibacterial agents. These situations
continue to serve as impetus for the development of novel
and more effective antibacterial agents.
Although the judicious use of antibacterial agents is an im-
portant approach in attempts to control the emergence of bac-
terial resistance, the discovery and development of newer
agents are desirable for the successful treatment of infections
caused by resistant pathogenic bacteria. Among the new
agents under development, only the oxazolidinone, cationic
peptide and lipopeptide antibiotics can be truly regarded as
novel mechanism agents [1]. A clinically useful member of
the oxazolidinone class of antibacterial agents, linezolid
(Fig. 1) is highly effective against multi-drug resistant
Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus (MRSA), methicillin-resistant coagu-
lase-negative staphylococci (MR-CNS), penicillin-resistant
Streptococcus pneumoniae (PRSP) and vancomycin-resistant
enterococcus (VRE) [2e4], which have been identified as
Recent developments in the modification of the C-5
position of the oxazolidinones have highlighted the bioisos-
teric replacement of the acetamide group by a triazole moiety
[13e15], which is exemplified by PH-027, and compounds of
general structures 1 and 2 (Fig. 1). We have previously
* Corresponding author. Tel.: þ965 498 6070; fax: þ965 534 2807.
E-mail addresses: dphillips@hsc.edu.kw (O.A. Phillips), edet@hsc.edu.kw
(E.E. Udo), santhosh_samuel@hotmail.com (S.M. Samuel).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.07.006

1096
O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
O
O
2
O
1
H
N
3
O
H
N
O
N
N
N
O
O
HO
CH3
5
N
N
N
CH3
4
O
O
F
F
F
Linezolid
Eperezolid
O
O
O
R
O
N
N
N
O
S
N
N
N
N
N
O
F
PH-027
1: R = H, CH3, CH3CH2, CN.
O
R
O
O
O
O
N
N
N
N
N
N
O
N
N
N
N
R
N
F
2: R = H, CH3.
F
3: R = CH3; CH2CH3; Cyclopentyl; Ph,
substituted aryl, heteroaryl
Fig. 1. Structures of antibacterial oxazolidinones.
elaborated on the structureeactivity relationships of the piper-
azine derivatives similar to eperezolid, namely, the novel al-
kyl-(C1e5) and 4-(phenylcarbonyl)piperazinyl 5-triazolylmethyl
oxazolidinones 3 (Fig. 1), with improved antibacterial activity
compared to the morpholine derivative PH-027 [16,17]. In ad-
dition, we have shown that substitution of the tolylsufonyl
groups at the distal piperazine N-4-position resulted in dimin-
ished antibacterial activity [17]. In the present communication
we investigated the effect of the alkyl group chain length at the
distal piperazine N-4-position on the antibacterial activity. The
structural variations were selected in order to investigate
optimal structureeactivity requirements for this novel class
of 5-triazolylmethyl oxazolidinone derivatives 8aeo and po-
tential correlations between selected 3D molecular descriptors
with the antibacterial activity. The molecular descriptors used,
included lipophilicity reported as calculated log of partition
coefficient (Clog P values), surface area (SA), molecular vol-
ume (MV), ovality, heat of formation (HOF), energies of the
cycloaddition reaction [19] with acetylene in dimethoxyethane
(DME) at 90 ꢁC in excellent yield [16]. This was followed by
the deprotection of the tert-butoxycarbonyl protecting group at
the piperazine N-4-position with trifluoroacetic acid in CH2Cl2
at 0 ꢁC to room temperature to give the key-intermediate tria-
zole 7a as a trifluoroacetic acid salt (quantitative). The inter-
mediate triazole 7a was subsequently reacted with
appropriate long chain alkyl chlorides in MeCN, using trie-
thylamine as base to give the respective target compounds
8fen in moderate to good yields. The bicyclo[2.2.1]heptan-
2-yl acetyl derivative was prepared by reaction of the interme-
diate triazole 7b with the activated bicyclo[2.2.1]heptan-2-yl
acetic acid, which was obtained by the reaction with 1-hydrox-
ybenzotriazole and dicyclohexylcarbodiimide in a mixture of
CH2Cl2 and CH3CN. All the compounds were characterized
by their physical, analytical and spectroscopic data (1H
NMR, 13C NMR, MS and IR) and melting points and were mi-
croanalyzed satisfactorily for C, H and N. Thorough structural
verification of a representative compound 8f was further per-
formed by 13C NMR decoupled, 13C DEPT-135 (Distortionless
enhancement by polarization transfer) and 13C APT (Attached
proton test) experiments.
lowest unoccupied (ELUMO) and the highest occupied (EHOMO
)
molecular orbitals, dipole, and net charge on the nitrogen of
the amide (INCaO), carbonyl carbon (INCaO), and oxygen
atom (INCaO) at the distal piperazine N-4-position. We now
report on the synthesis and structureeantibacterial activity of
hitherto unreported long chain (Cn¼5ꢀ18) alkylcarbonyl-
oxazolidinones 8feo.
3. Results and discussion
The C-5-triazolylmethyl oxazolidinones, exemplified by
PH-027 are novel bioisoteres of the C-5-acetamidomethyl ox-
azolidinones, based on the similarities in the dipole moment
and potential of the nitrogen atoms of the triazole and acet-
amide moieties to function as weak hydrogen bond acceptors
[20]. Furthermore, the observed comparable or superior anti-
bacterial activity [15,16] and reduced monoamine oxidase
inhibitory activity [4,14,15] of the triazolyl derivatives 1
(Fig. 1) served as impetus for establishing the structuree
antibacterial activity relationship of this class of compounds.
2. Chemistry
Compounds 8aee were previously reported [16], while the
other derivatives 8feo were prepared as follows. The synthesis
of the target compounds 8feo was carried out as outlined
(Scheme 1) from the chiral alcohol derivative 6, which was ob-
tained in multi-step reactions in good yield according to pub-
lished procedures [16,18]. Further chemical transformation of
6
to 7 involved the versatile Huisgen’s 1,3 dipolar

O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
1097
O
O
5 Steps
NO2
F
O
HN
NH
+
N
3 Steps
(i)
N
N
O
OH
O
F
F
4
5
6
O
O
O
O
N
N
N
N
(ii)
N
HN
.
N
O
N
N
N
N
N
F
F
CF3CO2H
7
7a
(iv)
(iii)
O
O
O
R
O
N
N
N
O
N
N
N
HN
N
N
N
N
N
F
N
F
F
7b
8f-n
[R as shown in Table 1]
(v)
O
O
O
N
N
N
N
N
8o
Scheme 1. Synthesis of acyl-piperazinyl oxazolidinone derivatives. (i) TEA, MsCl, CH2Cl2/DMF, NaN3/acetylene, DME, 90 ꢁC; (ii) TFA, 0 ꢁCert, CH2Cl2; (iii)
TEA, long chain alkylcarbonyl chlorides, 0 ꢁCert, CH3CN; (iv) KHCO3 aq; (v) 2-Norbornaneacetic acid, DCC, 1-hydroxybenzotriazole, CH2Cl2eCH3CN, rt.
The newly synthesized piperidinyl oxazolidinones (8feo)
having long acyl (C6e18) groups appended to the nitrogen
at the 4-position and the previously reported derivatives
(8aee) with shorter acyl groups were evaluated for antibac-
terial activity against a panel of standard and clinical isolates
of Gram-positive and Gram-negative bacteria strains to inves-
tigate the effects of carbon chain length on antibacterial
activity. Antibacterial activity was further evaluated against
S. aureus ATCC 25923 standard strain in the presence and
absence of 50% human plasma. The lipophilicity of the com-
pounds is obtained as calculated log P (Clog P) [21], and
the minimum inhibitory concentration (MIC, mg/ml) values
and MIC distribution are presented in Tables 1 and 2,
respectively.
Against all staphylococcal clinical isolates (MSSA, MRSA,
MS-CNS, MR-CNS) the MIC values showed a consistent
decrease in antibacterial activity as the number of carbon
atoms in the alkyl chain length increases from compound 8a
(R ¼ CH3; Clog P ¼ ꢀ0.95) to 8i (R ¼ CH3(CH2)7;
Clog P ¼ 2.50) with MIC value ranges of 0.25e1 and 4 to
>16 mg/ml (Table 1), respectively. Though increase in the
antibacterial effects of a series of N-alkylated imidazole deriv-
atives have been reported to correlate with increase in the
number of carbon atoms in the alkyl chain up to nine carbons
[22]. Moreover, other studies on a series of 1-alkyl-2-(4-pyri-
dyl)pyridinium bromides have also demonstrated that
compounds with alkyl chain length of between 11 and 16 car-
bon atoms are the most active [23]. Our data did not reveal
similar findings in this class of oxazolidinone derivatives;
rather a decrease in antibacterial activity was noticed with
increase in carbon chain length, which somewhat correlated
with increase in lipophilicity of the compounds.
Furthermore, compounds 8jen (Clog P ¼ 3.03e7.26) with
carbon atoms in the alkyl chain from nine and above showed
higher MIC values (MIC > 16 mg/ml) against all standard and
clinical strains tested, which is greater than the susceptibility
break-point for linezolid (MIC ꢂ 4 mg/ml) [24]. Similarly, all
these long acyl derivatives showed cumulative 0% inhibition
even at 16 mg/ml (Table 2) with the exception of compounds
8f (R ¼ CH3(CH2)4; Clog P ¼ 0.91), 8g (R ¼ CH3(CH2)5;
Clog P ¼ 1.44), 8h (R ¼ CH3(CH2)6; Clog P ¼ 1.97) and the
bicyclic derivative 8o (R ¼ bicyclo[2.2.1]heptan-2-yl)acetyl;
Clog P ¼ 1.72) that showed 100% cumulative inhibition of
all staphylococcal strains tested at 4 and 8 mg/ml. In addition,
compound 8o (Clog P ¼ 1.72), which contains an eight car-
bon atom relatively rigid bicyclic ring system showed im-
proved antibacterial activity (MIC range 2e4 mg/ml)
compared to derivative 8i (R ¼ CH3(CH2)7; Clog P ¼ 2.50)
having similar number of carbon atoms, which was signifi-
cantly less active (MIC range of 4 to >16 mg/ml) against all
strains tested. This difference between the eight carbon
atom derivatives 8i and 8o, could be due to the fact that the
rigid bicyclo[2.2.1]heptane ring system in 8o may favor for-
mation of an active conformation, which is somewhat acces-
sible to the active site, while the long acyl groups present
in 8i and other inactive derivatives 8jen facilitated adoption
of bio-inactive conformations that may be inaccessible to
the active site. Furthermore, the presence of the highly mobile
long chain acyl groups could also introduce increased bulki-
ness at the terminal piperazinyl N-4-position with

1098
O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
Table 1
Comparative MIC (mg/ml) and Clog P values of acyl-piperazinyl oxazolidinones against Gram-positive standard strains and clinical isolates
O
O
O
N
N
N
R
N
N
N
F
Compd eR
Minimum inhibitory concentrationsa (MICs, mg/ml) against
Clog P
S. aureusb S. aureusb MSSA
MRSA
MS-CNS MR-CNS S. pn
VSE
VRE
w/o
plasmac
þ 50%
(n ¼ 11) (n ¼ 10) (n ¼ 8)
(n ¼ 3) (n ¼ 6) (n ¼ 7) (n ¼ 4)
plasmac
d
8a
8b
8c
CH3
CH3CH2
ꢀ0.95
ꢀ0.42
ꢀ0.11
1
1
2
1
1
2
0.5e1
1
1e2
0.25e0.5 0.25e1
0.25e0.5 0.5e1 0.5e1
0.25
1
d
1
1e2
012e1
1e2
1
1e2
1 0.5e1
0.5e1 1e2
(CH3)2CHed
1e2
d
8d
0.52
2
4
1e2
1e2
1e2
1e2
1e2
1e2
1e2
d
8e
1.08
4
4
1e4
1e4
1e4
1e4
0.5e1 1e2
1e2
8f
CH3(CH2)4
CH3(CH2)5
CH3(CH2)6
CH3(CH2)7
CH3(CH2)8
CH3(CH2)9
CH3(CH2)12
CH3(CH2)14
CH3(CH2)16
0.91
1.44
1.97
2.50
3.03
3.56
5.14
6.20
7.26
4
4
16
>16
>16
>16
>16
>16
>16
>16
>16
4
2e4
4e8
2e4
2e8
2e8
1e4
1e4
2e8
1e4
2e4
2e8
2e4
4e8
>16
>16
>16
>16
>16
>16
>16
4
4
4
4
8g
8h
8i
8
4
4
>16
>16
>16
>16
>16
>16
8 to >16 4e16
4 to >16 4e8
8
8
8j
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
8k
8l
8m
8n
CH2
8o
1.72
0.63
4
1
16
1
2e4
2e4
2e4
2e4
4
2e4
4
1
O
N
O
N
PH-027
O
O
N
0.5e1
0.5e1
0.5e1
0.5e1
0.5e1 0.5e1
N
N
F
O
H
N
O
0.53 (0.55)e
n/d
2
2
2
2
1e2
1e2
0.5e2
0.5e1
0.25e2
1e2
1e2
0.5 0.5e2
2
CH3
Lzd
N
N
O
F
Van
1
0.5 0.25e2 >64
a
All compounds showed moderate to lack of activity against H. influenzae, M. catarrhalis and E. coli. (MIC ¼ ꢃ8 mg/ml).
b
c
d
e
ATCC 25923 strain.
Human plasma (w/o: without plasma).
Ref. [16].
Pharmacia UpJohn, Material Safety Data Sheet for Linezolid (2000).
concomitant increase in lipophilicity of the molecules, which
observed in the presence of 50% plasma indicating plasma bind-
ing potentials.
may possibly account for the diminished antibacterial po-
tency. This could be consistent with established oxazolidinone
SAR, which showed that excessive steric bulk on the aromatic
ring at the phenyl C-3 and/or C-5 positions could be injurious
to antibacterial activity [25]. From our data it was not possible to
clearly conclude whether the diminished antibacterial activity
was a result of increased lipophilicity or steric bulk. However,
both factors may play significant roles. Moreover, it is evident
that lipophilicity might be responsible for lack of antibacterial
activity in presence of plasma, which could be due to plasma
protein binding as Clog P values increase from 8f (0.91) to 8n
(7.26) including compound 8o. In all the long chain containing
derivatives, a four fold increase or greater MIC values was
Generally, a similar moderate to lack of antibacterial
activity was observed for compounds 8feo against other
Gram-positive clinical isolates including S. pneumoniae,
VSE and VRE with MIC range of 2 to >16 mg/ml, compared
with PH-027 (0.5e1 mg/ml), linezolid (0.5e2 mg/ml) and van-
comycin (0.25e2; and >64 mg/ml for VRE). In addition, all
the compounds were inactive against Gram-negative organ-
isms evaluated in this study, which included Haemophilus
influenzae and Moraxella catarrhalis clinical isolates and
Escherichia coli ATCC 25922 (data not shown).
In order to gain insight into the structural requirements for
antibacterial activity of these long chain acyl derivatives, we

O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
1099
Table 2
MIC (mg/ml) distribution of acyl-piperazinyl oxazolidinones against clinical isolates of staphylococci (n ¼ 32)
O
O
O
N
R
N
N
N
N
N
F
Compd
eR
Cumulative percent of isolates with specific MIC (mg/ml)
0.12
0.25
0.5
1
2
4
8
8a
8b
8c
CH3e
CH3CH2e
(CH3)2CHe
0
5
0
45
10
0
83
17
0
100
100
36
100
100
100
100
100
100
100
100
100
8d
8e
0
0
0
0
0
0
19
33
100
55
100
100
100
100
8f
CH3(CH2)4
CH3(CH2)5
CH3(CH2)6
CH3(CH2)7
CH3(CH2)8
CH3(CH2)9
CH3(CH2)12
CH3(CH2)14
CH3(CH2)16
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6
6
0
0
0
0
0
0
0
13
28
16
0
100
100
79
16
0
100
100
100
72a
0b
8g
8h
8i
8j
0
8k
8l
0
0
0b
0
0
0b
8m
8n
0
0
0b
0
0
0b
CH2
8o
0
0
0
0
0
0
47
100
100
100
100
O
N
O
N
O
O
N
PH-027
45
100
100
N
N
F
O
H
N
O
CH3
Lzd
N
0
0
5
0
14
24
86
93
100
100
100
100
100
100
N
O
F
Van
a
Showed MIC values of 16 and >16 mg/ml against 16% and 12% of the strains, respectively.
Showed MIC values of >16 mg/ml against all strains tested.
b
decided to investigate potential correlations between antibac-
molecular volume (MV), ovality, heat of formation (HOF), en-
ergies of the lowest unoccupied (ELUMO) and the highest occu-
pied (EHOMO) molecular orbitals, dipole, and net charge on the
nitrogen of the amide (INCaO), carbonyl carbon (INCaO), and
oxygen atom (INCaO) at the distal piperazine N-4-position
(Table 3). These molecular descriptors were derived as de-
scribed in the Section 4 of this manuscript.
The following conclusions could be deduced from the data:
The activity of the compounds against the S. aureus and
MRSA showed negative correlations (r ¼ ꢀ0.856 and
ꢀ0.836) to the Clog P values, since the activity decreased con-
sistently with increase in Clog P values. Moreover, heat of for-
mation correlated positively (r ¼ 0.846, p < 0.001) with
antibacterial activity. A similar correlation in a series of aryla-
cryloylpiperazin-1-yl oxazolidinones has been reported [28],
and affirmed that compounds with relatively high HOF (less
ꢀve value) would show good activity. The heat of formation
descriptor in QSAR model has been reported [28,29] to
terial activity and selected molecular descriptors, the outcome
of which may be helpful in predicting compounds that may as-
sume potential bioactive conformation and binding orienta-
tions that may result in desirable activity. Prediction of
bioactive conformations and binding orientations of ligands
is not an easy task, since bioactive conformations may differ
significantly from the unbound conformation [26]. We rea-
soned that any observable correlations might shed some light
on SAR, which might be helpful in designing further structural
modifications in this class of compounds, as suggested by
other studies [27e29]. Therefore, we performed linear regres-
sion analyses for the Clog P [21], steric and selected molecu-
lar descriptors [30] with antibacterial activity. The
antibacterial activity reported as MIC values (mg/ml, Tables
1 and 2), were transformed to pMIC (ꢀlog MIC) on a molar
basis and used as dependent variables in correlation with mo-
lecular descriptors such as Clog P, surface area (SA),

Table 3
Molecular descriptors of acyl-piperazinyl oxazolidinones used in regression analyses
O
O
O
N
N
R
N
N
N
N
F
Compd
R
Clog P log 1/MICa
log 1/MICa SA (A2) Ovality MV (A3) ELUMO
(eV)
EHOMO
(eV)
Dipole MM3 HF
INCaO
charge
INCaO INCaO
charge charge
(S. aureusb) (MRSA)
8a
8b
8c
CH3
CH3CH2
(CH3)2CHe
ꢀ0.95
ꢀ0.42
ꢀ0.11
2.59
2.60
2.32
3.19
2.60
2.62
438.88
450.41
465.41
1.85
1.84
1.86
342.72
359.76
370.76
ꢀ10.51 ꢀ10.52 4.85
ꢀ10.51 ꢀ10.56 5.73
ꢀ10.64 ꢀ10.80 4.95
ꢀ19.98 ꢀ0.262 0.167
ꢀ28.89 ꢀ0.261 0.170
ꢀ24.86 ꢀ0.262 0.173
ꢀ0.421
ꢀ0.420
ꢀ0.420
8d
8e
0.52
1.08
2.34
2.06
2.65
2.66
504.99
525.76
1.92
1.95
400.08
416.09
ꢀ10.56 ꢀ10.65 5.50
ꢀ10.49 ꢀ10.49 3.16
ꢀ23.31 ꢀ0.261 0.173
ꢀ35.91 ꢀ0.261 0.173
ꢀ0.420
ꢀ0.420
8f
CH3(CH2)4
CH3(CH2)5
CH3(CH2)6
CH3(CH2)7
CH3(CH2)8
CH3(CH2)9
CH3(CH2)12
CH3(CH2)14
CH3(CH2)16
0.91
1.44
1.97
2.50
3.03
3.56
5.14
6.20
7.26
2.05
2.06
2.07
1.78
1.50
1.51
1.54
1.56
1.58
2.35
2.36
2.37
2.09
1.50
1.51
1.54
1.56
1.58
519.87
532.85
551.91
596.59
621.09
638.55
682.33
747.59
781.76
1.95
1.96
1.98
2.06
2.10
2.11
2.13
2.22
2.25
410.77
421.27
438.38
462.70
479.55
496.34
539.27
580.72
609.47
ꢀ10.37 ꢀ10.50 4.83
ꢀ10.65 ꢀ10.85 5.19
ꢀ10.62 ꢀ10.80 4.70
ꢀ10.48 ꢀ10.50 4.06
ꢀ10.52 ꢀ10.53 0.43
ꢀ10.51 ꢀ10.55 0.89
ꢀ10.63 ꢀ10.80 5.67
ꢀ10.51 ꢀ10.52 3.81
ꢀ10.65 ꢀ10.82 5.36
ꢀ45.43 ꢀ0.261 0.170
ꢀ44.58 ꢀ0.016 0.231
ꢀ44.95 ꢀ0.015 0.232
ꢀ39.79 ꢀ0.261 0.170
ꢀ68.23 ꢀ0.261 0.170
ꢀ75.24 ꢀ0.261 0.170
ꢀ84.57 ꢀ0.263 0.170
ꢀ84.96 ꢀ0.261 0.078
ꢀ102.43 ꢀ0.007 0.078
ꢀ0.420
ꢀ0.391
ꢀ0.391
ꢀ0.420
ꢀ0.420
ꢀ0.420
ꢀ0.420
ꢀ0.420
ꢀ0.396
8g
8h
8i
8j
8k
8l
8m
8n
CH2
8o
1.72
2.08
n/d
2.38
n/d
533.40
431.72
1.93
1.82
433.63
343.79
ꢀ10.64 ꢀ10.76 5.56
ꢀ10.98 ꢀ11.46 3.74
ꢀ22.87 ꢀ0.261 0.078
ꢀ108.05 ꢀ0.015 0.214
ꢀ0.420
ꢀ0.358
O
O
H
N
HO
N
O
CH3
Epzd
ꢀ1.09
N
N
O
F
O
O
N
PH-027
Lzd
O
O
N
N
0.63
0.53
n/d
n/d
n/d
n/d
392.87
372.03
1.80
1.73
302.04
295.28
ꢀ10.46 ꢀ10.50 4.47
ꢀ10.95 ꢀ11.47 1.11
1979.78 n/a
1864.19 n/a
n/a
n/a
n/a
n/a
N
N
N
F
O
H
N
O
CH3
N
O
F
SA: surface area; MV: molecular volume; HF: heat of formation (kcal/mol); n/d: not determined; n/a: not applicable.
a
Lower MIC values.
ATCC 25923 strain.
b

O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
1101
indicate conformational stability, which may favor better bind-
ing and improved activity at the molecular level. In our study,
no correlation could be established with ELUMO, an electronic
parameter that measures electrophilicity of the molecule. This
finding is contrary to a previous report on the arylacryloylpi-
perazin-1-yl oxazolidinones series, which indicated that com-
pounds with high heats of formation and low ELUMO (highly
ꢀve value) would show good antibacterial activity [28]. Sim-
ilarly no correlation with antibacterial activity was observed
for EHOMO, dipole and net charge on the nitrogen of the amide
(INCaO), carbonyl carbon (INCaO), and oxygen atom (INCaO) at
the distal piperazine N-4-position. This is in agreement with
findings from previous studies [28,29].
In conclusion, a series of piperazinyl oxazolidinones having
long chain acyl groups at the distal piperazinyl N-4-position
were synthesized and evaluated for antibacterial activity. At-
tempts were made to correlate antibacterial activity with se-
lected molecular descriptors. Activity was observed to
decrease with increase in carbon chain length with significant
decrease in antibacterial activity with compounds having nine
carbon atoms or more. In general, antibacterial activity corre-
lated positively to the heat of formation of the compounds,
which has been suggested to indicate favorable conformational
stability and better binding and activity at the receptor site. On
the other hand, the activity of the compounds correlated neg-
atively with Clog P values, surface area, ovality and molecular
volume, suggesting consistent decrease in activity with in-
crease in the size of the acyl chain. However, no significant
correlation was observed between activity and ELUMO, EHOMO
and dipole, respectively. This study contributes to the under-
standing of the structureeantibacterial activity requirements
for this novel class of compounds, and highlights vital molec-
ular descriptors that could be used in designing novel and
more active derivatives.
System 2000 FT-IR spectrometer. Elemental analyses were
performed on a LECO elemental analyzer CHNS 932 appara-
tus, and analyses indicated by the symbols of the elements
were within ꢄ0.4% of the theoretical values.
The structures of the synthesized oxazolidinone derivatives
8aeo were sketched using ChemDraw Ultra 8.0 [21] and were
exported to Alchemy 2000 (Alchemy32) 2.05 [30]. Three di-
mensional (3D) structures of the molecules were generated
and saved for database processing using geometry optimiza-
tion method. The following molecular descriptors were ob-
tained for the entire molecule: surface area (SA), molecular
volume (MV), ovality, heat of formation (HOF), energy of
the lowest unoccupied (ELUMO) and the highest occupied
(EHOMO) molecular orbitals, dipole, and net charge on the ni-
trogen of the amide (INCaO), carbonyl carbon (INCaO), and car-
bon oxygen atom (INCaO) at the distal piperazine N-4-position.
The Clog P values were calculated using ChemDraw Ultra
8.0. Nonparametric Spearman’s correlation coefficient was
performed using SPSS v13.0 at p < 0.001.
5. Syntheses
5.1. General procedure for the long chain alkylcarbonyl-
oxazolidinones 8fen
A solution of the 5-((1H-1,2,3-triazol-1-yl)methyl)-3-
(3-fluoro-4-(piperazinium-1-yl) phenyl)oxazolidin-2-one tri-
fluoroacetic acid salt 7a (1.00 g, 2.17 mmol) in acetonitrile
(10 ml) cooled to 0 ꢁC was treated with triethylamine (1 ml)
and an appropriate long chain alkylcarbonyl chloride
(3.26 mmol) and stirred to room temp overnight. Dichlorome-
thane (20 ml) was added to the reaction mixture and the solu-
tion was washed with water (3 ꢅ 10 ml). The organic layer
was washed with brine, dried (anhydrous Na2SO4), filtered
and concentrated to give a solid, which was triturated with
ether to give a solid. The crude solid was recrystallized in
appropriate solvent systems to give the pure products.
4. Experimental
All common reagents and solvents were obtained from
commercial sources and used without further purification. Ex-
tracted solvents were dried over anhydrous Na2SO4, followed
by evaporation in vacuo, and column chromatography was car-
ried out with silica gel (Kieselgel 60, 70e230 mesh; Aldrich).
TLC was conducted on 0.25 mm pre-coated silica gel plates
(60F254, Merck). Melting points were determined on a Stuart
Scientific SMP1 melting point apparatus and are uncorrected.
The Science Analytical Facilities (SAF), Faculty of Science,
Kuwait University, performed all the instrumental analyses.
1H NMR spectra for all compounds were recorded on Bruker
DPX 400 NMR spectrometer using DMSO-d6 as solvent and
tetramethylsilane (TMS) as an internal reference, and chemi-
cal shifts were reported in ppm. 13C NMR spectrum of repre-
sentative compound 8f was recorded on Bruker Avance II 600
NMR spectrometer using DMSO-d6 as solvent and tetrame-
thylsilane (TMS) as an internal reference, and chemical shifts
were reported in ppm. The mass spectrometry measurements
were performed on a Finnigan MAT INCOS XL mass spec-
trometer. Infrared (IR) spectra were recorded on Perkin Elmer
5.1.1. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-hexanoylpiperazin-1-yl) phenyl)oxazolidin-2-one 8f
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (381 mg, 39%,
yield), mp 194e195 ꢁC. 1H NMR (DMSO-d6): d 8.17 (s,
1H, triazole H), 7.77 (s, 1H, triazole H), 7.42 (dd, 1H,
J ¼ 2.3 Hz, 14.7 Hz, phenyl H), 7.13 (dd, 1H, J ¼ 2.1 Hz,
9.0 Hz, phenyl H), 7.06 (t, 1H, J ¼ 9.0 Hz, phenyl H), 5.09e
5.14 (m, 1H, CH2CHCH2eNeNaN), 4.83 (d, 2H,
J ¼ 5.0 Hz, CH2CHCH2eNeNaN), 4.20 (t, 1H, J ¼ 9.2 Hz,
CHHCHCH2eNeNaN), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz,
CHHCHCH2eNeNaN), 3.59 (s, 4H, piperazine H), 2.90e
2.96 (m, 4H, piperazine H), 2.33 (t, 2H, J ¼ 7.5 Hz, CH3CH2
CH2CH2CH2CO), 1.47e1.54 (m, 2H, CH3CH2CH2CH2
CH2CO), 1.27e1.29 (m, 4H, CH3CH2CH2CH2CH2CO), 0.87
(t, 3H, J ¼ 6.7 Hz, CH3CH2CH2CH2CH2CO). 13C NMR
(600 MHz, DMSO-d6): d 13.86, 21.93, 24.46, 30.98, 32.14,
40.93, 44.96, 47.06, 50.28, 50.73, 51.68, 70.75, 106.63,
106.80, 114.23, 114.24, 119.70, 119.73, 125.83, 133.23,

1102
O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
153.72, 170.65. IR (KBr pellet, cmꢀ1): n 2958, 2920, 2855,
1749, 1623, 1518, 1438, 1417, 1325, 1224, 1111, 1036. m/
z 444.6 (Mþ). Anal CHNS: calc C 59.44, H 6.58, N 18.91,
found: C 59.25, H 5.90, N 18.62.
(s,1H), 7.77 (s,1H), 7.42 (dd,1H, J ¼ 2.2 Hz, 14.7 Hz), 7.13
(dd, 1H, J ¼ 2 Hz, 9.0 Hz), 7.06 (t, 1H, J ¼ 9.0 Hz), 5.11e
5.14 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.21 (t, 1H,
J ¼ 9.2 Hz), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H),
2.90e2.95 (m, 4H), 2.33 (t, 2H, J ¼ 7.4 Hz), 1.50 (m, 2H),
1.26 (br s, 12H), 0.86 (t, 3H, J ¼ 6.7 Hz). IR (KBr pellet,
cmꢀ1): n 2922, 2851, 1739, 1637, 1523, 1419, 1384, 1223,
1138, 1036. m/z 500.2 (Mþ). Anal CHNS: calc C 62.38, H
7.45, N 16.79, found C 62.07, H 7.39, N 16.83.
5.1.2. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-heptanoylpiperazin-1-yl) phenyl)oxazolidin-2-one 8g
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (559 mg, 56%,
yield), mp 175e177 ꢁC. 1H NMR (DMSO-d6): d 8.17 (s,
1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz, 14.7 Hz), 7.13
(dd, 1H, J ¼ 2.0 Hz, 9.0 Hz), 7.06 (t, 1H, J ¼ 9.0 Hz), 5.10e
5.16 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.20 (t, 1H,
J ¼ 9.2 Hz), 3.86: (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H),
2.93 (m, 4H), 2.33 (t, 2H, J ¼ 7.5 Hz), 1.47e1.52 (m, 2H),
1.27e1.31 (m, 4H), 0.87 (t, 3H, J ¼ 6.7 Hz). IR (KBr pellet,
cmꢀ1): n 2856, 2926, 1746, 1628, 1518, 1463, 1436, 1417,
1327, 1225, 1195, 1113, 1099, 1040. m/z 458.4 (Mþ). Anal
CHNS: calc C 60.25, H 6.81, N 18.33, found C 60.08, H
6.36, N 18.51.
5.1.6. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-undecanoylpiperazin-1-yl)phenyl)oxazolidin-2-one 8k
Prepared according to the general procedure. Recrystalliza-
tion from MeCN and EtOAc afforded a crystalline solid
1
(280 mg, 50%, yield), mp 149e151 ꢁC. H NMR (DMSO-
d6): d 8.18 (s, 1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz,
14.7 Hz), 7.13 (dd, 1H, J ¼ 2.2 Hz, 9.0 Hz), 7.06 (t, 1H,
J ¼ 9.0 Hz), 5.11e5.14 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz),
4.21 (t, 1H, J ¼ 9.2 Hz), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz),
3.59 (s, 4H), 2.90e2.95 (m, 4H), 2.33 (t, 2H, J ¼ 7.5 Hz),
1.50 (m, 2H), 1.25 (br. s, 14H), 0.86 (t, 3H, J ¼ 6.6 Hz). IR
(KBr pellet, cmꢀ1): n 2922, 2851, 1738, 1636, 1522, 1418,
1223, 1190, 1163, 1038. m/z 514.2 (Mþ). Anal CHNS: calc
C 63.01, H 7.64, N 16.33, found C 62.92, H 7.61, N 16.16.
5.1.3. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-octanoylpiperazin-1-yl) phenyl)oxazolidin-2-one 8h
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (567 mg, 55%,
yield), mp 150e152 ꢁC. 1H NMR (DMSO-d6): d 8.17 (s,
1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz), 7.13 (dd, 1H,
J ¼ 2.1 Hz, 9.0 Hz), 7.06 (t, 1H, J ¼ 9.0 Hz), 5.11e5.14 (m,
1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.21 (t, 1H, J ¼ 9.2 Hz), 3.86
(dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H), 2.90e2.95 (m,
4H), 2.33 (t, 2H, J ¼ 7.5 Hz), 1.49e1.52 (m, 2H), 1.28 (m,
8H), 0.87 (t, 3H, J ¼ 6.7 Hz). IR (KBr pellet, cmꢀ1): n 2922,
2853, 1740, 1636, 1523, 1443, 1418, 1327, 1283, 1163,
1026. m/z 472.4 (Mþ). Anal CHNS: calc C 60.99, H 7.04, N
17.79, found C 60.79, H 6.57, N 17.93.
5.1.7. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-tetradecanoylpiperazin-1-yl)phenyl)oxazolidin-2-one 8l
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (392 mg, 65%,
yield), mp 157e159 ꢁC. 1H NMR (DMSO-d6): d 8.18 (s,
1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz, 14.7 Hz), 7.13
(dd, 1H, J ¼ 2.2 Hz, 9.0 Hz), 7.05 (t, 1H, J ¼ 9.0 Hz), 5.11e
5.14 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.20 (t, 1H,
J ¼ 9.0 Hz), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H),
2.90e2.95 (m, 4H), 2.33 (t, 2H, J ¼ 7.5 Hz), 1.49 (m, 2H),
1.24 (br. s, 20H), 0.86 (t, 3H, J ¼ 6.7 Hz). IR (KBr pellet,
cmꢀ1): n 2920, 2851, 1738, 1637, 1524, 1420, 1221, 1163,
1028. m/z 556.4 (Mþ). Anal CHNS: calc C 64.72, H 8.15, N
15.10, found C 64.52, H 8.02, N 15.10.
5.1.4. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-nonanoylpiperazin-1-yl) phenyl)oxazolidin-2-one 8i
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (340 mg, 32%,
yield), mp 133e135 ꢁC. 1H NMR (DMSO-d6): d 8.17 (s,
1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz, 14.7 Hz), 7.13
(dd, 1H, J ¼ 2.0 Hz, 9.0 Hz), 7.06 (t, 1H, J ¼ 9.0 Hz), 5.11e
5.14 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.21 (t, 1H,
J ¼ 9.0 Hz), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H),
2.90e2.95 (m, 4H), 2.33 (t, 2H, J ¼ 7.5 Hz), 1.49e1.52 (m,
2H), 1.28 (m, 10H), 0.86 (t, 3H, J ¼ 6.6 Hz). IR (KBr pellet,
cmꢀ1): n 2927, 2853, 1740, 1638, 1523, 1443, 1418, 1328,
1220, 1032. m/z 486.1 (Mþ). Anal CHNS: calc C 61.71, H
7.25, N 17.27, found C 61.59, H 7.22, N 17.30.
5.1.8. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-palmitoylpiperazin-1-yl) phenyl)oxazolidin-2-one 8m
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (290 mg, 23%,
yield), mp 155e156 ꢁC. 1H NMR (DMSO-d6): d 8.18 (s,
1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz, 14.7 Hz), 7.13
(dd, 1H, J ¼ 2.2 Hz, 9.0 Hz), 7.06 (t, 1H, J ¼ 9.0 Hz), 5.11e
5.14 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.21 (t, 1H,
J ¼ 9.2 Hz), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H),
2.90e2.95 (m, 4H), 2.33 (t, 2H, J ¼ 7.5 Hz), 1.49 (br. s,
2H), 1.24 (br. s, 22H), 0.86 (t, 3H, J ¼ 6.6 Hz). IR (KBr pellet,
cmꢀ1): n 2920, 2851, 1738, 1637, 1524, 1420, 1225, 1165,
1035. m/z 584.5 (Mþ). Anal CHNS: calc C 65.73, H 8.45, N
14.38, found C 65.63, H 8.37, N 14.47.
5.1.5. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(4-(4-
decanoylpiperazin-1-yl)-3-fluoro phenyl)oxazolidin-2-one
8j
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (490 mg, 45%,
yield), mp 138e140 ꢁC. 1H NMR (DMSO-d6): d 8.17

O.A. Phillips et al. / European Journal of Medicinal Chemistry 43 (2008) 1095e1104
1103
5.1.9. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(3-fluoro-4-
(4-stearoylpiperazin-1-yl)phenyl)oxazolidin-2-one 8n
(MICs, mg/ml) were determined on MuellereHinton (MH)
agar with medium containing dilutions of antibacterial agents
ranging from 0.12 to 16 mg/ml, and up to 64 mg/ml for vanco-
mycin against enterococci. The test compounds were dis-
solved in 20% water in DMSO, while linezolid and
vancomycin were dissolved in 40% water in ethanol and wa-
ter, respectively. The tests were performed using MH agar
plates for all staphylococci and enterococci, and on MH agar
plates supplemented with 5% sheep blood to facilitate the
growth of S. pneumoniae, H. influenzae and M. catarrhalis.
The Gram-positive organisms utilized in this study consisted
of methicillin-resistant S. aureus (MRSA, n ¼ 10), methicil-
lin-susceptible S. aureus (MSSA, n ¼ 11), methicillin-resistant
coagulase-negative staphylococci (MR-CNS, n ¼ 3), methicil-
lin-sensitive coagulase-negative staphylococci (MS-CNS,
n ¼ 8), S. pneumoniae (n ¼ 6), vancomycin-sensitive (VSE,
n ¼ 7) and vancomycin-resistant (VRE, n ¼ 4) enterococci.
The Gram-negative organisms tested included H. influenzae
(n ¼ 5) and M. catarrhalis (n ¼ 3) clinical isolates; and
E. coli ATCC 25922. The reference strains, S. aureus ATCC
25923, Staphylococcus epidermidis ATCC 12228 and Entero-
coccus faecalis ATCC 29212, E. coli ATCC 25922 and H. in-
fluenzae ATCC 49247 were used as controls. The final
bacterial concentration for inocula was 107 CFU/ml, and was
incubated at 35 ꢁC for 18 h. The test compounds were also
evaluated against S. aureus ATTC 25923 in MH broth supple-
mented with 50% human plasma. The MIC was defined as the
lowest drug concentration that completely inhibited growth of
the bacteria. PH-027, prepared according to literature methods
[13], and linezolid and vancomycin obtained from commercial
sources were used as reference antibacterial agents.
Prepared according to the general procedure. Recrystalliza-
tion from MeCN afforded a crystalline solid (398 mg, 60%,
yield), mp 148e149 ꢁC. 1H NMR (DMSO-d6): d 8.18 (s,
1H), 7.77 (s, 1H), 7.42 (dd, 1H, J ¼ 2.3 Hz, 14.7 Hz), 7.13
(dd, 1H, J ¼ 2.2 Hz, 9.0 Hz), 7.06 (t, 1H, J ¼ 9.0 Hz), 5.11e
5.14 (m, 1H), 4.83 (d, 2H, J ¼ 5.0 Hz), 4.21 (t, 1H,
J ¼ 9.2 Hz), 3.86 (dd, 1H, J ¼ 5.7 Hz, 9.2 Hz), 3.59 (s, 4H),
2.90e2.95 (m, 4H), 2.33 (t, 2H, J ¼ 7.5 Hz), 1.50 (m, 2H),
1.24 (br. s, 28H), 0.86 (t, 3H, J ¼ 6.6 Hz). IR (KBr pellet,
cmꢀ1): n 2918, 2851, 1738, 1639, 1524, 1421, 1225, 1161,
1026. m/z 612.6 (Mþ). Anal CHNS: calc C 66.63, H 8.72, N
13.72, found C 66.62, H 8.75, N 13.20.
5.1.10. (R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(4-(4-(2-
(bicyclo[2.2.1]heptan-2-yl)acetyl) piperazin-1-yl)-3-
fluorophenyl) oxazolidin-2-one 8o
The trifluoroacetic acid salt 7a (1.50 g, 6.52 mmol) was
triturated with a saturated potassium carbonate solution
(10 ml), and the precipitate was collected and dried to give
the free base 7b (0.930 g). In a separate flask, a solution of
2-norbornaneacetic acid (1.00 g, 0.939 ml, 6.49 mmol) in
DCM (20 ml) was treated with dicyclohexyl carbodimide
(1.61 g, 7.78 mmol) and 1-hydroxybenzotriazole (1.05 g,
7.78 mmol). The reaction mixture was stirred at room temper-
ature for 2 h and was filtered directly into a flask containing
a solution of the free base 7b in MeCN. The reaction mixture
was stirred at room temperature overnight. The mixture was
concentrated, redissolved in ethyl acetate and washed with wa-
ter, brine, and the organic layer was dried (Na2SO4). Recrys-
tallization from MeCNeEtOAc afforded a crystalline solid
1
(448 mg, 35%, yield), mp 177e179 ꢁC. H NMR (DMSO-
Acknowledgment
d6, 400 MHz): d 8.18 (s, 1H), 7.77 (s, 1H), 7.42 (dd, 1H,
J ¼ 2.0 Hz, 15.0 Hz), 7.13 (dd, 1H, J ¼ 2.0 Hz, 9.0 Hz), 7.06
(t, 1H, J ¼ 9.0 Hz), 5.11e5.14 (m, 1H), 4.83 (d, 2H,
J ¼ 5.0 Hz), 4.21 (t, 1H, J ¼ 9.0 Hz), 3.86 (dd, 1H,
J ¼ 6.0 Hz, 9.0 Hz), 3.59 (br. s, 4H), 2.90e2.95 (m, 4H),
2.33 (dd, 1H, J ¼ 8.0 Hz, 15.0 Hz), 2.18 (dd, 1H, J ¼ 8.0 Hz,
15.0 Hz, overlaps partly with br. s, at 2.17), 2.17 (br. s, 1H),
1.95 (br. s 1H), 1.83e1.80 (m, 1H), 1.46e1.34 (m, 4H),
1.17e1.03 (m, 4H). IR (KBr pellet, cmꢀ1): n 2948, 2853,
1742, 1630, 1521, 1441, 1420, 1325, 1224, 1035. m/z 482
(Mþ). Anal calc for C25H31FN6O3: C 62.22, H 6.48, N
17.42, found C 62.60, H 6.96, N 17.11.
This work was supported by the Research Administration,
Kuwait University Research Grant PC01/02 (OAP), and In-
strument Grants GS01/01, GS03/01 and GS01/03 awarded to
the Science Analytical Facilities (SAF). Thanks to Dr. Prem
Sharma, Health Sciences Computer Center, Kuwait University
for performing the statistical analysis.
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