Phenylpropenamide derivatives: Anti-hepatitis B virus activity of the Z isomer, SAR and the search for novel analogs

Article abstract of DOI:10.1016/j.bmcl.2011.05.077

Phenylpropenamides have been reported to be a class of non-nucleoside inhibitors of the hepatitis B virus (HBV). This class of compounds was explored with the objective of developing potent anti-HBV agents, with a novel mechanism of action, that could be combined with nucleos(t)ide analogs currently used to treat HBV infection. To accomplish this objective a series of substituted arylpropenamide derivatives were prepared and the E and Z geometrical isomers were separated. The structural identity of each of the E and Z isomers was determined by single crystal X-ray crystallography. Contrary to previous reports, the activity of this class of molecules resides in the Z isomer. Further structure-activity relationship studies around the active Z isomer identified compounds that displayed potent antiviral activity against HBV with EC₉₀ value of approximately 0.5 μM in vitro. Attempts to develop ring constrained analogs did not lead to active HBV inhibitors.

Full text of DOI:10.1016/j.bmcl.2011.05.077

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4642–4647
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Phenylpropenamide derivatives: Anti-hepatitis B virus activity of the Z isomer,
SAR and the search for novel analogs
Peiyuan Wang, Devan Naduthambi, Ralph T. Mosley, Congrong Niu, Phillip A. Furman, Michael J. Otto,
⇑
Michael J. Sofia
Pharmasset, Inc., 303-A College Road East, Princeton, NJ 08540, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenylpropenamides have been reported to be a class of non-nucleoside inhibitors of the hepatitis B virus
(HBV). This class of compounds was explored with the objective of developing potent anti-HBV agents,
with a novel mechanism of action, that could be combined with nucleos(t)ide analogs currently used
to treat HBV infection. To accomplish this objective a series of substituted arylpropenamide derivatives
were prepared and the E and Z geometrical isomers were separated. The structural identity of each of the
E and Z isomers was determined by single crystal X-ray crystallography. Contrary to previous reports, the
activity of this class of molecules resides in the Z isomer. Further structure–activity relationship studies
around the active Z isomer identified compounds that displayed potent antiviral activity against HBV
Received 23 March 2011
Revised 18 May 2011
Accepted 20 May 2011
Available online 6 June 2011
Keywords:
Hepatitis B virus
Antivirals
Phenylpropenamides
HBV inhibitors
with EC90 value of approximately 0.5
lead to active HBV inhibitors.
l
M in vitro.Attempts to develop ring constrained analogs did not
Ó 2011 Elsevier Ltd. All rights reserved.
Pregenomic RNA packaging
Hepatitis B virus (HBV) infection is a major health problem that
leads to chronic liver disease, estimated to affect more than 5% of
the world’s population.1 HBV can cause both acute and chronic
infections. Chronic HBV infection can progress to liver cirrhosis
and hepatocellular carcinoma with high mortality. There are
approximately 350À400 million chronically infected individuals,
resulting in 0.5À1.2 million deaths annually.2,3
We were interested in further investigating arylpropenamides
as inhibitors of HBV with the hope of developing combination
therapies with current nucleos(t)ide therapies. Earlier reports
describing the identification and activity of phenylpropenamides
as HBV inhibitors reported the propenamide double bond having
NH2
NH2
N
O
The current agents approved for the treatment of HBV infection
N
N
include interferon-
logues lamivudine, telbivudine,4 entecavir,5 adefovir and tenofo-
vir6 ( Fig. 1). Unfortunately, the use of interferon-
is limited
a, pegylated interferon a-2a, nucleoside ana-
N
NH
N
N
O
O
HO
N
O
a
OH
NH2
O
OH
because of its low success rate, high cost and serious side effects.7,8
The nucleoside analogues all inhibit HBV replication by inhibiting
the viral polymerase. As is the case for HIV infection, developing
combination therapies containing agents with complimentary
mechanisms of action for treating HBV infection is highly desirable.
However, there are no direct acting antiviral agents that inhibit
HBV via a non-polymerase mechanism of action currently in clini-
cal development.
S
HO
OH
Lamivudine
Entecavir
Telbivudine
NH2
NH2
N
N
N
N
N
N
N
Phenylpropenamides were reported as a non-nucleoside class of
inhibitors of HBV replication in cell culture.9 It was also reported
that phenylpropenamides were specific inhibitors of HBV replica-
tion and most likely inhibited replication by interfering with the
packaging of pregenomic RNA into immature core particles.10
O
O
N
O
O
P
O
O
O
O
O
P
OH
OH
O
Adefovir dipivoxil
Tenofovir
⇑
Corresponding author. Tel.: +1 609 613 4123; fax: +1 609 613 4150.
E-mail address: michael.sofia@pharmasset.com (M.J. Sofia).
Figure 1. Agents for the treatment of hepatitis B infection.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.077

P. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4642–4647
4643
O
The final products were characterized by 1H NMR, NOE studies
and MS.12 Since the double bond geometries could not be unequiv-
ocally assigned using NMR spectral data, the stereochemistry of
the double bond moiety, was determined by obtaining single crys-
tal X-ray structures. Thus, the major isomer was determined to
Cl
N
O
HN
have the
Z configuration, (Z)-N-(1-chloro-3-oxo-1-phenyl-3-
(piperidin-1-yl)prop-1-en-2-yl)benzamide (10Z) and the minor
isomer the E-configuration, 10E (Fig. 4).
10E
The anti-HBV activity for both E and Z isomers was evaluated in
the Hep AD38 cellular assay.13 Contrary to previous reports,9 it was
determined that the anti-HBV activity of this class of molecules re-
sides predominantly in the Z isomer. The E isomers were shown to
be weakly active or not active against HBV (data not shown). For
example, the Z isomer 10Z (Fig. 3) exhibited anti-HBV activity with
Figure 2. Reported active propenamide having the
EC50 = 0.6–5.7
M).9,10
E configuration (reported
l
O
an EC90 of 5.51 lM, whereas the E isomer, compound 10E (Fig. 2),
which was reported to have an EC50 of 1.2
in fact was shown to be inactive up to 100
tration we tested.
l
M and EC90 of 13
l
M,9
Cl
N
O
HN
lM, the highest concen-
SAR investigation of A-ring modification of the Z propenamides
is summarized in Table 1. Compounds 11, 12, 13, and 10Z showed
good activity with EC90’s of 1.71, 1.80, 1.81, and 5.51 lM, respec-
10Z
Figure 3. Active compound 10Z having Z configuration.
tively. The ortho-substitution on the A-ring provided improved
anti-HBV activity, such as seen for compounds 11, 12, and 13.
Benzo[1,3]dioxo-4-yl derivative 14 was less potent than com-
pounds containing an o-substituted or unsubstituted phenyl group.
Para-substitution on the A-ring, such as p-OMe, p-Me, and p-Cl,
decreased the antiviral activity.
Further SAR assessment focused on the substitutions on the
B-ring (Table 2). Among the B-ring modifications, the p-NO2 analog
18, p-chloro analog 19, and p-fluoro analog 21 displayed activity.
Propenamides with a p-methyl (20), p-bromo (22), or a 2-bromo-
4-nitro (25) substituent on the B-ring also showed good activity.
However, some para-substitutions on the B-ring, such as p-OMe
23 and 4-MeSO2 24 resulted in significant loss in antiviral activity.
Similarly, several 2,4-disubstituted B-ring compounds, such as 26,
the E configuration (trans) (Fig. 2). However, there was no discus-
sion regarding the assignment of the double bond geometry or
activity of the molecule having the Z-configuration (cis).
Here we report the definitive structural assignment of phenyl-
propenamide derivatives and the structure–activity relationship
of the active Z isomers.
In our effort to explore more completely propenamides as
inhibitors of HBV, we chose to study the SAR around propenamide
templates 10Z (Z isomer) and 10E (E isomer). As previously re-
ported, the phenylpropenamides were prepared as shown in
Scheme 1. Reaction of substituted benzoyl chloride 1 with glycine
2 gave the N-benzoylglycine (hippuric acid 3). Condensation of 3
with a benzaldehyde 4 in acetic anhydride (100 °C) provided the
oxazolones 5. Amination of the oxazolones 5 by reaction of either
piperidine or other desired amines afforded N-(3-amino-3-oxo-
1-phenylprop-1-en-2-yl)benzamide derivatives 7.
27, and 28, did not show anti-HBV activity up to 10 lM.
In Table 3 we summarize the SAR for the amide moiety. The
non-substituted piperidine analog 10Z exhibited good activity
with an EC90 value of 5.51
lM. 3-Methyl-piperidin-1-yl derivative
29 was found to have similar activity with an EC90 of 6.43
lM.
Other substituted piperidine amides, such as 30 having the
3,3-di-fluoro-piperidine, provided reduced activity or no activity
Halogenation of 7 with bromine in the presence of CaCO3 or sul-
furyl dichloride afforded the propenamides as a mixture of Z and E
isomers. E and Z isomers were subsequently separated by either
HPLC or SFC chromatography. Based on isolated yields, the ratio
of Z/E isomers was approximately 2.5ꢀ10:1.
(up to 10
also less potent (EC90 > 10
with an o-OMe on the A-ring and a p-NO2 on the B-ring, exhibited
the most potent activity, with an EC90 value of 0.56 M. The
lM). 4-Methyl-piperazine 31 and morpholine 32 were
lM). Piperidine amide derivative 33,
l
O
CHO
R1
O
O
1. NaOH (aq)
4
R1
,
O
N
+
H2N
COOH
Cl
N
H
COOH
2. Con. HCl
AcONa/Ac2O, 100 o
C
R2
1
2
R2
3
5
R2
R1
A
R3
O
X
O
B
R3
R3'
HN
X2, 8
R3'
6
R3
R3'
O
N
O
R3
N
O
R1
X
N
+
R1
A
HN
CHCl3, 0 o
C
R3'
HN
CaCO3/CHCl3, 0 o
C
HN
O
or
O
B
R2
Cl S Cl
O
b)
9
R2
R2
Z isomers
Scheme 1. Synthesis of arylpropenamides.
7
E isomers

4644
P. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4642–4647
Figure 4. ORTEP drawing of compound 10Z (Z isomer) and 10E (E isomer).11
Table 1
Table 2
Modification on the A-ring
Modification on the B-ring
A
O
O
N
Cl
HN
O
Cl
N
O
HN
B
Compd
A (A-ring)
EC90
(lM)
CC90 (lM)
Compd
B (B-ring)
EC90
(l
M)
CC90 (lM)
10Z
11
12
Ph
5.51
1.71
1.80
1.81
>10
>10
>10
>10
10Z
18
19
20
21
22
23
24
25
26
27
28
Ph
4-NO2-Ph
4-Cl-Ph
4-Me-Ph
4-F-Ph
4-Br-Ph
4-MeO-Ph
4-MeSO2-Ph
2-Br-4-NO2-Ph
2-MeO-4-4NO2-Ph
2-CF3-4-NO2-Ph
2,4-Di-NO2-Ph
5.51
1.67
1.25
2.90
2.17
6.04
>10
>10
4.06
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
2-MeO-Ph
2-Me-Ph
2-F-Ph
13
O
14
9.9
>10
O
15
16
17
4-Cl-Ph
4-Me-Ph
2-MeO-Ph
>10
>10
>10
>10
>10
>10
Anti-HBV activity was evaluated in the Hep AD38 cellular assay.13
EC90 = concentration of the compound (in M) which inhibits the synthesis of viral
M) which reduces cell viability by
l
Anti-HBV activity was evaluated in the Hep AD38 cellular assay.13
EC90 = concentration of the compound (in M) which inhibits the synthesis of viral
M) which reduces cell viability by
DNA by 90%. CC90 = concentration of drug (in
l
l
90%.
DNA by 90%. CC90 = concentration of drug (in
l
90%.
corresponding pyrrolidine derivative 34 was less potent. These re-
sults revealed that unsubstituted piperidine and pyrrolidine
amides are preferred.
The effect on HBV activity of chlorine vs bromine substitution
on the double bond of the phenylpropenamides is presented in
Table 4. In general, most vinyl bromide derivatives were more po-
tent than the corresponding vinyl chloride derivatives, such as 41
versus 34 (ꢀ4-fold). Compounds (34 and 41) having the Z configu-
ration and the substitutions X = Cl or Br, R1 = o-OMe, R2 = p-NO2
and Y = pyrrolidinyl showed excellent anti-HBV activity with the
With the establishment of the correct double bond configura-
tion, we turned our attention to identifying analogs that replace
the vinyl halide with a more pharmacologically attractive system.
First, we explored whether the vinyl halide could be replaced
with an alkyl substituted alkene. A methyl group is considered to
be isosteric with Cl and Br.14 This substitution was also supported
by superposition of the modeled conformers of 10Z and 42, the
methyl substituted derivative, for which the lowest energy con-
former of each is depicted in Figure 5a.15 Therefore we synthesized
1-methyl substituted propenamide 42 and 43 from the corre-
sponding 1-bromopropenamides via vinyllithiation and methyl io-
dide treatment.16
EC90’s of 1.69 and 0.39 lM, respectively.
The SAR of the propenamides having the Z double bond geom-
etry is consistent with previously reported SAR for compounds as-
signed as having an E configuration, indicating that the compounds
originally reported were likely to have had predominately Z
geometry.
Compounds 42 and 43 exhibited comparable anti-HBV activity
to their corresponding vinyl halide analogs 19 and 22 with EC90
values of 1.92 and 3.92 lM, respectively.

P. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4642–4647
4645
Table 3
Table 4
Amide variants
Comparison of vinyl chloride vs bromide derivatives
R1
R1
A
A
O
O
Cl
X
Y
Y
HN
R2
HN
R2
O
O
B
B
Compd R1 (A-ring) R2 (B-ring)
Y
EC90
5.51
6.43
(l
M) CC90
>10
(
lM)
Compd
X
R1 (A-ring)
R2 (B-
ring)
Y
EC90
M)
CC90
M)
(l
(l
N
10Z
H
H
H
H
10Z
35
19
36
37
38
Cl
Br
Cl
Br
Cl
Br
H
H
H
H
H
5.51
5.90
1.25
0.91
4.66
1.25
>10
>10
>10
>10
>10
>10
N
N
N
N
N
N
29
>10
N
N
H
F
30
H
H
>10
>10
4-Cl
4-Cl
4-NO2
4-NO2
F
N
31
32
H
H
H
H
>10
>10
>10
>10
N
2,3-Dimethyli-
denedioxy–
2,3-Dimethyli-
denedioxy–
O
N
N
N
33
34
2-MeO
2-MeO
4-NO2
4-NO2
0.56
1.69
>10
>10
O
O
39
40
Cl
2-MeO
2-MeO
H
H
4.72
2.78
>10
>10
N
Anti-HBV activity was evaluated in the Hep AD38 cellular assay.13
EC90 = concentration of the compound (in M) which inhibits the synthesis of viral
M) which reduces cell viability by
Br
N
N
N
N
N
l
DNA by 90%. CC90 = concentration of drug (in
l
34
41
42
43
Cl
2-MeO
2-MeO
H
4-NO2
4-NO2
4-Cl
1.69
0.39
1.92
3.92
>10
>10
>10
>10
90%.
Br
Knowing that the preferred double bond geometry is Z and that
methyl is tolerated in place of the halogen on the double bond, we
proceeded to introduce ring systems that would link the amide
group and the far end of the double bond. We hypothesized that
these would maintain the overall conformation of the molecule
while providing additional opportunities to explore other potential
binding interactions. Therefore, we designed the novel ring con-
strained propenamide type derivatives by incorporating the dihy-
dropyrrole (A), pyrrolidine (B) and pyrrole (C) skeletons into the
structure of the propenamides (Table 5).
CH3
CH3
H
4-Br
Anti-HBV activity was evaluated in the Hep AD38 cellular assay.13
EC90 = concentration of the compound (in M) which inhibits the synthesis of viral
M) which reduces cell viability by
l
DNA by 90%. CC90 = concentration of drug (in
l
90%.
Two consequences of the propenamide cyclized constructs are
the conversion of the conformationally restricted secondary amide
into a flexible tertiary amide and concomitant loss of the H-bond
donor ability of the amide. Of the three classes of analogues, A
showed the greatest propensity to maintain the s-trans shape of
the secondary amide by ꢀ1 kcal/mol. All four diastereomers of B
were least capable of aligning well with the parent propenamide;
those conformers which did were ꢀ9 kcal/mol above the lowest
energy conformers found. The alignment of the lowest energy con-
formers of 10Z and the corresponding dihydropyrrole, 53, are de-
picted in Figure 5b.
Conformationally constrained analogues of the propenamides
were prepared as shown in Scheme 2. Diethyl 2-aminomalonate
(44) was reacted with benzoic acid 45 in the presence of 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide (EDC). The resulting
diethyl 2-benzamidomalonate 46 was subjected to condensation
with the
a,b-unsaturated aldehyde 47, followed by a deoxygen-
ation reaction using triethylsilane to afford 49. Saponification of
the diesters 49 with 1 equiv of sodium hydroxide followed by oxi-
dative decarboxylation gave the dihydropyrrole derivative 51.17
The desired dihydropyrroles 53–55 were obtained via a saponifica-
tion of the ester 51 with aqueous sodium hydroxide followed by
coupling of intermediate 52 with piperidine in the presence of
HATU and DIPEA. Hydrogenation using palladium hydroxide on
carbon gave pyrrolidine derivative 56 and 57. For the pyrrole-
carboxamide target, acylation followed by elimination of
Figure 5. (a) Superposition of the modeled lowest energy conformers for 10Z
(green carbons) and 42 (pink carbons) and (b) 10Z and 53 (purple carbons). The
higher energy s-cis conformer of 53 is displayed in wire.
5-hydroxy pyrrolidine 48 gave the dihydropyrrole diester 58.
Saponification of 58 with one equivalent of sodium hydroxide, oxi-
dative decarboxylation and further saponification afforded 59.

4646
P. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4642–4647
Table 5
Ring constrained derivatives
Coupling of 59 with piperidine and amidation with the appropriate
benzoic acid provided the desired 60 and 61. Unfortunately and
somewhat surprisingly, these constrained analogues were found
to be devoid of anti-HBV activity (Table 5).
R1
O
R1
O
R1
O
A
To evaluate the potential impact of the loss of the H-bond donor
function of the B-ring amide group, the N-methyl analog of com-
pound 36 was prepared via the reaction of compound 36 with
methyl iodide in the presence of sodium hydride in THF. Replace-
ment of the amide hydrogen of 36 with a methyl group resulted in
complete loss of activity (structure not shown). Molecular model-
ing showed that this methylation not only removed the capability
of the amide to function as an H-bond donor but also increased the
number of low energy conformers available beyond that seen with
the cyclic analogues. The desired s-trans conformer which mapped
with the active parent propenamide is energetically disfavored for
the N-methyl derivative by ꢀ1.3 kcal/mol over the s-cis lowest en-
ergy conformer. These results suggested that the lack of activity in
the cyclic analogues was due to either the loss of a critical H-bond
interaction, increased flexibility, increased steric interactions with
the biological target or a combination of these factors.
N
O
N
N
O
N
N
N
O
R2
R2
B
R2
A
C
B
Compd
Type
R1 (A-ring)
R2 (B-ring)
EC90
(l
M)
CC90 (lM)
53
54
55
56
57
60
61
A
A
A
B
B
C
C
H
H
H
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
4-Br
H
2-MeO
H
H
H
H
H
4-Br
H
4-Br
Anti-HBV activity was evaluated in the Hep AD38 cellular assay.13
EC90 = concentration of the compound (in M) which inhibits the synthesis of viral
M) which reduces cell viability by
In conclusion, a series of new 2-substituted-3-arylpropenamide
derivatives having the Z configuration were prepared and evalu-
ated as inhibitors of HBV replication. The stereochemistry of the
l
DNA by 90%. CC90 = concentration of drug (in
l
90%.
R1
R1
COOEt
HO
O
R2
O
O
O
O
O
O
O
O
H 47
COOEt
O
45
HN
O
O
N
EtONa, EtOH
NH2
EDC, DMAP
HO
R2
R2
44
46
48
R1
R1
R1
O
O
OH
Pb(OAc)4,
Cu(OAc)2
COOEt
1) NaOH, H2O
2) 1N HCl
O
O
Et3SiH/TFA
CH2Cl2
COOEt
O
COOEt
O
N
N
N
Pyridine, DMF
R2
R2
R2
50
51
49
R1
R1
R1
O
O
O
Piperidine
NaOH
OH
O
N
O
N
O
Pd(OH)2/C, H2
THF
N
N
N
EtOH, H2O
HATU, DIPE
R2
R2
R2
52
53-55
56,57
R1
R1
1) 2N NaOH
O
R1
O
COOEt
2) Pb(OAc)4
Cu(OAc)2
,
1) piperidine,
HATU, DIPEA
N
O
COOEt
O
CH3COCl, DIPE
N
N
48
OH
2) NaH, THF
3) NaOH, H2O
Toluene, 90 o
C
3) R2-Ph-COCl
NH
R2
R2
58
59
60,61
Scheme 2. Synthesis of ring constrained propenamides.

P. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4642–4647
4647
8. Perrillo, R. P.; Schiff, E. R.; Davis, G. L.; Bodenheimer, H. C., Jr.; Lindsay, K.;
Payne, J.; Dienstag, J. L.; O’Brien, C.; Tamburro, C.; Jacobson, I. N. Engl. J. Med.
1990, 323, 295.
9. Perni, R. B.; Conway, S. C.; Ladner, S. K.; Zaifert, K.; Otto, M. J.; King, R. W. Bioorg.
Med. Chem. Lett. 2000, 10, 2687.
final products was elucidated by X-ray crystallography. We deter-
mined that the activity of this class of molecules resides in the Z
isomer. Structure–activity relationship studies around the active
Z isomer showed that a number of compounds displayed potent
antiviral activity against hepatitis B virus in vitro and that the
halogen on the central double bond was not critical for activity.
Attempts to translate this SAR into ring constrained analogs did
not lead to compounds with anti-HBV activity.
10. King, R. W.; Ladner, S. K.; Miller, T. J.; Zaifert, K.; Perni, R. B.; Conway, S. C.; Otto,
M. J. Antimicrob. Agents Chemother. 1998, 42, 3179.
11. Structure of compound 10E in Figure 2 is reported as compound 6 in Ref. 9 and
as AT-61 in Ref. 10. CCDC 826064 & 826065 contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
12. For instance, compound 10Z: 1H NMR (400 MHz, DMSO-d6): d = 1.23 (m, 3H),
1.28 (m, 3H), 3.52 (m, 2H), 3.11 (m, 2H), 3.22–3.24 (m, 2H), 7.44–7.50 (s, 5H),
7.52–7.59 (s, 2H), 7.61–7.62 (s, 1H), 7.97–7.99 (s, 2H), 10.13 (m, 1H); MS, m/e
368.9 (M+1)+, 758.9 (2M+Na)+. For compound 10E: 1H NMR(400 MHz, DMSO-
d6): d = 1.52–1.54 (m, 2H), 1.62–1.66 (m, 4H), 3.52 (m, 2H), 3.67 (m, 2H), 7.34–
7.45 (s, 5H), 7.52–7.55 (s, 3H), 7.74–7.76 (s, 2H), 10.09 (m, 1H); MS, m/e 368.9
(M+1)+, 758.9 (2M+Na)+.
Acknowledgments
We would like to thank WuXi Apptec Co., Ltd for assistance in
preparation of the compounds and characterization; We would like
to thank Dr. Patrick Carroll of University of Pennsylvania for deter-
mining the X-ray structure.
13. Ladner, S. K.; Otto, M. J.; Barker, C. S.; Zaifert, K.; Wang, G. H.; Guo, J. T.; Seeger,
C.; King, R. W. Antimibrob. Agents Chemother. 1997, 41, 1715.
14. Meyer, A. Y. J. Chem. Soc., Perkin Trans. 2 1986, 1567.
15. Conformers were generated for every compound modeled using torsional
sampling (MCMM) (a) followed by energy minimization to a convergence
gradient of 0.005 using MMFFs with a distance dependent dielectric model of
2r. (b) An RMSD of 0.25 and a 15 kcal/mol energy window were used as
criterion to limit the number of conformers output with an upper limit of 1000
being possible. None of the compounds resulted in more than 100 conformers
given these limits. (MacroModel, version 9.8, Schrödinger, LLC, New York, NY,
2010.) (a) MCMM–Monte Carlo Multiple Minimum: Chang, G.; Guida, W. C.;
Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379 and Saunders, M.; Houk, K. N.; Wu,
Y.-D.; Still, C. W.; Lipton, M.; Chang, G.; Guida,W. C. J. Am. Chem. Soc. 1990, 112,
1419; (b) MMFFs: Halgren, T. A. J. Comput. Chem. 1999, 20, 720 and Halgren, T.
A. J. Comput. Chem. 1999, 20, 730.
References and notes
1. Lavanchy, D. J. Viral Hepat. 2004, 11, 97.
2. Sorrell, M. F.; Belongia, E. A.; Costa, J.; Gareen, I. F.; Grem, J. L.; Inadomi, J. M.;
Kern, E. R.; McHugh, J. A.; Petersen, G. M.; Rein, M. F.; Strader, D. B.; Trotter, H.
T. Ann. Intern. Med. 2009, 150, 104.
3. Dienstag, J. L. N. Engl. J. Med. 2009, 359, 1486.
4. Lui, Y. Y.; Chan, H. L. Expert Rev. Anti-Infect. Ther. 2009, 7, 259.
5. Cheng, P. N.; Chang, T. T. Expert Rev. Anti-Infect. Ther. 2008, 6, 569.
6. Shamliyan, T. A.; MacDonald, R.; Shaukat, A.; Taylor, B. C.; Yuan, J.-M.; Johnson,
J. R.; Tacklind, J.; Rutks, I.; Kane, R. L.; Wilt, T. J. Ann. Intern. Med. 2009, 150, 111.
7. Wong, D. K.; Cheung, A. M.; O’Rourke, K.; Naylor, C. D.; Detsky, A. S.; Heathcote,
J. Ann. Intern. Med. 1993, 119, 312.
16. Curtin, D. Y.; Johnson, H. W. Jr.; Steiner, E. G. J. Am. Chem. Soc. 1955, 77, 4566.
17. Osada, S.; Fumoto, T.; Kodama, H.; Kondo, M. Chem. Lett. 1998, 27, 675.