Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.03.047

New tricyclic HIV-1 integrase (IN) inhibitors were prepared that combined structural features of bicyclic pyrimidinones with recently disclosed 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. This combination resulted in the introduction of a nitrogen into the aryl ring and the addition of a fused third ring to our previously described inhibitors. The resulting analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays, with good selectivity for strand transfer relative to 3′-processing.

Full text of DOI:10.1016/j.bmcl.2011.03.047

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2986–2990
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing
HIV-1 integrase inhibitors
Xue Zhi Zhao a, , Kasthuraiah Maddali b, Mathieu Metifiot b, Steven J. Smith c, B. Christie Vu c,
⇑
Christophe Marchand b, Stephen H. Hughes c, Yves Pommier b, Terrence R. Burke Jr. a,
⇑
a Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health,
Frederick, MD 21702, United States
b Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
c HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
New tricyclic HIV-1 integrase (IN) inhibitors were prepared that combined structural features of bicyclic
pyrimidinones with recently disclosed 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. This combination
resulted in the introduction of a nitrogen into the aryl ring and the addition of a fused third ring to
our previously described inhibitors. The resulting analogues showed low micromolar inhibitory potency
in in vitro HIV-1 integrase assays, with good selectivity for strand transfer relative to 30-processing.
Published by Elsevier Ltd.
Received 12 January 2011
Revised 10 March 2011
Accepted 14 March 2011
Available online 21 March 2011
Keywords:
HIV-1 integrase
Inhibit
Raltegravir
Cycloaddition
After more than two decades of intensive research, approxi-
mately 30 drugs have been approved by the FDA for the treatment
of HIV/AIDS. Included among these is Merck’s Isentress™
(MK-0518 or Raltegravir, 1, Fig. 1), which in 2007 became the first
marketed drug targeting HIV-1 integrase (IN).1 Raltegravir is one of
a number of compounds that inhibit IN by selectively blocking the
strand transfer (ST) reaction as opposed to the 30-processing
reaction (30-P).2 More recently, bicyclic pyrimidinones such as 2
have been reported, which represent an evolution of the N-methyl-
pyrimidinone motif found in Raltegravir.3 We have previously
described 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones (3) as struc-
turally simple IN inhibitors that exhibit good potency and ST
other key features. Based on this rationale, we designed tricyclic
hydroxy-pyrrolopyridine-triones (4). These analogues represent a
new structural class of IN inhibitors that combine features of 2
with 3 (Fig. 1). We report here the highly efficient preparation of
these compounds by cycloaddition chemistries and the biological
and biochemical evaluation of the compounds.
OH
O
OH
O
O
O
N
N
H
H
N
N
N
n
N
selectivity in the presence of cofactor Mg2+ 4–6
It should be noted
.
F
F
that the 1-carbonyl bridge in 3 serves to constrain three critical
oxygen atoms (indicated in 3 by ‘⁄’) into a co-planar arrangement
designed to enhance chelation with the two catalytic divalent me-
tal ions (Fig. 1).7
The therapeutic utility of compounds such as 3 is potentially
limited by cytotoxicity arising from the embedded catechol
functionality. We hypothesized that introduction of a nitrogen
substituent into the aryl ring could remove the catechol nature
of these inhibitors, but that the resulting derivatives would retain
HN
n = 0, 1, 2
O
O
1
2
N
N
Raltegravir
Bicyclic pyrimidinones
OH
OH
O
*
O
*
4
7
6
3
1
X
HO
*
O
X
1
2
N
5
C
B
N
2
5N
3
4
n
O
3
A
O
4
⇑
Corresponding authors. Tel.: +1 301 846 5906; fax: +1 301 846 6033 (T.R.B.).
1H-isoindole-1,3(2H)-diones
Hydroxy-pyrrolopyridine triones
E-mail addresses: xuezhi.zhao@nih.gov (X.Z. Zhao),
tburke@helix.nih.gov
(T.R. Burke).
Figure 1. Structures of HIV-1 integrase inhibitors discussed in the text.
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2011.03.047

X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2986–2990
2987
Et
O
O
Et
O
O
S
O
S
SEt
H
SEt
O
NaIO4
O
HO
Ac2O
O
N
O
N
n
n
(COCl)2, Benzene
N
n
N
n
5
6
7
8
O
X
N
X
X
SEt
O
SEt
O
OH
O
O
O
O
10
O
O
BF3-OEt2
N
N
pTsOH, Toluene
N
n
N
n
N
n
O
O
9
11
4
b n = 1; c n = 2; d n = 3
Scheme 1. Synthesis of substituted 3-hydroxy-2(1H)-pyridones (4) using a ‘Pummerer cyclization deprotonation cycloaddition’ cascade of imidosulfoxides (7).
The efficient synthesis of the key 7-hydroxy-1H-pyrrolo[3,4-
c]pyridine-1,3,6(2H,5H)-trione skeleton of 4 (ring numbering is
indicated inFig. 1) was achieved by application of Padwa’s ‘Pummer-
er cyclization deprotonation cycloaddition’ cascades of imidosulfox-
ides (Scheme 1).8,9 Conversion of amides 5 to imidosulfoxides 7 via
those of our previously reported isoindolediones (3, Fig. 1).4–6
A
triad of oxygens (Fig. 1 indicated in 3 by ‘⁄’) has been hypothesized
to chelate Mg2+ ions involved with IN catalysis, while the haloge-
nated N-benzyl group has been proposed to interact with the pen-
ultimate cytosine as the 30-end of the viral DNA in the INꢀDNA
complex.13,14 As reported herein, modification of the known inhib-
itors 2 by introduction of the 3-carbonyl (giving a third ‘C’-ring) was
done to facilitate this metal chelation by constraining the carbonyl
group at the 1-position of 4 into co-planar arrangement with the
oxygen atoms at the 6- and 7-positions of the ‘B’-ring of 4. A similar
approach has been shown to be highly effective in the design of 34–6
and in related IN inhibitors.7
sodium periodate oxidationof a-thioimides6 (obtainedby acylation
with freshly prepared 2-ethylthioacetyl chloride in benzene) and
reaction with acetic anhydride, led to the in situ formation of un-iso-
lated intermediates (8 and 9). These were subjected to 1,3-dipolar
cycloaddition with suitable alkenes (10) to form oxide-bridged
products (11). Further treatment with Lewis acids, such as BF3ꢀOEt2,
provided an efficient synthesis of 2(1H)-pyridones 4.8,9
Synthesis of the analogue 4a, containing a five-membered ‘A’ ring
proved to be problematic using the above approach. Therefore, an
alternate route was used that employed the [3+2] cycloaddition of
phenylsulfonyl-substituted mesoionic oxazolium ylide (isomünch-
Because for the parent compounds 2, inhibitory potency has
been shown to vary with ring size, we generated and tested ana-
logues with ‘A’-rings ranging in size from five to eight members.3
Using 4-fluoro-3-chloro substituents on the N-benzyl group, the
resulting tricyclic analogues were shown to be highly selective
for the ST step relative to the 30-P reactions (Table 1). Inhibitory
potencies increased slightly with ring size, such that analogue
4d–1, having an eight-membered A-ring was two-fold more potent
than 4a–1, having a five-membered ring A-ring.
none) dipole intermediates (Scheme 2).10,11 Treatment of
a-phenyl-
sulfony-containing imide 12 with p-acetamidobenzenesulfonyl
azide (13)12 and triethylamine in acetonitrile, provided the diazoi-
mide 14. Reaction of 14 with a catalytic amount of rhodium(II) ace-
tate (benzene at 80 °C) resulted in formation of the corresponding
isomünchnone dipole (15), which was trapped by [3+2] cycloaddi-
tion with N-(30-chloro-40-fluoro-benzyl)maleimide 10–1, to yield
the oxide-bridged product (16). Refluxing 16 with BF3ꢀOEt2 in
CH2Cl2, resulted in ring opening to form the 7-hydroxy-1H-pyrrol-
o[3,4-c]pyridine-1,3,6(2H,5H)-trione (4a–1, Scheme 2).
For the parent compounds 34–6 and numerous other ST-selec-
tive IN inhibitors,7 potency is highly dependent on the nature of
the N-benzyl group: In general, benzyl rings with halogen substit-
uents are favored. Using the 7-membered A-ring-containing 4c as a
platform, amides containing halogenated (4c–1 through 4c–4) as
well as non-halogenated (4c–5 and 4c–6) groups were prepared
and compared with the corresponding 4,5-dihydroxy-1H-isoin-
The tricyclic hydroxy-pyrrolopyridine-triones (4) were designed
to combine features of Merck’s bicyclic pyrimidinones (2)3 with
SO2N3
O
O
SO2Ph
O
AcHN
SO2Ph
Rh2(OAc)4
13
N
N
O
SO2Ph
N
Et3N/CH3CN
N2
O
O
12
14
15
F
O
Cl
F
F
SO2Ph
N
OH
O
Cl
BF3-OEt2
O
Cl
O
O
10-1
O
O
N
N
N
N
Benzene
O
O
16
4a-1
Scheme 2. Synthesis of substituted 3-hydroxy-2(1H)-pyridone 4a–1 via an isomünchnone-based [3+2] cycloaddition approach.

2988
X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2986–2990
Table 1
co-crystal structures of ST inhibitors bound to the prototype foamy
virus (PFV) IN complexed to 30-processed DNA substrate have con-
firmed the critical roles of two catalytic divalent ions in the binding
of these inhibitors.13,14,16,17 Although Mg2+ is believed to be pre-
ferred by IN in vivo, assays either Mg2+ or Mn2+ can be used in vitro.
Activities of some ST inhibitors differ in assays with the two met-
als.4,18 In order to investigate the metal dependency of the newly
synthesized 7-hydroxy-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-
Integrase inhibitory potencies of tricyclic hydroxy-pyrrolopyridine
trionesa
F
OH
O
Cl
O
N
N
n
triones (Table 1), we performed assays using either Mg2+ or Mn2+
.
O
For Raltegravir (1), inhibitory potencies against both 30-P and ST
reactions were relatively similar when Mn2+ or Mg2+ was used. In
contrast, 4b–1 showed an increase in both 30-P and ST inhibitory
potencies in the presence of Mn2+ (Table 3). This indicated a differ-
ence in the interaction of 4b–1 and the metal cofactors compared to
Raltegravir.
No.
n
30-Processing IC50
M)
Strand transfer IC50
(lM)
(l
4a–1
4b–1
4c–1
4d–1
0
1
2
3
>111
>111
>111
>111
10.9 1.4
9.1 1.1
6.0 0.7
5.4 0.8
Resistance to Raltegravir (1) that arises in HIV-1 infected patients
frequently involves the following integrase mutations: G140S/
Q148H, Y143R and N155H.19 In order to test the susceptibility of
the 7-hydroxy-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-triones to
these mutations, IN was assayed in vitro using pre-cleaved (30-pro-
cessed) DNA with Mg2+ as the metal cofactor. Inhibitory potencies
were determined for a panel of enzymes that included the wild-type
(WT) IN and the three key mutant forms indicated above (Table 4).
Although none of the new compounds was as potent against the
wild-type IN as Raltegravir, the inhibitory potency of 4b–1 was less
susceptible to the Raltegravir resistant mutants. Raltegravir was
105-fold less potent against the G140S/Q148H mutant as compared
to the WT enzyme; however, inhibitor 4b–1 showed only a 6-fold
loss of potency. Inhibitor 4b–1 was also more than 10-fold less sen-
sitive than Raltegravir to the effects of the Y143R mutation and more
than 2-fold less sensitive to the effects of the N155H mutation (Table
4). Interpretation of thisdata shouldbe done withthe understanding
that the overall potency of 4b–1 is suboptimal.
a
Data was obtained from in vitro IN assays as described in Ref. 4.
dole-1,3(2H)-diones (3–1 through 3–6). Dramatic substituent-
dependent differences were observed (Table 2). In the new pyri-
done series deletion of halogen functionality resulted in either
complete (4c–5, IC50 >111
IC50 = 90 M) of ST inhibitory potency. Notably, for the parent cat-
echol-containing compounds, ST inhibitory activity was main-
lM) or near-complete loss (4c–6,
l
tained after deletion of halogen functionality (3–5, IC50 = 0.4
and 3–6, IC50 = 0.7
tended to be reduced after halogen removal (3–5, IC50 = 72
and 3–6, IC50 = 150
l
M
l
M, Table 2). However, 30-P inhibitory activity
lM
l
M, Table 2). All halogen-containing members
of the series 4c exhibited low micromolar ST inhibitory potency
and good selectivity relative to 30-P inhibition.
Divalent metal cofactors are essential both for the proper func-
tion of IN and inhibitory potencies of ST inhibitors.15 The recent
Table 2
Effects of N-arylmethyl substituents on integrase inhibitory potencies of hydroxy-pyrrolopyridine triones (4c) as compared with 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones (3)a
OH
OH
O
O
O
HO
N
R
N R
N
O
O
4c
3
No.
R
IC50
(l
M)
No.
IC50 (lM)
30-Processing
>111
Strand transfer
6.0 0.7
30-Processing
Strand transfer
0.17 0.06
Cl
F
4c–1
4c–2
4c–3
3–1
3–2
3–3
14
8
3
>111
>111
10.4 1.0
6.01
3
5.3 1.5
F
F
27
1
0.14 0.03
F
Cl
4c–4
4c–5
>111
>111
9.2 1.4
>111
3–4
3–5
25 16
72 23
1.7 0.8
F
0.39 0.21
4c–6
>111
90.5 4.7
3–6
150 36
0.72 0.25
a
Data was obtained from in vitro IN assays as described in Ref. 4.

X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2986–2990
2989
Table 3
Table 5
Metal-dependency of integrase inhibitory potencies in vitroa
Antiviral potencies in cells infected with HIV-1 containing wild-type or mutant
integrase enzymesa
No.
Metal cofactor
IC50 (lM)
No.
CC50
N/A
(
l
M)
EC50
(
l
M, WT)
Mutantsb
G140S/Q148H Y143R
30-P
ST
N155H
1
Mg2+
Mn2+
Mg2+
Mn2+
>4.5
>4.5
>111
0.067
0.074
9.1 1.1
1.2 0.3
1
0.004 0.002
61
425ꢁ
2ꢁ
53ꢁ
4ꢁ
35ꢁ
3ꢁ
4b–1
4b–1
291 51
9
28
2
a
Data was obtained as indicated in the Supplementary data.
Fold-loss of potency relative to virus containing wild-type (WT) enzyme.
a
b
Data was obtained from in vitro IN assays using the indicated metal cofactors as
described in the Supplementary data.
(in terms of a fold increase in IC50 value) as Raltegravir to the ef-
fects of mutations at Y143.
To complement the in vitro data, we developed HIV-1 vectors
that replicated the resistant IN mutants G140S/Q148H, Y143R
and N155H. These mutant vectors were challenged with Raltegra-
vir (1) and 4b–1 in cultured cells. One of the design rationales for
introducing a nitrogen into the parent 4,5-dihydroxy-1H-isoin-
dole-1,3(2H)-diones (3) was to remove catechol functionality and
thereby reduce cytotoxicity. As shown in Table 5, the cytotoxicity
Compound 4b–1 is also less susceptible (in terms of the
increase in IC50 value) to the effects of the G140S/Q148H double
mutant. In this case, the new PFV IN structural data does not provide
as clear an answer to the question of why the two compounds dif-
fer in their relative susceptibility to the two mutants. However, the
tricyclic hydroxy-pyrrolopyridine triones (4) showed differential
activity in the presence of Mn2+, which Raltegravir (1) does not.
This suggests the possibility that there are subtle differences in
the way(s) in which the two compounds interact with metals at
the active site. It is possible that the G140S/Q148H double mutant
changes the active site in a way that alters the interactions of Ral-
tegravir with metals, and because 4b–1 interacts differently with
metals, it is less susceptible.
The range of inhibitory potencies shown by our title inhibitors
is less than we expected based on the structures of other highly po-
tent ST inhibitors7 and recent co-crystal data of inhibitors bound to
the homologous PFV integrase.13,14,16,17 In spite of their modest
(low micromolar) potencies, these new compounds, which should
be viewed as a new structural class, are promising. We are partic-
ularly interested in understanding why the new compounds retain
activity against the G140S/Q148H double mutant. If this property
could be incorporated into more potent derivatives, they would
have real potential for the treatment of drug-resistant viruses.
of 4b–1 (CC50 = 291
ported value of the related catechol-containing analogue 3–1
(CC50 = 9.5
M),5 In addition, consistent with the in vitro data ob-
lM) was 30-fold lower than the previously re-
l
tained for the Raltegravir-resistant IN mutants (Table 4), Raltegra-
vir showed a greater than 400-fold loss of antiviral efficacy with
the G140S/Q148H vector as compared to the wild-type IN vector
(Table 5). In contrast to Raltegravir, inhibitor 4b–1 displayed only
a 2-fold loss of potency when challenged with the G140S/Q148H
mutant vector, thereby making it 200-times less sensitive to the ef-
fects of this mutation. Similarly, consistent with the in vitro data in
Table 4, analogue 4b–1 showed a 10-fold lower loss of potency
compared to Raltegravir, with vectors that individually carry the
Y143R (53-fold loss for Raltegravir and 4-fold loss for 4b–1) and
N155H mutations (35-fold loss for Raltegravir and 3-fold loss for
4b–1).
The tricyclic hydroxy-pyrrolopyridine triones (4) combine fea-
tures of bicyclic pyrimidinones (2) with those of our previously re-
ported isoindolediones (3). Introduction of the 2(1H)-pyridone
moiety into the previously 1H-isoindole-1,3(2H)-dione-based ana-
logues significantly increases the requirement for halogen substi-
tuent(s) within the key benzylamide pharmacophore. The
tricyclic hydroxy-pyrrolopyridine trione inhibitors (4) maintain
good selectivity for ST reactions relative to the 30-P reactions and
exhibit reduced cytotoxicity relative to the catechol-containing
compounds (3). In both in vitro and in vivo assays the new
analogue 4b–1 was less sensitive than Raltegravir to resistance
incurred by G140S/Q148H, Y143R and N155H mutations in
integrase. The enhanced activity toward the Y143R mutation rela-
tive to Raltegravir is consistent with recent findings based on co-
crystal structures of the homologous PFV integrase, which show
Acknowledgments
This work was supported in part by the Intramural Research
Program of the NIH, Center for Cancer Research, NCI-Frederick
and the National Cancer Institute, National Institutes of Health
and the Joint Science and Technology Office of the Department of
Defense. The content of this publication does not necessarily reflect
the views or policies of the Department of Health and Human
Services, nor does mention of trade names, commercial products,
or organizations imply endorsement by the U.S. Government.
Supplementary data
that p–p stacking interactions occur between Y212 (corresponding
to Y143 in the HIV-1 IN) and the oxadiazole ring of bound Raltegra-
vir.13,14,16,17 The new compound 4b–1, does not contain equivalent
functionality and 4b–1 would not be expected to be as susceptible
Supplementary data (biological and synthetic experimental
procedures and analytical data for synthetic products) associated
with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2011.03.047.
References and notes
Table 4
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N155H
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