Rationally designed dual inhibitors of HIV reverse transcriptase and integrase

Article abstract of DOI:10.1021/jm070512p

Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)^a1 non-nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA) integrase (IN) inhibitors. Biochemical studies r

Full text of DOI:10.1021/jm070512p

3416
J. Med. Chem. 2007, 50, 3416-3419
(TOA) experiments support an inhibitory profile corroborating
IN activity only.14 3,7-Dihydroxytropolones (2) primarily target
the metal cofactors, and their therapeutic use is limited by poor
selectivity.9 Inhibitory activities against RT and IN were reported
with naphthol-based urea derivatives (3), which were identified
through screening.15,16 The exploration of such multifunctional
ligands has proven valuable for various diseases. However, many
multifunctional scaffolds were first discovered by serendipity
or screening; rational design by combining existing monofunc-
tional scaffolds remains an enormous challenge.17-19
Rationally Designed Dual Inhibitors of HIV
Reverse Transcriptase and Integrase
Zhengqiang Wang, Eric M. Bennett, Daniel J. Wilson,
Christine Salomon, and Robert Vince*
Center for Drug Design, Academic Health Center, UniVersity of
Minnesota, 308 HarVard Street SE, Minneapolis, Minnesota 55455
ReceiVed May 2, 2007
Abstract: Bifunctional inhibitors were designed and synthesized based
on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)a1 non-
nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA)
integrase (IN) inhibitors. Biochemical studies revealed activity against
RT and IN at low nanomolar and low micromolar concentrations,
respectively. Exceptionally low IC50 values from a cell-based assay
were achieved along with remarkably high therapeutic indices. Com-
pound 7 was identified as the best compound of the series (IC50: 24
nM against RT, 4.4 µM against IN, and 10 nM against HIV-1).
Inhibitors of HIV RT and protease (PR) constitute the core
of chemotherapy for AIDS treatment.1 The therapeutic effect
of nucleoside RT inhibitors (NRTIs) is greatly hampered by
their intrinsic toxicity,2,3 whereas the less toxic protease inhibi-
tors (PIs) and non-nucleoside RT inhibitors (NNRTIs) are
severely compromised by the quick emergence of resistant viral
strains.4,5 In general, disease resistant to a single-target therapy
can be mitigated by developing multitarget therapies. In the case
of AIDS, highly active antiretroviral therapy (HAART)6 com-
bines NRTIs with NNRTIs or PIs and successfully suppresses
HIV viral load to an undetectable level, dramatically improving
the life quality of AIDS patients.7 Unfortunately, the efficacy
of this primary treatment for AIDS requires nearly perfect
adherence,8 which is extremely difficult to achieve because of
complicated dosing and intolerable short- and long-term tox-
icities. Suboptimal adherence normally results in viral rebound
and, even worse, multidrug resistance. In this context, we
envision that multitarget therapy using a single drug to inhibit
two viral enzymes could yield lower toxicity, simplified dosing,
and improved patient adherence, thus reducing the likelihood
of drug resistance.
HIV replication involves the synthesis and integration of
proviral DNA into the host genome, a process catalyzed
sequentially by RT and IN. IN is the third virally encoded
enzyme that lacks a mammalian counterpart and represents a
validated target for anti-HIV chemotherapeutics.7-9 Intriguingly,
active sites for RT and IN require one or two Mg2+ ions.9
Furthermore, catalytic cooperation and even physical interaction
between RT and IN are well-documented; certain peptide
fragments from RT inhibit IN activity in vitro.10-13 These
relationships prompted efforts to search for common inhibitors,
mainly through screening. As a result, a few compounds with
activity against both enzymes have been found (Figure 1).
Among these compounds, pyranodipyrimidines (PDP, 1) are
generally mentioned as IN inhibitors because time-of-addition
Figure 1. Structures of reported compounds active against RT and
IN.
Morphy and Rankovic18 reviewed designed multifunctional
ligands and proposed nomenclature based on whether the
scaffolds were combined by a linker (a “conjugate”), directly
coupled with no linker (“fused”), or integrated into a single
scaffold sharing common features (“merged”). However, clas-
sification based on the targeted binding sites is also possible.
For example, the sites may (a) be adjacent pockets of a single
protein,20,21 (b) be located on different proteins but recognize
similar endogenous ligands,22,23 or (c) be located on different
proteins and recognize dissimilar or no endogenous ligands.24-26
We propose the term portmanteau inhibitor27 to define what is
arguably the most challenging design problem under these
classifications: two scaffolds merged into one scaffold, which
binds multiple sites that do not recognize similar endogenous
ligands. The classification based on the types of binding sites
differs from that of Morphy and Rankovic, which is based solely
on the ligand structure. Here, we report a series of these
inhibitors (Figure 2) targeting IN and the non-nucleoside RT
site. The compounds show activity against live virus and have
low cytotoxicity.
Figure 2. Design of portmanteau inhibitors against RT and IN,
combining RT inhibitor 4b with IN inhibitor 5.
a Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired
immunodeficiency syndrome; HEPT, 1-[(2-hydroxyethoxy)methyl]-6-(phe-
nylthio)thymine; RT, reverse transcriptase; IN, integrase; PR, protease;
NNRTIs, non-nucleoside reverse transcriptase inhibitors; NRTIs, nucleoside
reverse transcriptase inhibitors; DKA, diketoacid; FDA, Food and Drug
Administration; TI, therapeutic index.
Our design began with the general knowledge that a DKA
group and an immediately connected aromatic ring are the two
indispensable structural features for the DKA class of IN
inhibitors, as in 5.28,29 A portmanteau inhibitor would require
incorporation of these two features into an RT inhibitor. Crystal
structures of FDA-approved RT inhibitors nevirapine and
* To whom correspondence should be addressed. Phone: 612-624-9911.
Fax: 612-626-6891. E-mail: vince001@umn.edu.
10.1021/jm070512p CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/04/2007

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3417
Scheme 1a
a Reagents and conditions: (a) NaHB(OAc)3, THF, 65 °C, 83%; (b)
(HCHO)n, TMSCl, room temp; (c) CH3C(OTMS)dNTMS (BSA), CH2Cl2,
room temp, then 12, tetrabutylammonium iodide (TBAI), 76%; (d) NaOEt/
EtOH, diethyl oxalate; (e) NaOH (1 N), EtOH/CH2Cl2, room temp, 79%
over two steps.
Figure 3. Docking of 7 (colored by element) in the NNRTI binding
pocket, with a hydrogen bond (yellow) to the Ser105 side chain. This
conformation is 0.3 kcal/mol above the global minimum, which is
shown in Figure S1 of Supporting Information. The X-ray structure of
4b is shown in orange. The protein surface is transparent green except
for the surface of Pro236 (blue) and Trp229 (red). Except for the tail
of the DKA, the inhibitor is behind the protein surface. The surface
excludes Ser105.
Table 1. Anti-RT, Anti-IN, and Antiviral Activities of Inhibitors 6-9
RT IC50 IN IC50 HIV-1 EC50 HIV-1 CC50
inhibitor
(µM)
(µM)
(µM)
(µM)
TI
6
7
8
9
0.23
1.8
4.4
2.4
7.7
0.30
1.1
0.70
>100
0.093
0.052
0.0097
0.033
0.017
8.9
>10
>190
>1000
>310
>600
14
0.024
0.057
0.0092
4.8
1.2
0.39
>10
>10
>10
120
6.0
114
29
efavirenz30 show that these compounds are almost entirely
enclosed by the NNRTI binding pocket, which is largely
hydrophobic and not an appropriate environment for the DKA
group. Other inhibitor families, such as bis(heteroaryl)piperazine
(BHAP)31 and HEPT,32 contain members that extend from the
NNRTI pocket toward solution and thus present a more
attractive site for incorporating a DKA moiety. HEPT com-
pounds are an important class of NNRTIs, even though the best
compound of this family, 6-benzyl-1-(ethoxymethyl)-5-isopro-
pyluracil (emivirine, 4a),32,40 was dropped after a phase III
clinical trial.33 We chose to incorporate a DKA moiety into
6-benzyl-1-(benzyloxymethyl)-5-isopropyluracil (4b),34 a very
potent second-generation HEPT RT inhibitor. Comprehensive
SAR studies on 4b have shown a general intolerance toward
modifications at C2-C6 of the central pyrimidine ring.34,35
X-ray crystallography of RT bound with 4b, however, reveals
that the N-1 substituent’s phenyl group is positioned near the
binding pocket opening controlled by the Pro236 loop, which
adjusts position based on the size of the NNRTI inhibitor
bound.31,34 Because this phenyl group sits at the protein/solvent
interface near a region of the protein known to be flexible, it
might tolerate substitution by a DKA moiety as in 6-9,
satisfying both requirements for the DKA class of IN inhibitors.
Docking of 7 to RT confirmed this design, showing that the
DKA functionality is positioned at the protein/solvent interface
and does not disturb the binding mode of the NNRTI core
structure (Figures 3 and S1). Modeling showed possible
interactions between the DKA group oxygens and the Ser105
side chain or the Val106 backbone nitrogen, but the entire
functional group may also be solvated with no hydrogen bonds
to the protein.
3.0
2.0
339
4b34,40
541
0.016
>100
0.016
0.16
>10
>10
>610
>61
reduction with NaHB(OAc)3. Preparation of the key intermediate
ketone 14 was effected by a regioselective N-1 alkylation via a
2,4-oxo-bis-silylated intermediate.25 A condensation between
ketone 14 and diethyl oxalate provided a diketo ester, which
was then hydrolyzed39 to produce the desired DKA compound
8. Compounds 6, 7 and 9 were prepared similarly.
IC50 values against RT and IN were calculated using dose
response curves and are summarized in Table 1. Significantly,
the separate scaffolds are active against only one target; 4b
showed no activity against IN, while 5 had no activity against
RT. However, all of the portmanteau inhibitors (6-9) show
nanomolar IC50 values against RT, which are similar to the
related RT inhibitor 4b. The retention of high potency confirms
our prediction that the open channel surrounding the N-1 phenyl
would tolerate structural modifications. Conforming to the SAR
of HEPT compounds,38 we observed that the C-5 isopropyl
group leads to better activity than an ethyl substituent. We also
found that the m-dimethyl substitution on the phenyl ring
benefits RT binding, presumably by providing additional
hydrophobic interactions. These additional binding interactions
have proved crucial for improving resistance profiles of HEPT
inhibitors.35 On the other hand, anti-IN assay of our compounds
produced IC50 values in the low micromolar range, with the
most potent about 1 order of magnitude lower than that of the
known IN inhibitor 5. Because only marginal differences in anti-
IN activities were observed, there does not appear to be
significant binding interference between the pyrimidine core and
DKA moieties.
The chemistry involved in this study is represented by the
synthesis of inhibitor 8 outlined in Scheme 1. 6-Benzyl-5-
isopropylpyrimidine 13 was prepared according to known
procedures.36 The alkylating agent, chloromethyl ether 12, was
freshly prepared from benzyl alcohol 11 and paraformaldehyde
suspended in TMSCl.37 It is noteworthy that similar transforma-
tion under the action of dry HCl produced a significant amount
of benzyl chloride byproduct. The benzyl alcohol intermediate
11 was obtained from aldehyde 10 via a chemoselective
A cell-based antiviral assay was performed against HIV-
1NL4-3 in human peripheral blood mononuclear cells. As shown
in Table 1, the portmanteau compounds demonstrate magnificent
anti-HIV activity and low toxicity. As a result, their therapeutic
indices are far superior to those of 1-3. With the exception of
inhibitor 9, all portmanteau inhibitors showed higher (2- to
5-fold) potency against HIV than RT. Although the contribution

3418 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Letters
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Acknowledgment. This research was supported by the
Center for Drug Design at the University of Minnesota. We
thank Christine Dreis for RT assay data and Dr. Roger Ptak at
Southern Research Institute for the cell-based assay. We also
thank Dr. William M. Shannon for advice on the antiviral testing
and interpretation of data, the Minnesota Supercomputing
Institute for computer time, and Dr. Robert Craigie of NIH for
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Supporting Information Available: Synthesis of 6-9, experi-
mental details (1H and 13C NMR, HRMS, HPLC) for intermediates
and final products, assay and molecular modeling methods. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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