Development of a series of 3-hydroxyquinolin-2(1H)-ones as selective inhibitors of HIV-1 reverse transcriptase associated RNase H activity

Article abstract of DOI:10.1016/j.bmcl.2012.04.096

We report herein the synthesis of a series of 3-hydroxyquinolin-2(1H)-one derivatives. Esters and amide groups were introduced at position 4 of the basis scaffold and some modulations of the benzenic moiety were performed. Most compounds presented selecti

Full text of DOI:10.1016/j.bmcl.2012.04.096

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3988–3992
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of a series of 3-hydroxyquinolin-2(1H)-ones as selective
inhibitors of HIV-1 reverse transcriptase associated RNase H activity
Virginie Suchaud a,b, Fabrice Bailly a,b, , Cédric Lion a,b, Enzo Tramontano c, Francesca Esposito c,
⇑
Angela Corona c, Frauke Christ d, Zeger Debyser d, Philippe Cotelle a,b
a Université Lille Nord de France, F-59000 Lille, France
b USTL, EA 4478 Chimie Moléculaire et Formulation, F-59655 Villeneuve d’Ascq, France
c Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato (Cagliari), Italy
d Molecular Medicine, K. U. Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the synthesis of a series of 3-hydroxyquinolin-2(1H)-one derivatives. Esters and amide
Received 2 March 2012
Revised 17 April 2012
Accepted 20 April 2012
Available online 30 April 2012
groups were introduced at position 4 of the basis scaffold and some modulations of the benzenic moiety
were performed. Most compounds presented selective inhibitory properties in the 10–20 lM range
against HIV-1 reverse transcriptase associated ribonuclease H activity, without affecting the integrase
and reverse transcriptase DNA polymerase activities. Unfortunately all tested compounds exhibited high
cellular cytotoxicity in cell culture which limited their applications as antiviral agents.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
3-Hydroxyquinolin-2(1H)-one
Ribonuclease H
Magnesium complexation
Antiretroviral
Since the discovery of the human immunodeficiency virus (HIV)
28 years ago, the progress made toward developing effective anti-
HIV therapies has superseded that of any other antiviral drug dis-
covery initiative. Highly active antiretroviral therapies (HAART)
combining several drugs have shown effectiveness and moved
the prognosis of HIV patients from that of high morbidity and mor-
tality to, for many at least, a chronic, manageable but still complex
disease.1,2 However, this type of treatment has important limita-
tions such as cost, patient’s observance, occurrence of various side
effects due to drug toxicity and, most importantly, loss of activity
due to the development of multidrug and cross resistance.3,4 In or-
der to minimize the appearance of such multiple resistant strains,
novel classes of HIV drugs are therefore needed.
In this regard, there has been considerable interest in the ribo-
nuclease H (RNase H) function associated to the viral coded reverse
transcriptase (RT), as an attractive alternative target that may lead
to the next generation of anti-HIV drug. A few classes of RT RNase
H inhibitors have been identified in the recent years.5,6 Whereas
some may bind allosterically to a different site, these compounds
mainly interact with the magnesium metal cofactors within the
catalytic core of the enzyme. In particular, because of the structural
and functional similarities of the catalytic cores of HIV-1 integrase
(HIV-1 IN) and the RT RNase H function, compounds inhibiting
both activities have already been reported.7
In order to target the catalytic site of the RT RNase H function, we
decided to focus our attention on the 3-hydroxyquinolin-2(1H)-one
scaffold for several reasons. It was indeed shown to complex some
bivalent metals,8 and by introducing a carbonyl function at position
4 this scaffold comprises three oxygens, the topology of which
appears ideal to bind two divalent cations separated by 4–5 Å in
the case of an enzyme–metals–ligand ternary complex. Such a
pharmacophore can be observed in the structure of most recently
discovered RNase H inhibitors. We report herein the preparation
of a series of substituted 3-hydroxyquinolin-2(1H)-ones. The inhib-
itory properties of all synthesized compounds were evaluated
against RT associated RNase H and polymerase functions, together
with integrase. Their physico-chemical properties regarding mag-
nesium chelation were also studied, and antiviral activities were
investigated. Additionally, an in silico molecular docking method
for RT RNase H binding was developed in order to assess the ability
of our molecules to fit in the RNase H active site.
A series of nineteen 3-hydroxy-2-oxoquinoline-4-carboxylic
acids (3a–e), ethyl 3-hydroxy-2-oxoquinoline-4-carboxylates
(2a–f) and 3-hydroxy-2-oxoquinoline-4-carboxamides (4a–g)
mostly substituted at positions 6 and 8 of the quinoline moiety
was elaborated (Table 1). Esters 2a–e were prepared and used as
versatile precursors of the acids, amides and decarboxylated com-
pounds. Commercial substituted isatins were thus reacted with
⇑
Corresponding author. Tel.: +33 320 33 72 31; fax: +33 320 33 63 09.
E-mail address: fabrice.bailly@univ-lille1.fr (F. Bailly).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.096

V. Suchaud et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3988–3992
3989
Table 1
Biological activities of the 3-hydroxyquinolin-2(1H)-one derivatives
R4
IC50 (lM)
HIV-1 RT polymerasee
HIV-1 INf
R6
OH
O
c
d
R4
H
R6
R8
IC50
(
l
M) RT RNase Ha
EC50
(l
M)
CC50 (lM)
N
H
R8
5a
3a
H
H
H
H
>100 (97%)b
59
>115
>250
115
—
—
—
—
CO2H
CO2H
CO2H
CO2H
CO2H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
>250
3b
3c
3d
3e
2a
2b
2c
2d
2e
2f
NO2
Cl
H
H
H
F
97
>250
>250
>250
>250
>210
>118
>117
>134
>238
>250
>250
>250
250
>250
210
118
117
134
238
250
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
>100 (100%)
>100 (100%)
>100 (88%)
16
F
H
H
H
H
H
H
F
NO2
Cl
64
>100 (100%)
>100 (100%)
>100 (100%)
>100 (100%)
F
H
NH2
H
O
N
H
4a
4b
4c
4d
4e
H
Cl
F
H
H
H
F
19
18
22
75
19
74
>29
>28
>24
29
28
24
8
>250
>250
>250
—
>250
>250
>250
—
F
O
O
O
O
O
O
N
H
F
N
H
F
N
H
H
F
>6.8
F
N
H
H
>29
29
>250
>250
OMe
OMe
N
H
4f
H
H
F
F
>8
8
—
—
—
—
4g
49
13
>22
22
N
H
RDS 1643
a
b
c
Concentration required to inhibit by 50% the in vitro RT associated RNase H activity.
Percentage of enzyme activity measured at 100 M compound concentration.
Effective concentration required to reduce HIV-1-induced cytopathic effect by 50% in MT-4 cells.
l
d
Cytotoxic concentration required to reduce MT-4 cell viability by 50%.
e,f
Concentration required to inhibit by 50% the in vitro RT associated RNA dependent polymerase and integrase activities, respectively.
ethyl diazoacetate in the presence of diethylamine, and the 3-
hydroxyquinolin-2-(1H)-one scaffold was obtained via subsequent
Eistert ring expansion of the crude adducts after dilute aqueous
acidic treatment, as depicted in Scheme 1.9,10 Reduction of 2b by
catalytic hydrogenation yielded amine 2f. Saponification of esters
2a–e led to the corresponding carboxylic acid series 3a–e, and
the decarboxylated counterpart 5a was obtained after prolonged
heating of 3a in basic conditions. The carboxylic acids were then
converted into intermediate acid chlorides and submitted to
addition-elimination with the adequate primary amines to afford
amides 4a–g.
Firstly, we investigated the magnesium chelating properties of
these compounds. A detailed study using UV spectrophotometry,
1H NMR and 13C NMR spectrometries was carried out on amide
4a. Its incubation with magnesium acetate provoked large
hyperchromic effects in the 240–250 nm and 310–340 nm regions
of its UV spectrum. It was very slightly modified in presence of
sodium acetate whereas it kept unchanged in presence of

3990
V. Suchaud et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3988–3992
N2
COOEt
OH
O
HO
R6
R6
R6
COOEt
a
b
O
O
N
H
N
H
N
H
O
R8
1a-f
R8
R8
c
2a-f
COOH
R6
OH
N
H
O
R8
R6 = H, NO2, NH2, Br, Cl, F; R8 = H, F
3a-e
e
d
'
R4 HN
O
R6
OH
O
R6
OH
N
H
N
H
O
R8
R8
4a-g
5a
Scheme 1. Reagents and conditions: (a) N2CHCO2Et, Et2NH, EtOH, rt, 72 h; (b) aq. 6 M HCl, rt, 2 h; (c) NaOH, EtOH, reflux, 2 h; (d) aq. 2 M NaOH, EtOH, reflux, 12 h; (e) (i)
SOCl2, AcOEt reflux, 30 min; (ii) R40NH2, iPr2EtN, rt, 12 h.
magnesium chloride. The Job method of continuous variation was
applied in order to determine the stoichiometry of the detected
magnesium complexes, and maximum effects were obtained at
330 or 340 nm for ligand volumic fractions of 0.5 and 0.67, evi-
dencing two metal/ligand stoichiometries in solution (1:2 and
1:1). 1H and 13C NMR experiments gave further insight into the
molecular complexation process. Upon addition of magnesium
acetate, lowfield shifts variations of 0.20, 1.36 and 0.32 ppm were
measured for the cyclic amide proton, the enolic proton and the
exocyclic amide proton, respectively. It is noteworthy that magne-
sium acetate did not induce the deprotonation of the enolic func-
tion. The signals for carbons C2 and C3 were also largely shifted
with deshieldings of 9.7 and 16.4 ppm, respectively. Nearby car-
bons C4 (ꢀ12.9 ppm), C4a (+4.6 ppm) and C8a (ꢀ3.9 ppm) were also
significantly affected. According to the formerly determined stoi-
chiometries, we also synthesized two magnesium complexes 4a0
and 4a00 by incubating the amide 4a with 0.5 and 1.0 equiv of mag-
nesium hydroxide, respectively. The 1H and 13C NMR spectra of
these two isolated solids were strictly identical to those reported
above for the complexes formed in situ. The proposed structures
according to the elemental analyses data are represented in Figure
1. Unfortunately, the association constants of the magnesium com-
plexes could not be determined in vitro due to irreproducible
values.
unsubstituted ester 2a (IC50 = 16
the acid series by comparing the properties of 3a (IC50 = 59
to those of 3b (IC50 = 97 M) and 3c–e (IC50 > 100 M). Decarbox-
l
M). This was also the case in
lM)
l
l
ylated compound 5a was devoid of any inhibitory property, indi-
cating that our molecules might indeed bind to the active site via
chelation of the two magnesium cofactors by the three-oxygen
pharmacophore. The introduction of an amide function at position
4 proved to be advantageous since it led to a reproducible activity
of almost the entire series of amides 4a–g. Among these com-
pounds, the para-fluorophenylacetamido (4a–c) and para-meth-
oxyphenylacetamido (4e) groups were particularly favorable for
the HIV-1 RNase H inhibition. For these amide derivatives, the
measured inhibitory properties proved to be lower for compounds
substituted at position 8 by a fluorine atom, which may be due to
its electronic effect on the heterocyclic moiety. For instance, there
was a fourfold increase of the IC50 value upon substitution of com-
pound 4a (IC50 = 19 lM) by a fluorine atom (4d, IC50 = 75 lM). Fi-
nally the antiviral activities of all the compounds in MT-4 cells
were evaluated, but this study was unfortunately impaired by
the relatively high cytotoxicities.
In order to evaluate the selectivity of this scaffold, the most
active compounds 4a–c and 4e were also tested against two mag-
nesium-dependent viral enzymes, HIV-1 RT associated RNA
dependent DNA polymerase and HIV-1 integrase (Table 1). Inter-
estingly, none of the newly synthesized compounds were able to
inhibit the HIV-1 IN activities and RT polymerase at concentra-
Table 1 reports the biological data for this series of 3-hydroxy-
quinolin-2(1H)-ones. Encouraging inhibitory properties were de-
tected on the RT associated RNase H function. The most active
compounds were ester 2a and amides 4a–4c, and 4e with IC50 val-
tions up to 250
lM (IC50 > 250
lM), indicating a selective prefer-
ence for the RNase
H
domain. In addition, the ability of
ues between 16 and 22
ence compound RDS1643 (IC50 = 13
benzenic ring by nitro (IC50 = 64 M), halogeno and amino func-
M) sharply decreased the inhibitory potency of
l
M, close to that of the diketoacid refer-
compound 4a to bind to the isolated RNase H domain (p15)
was measured to confirm the hypothesis that the 3-hydroxyquin-
olin-2(1H)-ones might bind to the RNase H active site. In fact,
since the RNase H domain contains one tryptophan and six tyro-
sine residues as intrinsic fluorophores, it has been reported that
when the p15 domain is excitated at a wavelength of 290 nm
the contribution of tryptophan to the fluorescence signal is
maximized, whereas the fluorescence energy transfer from the
tyrosine residues to the tryptophan residue is minimized. Upon
binding of a ligand within its active site, the intrinsic fluorescence
l
M).7 The substitution of the
l
tions (IC50 > 100
l
F
F
F
HN
HO
O
O
NH
OH
NH
OH
O
H2O
H
H
-
O
2+
H
H
O
of the HIV-1 RT-associated RNase
H domain is therefore
2+
Mg
Mg
quenched.11 Importantly, compound 4a was thus shown to bind
into the RNase H catalytic site as it completely quenches the
p15 isolated domain intrinsic fluorescence (Fig. 2). As previously
described,12 2-hydroxy-1,2,3,4-tetrahydroisoquinoline-1,3-dione
(HTHI) was used as a positive control.
O
N
H
N
H
O
-
O
N
H
O
O
4a'
4a"
Figure 1. Proposed structures for the isolated complexes 4a0and 4a00.

V. Suchaud et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3988–3992
3991
Given the ability of the 4-amido series to inhibit the RT RNase H
associated activity by interacting with the RNase H active site, we
decided to perform in silico docking studies in order to determine a
possible binding mode with the target and to propose some phar-
macomodulated structures for ligand/protein interactions
improvement. To our knowledge, there is only one report of molec-
ular docking on specific RT RNase H inhibition in the literature.13
However, this work was carried out on the basis of the crystallo-
graphic structure PDB:1RTD,14 which does not contain an intact
and active RNase H domain, and we believe those docking results
to be seriously flawed. In this RT complex, Glu478 was indeed mu-
tated into Gln478, precisely to inhibit RNase H activity, while the
ligand is bound to the polymerase site. Consequently, the RNase
H catalytic site of this crystal structure is not operational: the puta-
tive positions of the metal cations greatly differ from that in the ac-
tive protein and the physico-chemical properties of the cavity are
profoundly changed (see Supplementary data, Fig. 1). After a
screening of all available crystal structures, we eventually selected
structure PDB:3K2P of the dimerized HIV-1 RT RNase H domain
co-crystallized with b-thujaplicinol and two manganese cofactors
as the most relevant option for molecular docking. Taking into
account the NMR data obtained for the synthesized magnesium
complexes of our molecules, we used the enol form for the 4-amido
substituted series and the enolate form for the ester series. The
docking method was developed using b-thujaplicinol as a template
and CHEMPLP was eventually chosen among the various fitness
functions available in the CCDC Gold Suite.15 After validation of
the procedure, the statistically relevant highest ranked clusters
were examined for amides 4a–g and ternary complexes were
minimized.
As expected, the results confirm the ability of this three oxygen
pharmacophore to chelate both metal cofactors within the active
site and the putative binding mode is consistent throughout the
whole series (Fig. 3A). In addition to the complexation with both
cations, the quinoline scaffold is placed in such a way that the oxy-
gen of the carbonyl at position 2 may also interact with Arg557
through hydrogen bonding, while the lipophilic side chain at posi-
tion 4 is able to occupy the small hydrophobic pocket created by
residues Gln475, Gln500, Tyr501 and Trp535 (Fig. 3B). In the case
of active amides 4a–g the occupancy of this cavity by the substitu-
ent seems to be much better optimized than it is for esters 2a–f
(see Supplementary data), which may be due to the greater
propensity of the aromatic ring to bury itself because of its high
lipophilicity. This factor, together with the difference of ligand
ionic state observed experimentally in the synthesized complexes,
may explain the difference of activity between the amide and ester
series. It is unclear, however, as to why ester 2a inhibits RNase H
activity while the other esters are found to be inactive.
The recent discovery of more potent RT RNase H inhibitors such
as pyrimidinol carboxylic acids, N-hydroxyquinazolinediones or N-
hydroxynaphthyridinones17–19 indicate that lipophilic aromatic
side chains may be able to interact favorably either with His539
via -stacking or occupy a closeby hydrophobic pocket created by
residues Asn447, Arg448, Glu449, Ile556 and Arg557. The former
interactions are suggested by the crystallographic data and the lat-
ter ones by the predicted binding of the most active naphthyridi-
none18 according to our docking method (see Supplementary
data). In order to propose improved structures, we decided to
investigate possible substituted analogues of 4a with our docking
protocol. Although simultaneous interactions with His539 and
both metallic cofactors do not appear to be possible with our phar-
macophore, the introduction of an aromatic side chain at position 8
of our scaffold might thus lead to more potent inhibitors. For in-
stance, a 8-phenethyl, a 8-benzenesulfonamide or a 8-benzamide
substituent would be able to occupy the second hydrophobic pock-
et and greatly improve hydrophobic interactions while maintain-
ing strong metal chelation (see supporting information). Whereas
substitutions at position 1 of the heterocyclic scaffold did not yield
any promising consistent mode of binding according to our model,
an aromatic side chain in position 7 might also be able to fit in this
cavity, although it would require more internal ligand strain.
In summary, this novel series of 3-hydroxyquinolin-2(1H)-ones
was designed to target the magnesium cations within the catalytic
core of RT RNase H function. The complexation processes charac-
terized in solution involve the two oxygen atoms of the carbonyl
and enolic functions in positions 2 and 3 and docking calculations
yielded poses with a consensual binding mode in the RNase H cat-
alytic core. Reproducible inhibitory activities of RT RNase H func-
tion with IC50 values around 20 lM were obtained for a panel of
molecules, which mostly includes compounds substituted at posi-
tion 4 by an amide function. These RNase H inhibitory activities are
encouraging since they are close to that of the reference diketoacid,
RDS1643. However, they are moderate when compared to other re-
cently reported RNase H inhibitors.16–18 Although we clearly dem-
onstrated that 3-hydroxyquinolin-2(1H)-ones bind to the RNase H
active site, a weak association constant of the magnesium com-
plexes combined with insufficient secondary interactions with pro-
teic residues may provide an explanation for the moderate
enzymatic inhibitory properties. The kinetics of the complexation
process could have an unfavorable effect as well. By comparing
the structures of known potent inhibitors, Kirschberg et al. pro-
posed several structural features for the pharmacophore of RNase
H inhibitors.19 According to them, it must present at least two alco-
holic (or phenolic) functions and aromatic electronic forms. Herein
our basic scaffold presents two carbonyl and only one alcoholic
(enolic) functions. In course of the physicochemical studies, the
NMR data of the different ligands alone or complexed with magne-
sium cations never evidenced any enolization of the cyclic carbonyl
function at position 2 of the heterocycle.
p15 alone
70
p15 + HTHI 100µM
60
p15 + 4a 100µM
50
We clearly evidenced at least a 12-fold selectivity of these com-
pounds for the RNase H function versus RT polymerase and integr-
ase. This selectivity may be higher since enzymatic assays were
40
30
20
10
only performed at concentrations up to 250 lM and matches the
initial selection criteria of some recently reported thiocarbamates
and triazoles.20 Although none of the tested compounds displayed
activity in the MT-4 HIV infectivity assay due to limiting cytotox-
icity, this should not represent an insurmountable challenge. The
CC50 values of our compounds (around 30
to those of antiviral RNase H inhibitors like naphthyridinones18
(CC50 = 2-10
M) or comparable to those of hydroxytropolones.21
lM) are indeed superior
0
300 310 320 330 340 350 360 370 380 390 400 410 420
l
wavelength (nm)
One or more reasons which might account for this lack of antiviral
Figure 2. p15 Intrinsic fluorescence quenching assay.
activity may be insufficient intrinsic potency, low cell permeability

3992
V. Suchaud et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3988–3992
Figure 3. (A): Superimposition of the minimized highest ranked docking solutions of amides 4a (pink),4b (green), 4c (blue), 4d (red), 4e (violet), 4f (yellow) and 4g (orange)
in the HIV-1 RT RNase H catalytic site. The Connolly isosurface is depicted in blue for the most hydrophilic residues to orange for the most hydrophobic residues. The
manganese cofactors are depicted in orange. (B): Putative mode of binding of amide 4a in the RT RNase H catalytic site.
or high protein binding, and the modest inhibitions of the RNase H
function, albeit not solely responsible, indeed represent an impor-
tant limiting factor. Nevertheless, the encouraging hits of RT RNase
H activity on this series of compounds, as well as their selectivity
for the HIV-1 RT RNase H site versus the HIV-1 IN and RT polymer-
ase sites, lay the ground for further improvements, and according
to our docking studies appropriate substitution of the scaffold by
an extended aromatic lipophilic chain might lead to improved
activity. Correlating with our molecular docking output, it can be
noted that the most potent RNase H inhibitors acting in the submi-
cromolar range all bear bi- or tricyclic (possibly condensed) moie-
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´
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Acknowledgments
This work was financially supported by le Ministère de l’Ens-
eignement Supérieur et de la Recherche Française and by Fondaz-
ione Banco di Sardegna. Francesca Esposito was supported by RAS
fellowships, co-financed with funds of PO Sardinia FSE 2007–2013
and of LR 7/2007, projects CRP2_683. Angela Corona was supported
by MIUR fellowship DM 198/2003. The Mass Spectrometry facility
used in this study was funded by the European Community (FED-
ER), the Région Nord-Pas de Calais (France), the CNRS, and the Uni-
versité des Sciences et Technologies de Lille. We are grateful to
Martine Michiels, Nam JooVanderveken, Barbara Van Remoortel
and Catherine Meliet for excellent technical assistance.
21. Chung, S.; Himmel, D. M.; Jiang, J. K.; Wojtak, K.; Bauman, J. D.; Rausch, J. W.;
Wilson, J. A.; Beutler, J. A.; Thomas, C. J.; Arnold, E.; Le Grice, S. J. Med. Chem.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.
096.