3-Iodo-4-phenoxypyridinones (IOPY's), a new family of highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

Article abstract of DOI:10.1016/j.bmcl.2003.09.045

Building upon the potent anti-HIV-1 activities observed for the 3-dimethylamino-4-benzylpyridinone 2, and the corresponding 4-aryloxypyridinone analogue 3, a concise and efficient route to the 3-iodo-4-aryloxypyridinones 14a-c (IOPY's) was developed. This

Full text of DOI:10.1016/j.bmcl.2003.09.045

Bioorganic & Medicinal Chemistry Letters 13 (2003) 4309–4312
3-Iodo-4-phenoxypyridinones (IOPY’s), a New Family of Highly
Potent Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase
Abdellah Benjahad,a,* Jerome Guillemont,b Koen Andries,c Chi Hung Nguyena,* and
David S. Griersona
aUMR 176 CNRS-Institut Curie, Laboratoire de Pharmacochimie, Section de Recherche, Batiment 110, Centre Universitaire,
91405 Orsay, France
bJohnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry Department,
Campus de Maigremont BP315, Val de reuil, France
cJohnson & Johnson Pharmaceutical Research and Development, Virology Drug Discovery,
Tumhoutseweg 30 B-2340 Beerse, Belgium
Received 25 July 2003; revised 22 September 2003; accepted 23 September 2003
Abstract—Building upon the potent anti-HIV-1 activities observed for the 3-dimethylamino-4-benzylpyridinone 2, and the corre-
sponding 4-aryloxypyridinone analogue 3, a concise and efficient route to the 3-iodo-4-aryloxypyridinones 14a–c (IOPY’s) was
developed. This involved reaction of the 4-hydroxy substituted pyridinone 10 with the requisite dichloroiodobenzene reagent 11.
IOPY compound 14c is active at IC50=1–45 nM against wild type HIV-1 and a panel of six major simple/double HIV mutant
strains.
# 2003 Elsevier Ltd. All rights reserved.
The introduction of highly active antiretroviral therapy
(HAART) involving the use of drug combinations to
treat AIDS has had a dramatic impact on the morbidity
and mortality of individuals infected by the human
immunodeficiency virus (HIV).1,2 However, in spite of
this success there are continuing problems of toxicity
and drug resistance, including the emergence of multi-
drug-resistant strains of HIV-1.3,4 It is thus important
to continually develop more potent and less aggressive
drugs for the treatment of HIV. In this context, non-
nucleoside reverse-transcriptase inhibitors (NNRTIs)
are finding increasing use in multi-drug regimens.5 At
present, only three molecules of this family, nevirapine
(Viramune), delavirdine (Rescriptor) and efavirenz (Sus-
tiva), are approved for the treatment of HIV infected
patients.6
this series has led to the identification of the 3-dimethyl-
amino-4-benzylpyridinone 2 as a promising lead com-
pound.8 As part of an extensive optimisation
programme on this new family of HIV-1 RT inhibitors,
A contribution from our laboratories to this effort was
the discovery that 3-amino-4-arylthiopyridinones7 of
general structure 1 (Fig. 1) are potent inhibitors of wild
type HIV-1 reverse transcriptase. Preliminary SAR on
*Corresponding author. Tel.: +33-1-6986-7115; fax: +33-1-6907-
5381; e-mail: abdellah.benjahad@curie.u-psud.fr
Figure 1.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.09.045

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A. Benjahad et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4309–4312
we wanted to evaluate the potential of compound 3, the
corresponding aryloxypyridinone analogue of 2. In a
further, and larger context, our objective was to develop
a synthetic route which would give easy and rapid
access to a wide range of aryloxypyridinone analogues
which are modified at the C-3 position. The develop-
ment of such an approach based upon the reaction of 4-
hydroxy-2-pyridinones with hypervalent iodine reagents
leading to a highly potent lead compound 14c in the
aryloxypyridinone series is the subject of the present
communication.
Thus, as a general approach for subsequent analogue
synthesis this route did not appear sufficiently attractive
for our needs. For this reason, our attention was focused
to a report by Kappe and El-Mariah concerning the
reaction of 4-hydroxyquinolin-2-ones with (dichloro-
iodo)benzene.10 In this transformation both an aryloxy
and an iodo substituent are introduced adjacent to each
other on the pyridinone nucleus in essentially a single
operation. Applying this methodology (Scheme 2), it
was found that the reaction of 4-hydroxypyridinone 10
with the (dichloroiodo)arenes 11a–c, prepared by reac-
tion of iodobenzene, 3-methyliodobenzene or 3,5-dime-
thyliodobenzene with chlorine gas, gave direct access to
the 3-iodo-4-phenoxy substituted pyridinones 14a–c in
excellent yields. The first step in this process involves
formation of the aryliodonium ylides 12a–c, which on
heating rearranges via the spiro-Meisenheimer11 inter-
mediates 13a–c, to the observed product. This result was
highly promising, as the presence of the iodo substituent
at C-3 in compounds 14 opens up a broad range of
opportunities to introduce diverse substituents at C-3
[particularly by halogen–metal exchange, Pd(0) and
Cu+ based coupling techniques]. Pertinent to the pre-
sent report, the formation of compounds 14 provided
the opportunity to evaluate the influence of the iodine at
the C-3 position on anti-HIV activity in the pyridinone
series.
Chemistry
4-Thioarylpyridinones 1 are prepared by condensation
of a requisite 4-chloropyridinone with a thiophenol
derivative in a Michael addition/retro-Michael process.7
This transformation is dependent upon the presence of
an electron withdrawing (ester or nitro) substituent at
the C-3 position of the pyridinone ring. Following this
strategy, the 4-chloro-3-carbethoxy-2-pyridinone 5 was
reacted with the potassium anion of 3,5-dimethylphenol
in refluxing DMF9 (Scheme 1). The derived condensa-
tion product 6 (94%) was then heated in aqueous HCl
to effect hydrolyse–decarboxylation to giving the inter-
mediate 7 (86%). Treatment of 7 with fuming nitric acid
in acetic acid afforded the 3-nitropyridone 8 (55%).
Reduction of the nitro group using tin(II) chloride
dihydrate in ethyl acetate provided amine 9 (70%),
which was subsequently converted to the target N,N-
dimethyl substituted benzyloxypyridinone
3 under
reductive alkylation conditions [HCHO (37 wt. % in
water), NaBH3CN, MeCN; 85%]. Overall, eight steps
were required to obtain 3, and although the yield of
certain operations were high the conversion of 4 to 5 on
reaction with POCl3 (average yield 40%) has proven
difficult to optimise.7
Scheme 2. (a) 2 N HCl, reflux; (b) Na2CO3, H2O, rt; (c) DMF, reflux.
Table 1. Activity (IC50, mM) versus HIV-112
Compd
LAI
SIb
K103N
Y181C
3
7
8
14a
14b
14c
0.004
0.500
0.004
0.0016
0.0016
0.0013
0.008
0.008
0.001
25,000
200
2500
63,000
19,900
9000
12,500
1260
52,000
0.050
nd
0.158
nd
0.100
0.040
0.032
0.003
0.032
0.8
0.158
0.316
0.051
0.020
0.100
2
2
Scheme 1. (a) POCl3, BnEt3NCl, MeCN, reflux (30–60%); (b) potas-
sium phenolate (1 equiv), DMF, reflux (ꢀ94%); (c) 2N HCl, reflux
MKC442
GCA-186a
0.04
0.18
.
(86%); (d) HNO3 (3 equiv), AcOH, 5–90 C (55%); (e) SnCl2 2H2O
aLiterature values.14
bSI is the ratio of 50% cytotoxic concentration to IC50
(5 equiv), EtOAc, reflux (70%); (f) HCHO (10 equiv), NaBH3CN
(3 equiv), CH3CN, reflux (85%).
.

A. Benjahad et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4309–4312
Table 2. Activity (IC50, mM) versus HIV-112
4311
Compd
LAI
K103N
K100I
Y181C
Y188L
K103N+K100I
K103N+Y181C
14c
2
Nevirapine
Delavirdine
Efavirenz
0.0013
0.008
0.032
0.063
0.001
0.003
0.032
6.3
2.5
0.040
0.006
0.05
>10
0.020
0.1
10
1.9
0.002
0.045
0.3
>10
1.3
0.2
0.020
nd
>10
>10
0.040
0.8
>10
>10
2.5
0.040
>10
0.040
Anti-HIV-1 Test Results and Discussion
all the mutant strains, and in particular a 20-fold
improvement in activity against the K103N+Y181C
double mutant. In addition, with the exception of the
values found for the Y181C mutant, this molecule has a
much better profile in vitro than efavirenz, the current
NNRTI standard in combination therapy. Note in par-
ticular that efavirenz is inactive against K103N+K100I,
and that both efavirenz and 14c remain equipotent
against the K103N+Y181C double mutant.
Compounds 3 and 14a–c were evaluated for their anti-
HIV activity,12 and the results were compared to those
for lead compound 2 (Table 1). To obtain a clear indi-
cation of the potential worth of the aryloxypyridinones,
and in particular the 3-iodo substituted compounds
14a–c, a comparison was also made to the related
HEPT analogues MKC-44213 and GCA-186,14 and to
the three currently used NNRTI type drugs, nevirapine,
delavirdine and efavirenz (Table 2).
Compound 14c thus represents an interesting new lead
molecule for the development of pyridinone based anti-
HIV agents. This avenue of research is actively being
persuaded, as is the original objective of using the iodo
substituent in these pyridinones as a ‘handle’ to intro-
duce varied and diverse functionality at C-3 of the
pyridinone ring.
In an initial screen against wild-type HIV-1 and the two
major mutant strains Y181C and K103N,15 it was found
that replacement of the bridging CH2 group in 2 by an
oxygen atom does not result in either a net gain or loss
in activity. Both pyridinones 2 and 3 were found to be
10 times more active than MKC-442, but in the more
direct comparison with GCA-186 (literature values),14
which also possesses the 3,5-dimethyl substitution in the
phenyl ring, one sees that all three compounds are
comparable in activity. Thus, the CH2 for O exchange is
acceptable, indicating that we can incorporate this
modification in further analogue studies. Looking next
at the three iodo substituted pyridinone analogues 14a–
c. Nanomolar range activities were again observed for
these molecules against the LAI strain. This result con-
trasts sharply with the only marginal activity reported
for the corresponding iodo-HEPT compound 15
(IC50=3.6 mM).16 Noteworthy was the observation that
introduction of the methyl groups on the phenyl ring in
compounds 14 resulted in a considerable improvement
in the activities against the two mutant strains, and in
particular K103N (14c; IC50=0.003 mM). Indeed 14c is
10 times more active against this major mutant than
either compound 2 or GCA-186. A further 5–10 times
improvement in activity was also observed against the
Y181C mutant.
Acknowledgements
Financial support from ‘Ensemble contre le SIDA—
Sidaction’ for the acquisition of a NMR spectrometer is
gratefully acknowledged.
References and Notes
1. Gallant, J. E. J. Clin. Virol. 2002, 25, 317.
2. Rossum, A.; Fraaij, P.; De Groot, R. Lancet Infect. Dis.
2002, 2, 93.
3. Carr, A.; Cooper, D. A. Lancet 2000, 356, 1423.
4. Iversen, A. K.; Shafer, R. W.; Wehrly, K.; Winters, M. A.;
Chesebro, B.; Merigan, T. C.; Mullins, J. I. J. Virol. 1996, 70,
1086.
5. (a) Carr, A.; Samaras, K.; Thorisdottir, A.; Kaufmann,
G. R.; Ghisholm, D. J.; Cooper, D. A. Lancet 1999, 353, 2093.
(b) Jain, R. G.; Furfine, E. S.; Pednrault, L.; White, A. J.;
Lenhard, J. M. Antiviral Res. 2001, 51, 151.
6. (a) Mao, C.; Sudbeck, E. A.; Venkatachalam, T. K.;
Uckun, F. M. Biochem. Pharmacol. 2000, 60, 1251. (b) De
Clercq, E. Biochim. Biophys. Acta 2002, 1587, 258.
7. Dolle, V.; Fan, E.; Nguyen, C. H.; Aubertin, A.-M.; Kirn,
A.; Andreola, M. L.; Jamieson, G.; Tarrago-Litvak, L.;
Bisagni, E. J. Med. Chem. 1995, 38, 4679.
The presence of the iodine atom in the aryloxpyr-
idinones 14a–c thus has a positive impact on activity
(contrary to earlier indications).16 The exact nature of
the contribution of the iodine atom to the binding of
these NNRTI type molecules in RT is not understood at
present, but the hydrophobic properties of this sub-
stituent, its polarisability and/or its effective volume are
three factors which may favour binding, and thus dis-
tinguish compounds 14 from the corresponding com-
pound 7 (IC50=0.50 mM) in which this group is absent.
8. Dolle, V.; Nguyen, C. H.; Legraverend, M.; Aubertin, A.-
M.; Kirn, A.; Andreola, M. L.; Ventura, M.; Tarrago-Litvak,
L.; Bisagni, E. J. Med. Chem. 2000, 43, 3949.
9. Bishop, R. R.; Clavell, E. A. S.; Chapman, N. B. J. Chem.
Soc. 1952, 437.
In light of the interesting activities found for 14c, it was
tested against a larger panel of HIV-1 mutant strains
(Table 2). It is immediately seen that, relative to lead
molecule 2, there is a significant gain in activity against
10. El-Mariah, F. A.; Kappe, T. Croatica Chem. Acta 1986,
59, 171.
11. Kokil, P. B.; Nair, P. M. Tetrahedron Lett. 1977, 28, 4113.
12. (a) All compounds were tested for potency (IC50, mM) to

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A. Benjahad et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4309–4312
achieve 50% protection of MT-4 cells from HIV-1 cytopathi-
city as determined by the MTT method (Pauwels, R.; Balzar-
ini, J.; Baba, M.; Snoek, R.; Schols, D.; Herdewijn, P.;
Desmyter, J.; De Clercq, E. J. Virol. Methods 1988, 20, 309).
Unless noted otherwise, the LAI strain of HIV-1 was the
infecting virus. Other infecting mutant (in the reverse tran-
scriptase) strains of virus are characterised in the tables by the
mutated amino acid position and the one letter codes. For
instance, 181C refers to replacement of tyrosine at position
181 with cysteine. All determinations are average values for
three or more tests. (b) nd, not determined.
Inouye, N.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq,
E.; Miyasaka, T. J. Med. Chem. 1995, 38, 2860.
14. Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato,
M.; Stuart, D. I.; Stammers, D. K. J. Med. Chem. 1999, 42,
4500.
15. Hsiou, Y.; Ding, J.; Das, K.; Clark, A. D., Jr.; Boyer,
P. L.; Lewi, P.; Janssen, P. A. J.; Kleim, J.-P.; Rosner, M.;
Hughes, S. H.; Arnold, E. J. Mol. Biol. 2001, 309, 437.
16. Tanaka, H.; Baba, M.; Hayakawa, H.; Sakamaki, T.;
Miyasaka, T.; Ubasawa, M.; Takashima, H.; Sekiya, K.;
Nitta, I.; Inouye, N.; Shigeta, S.; Walker, R. T.; Balzarini, J.;
De Clercq, E. J. Med. Chem. 1991, 34, 349.
13. Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.;