New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1021/jm300477h

New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.

Full text of DOI:10.1021/jm300477h

Brief Article
pubs.acs.org/jmc
New Nitrogen Containing Substituents at the Indole-2-carboxamide
Yield High Potent and Broad Spectrum Indolylarylsulfone HIV-1
Non-Nucleoside Reverse Transcriptase Inhibitors
Giuseppe La Regina,† Antonio Coluccia,† Andrea Brancale,‡ Francesco Piscitelli,† Valeria Famiglini,†
Sandro Cosconati,∥ Giovanni Maga,# Alberta Samuele,# Emmanuel Gonzalez,¥ Bonaventura Clotet,¥
¥
§
,†
̂
Dominique Schols, Jose A. Este, Ettore Novellino, and Romano Silvestri*
́
́
†Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita
Piazzale Aldo Moro 5, I-00185 Roma, Italy
‡Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, U.K., Istituto di Chimica
̀
di Roma,
Biomolecolare, CNR, Piazzale Aldo Moro 5, I-00185 Roma, Italy
#Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy
¥IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, 08916 Badalona, Spain
̂
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
§Dipartimento di Chimica Farmaceutica e Tossicologica, Universita
Napoli, Italy
̀
di Napoli Federico II, Via Domenico Montesano 49, I-80131,
∥Dipartimento di Scienze Ambientali, Seconda Universita
̀
di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
S
* Supporting Information
ABSTRACT: New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide
inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective
against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98
HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1
clades A in PBMC.
The activity against mutant HIV-1 strains of indolylarylsulfone
(IAS) NNRTIs was significantly improved by introduction of
two methyl groups at positions 3′ and 5′ of the 3-phenylsulfonyl
moiety (1, 2).6 Coupling of the indole-2-carboxamide function-
ality with amino acid units (e.g., 3) resulted in potent IAS
derivatives.7 Similarly, a hydroxyethyl moiety at the indole-2-
carboxamide led to highly potent IAS derivatives.8 The addition
of a third heterocyclic nucleus to the parent compound resulted
in NNRTIs with broad spectrum of activity against the mutant
HIV-1 strains (e.g., DATAs, BIRL 355BS).9 Recently, we found
that IAS derivatives bearing a cyclic moiety at the 2-carboxamide
nitrogen linked through a short spacer group (e.g., 4−6) were
endowed with potent antiretroviral activity.10 Here, wehaveexpanded
the SAR studies by the introduction of a pyridinyl or 4-cyanophenyl
moiety at the 2-carboxamide nitrogen through a methylene/ethylene
bridge. The new IAS derivatives 7−17 showed potent HIV-1
inhibitory activity in the low nanomolar range (Chart 1) (Table 1).
INTRODUCTION
■
Acquired immune deficiency syndrome (AIDS) pandemic and
AIDS-related diseases remain among the leading causes of death
worldwide. At the end of 2010, an estimated 34 million people
were living with HIV globally, including 3.4 million children less
than 15 years, and there were 2.7 million new HIV infections.1
Combination therapies based on three (recommended) or more
different antiretroviral drugs designated as highly active antire-
troviral therapy (HAART) slow down the viral reproduction with
marked reduction of plasma viremia below the detection level in
most patients undergoing treatment for at least six months.2 Despite
major improvement achieved with HAART regimens, the manage-
ment of associated drug resistance and adverse effects remain
unsolved problems of chronic long-term treatments.3
HAART regimens containing first-generation non-nucleoside
reverse transcriptase inhibitors (NNRTIs), namely Nevirapine
(NVP), Delavirdine (DLV), or Efavirenz (EFV), may lead to
development of drug resistance. In particular, the K103N and
Y181C were the most prevalent mutations in clinical HIV-1
isolates. To overcome the drug resistance, new molecules with
better resistance profile are desirable.4 Among them, Etravirine
(ETV) and Rilpivirine (RPV) were approved for use in com-
bination with other antiretroviral agents for the management of
CHEMISTRY
■
Carboxamides 7−13 and 17 were synthesized by coupling
reaction of 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-in-
dole-2-carboxylic acid6 (18) with the appropriate amine in the
̈
HIV-1 infection in treatment-experienced and naıve adult patients,
Received: April 6, 2012
respectively.5
© XXXX American Chemical Society
A
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Journal of Medicinal Chemistry
Brief Article
a
Chart 1. New IASs 7−17 and Reference Compounds 1−6
Scheme 1. Synthesis of Compounds 7−17
a
Reagents and reaction conditions: (a) (7−13 and 17) amine, BOP
reagent, triethylamine, anhydrous DMF, 25 °C, 12 h, 35−80%; (b)
(14 and 16) (i) thionyl chloride, reflux temperature, 1.5 h, (ii) amine,
triethylamine, anhydrous THF, 25 °C, 1 h, 98%; (c) (15) (i) 1,1′-
carbonyldiimidazole, anhydrous THF, 25 °C, 3 h, (ii) 3-amino-
benzonitrile, 25 °C, 2 h, 45%.
RESULTS AND DISCUSSION
■
a
Table 1. Anti-HIV-1 Activity of 7-17 in MT-4 Cells
Initially, we synthesized new IAS derivatives 7−9. Independently
of the position of the nitrogen atom of the pirimidinylmethyl
moiety, derivatives 7−9 inhibited the NL4−3 HIV-1 strain in the
low nanomolar range of concentration (EC50 values: 7 and 9 =
2.0 nM; 8 = 2.2 nM; MTT method). Compounds 7−9 were all
superior to the reference drugs AZT, NVP, and EFV, being
≥3.5-, ≥368-, and ≥2.8-fold more potent, respectively (Table 1).
When tested for their cytotoxicity (CC50 values), 7−9 showed
selectivity indexes (SI values) ≥5007, which were higher than
those of all of the reference compounds, including IAS 3. The
molecular docking studies carried out following our previously
reported methodology10 suggested the possible binding mode
of 7−9 into the WT RT NNBS: (i) the indole NH established a
H-bond with the carbonyl oxygen of Lys101, (ii) the chlorine
atom at position 5 of the indole acceded to a hydrophobic
pocket surrounded by Val106 and Leu234, and (iii) the 3,5-
dimethylphenyl moiety lay in a hydrophobic cleft formed by
Tyr181, Tyr188, Trp229, and Pro95 residues establishing
hydrophobic interactions. Focusing on the p51/p66 interface
cleft, the pyridinyl ring of 7−9 was stabilized by hydrophobic
interactions with the side chains of Val179 (p66), Glu138, and
Thr139 (p51) (Figure 1S, Supporting Information).
In the case of the quinolin-4-ylmethyl compound 10, the
molecular docking experiments showed that, although the
quinoline ring could form the same hydrophobic interactions
as the pyridine analogue, part of the heterocycle was placed
outside the cleft and exposed to the solvent. This in silico
observation might justify the biological results obtained, as
derivative 10 showed an EC50 of 12 nM and was 6-fold less
potent than 7 and 9.
We synthesized the pirimidinylethyl derivatives 11−13,
which joined structural characteristics of highly potent IASs:
(i) the pirimidinyl group of 7−10 and (ii) the ethylene linker
of 6. In this case, the modeling predictions did not show any
significant differences in comparison with 7−9 and were in
good agreement with the biological results. Indeed, IAS deriva-
tives 11−13 (EC50s: 11 and 13 = 2 nM; 12 = 2.1 nM) were potent
inhibitors of the NL4−3 HIV-1 strain, with inhibitory
concentrations absolutely comparable to those of the correspond-
ing derivatives 7−10.
a
EC50: effective concentration (nM) to inhibit by 50% HIV-1 (NL4−3
strain) induced cell death, as evaluated with the MTT method in
MT-4 cells. CC50: cytotoxic concentration (nM) to induce 50% death
b
of noninfected cells, as evaluated with the MTT method in MT-4 cells.
c
d
SI: selectivity index calculated as CC50/EC50 ratio. Data of D,L racemic
mixture.
presence of (benzotriazol-1-yloxy)tris(dimethylamino)-
phosphonium hexafluorophosphate (BOP reagent) and triethyl-
amine in anhydrous DMF at 25 °C for 12 h. Alternatively,
the acid 18 was transformed into acid chloride by heating at
reflux with thionyl chloride for 1.5 h or into carboxylic acid
imidazolide with 1,1′-carbonyldiimidazole in anhydrous THF
at 25 °C for 3 h. Subsequent treatment of the activated acid
with the appropriate amine provided the carboxamides 14−16
(Scheme 1).
Finally, we synthesized the cyanophenyl derivatives 14−17.
We envisaged compounds 14−17 by pushing out the nitrogen
atom from the pirimidinyl ring while its distance from the
carboxamide nitrogen was kept fixed. The molecular modeling
suggested again that the aromatic ring would be stabilized by
hydrophobic interactions, independently on the position of the
B
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Journal of Medicinal Chemistry
Brief Article
cyano group. Compounds 14, 15, and 17 potently inhibited the
NL4−3 HIV-1 strain at EC50 values of 2 nM (14), 2.2 nM (15),
and 1.5 nM (17) and were equipotent to pyridinyl compounds
7−9 and 11−13.
Among the most potent compounds, IAS derivatives 8, 9, 12,
15, and 17, representing significant structural differences within
this series, were evaluated in MT4 cells against mutant HIV-1
strains harboring Y181C, Y188L, and K103N single amino acid
mutations in the RT (Table 2). Compounds 8, 9, 12, 15, and 17
Table 3. Anti-HIV-1 Activity of Compound 9 against Wild
Type HIV-1 NL4-3 and Mutant IRLL98 Strains in MT-4
Cells
a
EC50 (nM)
HIV-1 WT
(NL4−3)
HIV-1 mutant
(IRLL98)
compd
9
2
0.2
1
0.05
AZT
NVP
EFV
3.5 1.8
227 141
1.8 0.9
3.8 0.8
>18916
980 300
Table 2. Anti-HIV-1 Activity of Compounds 8, 9, 12, 15, and
a
a
EC50: effective concentration (nM) required to inhibit by 50% the
17 against Mutant HIV-1 Strains in MT-4 Cell Cultures
cell death induced by the indicated mutant HIV-1 strain, as evaluated
Y181C
Y188L
EC50 (nM)
FC
K103N
EC50 (nM)
FC
with the MTT method in MT-4 cells.
a
EC50 (nM)
b
compd
FC
To ascertain that the test compounds were also inhibitory in
primary T-lymphocyte cells using virus strains that belong to
different clades of HIV-1, the most potent, 9, was included in
this study (Table 4). Compound 9 proved to inhibit potently
8
8.8 2.9
4.4
44 15
20.0
37.8 22
17.2
9
2.2 2.2
1.1
22 15
10.0
8.8 2.2
4.4
12
6.3 0.0
3.0
504 273
240.0
27.3 4.2
13.0
Table 4. Inhibitory Activity of Compound 9 against Various
HIV-1 Clades in Peripheral Blood Mononuclear Cells
(PBMC)
15
44 8.8
20
1386 1144
630
19.8 15.4
9.0
ab
,
17
32.1 4.2
21.4
>10714
>7142
117.9 64.3
78.6
HIV-1 clade
EC50 range (nM)
clade A (UG273)
clade B (BaL)
0.6−1.2
0.1−0.4
0.4−0.8
0.3−0.4
0.4−0.6
0.6−0.9
0.6−0.8
1.7−1.8
AZT
NVP
EFV
1.6 0.4
0.2
11.7 7.8
1.5
15.6 11.7
2.0
clade C (DJ259)
clade C (SM145)
>3756
>2.5
>3756
>3756
>2.5
>2.5
c
clade D (UG270)
157.5 157.5
25
315.0 189.0
50
69.3 31.5
11.0
clade A/E (ID12)
clade F (BZ162)
a
EC50: effective concentration (nM) to inhibit by 50% cell death
induced by the indicated mutant HIV-1 strain, as evaluated with the
MTT method in MT-4 cells. FC: fold change obtained as ratio
between EC50s of drug resistant mutant HIV-1 strain and WT HIV-1
strain.
clade G (BCF-DIOUM)
a
Compound concentration required to inhibit HIV-1 p24 production
in virus-infected PBMC; mean values of two independent experiments
in two different PBMC donors. The clinical HIV-1 isolates were
sensitive to maraviroc (CCR5 antagonist) or AMD3100 (CXCR4
b
b
c
antagonist) in the 1−20 nM range. CXCR4-using clade.
were potent inhibitors of the mutant Y181C HIV-1 strain, with
EC50s ranging from 2.2 nM (9) to 44 nM (15). Against this
mutant, all the compounds were superior to EFV, and derivatives 8,
9, and 12 displayed comparable results to AZT. Against the Y188L
mutant strain, compounds 8 and 9 were 7- and 14-fold respectively
more potent than EFV and were comparable to AZT.
HIV-1 clades A, B, C, D, A/E, F, and G. With the exception of
clade G, the EC50 mean concentrations in two different PBMC
donors were in the higher picomolar range. Most of the clinical
isolates, in contrast to HIV-1 (NL4−3) (CXCR4-using), were
CCR5-using or CCR5-tropic. As reference compounds,
Maraviroc (CCR5 antagonist) or AMD3100 (CXCR4
antagonist) were used and were inhibitory in their expected nM
(1−20 nM) range. We also evaluated HIV-1 NL4.3 strain in PBMC,
and here we obtained an EC50 of 0.4−0.8 nM. No antiviral activity
was observed against an HIV-2 isolate (>200 nM). These results
point to a broad spectrum of anti-HIV-1 activity of this class of
compounds.
As inhibitors of the RT of HIV-1 WT, compounds 8 and 9
showed inhibitory concentrations comparable to the reference
ATI 3, were four and 20 times superior to NVP and EFV,
respectively, and two times inferior to ETV (Table 5).
Compounds 8 and 9 inhibited in the nanomolar range the
RT of K103N HIV-1, the major mutation emerging in patients
treated with EFV.11 Against the K103N RT, the most active
compounds 8 and 9 were notably more active than NVP and
EFV and the reference ATI 3. Compounds 8 and 9 were also
potent inhibitors of the L100I RT. Compound 8 was 140 and
>1000 times more potent than the reference ATI 3 and NVP,
respectively.
With the exception of 17, these inhibitors were more effective
than EFV against the K103N mutant, and two compounds, 9 and
15, were equipotent to AZT. The activity against the K103N
mutation is of particular therapeutic value because it is the major
mutation emerging in patients treated with EFV whose viral
loads rebounds after initial response to the drug.11 Compound 9
was uniformly potent against all the mutant HIV-1 strains, with
inhibitory concentrations in the low nanomolar range of
concentration. In particular, 9 was 71-, 14-, and 8-fold superior
to EFV against the Y181C, Y188L, and K103N mutations,
respectively. It is worth noting that against these mutants 9 was
absolutely comparable to AZT.
Compound 9 was evaluated against the multiresistant IRLL9812
HIV-1 strain bearing the K101Q, Y181C, and G190A mutations
conferring resistance to NVP, DLV, and EFV (Table 3).
Compounds 9 was more active against the mutant IRLL98 HIV-1
strain than the WT NL4−3 strain. In contrast, NVP and EFV
showed the typical drug resistance differential while AZT was
slightly less active against this strain.
C
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General Procedure for the Preparation of Derivatives 14 and
16. Example: 5-Chloro-N-(2-cyanophenyl)-3-((3,5-dimethyl-
phenyl)sulfonyl)-1H-indole-2-carboxamide (14). A mixture of
18 (150 mg, 0.41 mmol) and thionyl chloride (5 mL) was heated at
reflux temperature for 1.5 h. After evaporation to dryness, the residue
was dissolved in anhydrous THF (5 mL). Triethylamine (0.41 mg,
0.06 mL, 0.41 mmol) and 2-aminobenzonitrile (72 mg, 0.61 mmol)
were added, and the mixture was stirred at 25 °C for 1 h. Water and ethyl
acetate were added while shaking. The organic layer was washed with
brine and dried. Removal of the solvent gave a residue that was purified
by column chromatography (silica gel, ethyl acetate as eluent) to furnish
14 (186 mg, 98%), mp 282−285 °C (from ethanol). 1H NMR (DMSO-d6):
δ 2.29 (s, 6H), 7.25 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.47 (t, J = 8.1 Hz,
1H), 7.59 (d, J = 8.6 Hz, 1H), 7.67 (s, 2H), 7.74−7.79 (m, 2H), 7.91−
7.94 (m, 2H), 11.30 (br s, 1H, disappeared on treatment with D2O),
13.31 ppm (br s, 1H, disappeared on treatment with D2O). IR: ν 1656,
2224, 3230 cm−1. Anal. (C24H18ClN3O3S (463.94)) C, H, Cl, N, S.
5-Chloro-N-(3-cyanophenyl)-3-((3,5-dimethylphenyl)sulfo-
nyl)-1H-indole-2-carboxamide (15). 1,1′-Carbonyldiimidazole (120 mg,
0.75 mmol) was added to a suspension of 18 (250 mg, 0.69 mmol)
in anhydrous THF (15 mL). The reaction mixture was stirred at 25 °C
for 3 h, and then 3-aminobenzonitrile (150 mg, 1.25 mmol) was added.
The reaction mixture was stirred at 25 °C for 2 h and diluted with water
and extracted with ethyl acetate. The organic layer was washed with
brine and dried. Removal of the solvent gave a residue that was purified
by column chromatography (silica gel, ethyl acetate:n-hexane = 1:1 as
eluent) to furnish 15 (110 mg, 45%), mp 270 °C (from ethanol).
1H NMR (DMSO-d6): δ 2.34 (s, 6H), 7.27 (s, 1H), 7.36 (dd, J = 2.3 and
8.3 Hz, 1H), 7.58 (t, J = 8.2 Hz, 1H), 7.66−7.67 (m,4H), 7.94 (d, J =
2.1 Hz, 1H), 7.95−7.82 (m, 1H), 8.20 (s, 1H), 11.23 (br s, 1H,
disappeared on treatment with D2O), 13.31 ppm (br s, 1H, disappeared
on treatment with D2O). IR: ν 1678, 2232, 3235 cm−1. Anal.
(C24H18ClN3O3S (463.94)) C, H, Cl, N, S.
Table 5. HIV-1 RT Inhibitory Activity of Compounds 8, 9, 12,
15, and 17 against the WT and Mutant RTs Carrying Single
Amino Acid Substitutions
a
b
IC50 (nM)
compd
WT
K103N
L1001
8
20
21
32
45
8
11
9
12
15
17
40
162
>40
>10
190
7000
400
20
24
506
>10
23
287
>4
c
3
112
9000
NVP
EFV
ETV
400
80
d
nd
10
10
a
Data represent mean values of at least three separate experiments.
Compound concentration (IC50, nM) required to inhibit by 50% the
b
RT activity of the indicated strain. Literature7 nd: no data.
c
d
The binding modes of IASs into WT and mutated RTs are
discussed in Supporting Information
CONCLUSIONS
■
We synthesized new IAS derivatives 7−17 bearing nitrogen
containing substituents at the indole-2-carboxamide linked
through a methylene/ethylene spacer. The IASs 7−17 proved
to be potent inhibitors of the HIV-1 WT (NL4−3 strain) in MT-
4 cells in the low nanomolar concentrations and weakly
cytotoxic. Several compounds were potent inhibitors of the
mutant HIV-1 strains. Compound 9 was uniformly effective
against the mutant Y181C, Y188L, and K103N HIV-1 strains,
superior to EFV and equipotent to AZT. IAS 9 was highly active
against the multiresistant mutant IRLL98 HIV-1 strain bearing
the K101Q, Y181C, and G190A mutations conferring resistance
to NVP, DLV, and EFV. Compound 9 also potently inhibited in
the higher picomolar range various HIV-1 clades, independently
of their coreceptor use, in PBMC. ATI 9 emerged as a useful lead
compound for the development of new therapeutic tools for
EFV-based HIV-1 therapies which show the emergence of the
L100I and K103N mutations. We succeeded in the development
of new three-cycles containing ATIs as hybrides between two-
wings and horseshoe-conformation NNRTIs.9 Such results
provide useful information for further development of this
class of HIV-1 NNRTIs.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional chemical and biological information. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +39 06 4991 3800. Fax: +39 06 4969 3268. E-mail:
romano.silvestri@uniroma1.it.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are indebted to Istituto PasteurFondazione Cenci
Bolognetti (grant 2009), Finanziaria Laziale di Sviluppo
(FILAS, grant 2010), and the Spanish MICINN (projects
BFU2009-06958 and SAF201021617-C02) for financial support.
This work was supported by the K.U. Leuven (GOA no. 10/014
and PF/10/018) and the FWO (no. G.485.08), and we are
grateful to S. Claes and E. Fonteyn for excellent technical
assistance. A.C. thanks Istituto PasteurFondazione Cenci
Bolognetti for his Borsa di Studio per Ricerche in Italia.
EXPERIMENTAL SECTION
■
Chemistry. Combustion analysis was used as a method for
establishing compound purity. Purity of the tested compounds was
≥95%. See Supporting Information for details.
General Procedure for the Preparation of Derivatives 7−13
and 17. Example: 5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-
(pyridin-2-ylmethyl)-1H-indole-2-carboxamide (7). A mixture of
18 (300 mg, 0.82 mmol), 2-picolylamine (130 mg, 0.13 mL, 1.24 mmol),
BOP reagent (360 mg, 0.82 mmol), and triethylamine (250 mg,
0.35 mL, 2.48 mmol) in anhydrous DMF (10 mL) was stirred at 25 °C for
12 h. The reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed with brine and dried. Removal of the
solvent gave a residue that was purified by column chromatography (silica
gel, ethyl acetate as eluent) to furnish 7 (190 mg, 60%) as a white solid,
mp 229−231 °C (from ethanol). 1H NMR (DMSO-d6): δ 1.99 (s, 6H),
4.69 (d, J = 5.9 Hz, 2H), 7.26 (s, 1H), 7.30−7.36 (m, 2H), 7.54−7.58
(m, 2H), 7.66 (s, 2H), 7.82 (t, J = 7.7 Hz, 1H), 7.97 (s, 1H), 8.57 (d, J =
3.9 Hz, 1H), 9.59 (br t, J = 4.9 Hz, 1H, disappeared on treatment with
D2O), 13.1 ppm (br s, 1H, disappeared on treatment with D2O). IR: ν
1636, 3220, 3297 cm−1. Anal. (C23H20ClN3O3S (453.94)) C, H, Cl, N, S.
ABBREVIATIONS USED
■
IAS, indolylarylsulfone; HIV-1, human immunodeficiency virus
type 1; AIDS, acquired immune deficiency syndrome; RT,
reverse transcriptase; NNRTI, non-nucleoside reverse tran-
scriptase inhibitor; HAART, highly active antiretroviral therapy;
WT, wild type; NVP, nevirapine; EFV, efavirenz; ETV,
etravirine; RPV, rilpivirine; PBMC, peripheral blood mono-
nuclear cells
D
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REFERENCES
■
(1) Progress Report 2011: Global HIV/AIDS Response; World Health
Organization: Geneva, 2011.
(2) Este, J. A.; Cihlar, T. Current status and challenges of antiretroviral
research and therapy. Antiviral Res. 2010, 85, 25−33.
(3) (a) Menendez-Arias, L. Molecular basis of human immunodefi-
́
ciency virus drug resistance: an update. Antiviral Res. 2010, 85, 210−231.
(b) Cortez, K. J.; Maldarelli, F. Clinical management of HIV drug
resistance. Viruses 2011, 3, 347−378. (c) Howkins, T. Understanding
and managing the adverse effects of antiretroviral therapy. Antiviral Res.
2010, 85, 201−209.
́
(4) (a) de Bethune, M.-P. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs), their discovery, development, and use in the
treatment of HIV-1 infection: a review over the last 20 years (1989−
2009). Antiviral Res. 2010, 85, 75−90. (b) Sweeney, Z. K.; Klumpp, K.
Improving non-nucleoside reverse transcriptase inhibitors for first-line
treatment of HIV infection: the development pipeline and recent clinical
data. Curr. Opin. Drug Discovery Dev. 2008, 11, 458−470.
(5) (a) Haubrich, R.; Gubernick, S.; Yasothan, U.; Kirkpatrick, P.
Etravirine. Nature Rev. Drug Discovery 2008, 7, 287−288. (b) Drugs@
FDA. FDA approved drug products; http://www.accessdata.fda.gov/
scripts/ cder/drugsatfda/index.cfm (Accessed February 20, 2012).
(6) (a) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa,
S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. Novel
indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance
mutations: synthesis and SAR studies. J. Med. Chem. 2003, 46, 2482−
2493. (b) Silvestri, R.; Artico, M.; De Martino, G.; La Regina, G.; Loddo,
R.; La Colla, M.; La Colla, P. Simple, short peptide derivatives of a
sulfonylindolecarboxamide (L-737,126) active in vitro against HIV-1
wild-type and variants carrying non-nucleoside reverse transcriptase
inhibitor resistance mutations. J. Med. Chem. 2004, 47, 3892−3896.
(7) Piscitelli, F.; Coluccia, A.; Brancale, A.; La Regina, G.; Sansone, A.;
Giordano, C.; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; Cirilli, R.;
La Torre, F.; Lavecchia, A.; Novellino, E.; Silvestri, R. Indolyl-
arylsulfones bearing natural and unnatural amino acids. Discovery of
potent inhibitors of HIV-1 non-nucleoside wild type and resistant
mutant strains reverse transcriptase and Coxsackie B4 virus. J. Med.
Chem. 2009, 52, 1922−1934.
(8) (a) Ragno, R.; Artico, M.; De Martino, G.; La Regina, G.; Coluccia,
A.; Di Pasquali, A.; Silvestri, R. Docking and 3-D QSAR studies on
indolyl aryl sulfones (IASs). binding mode exploration at the HIV-1
reverse transcriptase non-nucleoside binding site and design of highly
active N-(2-hydroxyethyl)carboxyamide and N-(2-hydroxyethyl)-
carboxyhydrazide derivatives. J. Med. Chem. 2005, 48, 213−223.
(b) Ragno, R.; Coluccia, A.; La Regina, G.; De Martino, G.; Piscitelli,
F.; Lavecchia, A.; Novellino, E.; Bergamini, A.; Ciaprini, C.; Sinistro, A.;
Maga, G.; Crespan, E.; Artico, M.; Silvestri, R. Design, molecular
modeling, synthesis and anti-HIV-1 activity of new indolyl aryl sulfones.
Novel derivatives of the indole-2-carboxamide. J. Med. Chem. 2006, 49,
3172−3184.
(9) La Regina, G.; Coluccia, A.; Silvestri, R. Looking for an active
conformation of the future HIV-1 non-nucleoside reverse transcriptase
inhibitors. Antiviral Chem. Chemother. 2010, 20, 231−237.
(10) La Regina, R.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Gatti, V.;
Maga, G.; Samuele, A.; Pannecouque, C.; Schols, D.; Balzarini, J.;
Novellino, E.; Silvestri, R. Indolylarylsulfones as HIV-1 non-nucleoside
reverse transcriptase inhibitors. New cyclic substituents at the indole-2-
carboxamide. J. Med. Chem. 2011, 54, 1587−1598.
(11) Corbett, J. W.; Rodgers, J. D. Discovery of second generation of
quinazoline non-nucleoside reverse transcriptase inhibitors of HIV-1.
Prog. Med. Chem. 2002, 40, 63−105.
(12) Manetti, F.; Este, J. A.; Clotet-Codina, I.; Armand-Ugon, M.;
Maga, G.; Crespan, E.; Cancio, R.; Mugnaini, C.; Bernardini, C.;
Togninelli, A.; Carmi, C.; Alongi, M.; Petricci, E.; Massa, S.; Corelli, F.;
Botta, M. Parallel solution-phase and microwave-assisted synthesis of
new S-DABO derivatives endowed with subnanomolar anti-HIV-1
activity. J. Med. Chem. 2005, 48, 8000−8008.
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