Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: Synthesis, structure-activity relationship analysis, and biological activity

Article abstract of DOI:10.3109/14756366.2011.604851

Four series of forty-five nitrogen-containing polyhydroxylated aromatics based on caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase (IN) inhibitors. Most of these compounds inhibited IN catalytic activities in low micromolar range. Among these new analogues, compounds 9e and 9f were the most potent IN inhibitors with IC50 value of 0.7 μM against strand transfer reaction. Their key structure-activity relationships were also discussed.

Full text of DOI:10.3109/14756366.2011.604851

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(5): 628–640
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.604851
ReseaRch aRtIcle
Nitrogen-containing polyhydroxylated aromatics as HIV-1
integrase inhibitors: synthesis, structure-activity relationship
analysis, and biological activity
Shenghui Yu1, Linna Zhang2,#, Shifeng Yan1, Peng Wang1, Tino Sanchez3, Frauke Christ4,
Zeger Debyser4, Nouri Neamati3, and Guisen Zhao1
1Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong,
PR China, 2Qilu Hospital of Shandong University, Jinan, Shandong, PR China, 3Department of Pharmacology and
Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA, and 4Laboratory
for Molecular Virology and Gene erapy, Department of Molecular and Cellular Medicine IRC KULAK and KULeuven,
Leuven, Flanders, Belgium
abstract
Four series of forty-five nitrogen-containing polyhydroxylated aromatics based on caffeic acid phenethyl ester were
designed and synthesized as HIV-1 integrase (IN) inhibitors. Most of these compounds inhibited IN catalytic activities
in low micromolar range. Among these new analogues, compounds 9e and 9f were the most potent IN inhibitors with
IC50 value of 0.7 μM against strand transfer reaction. Their key structure-activity relationships were also discussed.
Keywords: HIV-1, integrase inhibitors, polyhydroxylated aromatics, structure-activity relationship
Introduction
chromosome (termed “strand transfer”, ST2,4). Due to the
absence of any known human homolog5, therefore, in
principle, selective inhibitors with few or no side effects
can be designed, which makes HIV-1 IN an attractive and
validated target for the development of novel anti-HIV-1
drugs.
Caffeic acid phenylethyl ester (CAPE 1, Figure 1), an
antioxidant component of the propolis, is one of the
first HIV-1 IN inhibitors reported. It also exhibits signifi-
cant anti-viral activity with little cytotoxicity in primary
human peripheral blood mononuclear cells (PBMC)
culture6,7. erefore, CAPE is a potential lead for further
structural optimization as potent IN inhibitors. e phe-
nolic hydroxyl group, as a pharmacophore of CAPE coor-
dinates with metal ions, like Mg2+ or Mn2+, blocking the
3´-P and ST8,9. However, the linker and the phenyl ring
are supposed to be accommodated at the hydrophobic
pocket around the active site domain to reinforce their
affinity and selectivity to IN10.
Human immunodeficiency virus type-1 (HIV-1) is the
etiological agent of acquired immunodeficiency syn-
drome (AIDS) that is a challenging pandemic of the
21st century. e highly active anti-retroviral therapy
(HAART), based on the use of a combination of reverse
transcriptase (RT) and protease (PR) inhibitors, effec-
tively inhibits the replication cycle of HIV-11,2. However,
prolonged therapy is associated with drug-related toxici-
ties, drug–drug/food interactions, and the emergence of
multidrug resistant viral strains. erefore, it is necessary
to develope novel inhibitors, which target other stages of
the viral life cycle3.
As one of the essential viral enzymes, integrase (IN)
catalyzes the insertion of proviral cDNA into the host
genome through two biochemical steps: (i) cleavage of
a dinucleotide from each 3´-end of viral cDNA (termed
“3´-processing”, 3´-P) and (ii) insertion of the two
newly processed 3´-viral DNA ends into the host-cell
Address for Correspondence: Guisen Zhao, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University,
Jinan, 250012, Shandong, PR China. E-mail: guisenzhao@sdu.edu.cn; Nouri Neamati, Department of Pharmacology and Pharmaceutical
Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA. E-mail: neamati@usc.edu
#Co-first author.
(Received 16 May 2011; revised 10 July 2011; accepted 10 July 2011)
628

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors 629
Figure 1. Conception of CAPE-like analogues IN inhibitors.
In our lead-optimization work based on CAPE, the
Materials and methods
galloyl group which was reported to have higher affin-
ity to metal ions had been introduced instead of the
catechol group as a necessary pharmacophore11. A
sulfanilamide was also been introduced replacing the
ester as the linker, because it was suggested that com-
pounds containing sulfanilamide groups show higher
anti-retroviral activities12. It has been reported that
halogen substitution on the aryl group showed signifi-
cant potency and selectivity against IN and viral repli-
cation in cell culture13. Several IN inhibitors containing
different halogen substitution on the aryl group had
been tested in the clinic, including MK-2048, GS-9137
Chemistry
Unless otherwise noted, all reagents were obtained from
commercial suppliers and used without further purifica-
tion. Melting points were determined on a Büchi capil-
lary melting point apparatus. Infrared (IR) spectra were
measured on KBr pellets, using a Nicolet Nexus 470FT-
IR and were expressed in cm−1. Proton nuclear magnetic
resonance (1H-NMR) spectra were recorded with a
Bruker Avance DRX600 spectrometer with DMSO-d6 as
the solvent and tetramethyl-silane (TMS) as the inter-
nal standard. e chemical shifts were reported in δ
(ppm). High resolution mass spectra (HRMS) data were
obtained using an Accela UPLC-LTQ Orbitrap Mass
Spectrometer. Petroleum ether used for column chro-
matography had a boiling range of 60–90°C.
and MK-0518 (Figure 1)14,15
. Especially MK-0518,
also known as raltegravir, was the first IN inhibitor
drug approved by the United States Food and Drug
Administration (US FDA). erefore, we introduced
diversity of halogen substitution on the aryl group to
investigate the roles of substitutions on the phenyl
portion. So a set of nitrogen-containing trihydroxyl-
ated aromatics had been synthesized. is set of com-
pounds exhibited potent IN inhibitory activities at low
micromolar concentrations and compound 9e and 9f
were the most potent ST inhibitors with IC50 value of 0.7
μM among these new analogues. However, when tested
for the ability to inhibit HIV replication in cell cultures,
they didn’t exhibit anti-viral activity at a concentra-
tion of 25 μM. Recently, it had been reported that the
compounds with the catechol group displayed strong
anti-viral activity at nanomolar concentrations16. So
another set of nitrogen-containing dihydroxylated aro-
matics have also been synthesized in order to increase
their anti-viral activity. is set of compounds showed
higher cytotoxicity although they exhibited improved
anti-viral activity.
General methods for preparing 4-amino-N-
substituted-benzenesulfonamides 3
To a stirred solution of substituted amine 2 (20 mmol)
in pyridine (129 mmol) 4-acetamidobenzene-1-sulfonyl
chloride (16 mmol) was added in portion with external
cooling. e reaction mixture was stirred at room tem-
perature for 4 h. en water (100 mL) was added and the
resulting solid was collected by filtration. e solid was
then dissolved in 10% NaOH and the precipitate was
removed by filtration. e solution was acidified with
hydrochloric acid solution (5 M) to pH 3–4. e precipi-
tate was collected and dissolved in 20 mL of NaOH (5 M)
and 12 mL of methanol. e solution was stirred at 70°C
for 3 h and then was acidified with hydrochloric acid solu-
tion (2 M) to pH 6. e resulting precipitate was collected
by filtration, and then was recrystallized from ethanol/
water to afford compound 3.
© 2012 Informa UK, Ltd.

630 S. Yu et al.
Hz, 2H), 5.92 (s, 2H), 4.04 (q, J= 7.8 Hz, 2H), 1.52 (t, J=
7.8 Hz, 3H).
4-Amino-N-(4-fluorophenyl)benzenesulfonamide (3a)
White powder, yield 76.9%, mp 130.9–132.4°C. H-NMR
1
(DMSO-d6) δ: 10.02 (s, 1H), 7.36 (d, J= 9.0 Hz, 2H), 7.15
(m, 2H), 6.65 (d, J= 7.2 Hz, 2H), 6.52 (d, J= 9.0 Hz, 2H),
5.94 (s, 2H).
4-Amino-N-(3,5-dimethylphenyl)benzenesulfonamide
(3j)
Orange yellow powder, yield 54.0%, mp 151.8–153.0°C.
1H-NMR (DMSO-d6) δ: 9.71 (s, 1H), 7.39 (d, J= 9.0 Hz,
2H), 6.68 (s, 2H), 6.59 (s, 1H), 6.52 (d, J= 9.0 Hz, 2H), 5.95
(s, 2H), 2.14 (s, 6H).
4-Amino-N-(3,4-difluorophenyl)benzenesulfonamide
(3b)
1
White powder, yield 75.9%, mp 178.5–180.0°C. H-NMR
(DMSO-d6) δ: 10.06 (s, 1H), 7.37 (d, J= 9.0 Hz, 2H), 7.30
(m, 1H), 7.03 (m, 1H), 6.84 (t, J = 4.8 Hz, 1H), 6.53 (d, J=
9.0 Hz, 2H), 6.03 (s, 2H).
4-Amino-N-(3-chloro-2-fluorophenyl)
benzenesulfonamide (3k)
White powder, yield 67.2%, mp 142.2–143.4°C. H-NMR
1
(DMSO-d6) δ: 9.95 (s, 1H), 7.36 (d, J= 8.4 Hz, 2H), 7.30 (t,
J= 7.2 Hz, 1H), 7.21 (t, J= 7.8 Hz, 1H), 7.12 (t, J= 7.8 Hz,
1H), 6.55 (d, J= 9.0 Hz, 2H), 6.04 (s, 2H).
4-Amino-N-(2,3,4-trifluorophenyl)
benzenesulfonamide (3c)
White powder, yield 82.6%, mp 169.5–171.1°C. H-NMR
1
(DMSO-d6) δ: 10.04 (s, 1H), 7.41 (d, J= 9.0 Hz, 2H), 7.32
(m, 1H), 7.09 (m, 1H), 6.51 (d, J= 9.0 Hz, 2H), 6.03 (s, 2H).
4-Amino-N-phenylbenzenesulfonamide (3l)
Yellowish powder, yield 79.1%, mp 197.2–198.8°C. 1H-
NMR (DMSO-d6) δ: 9.85 (s, 1H), 7.38 (d, J= 9.0 Hz, 2H),
7.20 (t, J= 7.8 Hz, 2H), 7.05 (d, J= 8.4 Hz, 2H), 6.96 (t,
J= 7.2 Hz, 1H), 6.53 (d, J= 9.0 Hz, 2H), 5.96 (s, 2H).
4-Amino-N-(4-bromophenyl)benzenesulfonamide (3d)
1
White powder, yield 80.9%, mp 216.3–217.7°C. H-NMR
(DMSO-d6) δ: 10.03 (s, 1H), 7.30 (d, J= 9.6 Hz, 2H), 7.21
(d, J= 9.6 Hz, 2H), 6.98 (d, J= 9.6 Hz, 2H), 6.42 (d, J= 9.6
Hz, 2H), 5.96 (s, 2H).
4-Amino-N-(4-chlorophenyl)benzenesulfonamide
(3m)
White powder, yield 59.6%, mp 198.1–201.1°C. H-NMR
(DMSO-d6) δ: 10.01 (s, 1H), 7.38 (d, J= 9.6 Hz, 2H), 7.26
(d, J= 9.6 Hz, 2H), 7.07 (d, J= 9.6 Hz, 2H), 6.53 (d, J= 9.6
Hz, 2H), 6.01 (s, 2H).
1
4-Amino-N-(3-bromophenyl)benzenesulfonamide (3e)
1
White powder, yield 66.2%, mp 142.8–144.0°C. H-NMR
(DMSO-d6) δ: 10.14 (s, 1H), 7.40 (d, J= 8.4 Hz, 2H), 7.21
(s, 1H), 7.16 (m, 2H), 7.07 (d, J= 7.8 Hz, 1H), 6.54 (d, J=
8.4 Hz, 2H), 6.04 (s, 2H).
4-Amino-N-(3,4-dimethylphenyl)benzenesulfonamide
(3n)
4-Amino-N-(2-bromophenyl)benzenesulfonamide (3f)
White powder, yield 68.2%, mp 170.8–171.5°C. H-NMR
(DMSO-d6) δ: 10.06 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.29
(t, J= 9.0 Hz, 1H), 7.17 (dd, J= 6.0 Hz, J= 2.4 Hz, 1H), 7.03
(m, 1H), 6.55 (d, J= 8.4 Hz, 2H), 6.04 (s, 2H).
Yellowish powder, yield 72.1%, mp 169.5–171.1°C. 1H-
NMR (DMSO-d6) δ: 9.61 (s, 1H), 7.35 (d, J= 9.6 Hz, 2H),
6.93 (d, J= 8.4 Hz, 1H), 6.83 (s, 1H), 6.78 (dd, J= 7.8 Hz,
J= 1.8 Hz, 1H), 6.51 (d, J= 8.4Hz, 2H), 5.93 (s, 2H), 2.08
(s, 6H).
1
4-Amino-N-(3,4-dichlorophenyl)benzenesulfonamide
(3g)
White powder, yield 70.0%, mp 169.5–171.1°C. H-NMR
(DMSO-d6) δ: 10.28 (s, 1H), 7.48 (d, J= 9.0 Hz, 1H), 7.41
(d, J= 8.4 Hz, 2H), 7.23 (d, J= 2.4 Hz, 1H), 7.05 (dd, J= 9.0
Hz, J= 2.4 Hz, 1H), 6.55 (d, J= 8.4 Hz, 2H), 6.07 (s, 2H).
4-Amino-N-(4-methoxyphenyl)benzenesulfonamide
(3o)
White powder, yield 75.3%, mp 202.1–204.3°C. H-NMR
(DMSO-d6) δ: 9.45 (s, 1H), 7.29 (dd, J= 9.0 Hz, J= 1.8 Hz,
2H), 6.94 (dd, J= 7.2 Hz, J= 1.8 Hz, 2H), 6.77 (dd, J= 7.2
Hz, J= 1.8 Hz, 2H), 6.50 (dd, J= 9.0 Hz, J= 1.8 Hz, 2H),
5.92 (s, 2H), 3.66 (s, 3H).
1
1
4-Amino-N-(4-butylphenyl)benzenesulfonamide (3h)
1
White powder, yield 78.5%, mp 163.7–164.9°C. H-NMR
4-Amino-N-(4-nitrophenyl)benzenesulfonamide (3p)
Orange yellow powder, yield 55.0%, mp 167.2–168.0°C.
1H-NMR (DMSO-d6) δ: 10.04 (s, 1H), 8.14 (d, J= 9.0 Hz,
2H), 7.60 (d, J= 9.0 Hz, 2H), 6.72 (d, J= 9.0 Hz, 2H), 6.59 (d,
J= 9.0 Hz, 2H), 5.96 (s, 2H).
(DMSO-d6) δ: 9.68 (s, 1H), 7.35 (d, J= 9.6 Hz, 2H), 7.01
(d, J= 8.4 Hz, 2H), 6.94 (d, J= 9.6 Hz, 2H), 6.51 (d, J= 8.4
Hz, 2H), 5.94 (s, 2H), 2.44 (t, J= 7.8 Hz, 2H), 1.45 (quintet,
J= 7.8 Hz, 2H), 1.24 (sextet, J= 7.2 Hz, 2H), 0.86 (t, J= 7.2
Hz, 3H).
4-Amino-N-(2-methylphenyl)benzenesulfonamide
(3q)
White powder, yield 75.0%, mp 153.0–155.0°C. H-NMR
(DMSO-d6) δ: 10.03 (s, 1H), 7.57 (d, J= 9.0 Hz, 2H), 6.82
(d, J= 9.0 Hz, 2H), 6.58 (dd, J= 6.0 Hz, J= 3.0 Hz, 1H), 6.45
4-Amino-N-(4-ethoxylphenyl)benzenesulfonamide (3i)
Orange yellow powder, yield 62.8%, mp 205.9–207.8°C.
1H-NMR (DMSO-d6) δ: 9.65 (s, 1H), 7.32 (dd, J= 9.0 Hz,
J= 1.8 Hz, 2H), 6.98 (dd, J= 7.2 Hz, J= 1.8 Hz, 2H), 6.80
(dd, J= 7.2 Hz, J= 1.8 Hz, 2H), 6.52 (dd, J= 9.0 Hz, J= 1.8
1
Journal of Enzyme Inhibition and Medicinal Chemistry

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors 631
(m, 2H), 6.32 (dd, J= 6.0 Hz, J= 2.4 Hz, 1H,), 5.91 (s, 2H),
2.18 (s, 3H).
pressure and the residue was purified by column chro-
matography using ethyl acetate/petroleum ether (1:1) as
eluent to yield compound 8.
4-Amino-N-(3-bromo-4-fluorophenyl)
benzenesulfonamide (3r)
Pink powder, yield 63.5%, mp 169.1–169.9°C. H-NMR
(DMSO-d6) δ: 10.04 (s, 1H), 7.37 (d, J= 7.8 Hz, 2H), 7.29
(d, J= 4.8 Hz, 1H), 7.25 (t, J= 9.0 Hz, 1H), 7.08 (t, J= 4.8
Hz, 1H), 6.55 (d, J= 8.4 Hz, 2H), 6.04 (s, 2H).
N-(4-(2-Bromophenylsulfamoyl)phenyl)-3,4,5-
triacetoxybenzamide (8g)
White powder, yield 76.1%, mp 187.1–189.3°C. H-NMR
(DMSO-d6) δ: 10.69 (s, 1H), 9.83 (s, 1H), 7.89 (d, J=7.8 Hz,
2H), 7.80 (s, 2H), 7.69 (d, J=7.8 Hz, 2H), 7.56 (d, J=8.4 Hz,
1H), 7.31 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 2.32
(s, 3H), 2.31 (s, 6H). IR (KBr, cm−1): υNH: 3313.66, 3278.59,
3244.09; υ=CH: 3111.59; υCH: 2937.43; υC=O: 1777.62, 16869.87;
1
1
4-Amino-N-(3-chloro-4-fluorophenyl)
benzenesulfonamide (3s)
White powder, yield 72.5%, mp 175.5–176.4°C. H-NMR
(DMSO-d6) δ: 10.06 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.29
(t, J= 9.0 Hz, 1H), 7.17 (dd, J= 6.6 Hz, J= 1.8 Hz, 1H), 7.04
(m, 1H), 6.55 (d, J= 9.0 Hz, 2H), 6.04 (s, 2H).
1
υ
υ
C=C: 1590.18, 1533.08, 1497.91; υS=O: 1328.26, 1198.19;
C-O: 1157.57; γ=C-H: 844.88, 755.64. HRMS (ESI) m/z for
C25H25N3O9BrS [M+NH4]+: calcd 622.0489, found 622.0504.
N-(4-(3-chloro-2-fluorophenylsulfamoyl)phenyl)-3,4,5-
triacetoxybenzamide (8l)
White powder, yield 73.2%, mp 228.3–229.1°C. H-NMR
(DMSO-d6) δ: 10.71 (s, 1H), 10.39 (s, 1H), 7.91 (d, J = 9.0
Hz, 2H), 7.81 (s, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.35 (t, J = 7.2
Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 2.33
(s, 3H), 2.30 (s, 6H). IR (KBr, cm−1): υNH: 3376.37, 3191.70;
4-Amino-N-(4-fluorobenzyl)benzenesulfonamide (3t)
Yellowish powder, yield 53.6%, mp 163.4–165.0°C. 1H-
NMR (DMSO-d6) δ: 7.65 (t, J= 6.6 Hz, 1H), 7.41 (d, J= 10.4
Hz, 2H), 7.27 (dd, J= 8.4 Hz, J= 5.4 Hz, 2H), 7.10 (m, 2H),
6.59 (d, J= 9.6 Hz, 2H), 5.93 (s, 2H), 3.85 (d, J= 6.0 Hz,
2H).
1
υ
=CH: 3070.52; υCH: 2936.09; υC=O: 1780.50, 1694.29; υC=C
:
4-Amino-N-(4-chlorobenzyl)benzenesulfonamide (3u)
White powder, yield 62.7%, mp 122.9–123.6°C. H-NMR
(DMSO-d6) δ: 7.62 (t, J= 6.6 Hz, 1H), 7.44 (d, J= 8.4 Hz,
2H), 7.28 (t, J= 7.2 Hz, 2H), 7.23 (m, 2H), 6.61 (d, J= 8.4
Hz, 2H), 5.93 (s, 2H), 3.87 (d, J= 6.6 Hz, 2H).
1591.55, 1532.28, 1486.11; υS=O: 1333.73, 1191.54; υC-O
:
1
1226.26, 1160.30; γ=C-H: 842.75, 729.80. HRMS (ESI)
m/z for C25H24N3O9FClS [M+H]+: calcd 596.0900, found
596.0911.
N-(4-Phenylsulfamoylphenyl)-3,4,5-
triacetoxybenzamide (8m)
White powder, yield 79.1%, mp 215.1–217.3°C. H-NMR
(DMSO-d6) δ: 10.65 (s, 1H), 10.22 (s, 1H), 7.88 (d, J= 8.4
Hz, 2H), 7.80 (s, 2H), 7.75 (d, J= 9.0 Hz, 2H), 7.23 (t, J= 7.8
Hz, 2H), 7.09 (d, J= 7.8 Hz, 2H), 7.02 (t, J= 7.2 Hz, 1H), 2.34
(s, 3H), 2.32 (s, 6H). IR (KBr, cm−1): υNH: 3341.36, 3294.47,
3112.12; υC=O: 1778.68, 1762.49, 1689.88; υC=C: 1589.19,
1531.64, 1495.69; υS=O: 1326.81, 1157.95; υC-O: 1201.45;
4-Amino-N-(4-fluorophenethyl)benzenesulfonamide
(3v)
Pink powder, yield 64.5%, mp 155.4–156.7°C. H-NMR
(DMSO-d6) δ: 7.40 (d, J= 8.4 Hz, 2H), 7.18 (m, 3H), 7.08
(t, J= 8.4 Hz, 2H), 6.59 (d, J= 8.4 Hz, 2H), 5.92 (s, 2H), 2.85
(m, 2H), 2.64 (t, J= 7.2 Hz, 2H).
1
1
General methods for preparing acyl chlorides 6 and 717,18
To a stirred solution of acetic anhydride (212.1 mmol)
and pyridine (61.9 mmol) compound 4 or 5 (20 mmol)
was added. e reaction mixture was stirred for 24h at
room temperature, and then water (200 mL) was added
to the mixture. e precipitate was collected by filtration
and was then recrystallized from acetone/cyclohexane
to afford white solid. e solid was dissolved in 20mL of
thionyl chloride and the solution was stirred at 80°C for
5 h. e solvent was concentrated under reduced pres-
sure at 50°C to obtain acyl chloride 6 or 7, which was
diluted with 20 mL of acetone and was used for the next
step without further purification.
γ
=C-H: 844.82, 758.59. HRMS (ESI) m/z for C25H23N2O9S
[M+H]+: calcd 527.1119, found 527.1129.
N-(4-(2-Methylphenylsulfamoyl)phenyl)-3,4,5-
triacetoxybenzamide (8s)
White powder, yield 84.0%, mp 201.4–203.0°C. 1H-NMR
(DMSO-d6) δ: 10.68 (s, 1H), 9.50 (s, 1H), 7.90 (d, J=9.0 Hz,
2H), 7.82 (s, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.12 (m, 3H), 6.98
(dd, J=6.0 Hz, J=3.0 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 6H), 2.02 (s,
3H). IR (KBr, cm−1): υNH: 3337.80; υCH: 2936.46; υC=O: 1776.04,
1687.54; υC=C: 1588.61, 1531.71, 1496.08; υS=O: 1328.19,
1196.03; υC-O: 1235.57; γ=C-H: 845.53, 754.37. HRMS (ESI) m/z
for C26H25N2O9S [M+H]+: calcd 541.1275, found 541.1287.
General methods for preparing target compounds 8
To a stirred solution of 4-amino-N-substituted-benze-
nesulfonamide 3 (2.8 mmol) and pyridine (2.6 mmol) in
acetone (10 mL) acyl chloride 6 (2.2 mmol) was added in
portion at 0°C. e reaction mixture was stirred at room
temperature for 20 h and the precipitate was removed by
filtration. e filtrate was concentrated under reduced
General methods for preparing target compounds 9
Following the aforementioned procedure, amidation
between compound 3 and compound 6 was carried out.
e product was added to a solution of tetrahydrofuran
(4mL), methanol (4mL) and concentrated hydrochloric
acid (37%, 2mL). e reaction mixture was stirred for 1h at
© 2012 Informa UK, Ltd.

632 S. Yu et al.
60°C. Evaporation of the solvent gave a residue, which was
recrystallized from ethanol/water to obtain compound 9.
N-(4-(3-Bromophenylsulfamoyl)phenyl)galloylamide
(9f)
White powder, yield 44.2%, mp 260.6–261.3°C. H-NMR
1
N-(4-(4-Fluorophenylsulfamoyl)phenyl)galloylamide
(9a)
(DMSO-d6) δ: 10.45 (s, 1H), 10.26 (s, 1H), 9.22 (s, 2H), 8.91
(s, 1H), 7.91 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 7.25
(s, 1H), 7.20 (d, J=4.8 Hz, 2H), 7.12 (m, 1H), 6.94 (s, 2H).
IR (KBr, cm−1): υOH: 3376.08; υC=O: 1653.00; υC=C: 1609.83,
Yellowish powder, yield 61.7%, mp 274.7–275.8°C. 1H-
NMR (DMSO-d6) δ: 10.24 (s, 1H), 10.13 (s, 1H), 9.22 (s,
2H), 8.92 (s, 1H), 7.89 (d, J= 9.0 Hz, 2H), 7.65 (d, J= 8.4 Hz,
2H), 7.09 (d, J= 7.2 Hz, 4H), 6.94 (s, 2H). IR (KBr, cm−1):
1590.78, 1521.10, 1473.20; υS=O: 1329.27, 1153.64; υC-O
:
1257.32, 1212.64; γ=C-H: 838.01, 755.03. HRMS (ESI) m/z for
C19H16N2O6BrS [M+H]+: calcd 478.9907, found 478.9920.
υOH: 3388.90; υC=O: 1652.96; υC=C: 1610.39, 1590.27, 1507.16,
1444.29; υS=O: 1317.34, 1153.40; υC-O: 1209.12; γ=C-H: 833.72,
757.35. HRMS (ESI) m/z for C19H15N2O6FS [M+H]+: calcd
419.0708, found 419.0718.
N-(4-(2-Bromophenylsulfamoyl)phenyl)galloylamide
(9g)
White powder, yield 49.3%, mp 241.6–243.4°C. H-NMR
1
N-(4-(3,4-Difluorophenylsulfamoyl)phenyl)
galloylamide (9b)
(DMSO-d6) δ: 10.27 (s, 1H), 9.77 (s, 1H), 9.23 (s, 2H), 8.92
(s, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 8.4 Hz, 2H),
7.25 (dd, J= 7.8 Hz, J= 1.8 Hz, 1H), 7.32 (td, J= 7.8 Hz,
J= 1.2 Hz, 1H), 7.19 (dd, J= 7.8 Hz, J= 1.8 Hz, 1H), 7.13 (td,
Yellowish powder, yield 58.6%, mp 265.1–266.7°C.1H-
NMR (DMSO-d6) δ: 10.41 (s, 1H), 10.26 (s, 1H), 9.22 (s,
2H), 8.91 (s, 1H), 7.91 (d, J= 8.4 Hz, 2H), 7.70 (d, J= 9.0
Hz, 2H), 7.33 (m, 1H), 7.10 (m, 1H), 6.94 (s, 2H), 6.89 (d,
J= 8.4 Hz, 1H). IR (KBr, cm−1): υOH: 3384.58; υCH: 2975.49;
J= 7.8 Hz, J= 1.2 Hz, 1H), 6.96 (s, 2H). IR (KBr, cm−1): υOH
3454.11, 3301.65; υNH: 3212.44; υCH: 2924.26, 2853.12; υC=O
1658.80; υC=C: 1603.47, 1588.64, 1524.84, 1475.51; υS=O
:
:
:
υ
υ
C=O: 1652.52; υC=C: 1614.13, 1590.56, 1519.04, 1445.08;
S=O: 1320.77, 1162.37; υC-O: 1252.83, 1210.51; γ=C-H: 837.12,
1311.38, 1156.59; υC-O: 1254.71, 1218.76; γ=C-H: 841.34,
755.98. HRMS (ESI) m/z for C19H16N2O6BrS [M+H]+: calcd
478.9907, found 478.9913.
757.97. HRMS (ESI) m/z for C19H15N2O6F2S [M+H]+: calcd
437.0613, found 437.0623.
N-(4-(3,4-Dichlorophenylsulfamoyl)phenyl)
galloylamide (9h)
N-(4-(2,3,4-Trifluorophenylsulfamoyl)phenyl)
galloylamide (9c)
White powder, yield 80.8%, mp 254.1–255.5°C. H-NMR
(DMSO-d6) δ: 10.29 (s, 1H), 10.27 (s, 1H), 9.23 (s, 2H),
8.92 (s, 1H), 7.93 (d, J= 9.0 Hz, 2H), 7.65 (d, J= 9.0 Hz, 2H),
7.28 (m, 1H), 7.01 (m, 1H), 6.97 (s, 2H). IR (KBr, cm−1):
Yellowish powder, yield 60.4%, mp 259.4–261.2°C. 1H-
NMR (DMSO-d6) δ: 10.61 (s, 1H), 10.27 (s, 1H), 9.22 (s,
2H), 8.91 (s, 1H), 7.93 (d, J= 9.0 Hz, 2H), 7.73 (d, J= 9.0
Hz, 2H), 7.51 (d, J= 9.0 Hz, 1H), 7.28 (d, J= 3.0 Hz, 1H),
7.28 (dd, J= 9.0 Hz, J= 2.4 Hz, 1H), 6.94 (s, 2H). IR (KBr,
cm−1): υOH: 3403.21; υC=O: 1662.34; υC=C: 1590.43, 1518.80,
1472.34; υS=O: 1321.73, 1159.18; υC-O: 1222.24; γ=C-H: 829.85,
756.69. HRMS (ESI) m/z for C19H15N2O6Cl2S [M+H]+: calcd
469.0022, found 469.0033.
1
υ
υ
OH: 3388.04; υC=O: 1661.31; υC=C: 1617.05, 1590.26, 1510.49;
S=O: 1335.16, 1160.41; υC-O: 1255.26, 1231.65, 1208.82;
γ
=C-H: 842.2, 757.07. HRMS (ESI) m/z for C19H14N2O6F3S
[M+H]+: calcd 455.0519, found 455.0527.
N-(4-(4-Fluorobenzylsulfamoyl)phenyl)galloylamide
(9d)
N-(4-(4-Butylphenylsulfamoyl)phenyl)galloylamide
(9i)
White powder, yield 73.4%, mp 260.5–261.4°C. H-NMR
(DMSO-d6) δ: 10.22 (s, 1H), 10.02 (s, 1H), 9.22 (s, 2H),
8.91 (s, 1H), 7.88 (d, J= 9.0 Hz, 2H), 7.66 (d, J= 9.0 Hz, 2H),
7.04 (d, J= 7.8 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.94 (s, 2H),
2.45 (t, J= 7.8 Hz, 2H), 1.46 (quintet, 2H), 1.24 (sextet,
2H), 0.85 (t, J= 7.2 Hz, 3H). IR (KBr, cm−1): υOH: 3433.45;
Yellowish powder, yield 58.3%, mp 225.4–227.1°C. 1H-
NMR (DMSO-d6) δ: 10.59 (s, 1H), 9.20-9.80 (br, 3H), 8.03
(s, 1H), 7.87 (d, J= 8.4 Hz, 2H), 7.77 (d, J= 9.0 Hz, 2H), 7.26
1
(m, 6H), 3.95 (s, 2H). IR (KBr, cm−1): υNH: 3269.41; υCH
2976.42; υC=O: 1608.98; υC=C: 1591.15, 1512.59, 1445.86;
:
υ
S=O: 1325.20, 1154.31; υC-O: 1231.19; γ=C-H: 824.18, 757.05.
HRMS(ESI)m/zforC20H18N2O6FS[M+H]+:calcd433.0864,
found 433.0873.
υNH: 3333.27, 3223.55; υCH: 2954.15, 2927.03, 2858.20; υC=O
:
:
:
1667.19; υC=C: 1592.20, 1529.40, 1512.43, 1442.07; υS=O
1341.85, 1159.04; υC-O: 1311.75, 1263.80, 1219.59; γ=C-H
N-(4-(4-Bromophenylsulfamoyl)phenyl)galloylamide
(9e)
White powder, yield 56.7%, mp 271.1–273.3°C. H-NMR
841.51, 760.55, 704.06. HRMS (ESI) m/z for C23H25N2O6S
[M+H]+: calcd 457.1428, found 457.1436.
1
(DMSO-d6) δ: 10.25 (s, 1H), 9.21 (br, 3H), 7.90 (d, J= 9.0
Hz, 2H), 7.70 (d, J= 9.0 Hz, 2H), 7.42 (d, J= 9.0 Hz, 2H),
N-(4-(4-Ethoxylphenylsulfamoyl)phenyl)galloylamide
(9j)
7.05(d, J= 9.0 Hz, 2H), 6.94 (s, 2H). IR (KBr, cm−1): υOH
:
White powder, yield 55.8%, mp 271.4–272.9°C.1H-NMR
(DMSO-d6) δ: 10.22 (s, 1H), 9.68 (s, 1H), 9.18 (br, 3H), 7.87
(d, J= 9.0 Hz, 2H), 7.60 (d, J= 9.0 Hz, 2H), 6.95 (m, 4H),
6.78 (d, J= 9.0 Hz, 2H), 3.91 (q, J= 7.2 Hz, 2H), 1.26 (t, J= 7.2
3397.52; υNH: 3157.91; υC=O: 1676.87; υC=C: 1589.25, 1504.69,
1445.40; υS=O: 1327.51, 1143.64; υC-O: 1306.20, 1246.77,
1210.30; γ=C-H: 825.04, 757.39, 708.40. HRMS (ESI) m/z for
C19H16N2O6BrS [M+H]+: calcd 478.9907, found 478.9916.
Hz, 3H). IR (KBr, cm−1): υOH: 3400.03; υNH: 3186.03; υCH3
:
Journal of Enzyme Inhibition and Medicinal Chemistry

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors 633
2983.01, 2937.89; υC=O: 1676.82; υC=C: 1589.77, 1509.67,
1445.41; υS=O: 1326.67, 1144.63; υC-O: 1253.28, 1212.47;
υNH: 3318.34; υC=O: 1671.22; υC=C: 1591.76, 1533.63, 1510.29,
1455.98; υS=O: 1321.46, 1142.46; υC-O: 1299.01, 1256.86,
1207.48; γ=C-H: 840.42, 773.10, 701.21. HRMS (ESI) m/z for
C20H18N2O6ClS [M+H]+: calcd 449.0569, found 449.0578.
γ
=C-H: 823.77, 756.19. HRMS (ESI) m/z for C21H21N2O7S
[M+H]+: calcd 445.1064, found 445.1074.
N-(4-(3,5-Dimethylphenylsulfamoyl)phenyl)
galloylamide (9k)
N-(4-(3,4-Dimethylphenylsulfamoyl)phenyl)
galloylamide (9p)
Yellowish powder, yield 78.3%, mp 266.8–267.7°C. 1H-
NMR (DMSO-d6) δ: 10.23 (s, 1H), 10.05 (s, 1H), 9.21 (s,
2H), 8.90 (s, 1H), 7.89 (d, J= 8.4 Hz, 2H), 7.70 (d, J= 9.0 Hz,
2H), 6.94 (s, 2H), 6.72 (s, 2H), 6.64 (s, 1H), 2.09 (s, 6H). IR
Yellowish powder, yield 50.5%, mp 273.4–275.1°C. 1H-
NMR (DMSO-d6) δ: 10.21 (s, 1H), 9.94 (s, 1H), 9.21 (s,
2H), 8.90 (s, 1H), 7.86 (d, J= 9.0 Hz, 2H), 7.67 (d, J= 8.4 Hz,
2H), 6.96 (d, J= 8.4 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 6.81
(d, J= 7.8 Hz, 1H), 2.10(s, 6H). IR (KBr, cm−1): υOH: 3442.41;
(KBr, cm−1): υOH: 3339.34; υCH: 2919.14; υC=O: 1661.65; υC=C
1590.17, 1519.36, 1440.46; υS=O: 1314.22, 1146.64; υC-O
:
:
υNH: 3254.22; υC=O: 1659.33; υC=C: 1590.35, 1522.84, 1443.73;
S=O: 1309.64, 1152.17; υC-O: 1254.57, 1216.87; γ=C-H: 864.39,
1253.37, 1226.94; γ=C-H: 837.99, 755.38. HRMS (ESI) m/z
υ
for C21H21N2O6S [M+H]+: calcd 429.1115, found 429.1123.
757.37. HRMS (ESI) m/z for C21H21N2O6S [M+H]+: calcd
429.1115, found 429.1125.
N-(4-(3-chloro-2-fluorophenylsulfamoyl)phenyl)
galloylamide (9l)
N-(4-(4-Methoxylphenylsulfamoyl)phenyl)
galloylamide (9q)
White powder, yield 73.9%, mp 269.8–271.7°C. H-NMR
White powder, yield 67.4%, mp 247.5–248.6°C. 1H-NMR
(DMSO-d6) δ: 10.32 (s, 1H), 10.28 (s, 1H), 9.27 (s, 2H), 8.94
(s, 1H), 7.92 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.36 (t,
J=7.8 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H),
6.96 (s, 2H). IR (KBr, cm−1): υOH: 3350.58; υCH: 2918.51, 2848.49;
1
(DMSO-d6) δ: 10.22 (s, 1H), 9.80 (s, 1H), 9.21 (s, 2H), 8.90
(s, 1H), 7.87 (d, J= 9.0 Hz, 2H), 7.62 (d, J= 9.0 Hz, 2H),
6.96 (m, 4H), 6.80 (d, J= 8.4Hz, 2H), 3.67(s, 3H). IR (KBr,
υC=O: 1779.88, 1662.78; υC=C: 1608.49, 1589.24, 1518.57; υS=O
:
cm−1): υOH: 3512.95, 3365.67; υNH: 3269.09, 3149.97; υC=O
1656.12; υC=C: 1624.31, 1591.57, 1524.28, 1444.13; υS=O
:
:
1325.02, 1159.47; υC-O: 1252.94, 1232.28, 1206.56; γ=C-H: 839.31,
818.89, 756.97, 728.04. HRMS (ESI) m/z for C19H15N2O6FClS
[M+H]+: calcd 453.0318, found 453.0325.
1317.11, 1143.35; υC-O: 1267.10, 1228.40; γ=C-H: 833.09,
793.31, 750.04. HRMS (ESI) m/z for C20H19N2O6S [M+H]+:
calcd 431.0907, found 431.0915.
N-(4-Phenylsulfamoylphenyl)galloylamide (9m)
Yellowish powder, yield 68.0%, mp 257.3–259.1°C. 1H-
NMR (DMSO-d6) δ: 10.22 (s, 1H), 10.17 (s, 1H), 9.21 (s,
2H), 8.90 (s, 1H), 7.88 (d, J= 9.0 Hz, 2H), 7.69 (d, J= 9.0 Hz,
2H), 7.23 (t, J= 8.4 Hz, 2H), 7.09 (d, J= 9.0 Hz, 2H), 7.02 (t,
J= 7.20 Hz, 1H), 6.93 (s, 2H). IR (KBr, cm−1): υOH: 3444.79;
N-(4-(4-Nitrophenylsulfamoyl)phenyl)galloylamide
(9r)
White powder, yield 52.3%, mp 256.1–257.5°C. H-NMR
1
(DMSO-d6) δ: 11.20 (s, 1H), 10.28 (s, 1H), 9.22 (s, 2H), 8.91
(s, 1H), 8.14 (d, J= 9.0 Hz, 2H), 7.94 (d, J= 9.0 Hz, 2H), 7.82
(d, J= 8.40 Hz, 2H), 7.31 (d, J= 9.0 Hz, 2H), 6.93 (s, 2H). IR
υNH: 3311.73, 3222.61; υC=O: 1667.96; υC=C: 1591.21, 1518.26,
1442.69; υS=O: 1342.43, 1159.67; υC-O: 1313.09, 1260.81,
1214.68; γ=C-H: 838.09, 757.59, 707.72. HRMS (ESI) m/z for
C19H17N2O6S [M+H]+: calcd 401.0802, found 401.0812.
(KBr, cm−1): υOH: 3431.20; υNH: 3193.81; υC=O: 1656.40; υC=C
:
1597.41, 1586.22, 1496.84; υNO2: 1524.80; υS=O: 1343.40,
1149.71; υC-O: 1240.82, 1195.61, 1182.13; γ=C-H: 850.10,
756.31. HRMS (ESI) m/z for C19H16N3O8S [M+H]+: calcd
446.0653, found 446.0665.
N-(4-(4-Chlorophenylsulfamoyl)phenyl)galloylamide
(9n)
1
White powder, yield 58.9%, mp 273.5–275.9°C. H-NMR
N-(4-(2-Methylphenylsulfamoyl)phenyl)galloylamide
(9s)
(DMSO-d6) δ: 10.28 (s, 1H), 10.24 (s, 1H), 9.21 (br, 2H),
8.85 (s, 1H), 7.90 (d, J= 9.0 Hz, 2H), 7.69 (d, J= 9.0 Hz,
2H), 7.30 (d, J= 9.0 Hz, 2H), 7.10 (d, J= 9.0 Hz, 2H), 6.94
1
White powder, yield 69.7%, mp 263.9–264.8°C. H-NMR
(DMSO-d6) δ: 10.25 (s, 1H), 9.44 (s, 1H), 9.22 (s, 2H), 8.91
(s, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H),
7.13 (dd, J = 6.0 Hz, J = 3.0 Hz, 1H), 7.10 (m, 2H), 7.0 (d,
J = 2.4 Hz, 1H,), 6.96 (s, 2H), 2.02 (s, 3H). IR (KBr, cm−1):
(s, 2H). IR (KBr, cm−1): υOH: 3397.19; υNH: 3156.01; υC=O
1678.21; υC=C: 1589.50, 1537.67, 1505.70, 1446.78; υS=O
1326.60, 1143.40; υC-O: 1306.79, 1246.77, 1209.73; γ=C-H
:
:
:
812.75, 757.20, 721.44. HRMS (ESI) m/z for C19H16N2O6ClS
[M+H]+: calcd 435.0412, found 435.0422.
υ
OH: 3449.51; υNH: 3329.29, 3231.72; υC=O: 1665.62; υC=C
:
:
1591.26, 1522.43, 1442.05; υS=O: 1309.67, 1152.55; υC-O
1257.98, 1210.03; γ=C-H: 839.62, 754.00. HRMS (ESI) m/z
N-(4-(4-Chlorobenzylsulfamoyl)phenyl)galloylamide
(9o)
White powder, yield 52.1%, mp 217.2–217.8°C. H-NMR
(DMSO-d6) δ: 10.26(s, 1H), 8.80-9.35 (br, 3H), 8.04 (s,
1H), 7.95 (d, J= 9.0 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H), 7.29
(dd, J= 7.8 Hz, J= 6.0 Hz, 2H), 7.12 (t, J= 9.0 Hz, 2H), 6.98
(s, 2H), 3.95 (s, 2H). IR (KBr, cm−1): υOH: 3553.90, 3519.08;
for C20H19N2O6S [M+H]+: calcd 415.0958, found 415.0968.
1
General methods for preparing target compounds 10
To a stirred solution of 4-amino-N-substituted-benze-
nesulfonamide 3 (2.2 mmol) and pyridine (2.2 mmol) in
acetone (8 mL) acyl chloride 7 (1.8 mmol) was added in
portion at -5°C. e reaction mixture was stirred at room
© 2012 Informa UK, Ltd.

634 S. Yu et al.
temperature for 16 h and the precipitate was removed by
filtration. e filtrate was concentrated under reduced
pressure and the residue was purified by column chro-
matography using acetone/petroleum ether (1:1) as elu-
ent to yield compound 10.
1343.53, 1165.62; υC-O: 1258.58, 1215.36; γ=C-H: 839.78.
HRMS (ESI) m/z for C25H21N2O7FClS [M+H]+: calcd
547.0737, found 547.0738.
General methods for preparing target compounds 11
Following the aforementioned procedure, amidation
between compound 3 and compound 7 was carried out.
e product was added to a solution of tetrahydrofuran
(3 mL), ethanol (3 mL) and concentrated hydrochloric
acid (37%, 1.5 mL). e reaction mixture was stirred for
0.5 h at 65°C. Evaporation of the solvent gave a residue,
which was recrystallized from ethanol/water to obtain
compound 11.
(E)-3-(3,4-Diacetoxyphenyl)-N-(4-(3,4-
Difluorophenylsulfamoyl)phenyl)acrylamide (10b)
White powder, yield 74.0%, mp 219.1–221.2°C. 1H-NMR
(DMSO-d6) δ: 10.63 (s, 1H), 10.43 (s, 1H), 7.84 (d, J = 9.0
Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.61(d, J = 16.2 Hz, 1H),
7.58 (m, 2H), 7.34 (m, 2H), 7.10 (m, 1H), 6.89 (d, J = 8.4
Hz, 2H), 6.80 (d, J = 15.6 Hz, 1H), 2.31(s, 3H), 2.30(s, 3H).
IR (KBr, cm−1): υNH: 3350.16; υ=CH: 3137.78; υC=O: 1774.84;
υ
C=C: 1677.03, 1631.36, 1590.99, 1518.04; υS=O: 1341.07,
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(4-
1163.01; υC-O: 1256.67, 1209.85; γ=C-H: 836.15. HRMS
(ESI) m/z for C25H21N2O7F2S [M+H]+: calcd 531.1032,
found 531.1035.
Fluorophenylsulfamoyl)phenyl)acrylamide(11a)
Yellowish powder, yield 68.2%, mp 183.5–184.6°C. 1H-
NMR (DMSO-d6) δ: 10.44 (s, 1H), 10.13 (s, 1H), 9.54 (s,
1H), 9.24 (s, 1H), 7.81 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 9.0 Hz,
2H), 7.44(d, J= 15.6 Hz, 1H), 7.09 (d, J= 6.6 Hz, 4H), 7.98 (s,
1H), 6.93 (d, J= 8.4 Hz, 1H), 6.79 (d, J= 8.4 Hz, 1H), 6.53(d,
J= 15.6 Hz, 1H). IR (KBr, cm−1): υOH: 3363.42; υNH: 3258.97;
(E)-3-(3,4-Diacetoxyphenyl)-N-(4-(3,4-
Dichlorophenylsulfamoyl)phenyl)acrylamide(10h)
1
White powder, yield 69.8%, mp 246.7–247.8°C. H-NMR
(DMSO-d6) δ: 10.64 (s, 1H), 10.64 (s, 1H), 7.86 (d, J= 8.4
Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.61(d, J= 16.2 Hz, 1H),
7.59 (d, J= 1.8 Hz, 1H), 7.57 (dd, J= 6.6 Hz, J= 1.8 Hz, 1H),
7.51 (d, J= 9.0 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.28(d,
J= 8.4 Hz, 1H), 7.10 (dd, J= 9.0 Hz, J= 2.4 Hz, 1H), 7.80(d,
J= 16.2 Hz, 1H), 2.31(s, 3H), 2.30(s, 3H). IR (KBr, cm−1):
υ
=CH: 2975.16; υC=O: 1659.57; υC=C: 1610.17, 1591.22,
1524.05, 1506.90; υS=O: 1329.78, 1155.88; υC-O: 1278.26,
1256.35; γ=C-H: 833.42. HRMS (ESI) m/z for C21H18N2O5FS
[M+H]+: calcd 429.0915, found 429.0919.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3,4-
υNH: 3529.13; υ=CH: 3180.00, 3117.79; υC=O: 1780.80; υC=C:
Difluorophenylsulfamoyl)phenyl)acrylamide(11b)
Yellowish powder, yield 79.1%, mp 179.1–180.3°C. 1H-
NMR (DMSO-d6) δ: 10.46 (s, 1H), 10.41 (s, 1H), 9.54 (s,
1H), 9.23 (s, 1H), 7.83 (d, J= 9.0 Hz, 2H), 7.71(d, J= 9.0 Hz,
2H), 7.44(d, J= 16.2 Hz, 1H,), 7.33 (m, 1H), 7.10 (m, 1H),
7.01 (d, J= 1.8 Hz, 1H), 6.93 (dd, J= 8.4 Hz, J= 2.4 Hz, 1H),
6.88 (dd, J= 9.0 Hz, J= 5.4 Hz, 1H), 6.78 (d, J= 7.8 Hz, 1H),
1678.00, 1630.52, 1590.02, 1525.71, 1505.44; υS=O: 1320.85,
1152.62; υC-O: 1255.30, 1210.20; γ=C-H: 838.31. HRMS (ESI)
m/z for C25H21N2O7Cl2S [M+H]+: calcd 563.0441, found
563.0444.
(E)-3-(3,4-Diacetoxyphenyl)-N-(4-(3,5-
6.53(d, J= 15.6 Hz, 1H). IR (KBr, cm−1): υOH: 3330.64; υ=CH
2975.38; υC=O: 1671.56; υC=C: 1591.98, 1519.39, 1447.75;
:
Dimethylphenylsulfamoyl)phenyl)acrylamide(10k)
White powder, yield 75.4%, mp 188.5–189.3°C. 1H-
NMR (DMSO-d6) δ: 10.59 (s, 1H), 10.08 (s, 1H), 7.82 (d,
J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.61(d, J = 15.6
Hz, 1H), 7.57 (d, J = 4.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H),
6.80(d, J = 15.6 Hz, 1H), 6.72 (s, 2H), 6.64 (s, 1H), 2.31(s,
υ
S=O: 1333.14, 1162.93; υC-O: 1285.61, 1256.85; γ=C-H:
879.14. HRMS (ESI) m/z for C21H17N2O5F2S [M+H]+: calcd
447.0821, found 447.0826.
3H), 2.30(s, 3H). IR (KBr, cm−1): υNH: 3352.62; υ=CH
3124.55, 3038.96; υCH: 2937.62, 2814.11; υC=O: 1766.03;
:
(E)-3-(3,4-Dihydroxyphenyl)-N-(2,3,4-
Trifluorophenylsulfamoyl)phenyl)acrylamide(11c)
Yellowish powder, yield 71.2%, mp 165.7–167.2°C. 1H-
NMR (DMSO-d6) δ: 10.48 (s, 1H), 10.30 (s, 1H), 9.54 (s,
1H), 9.24 (s, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 8.4 Hz,
2H), 7.45(d, J= 15.6 Hz, 1H), 7.26 (d, J= 9.0 Hz, 1H), 7.02
(s, 1H), 7.0 (d, J= 3.0 Hz, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.79
(d, J= 8.4 Hz, 1H), 6.54(d, J= 15.6 Hz, 1H). IR (KBr, cm−1):
υ
: 1669.22, 1631.74, 1591.10, 1530.77, 1476.82;
υCS==OC: 1333.40, 1162.66; υC-O: 1255.80, 1214.97; γ=C-H
:
840.23. HRMS (ESI) m/z for C27H27N2O7S [M+H]+: calcd
523.1533, found 523.1536.
(E)-3-(3,4-Diacetoxyphenyl)-N-(4-(3-chloro-2-
fluorophenylsulfamoyl)phenyl)acrylamide (10l)
υ
NH: 3256.63; υ=CH: 2954.98, 2924.60; υC=O: 1669.82; υC=C:
White powder, yield 61.7%, mp 240.5–241.8°C. 1H-NMR
(DMSO-d6) δ: 10.64 (s, 1H), 10.35 (s, 1H), 7.85 (d, J = 9.0
Hz, 2H), 7.71 (d, J = 9.0 Hz, 2H), 7.62(d, J = 15.6 Hz, 1H),
7.58 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 7.2 Hz,
1H), 7.15 (t, J = 8.4 Hz, 1H), 6.81(d, J = 15.6 Hz, 1H),
2.31(s, 3H), 2.30(s, 3H). IR (KBr, cm−1): υNH: 3373.57,
3126.20; υCH: 2894.37, 2839.76; υC=O: 1780.48, 1756.71;
1591.16, 1511.81; υS=O: 1339.11, 1157.60; υC-O: 1284.13,
1255.86; γ=C-H: 812.00. HRMS (ESI) m/z for C21H16N2O5F3S
[M+H]+: calcd 465.0727, found 465.0732.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(4-
Fluorobenzylsulfamoyl)phenyl)acrylamide(11d)
White powder, yield 61.7%, mp 232.6–233.4°C. 1H-NMR
(DMSO-d6) δ: 10.45 (s, 1H), 9.54 (s, 1H), 9.24 (s, 1H),
υ
C=C: 1675.56, 1628.51, 1588.90, 1523.21; υS=O: 1369.15,
Journal of Enzyme Inhibition and Medicinal Chemistry

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors 635
7.51 (d, 1H, J= 9.0 Hz), 7.44(d, J= 16.2 Hz, 1H), 7.27 (d,
J= 2.4Hz, 1H), 7.09 (dd, J= 8.4 Hz, J= 2.4 Hz, 1H), 7.02 (s,
1H), 6.93(d, J= 7.8 Hz, 1H), 6.78 (d, J= 7.8 Hz, 1H), 6.52(d,
J= 16.2 Hz, 1H). IR (KBr, cm−1): υOH: 3350.13; υ=C-H: 2975.28;
8.05 (t, J = 6.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.74 (d,
J = 9.0 Hz, 2H), 7.46(d, J = 15.6 Hz, 1H), 7.28 (dd, J = 6.6
Hz, J = 2.4 Hz, 2H), 7.11 (t, J = 2.4 Hz, 2H), 7.03 (d, J = 1.8
Hz, 1H), 6.94 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.79(d,
J = 8.4 Hz, 1H), 6.56(d, J = 15.6 Hz, 1H), 3.96(d, J = 6.0 Hz,
2H). IR (KBr, cm−1): υOH: 3554.10; υNH: 3417.04, 3343.80,
3142.88; υ=CH: 2923.71; υC=O: 1673.54; υC=C: 1630.45,
υC=O:1671.24;υC=C:1590.80, 1528.13, 1473.75;υS=O:1303.19,
1158.09; υC-O: 1254.24, 1182.35; γ=C-H: 812.90. HRMS (ESI)
m/z for C21H17N2O5Cl2S [M+H]+: calcd 479.0230, found
479.0240.
1591.89, 1534.26, 1510.76; υS=O
: 1316.31, 1300.72,
1150.78; υC-O: 1263.14, 1226.07; γ=C-H: 834.15. HRMS
(ESI) m/z for C22H20N2O5FS [M+H]+: calcd 443.1071,
found 443.1074.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(4-
Butylphenylsulfamoyl)phenyl)acrylamide(11i)
Yellowish powder, yield 61.7%, mp 197.5–198.8°C. 1H-
NMR (DMSO-d6) δ: 10.43 (s, 1H), 10.03 (s, 1H), 9.54 (s,
1H), 9.23 (s, 1H), 7.79 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 9.0 Hz,
2H), 7.44(d, J= 15.6 Hz, 1H), 7.03 (t, J= 7.8 Hz, 3H), 7.98
(d, J= 8.4 Hz, 2H), 6.93 (d, J= 8.4 Hz, 1H), 6.78 (d, J= 8.4
Hz, 1H), 6.53(d, J= 15.6 Hz, 1H), 2.45(t, 2H), 1.46(qui, 2H),
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(4-
Bromophenylsulfamoyl)phenyl)acrylamide(11e)
Yellowish powder, yield 59.7%, mp 192.4–193.8°C. 1H-
NMR (DMSO-d6) δ: 10.45 (s, 1H), 10.37 (s, 1H), 9.54 (s,
1H), 9.24 (s, 1H), 7.82 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 8.4 Hz,
2H), 7.43(d, J= 15.6 Hz, 1H), 7.42 (d, J= 6.6 Hz, 2H), 7.09
(d, J= 9.0 Hz, 2H), 7.02 (s, 1H), 6.93 (dd, J= 8.4 Hz, J= 1.2
Hz, 1H), 6.78 (d, J= 7.8 Hz, 1H), 6.53(d, J= 15.6 Hz, 1H).
1.22(sxt, 2H), 0.85(t, 3H). IR (KBr, cm−1): υNH: 3254.37; υ=CH
:
2955.51, 2927.02; υCH: 2856.14; υC=O: 1661.42; υC=C: 1591.22,
1523.20, 1446.16; υS=O: 1332.40, 1154.78; υC-O: 1280.48,
1254.34; γ=C-H: 833.60. HRMS (ESI) m/z for C25H27N2O5S
[M+H]+: calcd 467.1635, found 467.1641.
IR (KBr, cm−1): υNH: 3252.48; υ=CH: 2973.66, 2923.03; υC=O
:
1658.84; υC=C: 1609.69, 1590.86, 1523.07; υS=O: 1329.76,
1155.90; υC-O: 1278.82, 1256.06; γ=C-H: 832.77. HRMS (ESI)
m/z for C21H18N2O5BrS [M+H]+: calcd 489.0114, found
489.0113.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(4-
Ethoxylphenylsulfamoyl)phenyl)acrylamide(11j)
Yellowish powder, yield 51.7%, mp 184.7–185.6°C. 1H-
NMR (DMSO-d6) δ: 10.40 (s, 1H), 10.40 (s, 1H), 9.74 (s,
1H), 9.37 (s, 1H), 7.78 (d, J= 9.0 Hz, 2H), 7.62 (d, J= 8.4 Hz,
2H), 7.43(d, J= 15.6 Hz, 1H), 7.01 (s, 1H), 6.95 (d, J= 8.4
Hz, 1H), 6.92 (d, J= 7.2 Hz, 1H), 6.78 (d, J= 8.4 Hz, 3H),
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3-
Bromophenylsulfamoyl)phenyl)acrylamide(11f)
1
White powder, yield 66.4%, mp 197.8–198.8°C. H-NMR
(DMSO-d6) δ: 10.48 (s, 1H), 10.46 (s, 1H), 9.53 (s, 1H),
9.23 (s, 1H), 7.83 (d, J= 8.4 Hz, 2H), 7.73 (d, J= 9.0 Hz,
2H), 7.43(d, J= 15.6 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J= 4.8
Hz, 2H), 7.10 (dd, J= 8.4 Hz, J= 4.8 Hz, 1H), 7.01 (d, J= 1.8
Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 6.52(d, J= 15.6 Hz, 1H). IR
6.52(d, J= 15.6 Hz, 1H). IR (KBr, cm−1): υNH: 3256.27; υ=C-H
2979.28, 2929.24; υC=O: 1667.04; υC=C: 1591.04, 1509.65;
:
υ
S=O: 1332.67, 1154.38; υC-O: 1282.50, 1252.17; γ=C-H: 836.69.
HRMS (ESI) m/z for C23H23N2O6S [M+H]+: calcd 455.1271,
found 455.1271.
(KBr, cm−1): υOH: 3373.22; υ=CH: 2974.84; υC=O: 1672.16; υC=C
1592.69, 1533.27, 1497.67, 1474.69; υS=O: 1335.92, 1159.47;
:
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3,5-
υ
C-O: 1286.96, 1257.41; γ=C-H: 879.69. HRMS (ESI) m/z for
C21H18N2O5BrS [M+H]+: calcd 489.0114, found 489.0118.
Dimethylphenylsulfamoyl)phenyl)acrylamide (11k)
Yellowish powder, yield 72.7%, mp 222.4–223.8°C. 1H-
NMR (DMSO-d6) δ: 10.42 (s, 1H), 10.05 (s, 1H), 9.52 (s,
1H), 9.22 (s, 1H), 7.80 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 8.4 Hz,
2H), 7.43(d, J= 15.6 Hz, 1H), 7.01 (d, J= 1.8 Hz, 1H), 6.92
(dd, J= 8.4 Hz, J= 2.4 Hz, 1H), 6.78 (d, J= 8.4 Hz, 1H), 6.71
(s, 2H), 6.64 (s, 1H), 6.52(d, J= 15.6 Hz, 1H), 2.15 (s, 6H). IR
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(2-
Bromophenylsulfamoyl)phenyl)acrylamide(11g)
White powder, yield 68.9%, mp 208.7–209.3°C. H-NMR
(DMSO-d6) δ: 10.46 (s, 1H), 9.77 (s, 1H), 9.54 (s, 1H), 9.24
(s, 1H), 7.83 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 8.4 Hz, 2H),
7.58(dd, J= 8.4 Hz, J= 1.8 Hz, 1H), 7.45(d, J= 15.6 Hz, 1H),
7.32 (m, 1H), 7.19 (dd, J= 8.4 Hz, J= 1.8 Hz, 1H), 7.14(dt,
J= 7.8 Hz, J= 1.8 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 6.93 (dd,
J= 7.8 Hz, J= 1.8 Hz, 1H), 6.78(d, J= 7.8 Hz, 1H), 6.54(d,
J= 15.6 Hz, 1H). IR (KBr, cm−1): υOH:3354.20; υC=O:1670.63;
1
(KBr, cm−1): υOH: 3349.14; υNH: 3245.78; υCH: 2919.73; υC=O
1670.03; υC=C: 1591.23, 1520.88; υS=O: 1357.42, 1150.45;
:
υ
C-O: 1285.02, 1253.35; γ=C-H: 839.76. HRMS (ESI) m/z for
C23H23N2O5S [M+H]+: calcd 439.1322, found 439.1327.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3-chloro-2-
fluorophenylsulfamoyl)phenyl)acrylamide (11l)
υ
υ
C=C:1589.37, 1514.80, 1476.41; υS=O:1332.90, 1153.28;
C-O:1282.67, 1253.48; γ=C-H: 817.01. HRMS (ESI) m/z for
1
C21H18N2O5BrS [M+H]+: calcd 489.0114, found 489.0120.
Yellowish powder, yield 76.7%, mp 229.5–230.8°C. H-
NMR (DMSO-d6) δ: 10.48 (s, 1H), 10.34 (s, 1H), 9.54 (s,
1H), 9.24 (s, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.69(d, J = 9.0
Hz, 2H), 7.45(d, J = 15.6 Hz, 1H), 7.37 (t, J = 6.6 Hz, 1H),
7.21 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 8.4 Hz, 1H), 7.02 (d,
J = 1.8 Hz, 1H), 6.93 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.78
(d, J = 8.4 Hz, 1H), 6.54(d, J = 16.2 Hz, 1H). IR (KBr,
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3,4-
Dichlorophenylsulfamoyl)phenyl)acrylamide(11h)
White powder, yield 77.4%, mp 226.8–228.1°C. H-NMR
(DMSO-d6) δ: 10.62 (s, 1H), 10.47 (s, 1H), 9.54 (s, 1H),
9.23 (s, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H),
1
© 2012 Informa UK, Ltd.

636 S. Yu et al.
J= 8.4 Hz, 1H), 6.52(d, J= 15.6 Hz, 1H). IR (KBr, cm−1): υOH
:
cm−1): υOH: 3353.47; υNH: 3251.51; υ=CH: 2923.67; υC=O
:
3348.49; υNH: 3262.00; υC=O: 1667.98; υC=C: 1590.60, 1526.70,
1497.30; υS=O: 1325.69, 1302.62, 1155.45; υC-O: 1256.54;
γ
1668.04; υC=C: 1591.11, 1522.04, 1498.29; υS=O: 1329.46,
1158.03; υC-O: 1281.46, 1253.84; γ=C-H: 816.97. HRMS
(ESI) m/z for C21H17N2O5FClS [M+H]+: calcd 463.0525,
found 463.0532.
=C-H: 814.94. HRMS (ESI) m/z for C21H17N2O5FClS [M+H]+:
calcd 463.0525, found 463.0527.
N-(4-phenylsulfamoylphenyl)3,4-
dihydroxybenzamidebenzamide (11w)
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-
phenylsulfamoylphenyl)acrylamide (11m)
1
Yellowish powder, yield 62.2%, mp 190.3–192.2°C. 1H-
NMR (DMSO-d6) δ: 10.42 (s, 1H), 10.18 (s, 1H), 9.52 (s,
1H), 9.22 (s, 1H), 7.80 (d, J= 8.40 Hz, 2H), 7.70 (d, J= 9.0
Hz, 2H), 7.43 (d, J= 15.60 Hz, 1H), 7.22 (t, J= 7.80 Hz, 2H),
7.09 (d, J= 7.80 Hz, 2H), 7.02 (t, J= 7.20 Hz, 2H), 6.92 (d,
J= 8.40 Hz, 1H), 6.78 (d, J= 7.80 Hz, 1H), 6.52 (d, J= 15.60
White powder, yield 77.6%, mp 257.9–258.6°C. H-NMR
(DMSO-d6) δ: 10.25 (s, 1H), 10.17 (s, 1H), 9.69 (br, 1H),
8.28 (br, 1H), 7.89 (d, J= 9.0 Hz, 2H), 7.70 (d, J= 8.4 Hz,
2H), 7.36 (d, J= 2.4 Hz, 1H), 7.33 (dd, J= 8.4 Hz, J= 1.8 Hz,
1H), 7.22 (t, J= 8.4 Hz, 2H), 7.09 (d, J= 7.8 Hz, 2H), 7.01
(t, J= 7.8 Hz, 1H), 6.82 (d, J= 7.8 Hz, 1H). IR (KBr, cm−1):
Hz, 1H). IR (KBr, cm−1): υOH: 3452.60; υNH: 3348.49; υC=O
1672.72; υC=C: 1607.40, 1590.00, 1524.01, 1494.62; υS=O
1296.63, 1151.19; υC-O: 1250.85, 1182.95, γ=C-H: 810.24,
754.32, 690.90. HRMS (ESI) m/z for C21H19N2O5S [M+H]+:
calcd 411.1009, found 411.1019.
:
:
υ
υ
υ
OH: 3477.24, 3395.34; υNH: 3304.26, 3225.24; υC=O: 1652.66;
C=C: 1589.62, 1521.36, 1440.46; υS=O: 1316.36, 1153.08;
C-O: 1252.05, 1228.84; γ=C-H: 835.70, 755.85, 720.74. HRMS
(ESI) m/z for C19H17N2O5S [M+H]+: calcd 385.0853, found
385.0869.
N-(4-(3-Bromophenylsulfamoyl)phenyl)3,4-
dihydroxybenzamide (11x)
White powder, yield 59.7%, mp 237.8–238.9°C. H-NMR
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(4-
Fluorophenethylsulfamoyl)phenyl)acrylamide(11t)
White powder, yield 60.9%, mp 219.7–220.8°C. H-NMR
1
1
(DMSO-d6) δ: 10.49 (s, 1H), 10.29 (s, 1H), 9.72 (s, 1H),
9.30 (s, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.73 (d, J= 9.0 Hz, 2H),
7.37(d, J= 2.4 Hz, 1H), 7.33 (dd, J= 7.8 Hz, J= 2.4 Hz, 1H),
7.25 (s, 1H), 7.20 (d, J= 3.6 Hz, 2H), 7.12 (m, 1H), 6.83(d,
J= 7.8 Hz, 1H). IR (KBr, cm−1): υOH: 3366.32; υNH: 3259.89;
(DMSO-d6) δ: 10.46 (s, 1H), 9.54 (s, 1H), 9.24 (s, 1H), 7.86
(d, J= 9.0 Hz, 2H), 7.72 (d, J= 9.0 Hz, 2H), 7.58(t, J= 6.0 Hz,
1H), 7.46(d, J= 15.6 Hz, 1H), 7.19 (m, 2H), 7.08 (m, 2H),
7.03 (d, J= 1.8 Hz, 1H), 6.94 (dd, J= 8.4 Hz, J= 1.8 Hz 1H),
6.79(d, J= 7.8 Hz, 1H), 6.56(d, J= 15.6 Hz, 1H), 2.94(m,
2H), 2.67(t, J= 7.2 Hz, 2H). IR (KBr, cm−1): υOH: 3531.21;
υC=O:1655.16;υC=C:1590.39, 1506.42, 1474.57;υS=O:1321.75,
1151.66; υC-O: 1290.01, 1251.33; γ=C-H: 841.39. HRMS (ESI)
m/z for C19H16N2O5BrS [M+H]+: calcd 462.9958, found
462.9962.
υ
NH: 3343.43, 3193.45; υ=CH: 2924.33; υC=O: 1676.65; υC=C:
1601.44, 1587.46, 1526.17, 1507.89; υS=O: 1311.10, 1298.07,
1147.08; υC-O: 1255.07, 1228.00; γ=C-H: 824.78. HRMS (ESI)
m/z for C23H22N2O5FS [M+H]+: calcd 457.1228, found
457.1231.
Biological assays
All compounds were dissolved in DMSO, and the stock
solutions were stored at−20°C. e γ[32P]ATP was pur-
chased from MP Biomedical. e expression systems
for the wild-type IN were generous gifts of Dr. Robert
Craigie, Laboratory of Molecular Biology, NIDDK, NIH,
Bethesda, MD.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3-bromo-4-
fluorophenylsulfamoyl)phenyl)acrylamide (11u)
White powder, yield 73.2%, mp 227.4–228.3°C. 1H-
NMR (DMSO-d6) δ: 10.47 (s, 1H), 10.38 (s, 1H), 9.54 (s,
1H), 9.24 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.69(d, J = 8.4
Hz, 2H), 7.44(d, J = 15.6 Hz, 1H), 7.32 (dd, J = 6.0 Hz,
J = 2.4 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 7.10 (m, 1H),
7.01 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.4 Hz, J = 1.8 Hz,
1H), 6.78 (d, J = 7.8 Hz, 1H), 6.53(d, J = 15.6 Hz, 1H). IR
(KBr, cm−1): υOH: 3347.33; υ=CH: 2923.74; υC=O: 1668.79;
Preparation of oligonucleotide substrates
e oligonucleotides 21 top, 5´-GTGTGGAAAATCTCTAG
CAGT-3´and 21 bot, 5´-ACTGCTAGAG- ATTTTCCACAC-3´
were purchased from the Norris Cancer Center Core Facility
(University of Southern California), and purified by UV
shadowing on a polyacrylamide gel. To analyze the extent
of 3´-processing and strand transfer using 5´-end-labeled
substrates, 21 top was 5´-end-labeled using T4 polynucleo-
tide kinase (Epicenter, Madison, WI) and γ[32P]ATP (MP
Biomedical). e kinase was heat-inactivated, and 21 bot
was added in 1.5-molar excess. e mixture was heated to
95°C, allowed to cool slowly to room temperature, and run
through a spin 25 mini-column (USA Scientific) to separate
the annealed double-stranded oligonucleotide from unin-
corporated material.
υ
υ
C=C: 1590.82, 1525.03, 1492.73; υS=O: 1302.36, 1155.37;
C-O: 1282.35, 1255.38; γ=C-H: 815.04. HRMS (ESI) m/z
for C21H17N2O5FBrS [M+H]+: calcd 509.0000, found
508.9988.
(E)-3-(3,4-Dihydroxyphenyl)-N-(4-(3-chloro-4-
fluorophenylsulfamoyl)phenyl)acrylamide (11v)
Yellowish powder, yield 79.1%, mp 220.3–221.3°C. 1H-
NMR (DMSO-d6) δ: 10.46 (s, 1H), 10.40 (s, 1H), 9.53 (s,
1H), 9.23 (s, 1H), 7.82 (d, J= 8.4 Hz, 2H), 7.69(d, J= 9.0
Hz, 2H), 7.44(d, J= 15.6 Hz, 1H), 7.32 (t, J= 9.0 Hz, 1H),
7.22 (dd, J= 6.6 Hz, J= 2.4 Hz, 1H), 7.06 (m, 1H), 7.01 (d,
J= 1.8 Hz, 1H), 6.93 (dd, J= 8.4 Hz, J= 1.8 Hz, 1H), 6.78 (d,
All biological assays were performed essentially as
previously described19.
Journal of Enzyme Inhibition and Medicinal Chemistry

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors 637
Results and discussion
Chemistry
The synthesis of compound 3, 6 and 7 series were
shown in Schemes 1. Using compound 2 series as
raw material, compound 3 series were synthesized
by direct mono-sulfonylation with 4-acetamidoben-
zene-1-sulfonyl followed by the acetyl removal under
alkaline conditions in methanol at room temperature.
Compound 4 and 5 series were protected with etha-
noyl in the presence of pyridine, and then reacted with
thionyl chloride under reflux at 80°C to give compound
6 and 7 series. Schemes 2 describes the synthesis of
compounds 8 and 9 series. Compounds 8 series were
synthesized through amidation between 3 and 6 in
acetone. Compound 9 series were finally synthesized
by esterolysis using tetrahydrofuran-methanol-con-
centrated hydrochloric acid (2:2:1, v/v/v) as a solvent
avoided the hydrolysis of the amide linkage. The syn-
thesis of compound 10 and 11 were similar with com-
pound 9 and 10 series with 3 and 7 as raw material as
shown in Schemes 3.
Scheme 1. Reagents and conditions: (i) 4-acetamidobenzene-
1-sulfonyl chloride, pyridine, 0°C− rt, 4 h; (ii) 5M NaOH, MeOH,
70°C, 4h; (iii) Ac2O, pyridine, rt, 24h; (iv) SOCl2, 80°C, 5h.
In series 9, installing weak electron-donating substitu-
ents on the terminal aromatic ring caused a drop of activity,
while introduction of electron-withdrawing substituents
resulted in similar or improved potency. However, intro-
duction of both electron-withdrawing and electron-donat-
ing substituents on the terminal aromatic in series 11 gave
slightly higher ST inhibitory potency while such introduc-
tion resulted in irregular diversifications in 3´-P inhibitory
potency. Either extending the chain length between the
Structure-activity relationships in HIV-1 IN inhibition
All compounds were initially tested in an in vitro assay
specific for IN. As shown in Tables 1, 2 and 3, these inhib-
itors demonstrated activities against IN-mediated 3´-P
and ST at micromolar concentrations.
Table 1. Inhibition of HIV-1 integrase catalytic activities of compounds 9a-s.
Inhibition of HIV-1 IN IC50 (μM)*
Inhibition of HIV-1 IN IC50 (μM)*
Code
9a
9b
9c
Code
9k
3´-P
7
ST
3´-P
ST
0.9 0.1
1.5
8
2
2.5 0.5
0.8 0.21
1.5 0.1
4
7
7
3
2
5
5
3
2
2
3
2
1
3
1
1
9l
1.3
3
2
2
1
9m
9n
9o
9p
9q
9r
7
6
5
8
3
2
2
3
9d
9e
9f
2
2
8
1
1
1
0.7 0.3
0.7 0.3
1.4 0.3
1.7
9g
9h
9i
5
4.5
4
7
2
3
3
2
0.2
1
2.5 0.5
1.3
9s
9j
6
*IC50, Inhibitory concentration 50% (inhibition of purified integrase).
Table 2. Inhibition of HIV-1 integrase catalytic activities of compounds 11a-m, t-x.
Inhibition of HIV-1 IN IC50 (μM)*
Inhibition of HIV-1 IN IC50 (μM)*
Code
11a
11b
11c
11d
11e
11f
Code
11j
3´-P
ST
3´-P
35 15
ST
8
11
29
24
3
1
9
8
5
1
1
1
4
4
9
2
1
3
9
1
1
6
4
1
1
2
6
11
9
11k
11l
5
1
4
14
12
10
4
22 12
11m
11t
16
14
8
5
1
2
2
35 15
49 23
8
22
9
11u
11v
11w
11x
11g
11h
11i
11
17
25
1
9
3
8
4
6
100
50 10
15
7
45
7
5
*IC50, Inhibitory concentration 50% (inhibition of purified integrase).
© 2012 Informa UK, Ltd.

638 S. Yu et al.
was maintained for both series 9 and 11, while 3´-P inhibi-
tory activity increased by 2-fold for series 9 and decreased
by 4-fold for series 11. Migration of the bromo substitu-
ent from the 4- to the 3-position or 2-position resulted in
diversity of results of inhibitory potencies for series 9 and
11. In series 9, bromo substituent at the 4- and 3-position
exhibited higher 3´-P and ST inhibitory activity relative
to 2-position analogue (9e v 9f v 9g). In series 11, the 4-
and 2-position Br analogues showed higher ST inhibitory
activity relative to 3-position analogue, while the 2-posi-
tion Br analogue displayed stronger 3´-P inhibitory activ-
ity relative to 3- and 4-position analogues (11e v 11f v 11g).
A noteworthy feature is that these halogens could be
incorporated in different combinations of substituted
positions to further improve potency, such as com-
pounds 9l, 11u and 11v. Compounds 9l is one of the best
inhibitors with IC50 values of 1.3 and 0.8 μM for 3´-P and
ST in series 9 and compounds 11u and 11v had the best
efficacy against ST in series 11 with an IC50 value of 4 μM.
ese observations suggested that halogen substitution
on the terminal aromatic ring showed improved potency,
consistent with the previous report13.
In series 11, compound 11m exhibited higher inhibi-
tory potencies relative to compound 11w, while com-
pound 11f exhibited a comparable inhibitory profile to
that of compound 11x, which suggested that a double
bond between the caffeoyl group and the amide group
had irregular effect on IN inhibitory potency.
Intrigued by the blockage from the phenolic hydroxyl
group, several acetylated derivatives have been synthe-
sized and studied. Masking of the phenolic hydroxyl
groups with acetylate group caused various IN inhibitory
Scheme 2. Reagents and conditions: (v) pyridine, acetone, 0°C−
rt, 20h; and (vi) MeOH, THF, HCl, 60°C, 1h.
terminal aromatic ring and the sulfonamide group (9a v
9d and 11a v 11d v 11t) or increasing the number of fluoro
substituents (9a v 9b v 9c and 11a v 11b v 11c) caused a
loss of ST inhibitory activity in both series 9 and 11. When
the 4-fluoro substituent was replaced by a 4-bromo group
(9a v 9e and 11a v 11e), intrinsic ST inhibition potency
Scheme 3. Reagents and conditions: (vii) pyridine, acetone, -5°C− rt, 16h; and (viii) EtOH, THF, HCl, 65°C, 0.5h.
Journal of Enzyme Inhibition and Medicinal Chemistry

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors 639
Table 3. Inhibition of HIV-1 integrase catalytic activities of compounds 8g, l, m, s and 10b, h, k, l.
Inhibition of HIV-1 IN IC50 (μM)*
3´-P ST
Inhibition of HIV-1 IN IC50 (μM)*
Code
8g
Code
10b
10h
10k
10l
3´-P
ST
12
7
3
1
60 0.01
75 35
80 28
50 18
11 0.01
8l
5
3
2
0.4
1.6
1.6
7
16
13
0.4
1
8m
8s
8
>10
7
*IC50, Inhibitory concentration 50% (inhibition of purified integrase).
Table 4. Anti-HIV activity and cytotoxicity of selected compounds in HIV-1 infected MT-4 cells.
Anti-HIV-1 activity
Cytotoxicity CC50
Anti-HIV-1 activity
Code
9g
EC50 (μM)§
(μM)¶ in MT-4
Code
11v
8g
EC50 (μM) §
Cytotoxicity CC50 (μM) ¶ in MT-4
>25
>25
20
>25
>25
22
>14
>25
>25
25
14
>25
>25
20
9l
11b
11e
11g
11k
11l
8l
>15
13
15
10b
10h
10k
10l
49
>20
>13
>25
20
>12
12
13
19
21
>25
§EC50 is the effective concentrations inhibiting 50% HIV replication.
¶CC50, cytotoxic concentration 50%.
activities diversity. Compounds 8g, 8l, 10b and 10k
showed slight weaker inhibitory activities against ST and
3´-P compared to 9g, 9l, 11b and 11k, while compounds
8m, 8s, 10h and 10l kept the important ST inhibitory
activity compared to 9m, 9s, 11h and 11l. We consider
that these acetylated compounds may be pro-inhibitors
which are deacetylated by the enzyme in the assay; or/
and the carbonyl, instead of the phenolic hydroxyl group,
bond to Mg2+ or Mn2+ to carry out inhibitory activities for
IN, which needs to be further investigated.
activities and anti-viral activities was resulted from off-
target effects and cell penetrance issues.
conclusion
In conclusion, four series of novel nitrogen-containing
polyhydroxylated aromatics with sulfanilamide linkers
have been identified as IN inhibitors. Most of the com-
pounds inhibited the catalytic activities of IN in micro-
molar concentrations and compounds 9e and 9f were
the most potent ST inhibitors with IC50 value of 0.7 μM.
e biological experimental results indicated that (1) the
role of the halogen substitution on the terminal aromatic
ring is important for potency; (2) the length of the linker
between the terminal aromatic ring and the sulfonamide
group has a weak deleterious effect on potency; (3)
masking of catechol or galloyl functionality with acetyl
group causes no substantial loss of inhibitory activities
against ST. ese results prompted us to carry out further
research mainly focusing on designing novel IN inhibi-
tors with the aim to further increase the IN inhibitory
activity and anti-viral activity and decrease the toxicities.
Inhibition of HIV replication in culture
To assess the potential utility of the new compounds as
anti-HIV agents, we tested some of synthesized com-
pounds for the ability to inhibit HIV replication in cell
cultures. e toxicity of the compounds was also evalu-
ated using MT-4 cells (Table 4).
At first, some of compounds 9 series with a gal-
loyl group (such as 9g and 9l) had been tested for their
anti-HIV activity and cytotoxicity; however, all of them
didn’t exhibit anti-viral activity at a concentration of 25
μM. Recently, it was reported that the compounds with
the catechol group displayed strong anti-viral activity at
nanomole concentrations16. So compounds series 11 had
also been synthesized in order to increase their anti-viral
activity. is set of compounds showed higher cytotoxic-
ity although they exhibited improved anti-viral activity.
Compounds 11b and 11l showed similar anti-viral activ-
ity and cytotoxicity at a concentration of around 20 μM.
Compound 11g exhibited a moderate anti-viral activity
with a therapeutic index of ~4. However, compounds 11b,
11l and 11g were less potent IN inhibitors compared with
compound 9l which was one of the best inhibitors but
didn’t exhibit anti-viral activity at a concentration of 25
μM. We believed that the disparity between IN inhibitory
Declaration of interest
is work was financially supported by the National
Natural Science Foundation of China (No20872082).
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