Identification of 1-aryl-1H-1,2,3-triazoles as potential new antiretroviral agents

Article abstract of DOI:10.2174/1573406413666170906121318

Background: Low molecular weight 1-Aryl-1H-1,2,3-triazoles are endowed with various types of biological activities, such as against cancer, HIV and bacteria. Despite the existence of six different classes of antiretroviral drugs in clinical use, HIV/AIDS

Full text of DOI:10.2174/1573406413666170906121318

2
42
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Medicinal Chemistry, 2018, 14, 242-248
RESEARCH ARTICLE
eISSN: 1 85 7 53 - 64 60 36 84
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.
Identification of 1-Aryl-1H-1,2,3-Triazoles as Potential New Antiretroviral
Agents
1
2
2
3
Daniel T.G. Gonzaga , Thiago M.L. Souza , Viviane M.M. Andrade , Vitor F. Ferreira and
1
,*
Fernando de C. da Silva
1
Universidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Campus do
2
Valonguinho, 24020-150, Niterói-RJ, Brazil; Fundação Oswaldo Cruz, Presidência da Fiocruz, Centro de Desen-
volvimento Tecnológico em Saúde, Instituto Oswaldo Cruz, Laboratório de Imunofarmacologia, 21040-360 - Rio de
3
Janeiro-RJ, Brazil; Universidade Federal Fluminense, Departamento de Tecnologia Farmacêutica, Faculdade de
Farmácia, 24241-002, Niterói-RJ, Brazil
Abstract: Background: Low molecular weight 1-Aryl-1H-1,2,3-triazoles are endowed with various
types of biological activities, such as against cancer, HIV and bacteria. Despite the existence of six dif-
ferent classes of antiretroviral drugs in clinical use, HIV/AIDS continue to be an on growing public
health problem.
Objective: In the present study, we synthesized and evaluated thirty 1-Aryl-1H-1,2,3-triazoles against
HIV replication.
A R T I C L E H I S T O R Y
Method: The compounds were prepared by Huisgen 1,3-dipolar cycloaddition protocol catalyzed by
Received: April 27, 2017
Revised: July 26, 2017
Cu(I) between aryl azides and propargylic alcohol followed by further esterification and etherification
from a nucleophilic substitution with acid chlorides or alkyl bromides in good yields. The compounds
were submitted to the inhibition of HIV replication and evaluation of their cytotoxicity. Initially, the
compounds were screened at 10 ꢀM and the most active were further evaluated in order to obtain some
pharmacological parameters.
Accepted: August 15, 2017
DOI:
1
0.2174/1573406413666170906121318
Results: Thirty molecules were evaluated, six were selected – because they inhibited more than 80%
HIV replication. We further showed that two of these compounds are 8-times more potent, and less cy-
totoxic, than nevirapine, an antiretroviral drug in clinical use.
Conclusion: We identified very simple triazoles with promissing antiretroviral activities that led to the
development of new drugs against AIDS.
Keywords: AIDS, antiretroviral agents, antiretroviral drug, Copper(I)-catalyzed azide alkyne cycloaddition (CuAAC), Huisgen
cycloaddition, inhibition of HIV.
1
. INTRODUCTION
chemokine receptors CCR5 or CXCR4 onto cellular surface.
During HIV-1 life cycle, viral RNA undergoes reverse tran-
scription, which is accomplished by the action of the viral
enzyme reverse transcriptase (RT), and the resulting cDNA
is further integrated in the host cell genome. New progeny
virions are assembled bud through the cell membrane and
get mature due to the effect of viral protease [2]. In order to
suppress HIV-1 replication and delay clinical progression to
AIDS, several drugs have been studied [3]. Currently, there
are 24 drugs approved for clinical use against HIV, these are
distributed in six distinct classes due to their mechanisms of
action and resistance [4] (Fig. 1): (i) nucleoside reverse tran-
scriptase inhibitors (NRTIs), such as azidovudine, better
known as AZT (1); (ii) non-nucleoside reverse transcriptase
inhibitors (NNRTIs), such as efavirenz (2); (iii) (iv) protease
inhibitors (PIs), like ritonavir (3); (iv) integrase inhibitors,
The acquired immunodeficiency syndrome (AIDS) is a
disease of the human immune system caused by the human
immunodeficiency virus (HIV). Despite the success of
highly active antiretroviral therapy (HAART), which in-
creases the lifespan of HIV-infected individuals, it is esti-
mated that over 35 million people are infected by this virus
worldwide. Among these, around 2 million people die of
AIDS yearly, of which 330,000 are children [1].
HIV-1 enters T helper lymphocytes, monocyte/macrophages
and dendritic cells, by using the CD4 molecule and
*
Address correspondence to this author at the Universidade Federal
Fluminense, Departamento de Química Orgânica, Instituto de Química,
Campus do Valonguinho, 24020-150, Niterói-RJ, Brazil;
E-mail: gqofernando@vm.uff.br
1
875-6638/18 $58.00+.00
© 2018 Bentham Science Publishers

Identification of 1-Aryl-1H-1,2,3-triazoles as Potential New Antiretroviral Agents
Medicinal Chemistry, 2018, Vol. 14, No. 3 243
O
H
O
O
N
H
N
NH
N
N
H
N
O
HO
N
O
Cl
HO
O
F3C
S
O
S
N
H
O
3
N
3
1
2
N
O
F
F
OH
F
N
H
N
N
O
5
HN
O
O
O
NH
N
4
N
N
N
N
N
Fig. (1). Representative molecules of the HAART.
O
2
H N
N
N
2
H N
N
N
N
O
NH2
O
O
S
NH
2
H
O
H
N
Cl
TBSO
O
S
N
O
O
N
N
N
N
N
HO
O
N
O
N
Cl
COOH
COOH
O OTBS
O
N
6
H
S
7
8
9
Cl
Fig. (2). Drugs containing the heterocycle 1,2,3-triazole.
for example raltegravir (4); (v) fusion inhibitors, e.g. enfu-
virtide, a 36 amino acids peptide; and (vi) coreceptor an-
tagonists as maraviroc (5). The above mentioned classes I to
V target viral proteins, whereas the sixth category aims at a
cellular component [4]. The combination of drugs from three
distinct classes composes the HAART, which aims to reduce
the viral load and thereby recover some cellular parameters
such as the number and functionality of CD4 + T cells [2].
However, this combination is not able to eliminate HIV-1
from infected tissues [2]. In addition, multiresistant strains
have been described [5-8]. It was expected that at least the
fitness of multiresistant viruses would be reduced, but sur-
prisingly, primary infections with these strains have been
described [5-9]. The combination of compounds that com-
prises HAART also presents another limitation, high cyto-
toxicity, which leads the host to metabolic disorders [4, 10].
Therefore, the continuous search for new antiretroviral drugs
is pivotal.
Recently, we can find some 1H-1,2,3-triazoles capable of
inhibition of HIV virus replication. Fang and coworkers [13]
synthesized a series of dihydroalkylthiobenzyl-oxopyrimidines
(S-DABO) derivatives with the substituted 1H-1,2,3-triazole
moiety with significative anti HIV-1 potency (EC50 up to
3.22 ꢀM) compared with the drug 3TC (EC50 2.24 ꢀM). In
another study, Wu et al. [14] developed new 1H-1,2,3-
triazoles conjugated with nucleosides leading to new com-
pounds that exhibited potent anti-HIV-1 activity with no
cytotoxicity at concentration up to 25 ꢀM.
As part of our research program on the synthesis of new
biologically active compounds, we prepared several new
triazoles and evaluated their inhibitory profile against the
HIV virus. We now report our results of the synthesis and in
vitro evaluation of low molecular weight 1-Aryl-1H-1,2,3-
triazoles against HIV virus growth.
2
. MATERIALS AND METHODS
A variety of biological activities are found for heterocy-
cles containing 1,2,3-triazole nucleus [11] and some exam-
ples of drugs with this core heterocycle (Fig. 2) are: antican-
cer carboxyanidatriazole (6), NNRTI known as TSAO (7)
and antibiotics beta-lactams such as tazobactam (8) and
cephalosporinacefatrizine (9) [12].
2.1. Chemistry
The reagents were purchased from Sigma-Aldrich Brazil
and were used without further purification. Column chroma-
tography was performed with silica gel 60 (Merck 70-230

2
44 Medicinal Chemistry, 2018, Vol. 14, No. 3
Gonzaga et al.
OR
N
N
O
R
N
Inhibition
N
N
N
8
9
9
8
8
8
9%
1%
0%
8%
5%
1%
O
11e, R = Propyl, X = 4-Cl
1
1
1
1h, R = Propyl, X = 2,5-Cl
1k, R = Propyl, X = 3,5-Cl
1n, R = Propyl, X = 4-OMe
R = Ribofuranose (Inhibition 63.6%)
Xylofuranose (Inhibition 64.7%)
X
12e, R = Hexanoyl, X = 2,5-Cl
12i, R = Hexanoyl, X = 4-OMe
Fig. (3). HIV inhibition of glycotriazoles versus 1-Aryl-1H-1,2,3-triazoles
.
mesh). Analytical thin layer chromatography was performed
with silica gel plates (Merck, TLC silica gel 60 F254), hex-
ane:ethyl acetate (7:3) as eluent, and the plots were visual-
ized using UV light or aqueous solutions of ammonium sul-
fate. The indicated yields refer to chromatographically and
spectroscopically homogeneous materials. Melting points
were obtained on a Fischer-Johns apparatus and were uncor-
rected. Infrared spectra were measured with KBr pellets on a
63.3, 71.5, 121.9, 122.2, 129.9, 133.1, 135.6, 145.7; Anal.
Calcd for. C12
H
14ClN O: C, 57.26; H 5.61; N, 16.69. Found:
3
C, 57.42; H, 5.82; N, 16.37.
2.1.4. 1-(2,5-Dichlorophenyl)-4-ethoxy-1H-1,2,3-Triazole
(11g)
-1
Obtained in 50 % as a yellow oil, R = 0.70; IR (KBr, cm ):
f
3
141, 2975, 2868, 1732, 1588, 1487, 1448, 1376, 1231,
Perkin-Elmer model 1420 FT-IR Spectrophotometer, and the
1
-
1
1097, 1038, 874, 809, 698, 671, 651; NMR H (500 MHz,
spectra were calibrated relative to the 1601.8 cm absor-
bance of polystyrene. NMR spectra were recorded on a Var-
DMSO-d
6
) ꢀ: 1.27 (3H, t, J 3.9 Hz); 3.67 (2H, q, J 3.9 Hz);
4
5
.70 (s, 2H); 7.84 (1H, dd, J 5.4 and 1.5 Hz); 7.92 (1H, d, J
.4 Hz); 8.02 (1H, d, J 1.5 Hz); 8.63 (1H, s); NMR 13C (125
) ꢀ: 14.9, 62.8, 65.0, 125.8, 127.4,
28.0, 131.2, 131.8, 132.4, 135.5, 144.4; Anal. Calcd for.
O: C, 48.55; H 4.07; N, 15.44. Found: C, 48.63;
H, 4.02; N, 15.37.
ian Unity Plus VXR (500 MHz) instrument in DMSO-d
6
solutions. The chemical shift data were reported in the units
of d (ppm) downfield from tetramethylsilane or the solvent,
either of which was used as an internal standard; coupling
constants (J) are reported in hertz and refer to apparent peak
multiplicities. CHN elemental analyses were performed on a
Perkin-Elmer 2400 CHN elemental analyzer.
MHz APT, DMSO-d
6
1
C
11
H
11Cl
2
N
3
2
.1.5. 1-(2,5-Dichlorophenyl)-4-propoxy-1H-1,2,3-triazole
(
11h)
2
.1.1. General Procedure for Preparing 1,2,3-Triazoles
-1
Obtained in 50 % as a yellow oil, R = 0.73; IR (KBr, cm ):
f
The protocols for preparing all of the 1H-1,2,3-triazoles
2
1
d
962, 2872, 1588, 1486, 1450, 1369, 1231, 1096, 1037,
and the physical and spectroscopic data for 10a-e, 11a, 11c-
d, 11f, 11i, 11m, 12a-e, 12g-h, 12j were previously reported
in our studies [15, 16]. All the triazoles were fully character-
1
000, 874, 811, 760, 694, 651; NMR H (500 MHz, DMSO-
6
) ꢀ: 0.99 (3H, t, J 7.0 Hz); 1.67 (2H, pent, J 7.0 Hz); 3.58
1
13
(2H, t, J 7.0 Hz); 3.61 (2H, t, J 6.9 Hz); 4.72 (2H, s); 7.85
ized by H NMR, C NMR, IR spectroscopy and CHN ele-
mental analysis.
(
1H, dd, J 9.0 and 2.5 Hz); 7.92 (1H, d, J 9.0 Hz); 8.01 (1H,
13
d, J 3.0 Hz); 8.66 (1H, s); NMR C (125 MHz APT,
DMSO-d ) ꢀ: 10.5, 22.4, 63.0, 71.3, 125.9, 127.5, 128.2,
31.4, 131.9, 132.5, 135.5, 144.4; Anal. Calcd for.
6
2
.1.2. 4-(Propoxymethtyl)-1-phenyl-1H-1,2,3-Triazole (11b)
Obtained in 62 % as a yellow oil, R = 0.82; IR (KBr,
1
C
f
12
H
13Cl
2
3
N O: C, 50.37; H 4.58; N, 14.68. Found: C, 50.24;
-
1
cm ): 2961, 2933, 2872, 1730, 1598, 1503, 1465, 1377,
H, 4.52; N, 14.88.
1
1
339, 1229, 1095, 1040, 989, 814, 757, 690; NMR H (500
) ꢀ: 0.87 (3H, t, J 7.0 Hz); 1.54 (2H, sext, J
.0 Hz); 3.45 (2H, t, J 7.0 Hz); 4.58 (2H, s); 7.75 (1H, t, J
.7 Hz); 7.59 (2H, t, J 7.7 Hz); 7.89 (2H, d, J 7.7 Hz); 8.76
MHz, DMSO-d
6
2.1.6. 1-(3,5-Dichlorophenyl)-4-(Dthoxymethyl)-1H-1,2,3-
triazole (11j)
7
7
1
3
Obtained in 54% as a yellow solid, R = 0.55, m.p. 49-50ºC;
f
(
1H, s); NMR C (125 MHz APT, DMSO-d
3.3, 71.5, 120.2, 122.2, 128.8, 130.0, 136.8, 145.6; Anal.
Calcd for. C12 O: C, 66.34; H, 6.96; N, 19.34. Found:
C, 66.54; H, 7.12; N, 18.89.
6
) ꢀ: 10.6; 22.5,
-
1
IR (KBr, cm ): 2974, 2927, 2865, 1728, 1585, 1475, 1440,
6
1
1
374, 1334, 1278, 1094, 1039, 851, 807, 666; NMR H (500
H
15
N
3
MHz, DMSO-d ) ꢀ: 1.28 (3H, t, J 6.5 Hz); 3.67 (2H, t, J 6.5
6
Hz); 4.71 (2H, s); 7.86 (1H, t, J 2.0); 8.19 (1H, d, J 2.0 Hz);
1
3
9
6
.03 (1H, s); NMR C (125 MHz APT, DMSO-d
3.0, 65.1, 118.6, 122.4, 127.9, 135.2, 138.3, 145.7; Anal.
O: C, 48.55; H 4.07; N, 15.44. found:
6
) ꢀ: 15.0,
2
.1.3. 1-(4-Chlorophenyl)-4-(Propoxymethyl)-1H-1,2,3-
triazole (11e)
Calcd for. C11
C, 48.66; H, 3.98; N, 15.40.
H
11Cl
2
N
3
Obtained in 45% as a yellow solid, R
f
= 0.74, m.p. 75-76ºC;
-
1
IR (KBr, cm ): 3160, 2968, 2932, 2871, 1721, 1563, 1502,
1
6
7
4
456, 1341, 1229, 1194, 1092, 984, 954, 837, 817, 783, 737,
1
2
.1.7. 1-(3,5-Dichlorophenyl)-4-(Propoxymethyl)-1H-1,2,3-
97, 753; NMR H (500 MHz, DMSO-d ) ꢀ: 0.99 (3H, t, J
6
triazole (11k)
Obtained in 68% as a yellow solid, R
.0 Hz); 1.66 (2H, sext, J 7.0 Hz); 3.56 (2H, t, J 7.0 Hz);
.70 (2H, s); 7.77-7.79 (2H, m); 8.05-8.07 (2H, m); 8.90
f
= 0.65, m.p. 49-50ºC;
IR (KBr, cm ): 3142, 3048, 2922, 2872, 1585, 1476, 1436,
(
1H, s); NMR 1 C (125 MHz APT, DMSO-d
3
6
) ꢀ: 10.6, 22.5,
-1

Identification of 1-Aryl-1H-1,2,3-triazoles as Potential New Antiretroviral Agents
Medicinal Chemistry, 2018, Vol. 14, No. 3 245
1
6
365, 1337, 1228, 1088, 1036, 1004, 955, 889, 853, 811,
C
19
H
25Cl
2
N
3
O
2
: C, 57.29; H, 6.33; N, 10.55. Found: C,
1
67; NMR H (500 MHz, DMSO-d
6
) ꢀ: 0.88 (3H, t, J 7.5
57.00; H, 6.25; N, 10.65.
Hz); 1.55 (2H, sext, J 7.5 Hz); 3.45 (2H, t, J 7.5 Hz); 4.58
(
(
2H, s); 7.74 (2H, t, J 2.0 Hz); 8.07 (2H, d, J 2.0 Hz); 8.91
2.1.12. (1-(4-Methoxyphenyl)-1H-1,2,3-triazole-4-il)metyl
hexanoate (12i)
1
3
1H, s); NMR C (125 MHz APT, DMSO-d
3.2, 71.4, 118.5, 122.3, 127.8, 135.2, 138.2, 145.7; Anal.
O: C, 50.37; H 4.58; N, 14.68. Found:
C, 50.44; H, 4.59; N, 14.34.
6
) ꢀ: 10.5, 22.4,
6
-1
Obtained in 55 % as a yellow oil R
f
= 0.58; IR (KBr, cm ):
Calcd for. C12
H
13Cl
2
N
3
2
1
932, 2870, 1734, 1611, 1518, 1462, 1304, 1253, 1164,
1
109, 1034, 989, 832, 770; NMR H (500 MHz, DMSO-d )
6
ꢀ
: 0,96 (3H, t, J 7.4 Hz); 1.35-1.40 (4H, m); 1.52 (2H, pent, J
.4 Hz); 2.45 (2H, t, J 7.34 Hz); 3.95 (3H, s); 5.33 (2H, s);
.25 (2H, d, J 9.0 Hz); 7,91 (2H, d, J 9.0 Hz); 8.82 (1H, s);
2
.1.8. 1-(3,5-Dichlorophenyl)-4-(butoxymethyl)-1H-1,2,3-
7
7
triazole (11l)
1
3
Obtained in 54% as a yellow solid, R
f
= 0.74, m.p. 47-48ºC;
NMR C (125 MHz APT, DMSO-d
6
) ꢀ: 13.7, 21.7, 24.1,
-
1
IR (KBr, cm ): 3139, 2932, 2863, 1586, 1475, 1443, 1371,
30.6, 33.3, 55.6, 56.9, 114.9, 121.8, 122.8, 130.0, 142.9,
159.4, 172.6; Anal. Calcd for. C16
1
1
335, 1264, 1091, 1040, 1003, 852, 810, 666; NMR H (500
MHz, DMSO-d ) ꢀ: 1.00 (3H, t, J 7.0 Hz); 1.45 (2H, pent, J
.0 Hz); 1.61-1.67 (2H, m); 3.61 (2H, t, J 7.0 Hz); 4.70 (2H,
s); 7.86 (1H, t, J 2.0, Hz); 8.19 (1H, d, J 2.0 Hz); 9.03 (1H,
H
21
N
3
3
O : C, 63.35; H,
6
6.98; N, 13.85. Found: C, 63.05; H, 7.12; N, 13.89.
7
2.2. Biological Assays
1
3
s); NMR C (125,0 MHz APT, DMSO-d
1.3, 63.2, 69.5, 118.6, 122.3, 127.8, 135.3, 138.3, 145.8;
Anal. Calcd for. C13 O: C, 52.01; H 5.04; N, 14.00.
Found: C, 52.24; H, 5.22; N, 14.30.
6
) ꢀ: 13.7, 18.8,
2
.2.1. Cells
3
H
15Cl
2
N
3
Peripheral blood mononuclear cells (PBMCs) from healthy
human donors were obtained by density gradient centrifuga-
tion (Hystopaque, Sigma). Cells were resuspended in RPMI
1640 (LGCBio, São Paulo, BR) supplemented with 10 %
heat-inactivated fetal bovine serum (FBS, Hyclone, Logan,
UT), penicillin (100 U/mL), streptomycin (100 ꢀg/mL), 2
mM glutamine and 10 mM HEPES, stimulated with 2 ꢀg/mL
of phytohemagglutinin (PHA, Sigma) during two to three
days. PHA-stimulated cells were further maintained in cul-
ture medium containing 5 U/mL of recombinant human in-
terleukin-2 (Sigma).
2
.1.9. 1-(4-Methoxyphenyl)-4-(proproxymethyl)-1H-1,2,3-
triazol (11n)
-
1
Obtained in 65% as a yellow oil, R
f
= 0.74; IR (KBr, cm ):
2
1
0
873, 1611, 1518, 1461, 1377, 1303, 1253, 1190, 1094,
1
037, 989, 832, 768, 695; NMR H (500 MHz, DMSO-d
6
) ꢀ:
.99 (3H, t, J 7.0 Hz); 1.67 (2H, sext, J 7.0 Hz); 3.56 (2H, t,
J 7.0 Hz); 3.95 (3H, s); 4.69 (2H, s); 7.23-7.26 (2H, m);
.90-7.94 (2H, m); 8.78 (1H, s); NMR 1 C (125 MHz APT,
3
7
DMSO-d
6
) ꢀ: 10.5, 22.4, 55.6, 63.3, 71.3, 114.9, 121.7,
2
.2.2. Effects of the Compounds on Cell Viability
1
6
22.0, 130.1, 145.1, 159.3; Anal. Calcd for. C13
H
17
N
3
2
O : C,
3.14; H 6.93; N, 16.99. found: C, 63.44; H, 6.72; N, 16.55.
To evaluate the safety of tested compounds to human
cells, activated human PBMCs were plated in 96-well cul-
ture plates (2 x 10 cells/well) and exposed to increasing
concentrations of the compounds for seven days. Thus, cell
viability was examined using the Trypan blue dye exclusion
assay, and the resulting CC50 values were calculated by lin-
ear regression [17].
5
2
.1.10. 4-(Butoxymethyl)-1-(4-metoxyphenyl)-1H-1,2,3-
triazole (11o)
Obtained in quantitative yield as brown solid, R
f
= 0.35,
m.p. 63-64 C; IR (KBr, cm ): 2932, 2866, 1610, 1517, 1462,
375, 1304, 1254, 1190, 1095, 1039, 989, 831, 767, 695;
o
-1
1
1
NMR H (500 MHz, DMSO-d
6
) ꢀ: 0.99 (3H, t, J 6.9 Hz);
.41-1.48 (2H, m); 1.60-1.67 (2H, m); 3.60 (2H, t, J 6.6 Hz);
.95 (3H, s); 4.68 (2H, s); 7.25 (2H, d, J 9.2 Hz); 7.92 (2H,
2
.2.3. Effect of Compounds on HIV-1 Replication
1
3
PBMCs were initially exposed during two to three hours
1
3
d, J 9.2 Hz); 8.78 (1H, s); NMR C (125 MHz APT,
to viral suspensions containing 10 ng/mL of HIV-1BA-L p24
Ag. Cells were washed, resuspended in complete medium,
DMSO-d
6
) ꢀ: 13.8, 18.9, 31.2, 55.6, 63.3, 69.4, 114.9, 121.8,
1
6
22.0, 130.2, 145.2, 159.3; Anal. Calcd for. C14
H
19
N
3
O
2
: C,
5
plated in 96-well culture plates (2x10 cells/well) in tripli-
4.35; H 7.33; N, 16.08. Found: C, 64.44; H, 7.13; N, 16.35.
cates, and treated with compounds at various concentrations
o
[
17]. After 7 days at 37 C in 5 % CO
2
, viral replication was
2
.1.11. (1-(2,5-Dichlorophenyl)-1H-1,2,3-triazol-4-
assessed by measuring the HIV-1 p24 Ag in culture super-
natants using an ELISA capture assay (ZeptoMetrix Co., Buf-
falo, NY). Viral replication was evaluated by measuring the
HIV-1 p24 Ag in culture supernatants, as described above.
yl)methyl decanoate (12f)
o
Obtained in 95% as a white solid, R
f
= 0.81, m.p. 35-36 C;
-
1
IR (KBr, cm ): 3664, 2919, 2852, 1741, 1588, 1489, 1451,
1
8
377, 1285, 1252, 1210, 1168, 1102, 1074, 1043, 1018, 874,
1
22, 722, 651; NMR H (500 MHz, DMSO-d ) ꢀ: 0.97 (3H,
6
3
. RESULTS AND DISCUSSION
t, J 7.0 Hz); 1.30-1.41 (12H, m); 1.59-1.67 (2H, m); 2.46
(
2H, t, J 7.0 Hz); 5.36 (2H, s, H-6); 7.85 (2H, dd, J 8.0 e 2.0
The 1,2,3-1H-triazoles (10a-e) were prepared by Huisgen
Hz); 7.93 (1H, d, J 8.0 Hz); 8.01 (1H, d, J 2,0 Hz); 8,42 (1H,
1,3-dipolar cycloaddition protocol in which a reaction of aryl
azides and propargylic alcohol was catalyzed by Cu(I), pro-
viding only regioisomer 1,4-disubstituted at high yields (65-
95%). The etherified (11a-n) and esterified (12a-q) deriva-
1
3
s); NMR C (125 MHz APT, DMSO-d
2
1
6
) ꢀ; 13.9, 22.0, 24.4,
8.4, 28.6, 28.8, 31.3, 33.4, 33.7, 56.7, 126.7, 127.5, 128.1,
31.5, 131.9, 132.5, 135.3, 142.3, 172.6; Anal. Calcd for.

2
46 Medicinal Chemistry, 2018, Vol. 14, No. 3
Gonzaga et al.
tives were made from acylation or alkylation reaction be-
tween the alcohol (10) and acid chlorides or alkyl bromides
in basic medium, respectively (Scheme 1).
Compounds
1g
11h
Substitutents
R = C
Inhibition (%)
2
H
5
1
0
X = 2,5-Cl
R = C
3
H
7
OR
91
35
66
90
54
27
88
23
X = 2,5-Cl
N
N
RBr, NaH
R = C
4
H
9
1
1i
1j
X = 2,5-Cl
N
11a-o
THF, Reflux
R = C
2
H
5
1
OH
X
X = 3,5-Cl
X
N
N
R = C H
3
7
1
1k
X = 3,5-Cl
N
O
R = C H
4
9
R
11l
X = 3,5-Cl
N
N
O
O
R = C
X = 4-OMe
2
H
5
1
0a-e
1
1m
N
R
Cl
12a-j
R = C
X = 4-OMe
3
H
7
CH Cl , Py , r.t.
2
2
11n
X
R = C
4
H
9
1
1o
Scheme 1. Synthesis of esters and ethers 1-aryl-1H-1,2,3-triazoles.
X = 4-OMe
O
X
Initially, the most active compounds were selected by
their ability to inhibit HIV replication at 10 ꢀM. We ob-
served the percentage of inhibition (%) superior to 80 % for
1
2a-j
N
R
N
O
N
R = COC
X = H
5
H
H
H
11
19
11
19
11
1
1
1
1
1
2a
2b
2c
2d
2e
54
35
11
20
85
20
20
53
81
27
6
out of the 30 compounds tested (Table 1). For comparison,
the NNRTI nevirapine (13) inhibited HIV replication by 98%.
R = COC
X = H
9
Table 1. Percentage of inhibition of 1H-1,2,3-triazoles.
R = COC
5
X = 4-Cl
Compounds
Substitutents
Inhibition (%)
R = COC H
X = 4-Cl
9
HO
X
10a-e
N
R = COC
5
H
N
X = 2,5-Cl
N
R = COC
X = 2,5-Cl
9
H
19
1
1
1
1
1
0a
X = H
32
29
28
32
29
1
2f
0b
0c
0d
0e
X = 4-Cl
R = COC
5
H
11
1
1
2g
2h
X = 2,5-Cl
X = 3,5-Cl
X = 4-OMe
X = 3,5-Cl
R = COC H
9
19
X = 3,5-Cl
R = COC
5
H
11
RO
X
12i
2j
X = 4-OMe
1
1a-o
N
N
N
R = COC H
9
19
1
X = 4-OMe
R = C
2
H
5
7
9
5
1
1
1
1
1
1a
37
63
20
21
89
21
X = H
R = C
3
H
1b
1c
1d
1e
9
8
X = H
R = C
4
H
X = H
R = C H
2
Among the aforementioned most active triazoles ana-
logues in Table 1, we further examined some pharmacologi-
cal parameters related with the antiviral potency and cytotox-
icity. We observed that all series of 1H-1,2,3-triazoles are
less cytotoxic than antiretrovirals in clinical use, such as
nevirapine (13, Table 2). With respect to antiretroviral po-
tency, the best triazole (11h) was up to 8 times more active
X = 4-Cl
R = C
3
H
7
X = 4-Cl
R = C
4
H
9
1
1f
X = 4-Cl
(
Table 1) Contd….

Identification of 1-Aryl-1H-1,2,3-triazoles as Potential New Antiretroviral Agents
Medicinal Chemistry, 2018, Vol. 14, No. 3 247
Table 2. IC50, CC50 and selective index of 1H-1,2,3-triazoles.
Compounds
IC50 (ꢀM)
CC50 (ꢀM)
Selective Index*
1
1
1
1
1
1e
1h
1k
1n
2e
0.4
0.1
0.1
0.5
1.3
0.3
0.8
1285
1349
1281
1089
1201
1345
890
3212
13490
12810
2178
924
1
2i
4483
1112
1
3
*
Selective index is calculated based on the ratio between CC50 and IC50 values.
than nevirapine (13, Table 2). Consequently, the hits were
over 10-fold more selective than reference antiretrovirals in
clinical use (Table 2) [4, 18] (Fig. 3).
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