Synthesis of nerol derivatives containing a 1,2,3-triazole moiety and evaluation of their activities against cancer cell lines

Article abstract of DOI:10.21577/0103-5053.20180203

In the present investigation, a collection of twenty two nerol derivatives, containing 1,2,3-triazolic appendages, was synthesized and screened in vitro for their cytotoxic activity against HL60, Nalm6, and Jurkat human leukemia cells as well as against B16F10 (melanoma cell line). In most cases, derivatives were able to reduce cell viability. The most potent compound (Z)-4-(((3,7-dimethylocta-2,6-dien-1-yl)oxy)methyl)-1-(4-(trifluoromethoxy)benzyl)-1H-1,2,3 triazole showed antiproliferative activity against Jurkat cells and reduced B16F10 cell migration. Physicochemical properties of the compounds were calculated in order to evaluate their potential for drug development. Most of the evaluated physicochemical parameters seemed to be favorable for drug development. In addition, for a better understanding of the biological activity results, 3D quantitative structure-activity relationship (QSAR) studies were carried out. 3D-QSAR studies indicate that the anticancer activities observed for the cell lines HL60 and Jurkat may occur by a similar mechanism of action and the same was found for the Nalm6 and B16F10 cell lines.

Full text of DOI:10.21577/0103-5053.20180203

http://dx.doi.org/10.21577/0103-5053.20180203
J. Braz. Chem. Soc., Vol. 30, No. 3, 541-561, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Article
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of
Their Activities against Cancer Cell Lines
Róbson R. Teixeira, *,a Adalberto M. da Silva,b Raoni P. Siqueira,c Victor Hugo S. Gonçalves,c
Higor S. Pereira,c Rafaela S. Ferreira,d Adilson V. Costa,e Eduardo B. de Melo,f Fávero R. Paula,g
Márcia M. C. Ferreira h and Gustavo C. Bressanc
aDepartamento de Química, Universidade Federal de Viçosa,
Av. P.H. Rolfs, S/N, 36570-900 Viçosa-MG, Brazil
bInstituto Federal de Educação, Ciência e Tecnologia Catarinense, Campus Araquari,
Rodovia BR 280, km 27, CP 21, 89245-000 Araquari-SC, Brazil
cDepartamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa,
Av. P.H. Rolfs, S/N, 36570-900 Viçosa-MG, Brazil
dDepartamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais,
Av. Antônio Carlos 6627, 31270-901 Belo Horizonte-MG, Brazil
eDepartamento de Química e Física, Universidade Federal do Espírito Santo,
Alto Universitário, S/N, Guararema, 29500-000 Alegre-ES, Brazil
fLaboratório de Química Medicinal e Ambiental Teórica (LQMAT), Departamento de Farmácia,
Universidade Estadual do Oeste do Paraná (UNIOESTE), Rua Universitária 2069,
85819-110 Cascavel-PR, Brazil
gDepartamento de Farmácia, Universidade Federal do Pampa (UNIPAMPA),
BR 472, km 592, P.O. Box 118, 97500-970 Uruguaiana-RS, Brazil
hInstituto de Química, Universidade Estadual de Campinas, 13084-971 Campinas-SP, Brazil
In the present investigation, a collection of twenty two nerol derivatives, containing
1,2,3-triazolic appendages, was synthesized and screened in vitro for their cytotoxic activity
against HL60, Nalm6, and Jurkat human leukemia cells as well as against B16F10 (melanoma
cell line). In most cases, derivatives were able to reduce cell viability. The most potent
compound (Z)-4-(((3,7-dimethylocta-2,6-dien-1-yl)oxy)methyl)-1-(4-(trifluoromethoxy)benzyl)-
1H-1,2,3 triazole showed antiproliferative activity against Jurkat cells and reduced B16F10 cell
migration. Physicochemical properties of the compounds were calculated in order to evaluate their
potential for drug development. Most of the evaluated physicochemical parameters seemed to be
favorable for drug development. In addition, for a better understanding of the biological activity
results, 3D quantitative structure-activity relationship (QSAR) studies were carried out. 3D-QSAR
studies indicate that the anticancer activities observed for the cell lines HL60 and Jurkat may occur
by a similar mechanism of action and the same was found for the Nalm6 and B16F10 cell lines.
Keywords: nerol, 3D-QSAR, leukemia, melanoma, click chemistry
Introduction
screening of natural products from plants, animals, marine
organisms and microorganisms. In the particular case of
cancer, from 1/1/1981 to 12/31/2014, Newman an Cragg7
pointed out that among 174 new chemical entities approved
as anticancer drugs, 136 (78%) corresponded to small
molecules. Moreover, 113 out of 136 (83%) were either
natural products per se or based on them, or mimicked
Mother Nature is a formidable reservoir of compounds
that can be explored for the search and development of
pharmaceuticals.1-6 Several drugs have been discovered via
*e-mail: robsonr.teixeira@ufv.br

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Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
natural products in one form or another.7 Vincristine,
irinotecan, etoposide and paclitaxel are examples of
natural product based drugs that have been used in cancer
chemotherapy.8 It should be mentioned that compounds
from natural sources have been optimized through evolution
process and present physicochemical properties well-suited
for successful drug development into the market.
In the discovery of new chemotherapeutic agents, one
important aspect is the use of synthetic strategies that
allow the rapid construction of compounds or libraries
of compounds during the process of drug discovery or
lead optimization. The very fast preparation of groups
of bioactive compounds speeds up the process of drug
discovery and lead optimization. The click chemistry has
emerged as one powerful tool in drug discovery.17-19 As
defined by Sharpless and co-workers,20 the click chemistry
refers to reactions that are regiospecific in nature and can
be performed easily, yielding highly pure compounds
with fewer efforts. The most popular reaction that meet
the aforementioned criteria is the copper(I)-catalyzed
azide-alkyne cycloaddition (CuAAC reaction). In this
transformation, a 1,2,3-triazole ring 1,4-disubstituted is
obtained from a terminal alkyne and an azide and it is
commonly known in the literature as click reaction. A
variety of bioactive compounds,21 including anticancer
agents,22-27 have been synthesized using the click reaction
as the key step. It should be mentioned that 1,2,3-triazole
ring is an attractive unit, since it is stable to metabolic
degradation, oxidative/reducing conditions, and improves
solubility by actively binding to biomolecular targets.28
This ring is also known as the pharmacophoric group.21
Considering the cytotoxicity activity of nerol, the
necessity to develop new chemotherapeutic agents for
cancer treatment, and the anticancer activity related
to 1,2,3-triazole derivatives, we herein described the
structural modification of nerol into derivatives containing
1,2,3-triazole portions (Figure 1).
Essential oils can be defined as odorous and volatile
mixtures found in 10% of the plant kingdom and stored in
special delicate secretory structures. They are composed
of very complex natural mixtures containing hydrocarbons
(mainly terpenoids) and oxygenated compounds (alcohols,
esters, ethers, aldehydes, ketones, lactones, phenols and
phenol ethers). Essential oils are widely used in medicine,
in perfumes, cosmetics and bath products, as flavoring
agents in food and drink, and in many other manufacturing
areas. Since immemorial times, their therapeutic value has
been recognized by man.9 These oils are a valuable source
of very interesting and powerful natural plant products.
One very common compound found in essential oil
is nerol [(2Z)-3,7-dimethylocta-2,6-dien-1-ol]. From the
chemical standpoint, nerol (Figure 1) is a monoterpene
commonly used in fragrances, soaps, shampoos, cleaners
and detergents. Moreover, this compound is found in
several medicinal plants such as Lippia spp. and Melissa
officinalis L. Investigations have ascribed antimicrobial,
antioxidant, antiviral and anxiolytic activities to these
plant species which, in turn, have been attributed to the
presence of nerol.10
Yamamoto et al.11 investigated the effect of
phosphatidylated terpenes alcohols on human prostate PC-3
and human leukemia HL60 cell lines. Treatment of these
cell lines with phosphatidyl-nerol derivative (Figure 1) at
100 µmol L-1 and after 72 h led to a decrease of 70% in cell
viability. Nerol itself had no effect on cell line viabilities
even at 400 µmol L-1.11
Nowadays, several chemotherapeutic regimes have been
successfully implemented for fighting cancer. However,
most treatments are associated with severe side-effects and
resistance, highlighting the necessity of a constant effort
toward the development of novel therapies.12-16
The key reaction involved in the preparation of
twenty two nerol analogues corresponded to the click
reaction between several benzyl azides and alkylated
nerol derivatives. The cytotoxicity of the synthesized
compounds was evaluated against human leukemias and
murine melanoma cell lines. Physicochemical properties
were also calculated in order to evaluate the potential of
the synthesized nerol derivatives for drug development. 3D
quantitative structure-activity relationship (QSAR) studies
were carried out in order to have a better understanding
about the anticancer mechanism against each cell line.
Figure 1. Structures of nerol and nerol derivatives.

Vol. 30, No. 3, 2019
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543
Experimental
these compounds were in agreement with those reported
in the literature.29
Generalities
Synthesis of azidomethylbenzene (3a)
Solvents were purchased from Vetec (Rio de
Janeiro, Brazil). Nerol, benzyl alcohols, pent-4-yn-1-ol,
methanesulfonyl chloride, sodium azide, triethylamine and
propargyl bromide solution (80 wt.% in toluene, containing
0.3% of magnesium as stabilizer) were procured from
Sigma-Aldrich (St. Louis, MO, USA) and used as received.
1H and 13C nuclear magnetic resonance (NMR) spectra were
recorded on aVarian Mercury 300 instrument (Varian, Palo
Alto, CA, USA) at 300 and 75 MHz, respectively, using
CDCl3 as solvent. 1H NMR data are presented as follows:
chemical shift (d) in ppm, multiplicity, number of protons,
J values in hertz (Hz). Multiplicities are shown as the
following abbreviations: s (singlet), brs (broad singlet), d
(doublet), dd (double of a doublet), t (triplet), dt (double
of a triplet), q (quartet), quint (quintet), m (multiplet).
For fluorine containing derivatives, the multiplicity of
some carbon signals are described along with J values in
hertz. Infrared (IR) spectra were obtained using a Varian
660-IR equipped with GladiATR (Varian, Palo Alto, CA,
USA) scanning from 4000 to 500 cm-1. Analytical thin
layer chromatography (TLC) analyses were conducted on
aluminum backed precoated silica gel plates using different
solvent systems and were visualized using potassium
permanganate solution, phosphomolybdic acid solution
and/or UV light. Column chromatography was performed
using silica gel (60-230 mesh).
Benzyl methanesulfonate (2a) (930 mg, 5.00 mmol) was
added to a 50 mL round-bottom flask containing 10 mL of
DMSO (dimethyl sulfoxide) and 1.33 g (20.0 mmol) of
sodium azide. The reaction mixture was stirred at room
temperature for 6 h. After that, 10 mL of water (5 °C) were
added to the reaction mixture and the resulting aqueous
phase was extracted with ethyl acetate (3 × 15 mL). The
organic extracts were combined and the resulting organic
phase was washed with saturated NaCl aqueous solution
(3 × 15 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. Compound 3a was obtained in
97% yield (650 mg, 4.88 mmol) and it was not submitted
to any further purification procedure.
Benzyl azides 3b-3k (Scheme 1) were synthesized
using this same methodology. The spectroscopic data of
these compounds are in agreement with those reported in
the literature.29
Synthesis of (Z)-3,7-dimethyl-1-(prop-2-yn-1-yloxy)octa-
2,6-diene (7)
A 125 mL round bottom flask, under nitrogen
atmosphere, was charged with sodium hydride (480 mg,
20.0 mmol) and 10 mL of anhydrous THF (tetrahydrofuran).
The resulting mixture was heated to 40 °C. Then,
(2Z)-3,7-dimethylocta-2,6-dien-1-ol (nerol, compound 6 in
Scheme 1), dissolved in 2 mL of anhydrous THF was added
slowly. The system was kept at 40 °C and magnetically
stirred for 15 h. After that, a solution of propargyl bromide
(1.33 mL, 15.0 mmol) in THF (2 mL) was slowly added.
The reaction mixture was maintained at 40 °C and
magnetically stirred for additional 7 h. Upon completion of
the reaction as noticed by TLC analysis, 20 mL of 2 mol L-1
HCl aqueous solution were added. The aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The organic phases
were combined and the resulting organic layer was washed
with water (20 mL) and brine (20 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The
crude reaction product was purified by silica gel column
chromatography using a solvent mixture of hexane/ethyl
acetate (10:1 v/v). Compound 7 was obtained as brown oil
in 97% yield (1.88 g, 9.70 mmol). TLC: Rf = 0.50 (hexane/
Synthesis
Synthesis of benzyl methanesulfonate (2a)
Benzyl alcohol (1.08 g, 10.0 mmol) and anhydrous
dichloromethane (DCM, 20 mL) were added to a 50 mL
round-bottom flask under nitrogen atmosphere. The mixture
was cooled to –50 °C and then triethylamine (2.78 mL,
20.0 mmol) was added, followed by slow addition of
methanesulfonyl chloride (Ms-Cl, 1.20 mL, 15.0 mmol).
The progress of the reaction was monitored by TLC. After
its completion, 20 mL of water were added. The layers
were separated and the organic layer was washed with
1% m/v HCl aqueous solution (3 × 15 mL), followed by
NaHCO3 saturated aqueous solution (3 × 5 mL), dried over
MgSO4, and concentrated under reduced pressure. The
compound 2a was obtained in 87% yield (1.63 g, 8.76 mmol)
and it was not submitted to any further purification
procedure.
ethyl acetate 10:1 v/v); IR (ATR)
/ cm-1 3303, 2965,
2926, 2855, 2114, 1666, 1591, 1444, 1376, 1251, 1070,
932, 828, 664, 628; 1H NMR (300 MHz, CDCl3) d 1.60 (s,
3H), 1.68 (s, 3H), 1.75 (s, 3H), 2.09 (s, 4H), 2.40 (t, 1H,
J 2.3 Hz), 4.05 (d, 2H, J 7.0 Hz), 4.11 (d, 2H, J 2.3 Hz),
5.09 (brs, 1H), 5.33 (t, 1H, J 7.0 Hz); 13C NMR (75 MHz,
Ester sulfonates 2b-2k (Scheme 1) were synthesized
using this same methodology. The spectroscopic data of

544
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
Scheme 1. Reagents and conditions: (i) and (iii) TEA, Ms-Cl, DCM, –50 °C; (ii) NaN3, DMSO, r.t.; (iv) NaH, THF, propargyl bromide, 40 °C; (v) NaH,
THF, compound 5, 40 °C; (vi) and (vii) sodium ascorbate, CuSO4∙5H2O, CH2Cl2/H2O.
CDCl3) d 17.6, 23.5, 25.6, 26.7, 32.2, 56.7, 65.7, 74.1, 80.0,
120.9, 123.8, 132.0, 141.7; mass spectrometry-electron
ionization (MS-EI), m/z (%): 192 (3) C13H20O [M+•], 177
(2), 153 (2), 149 (3), 136 (6), 121 (25), 107 (13), 93 (60),
80 (31), 69 (100), 55 (16), 41 (81).
and triethylamine (5.60 mL, 40.0 mmol) was added. After
that, methanesulfonyl chloride was added slowly (2.32 mL,
30.0 mmol) to the reaction mixture under continuous
stirring. The progress of the reaction was monitored by
TLC. After completion of it, 10 mL of water were added.
The organic phase was washed with 1% HCl aqueous
solution (3 × 15 mL) followed by saturated NaHCO3
aqueous solution (3 × 5 mL), dried over MgSO4, and
concentrated under reduced pressure. Compound 5 was
obtained as yellow oil in 92% yield (3.00 g, 18.0 mmol) and
Synthesis of pent-4-yn-1-yl methanesulfonate (5)
Pent-4-yn-1-ol (1.68 g, 20.0 mmol) and dichloromethane
(20 mL) were added to a 50 mL round-bottom flask under
nitrogen atmosphere. The mixture was cooled to –50 °C

Vol. 30, No. 3, 2019
Teixeira et al.
545
it was not submitted to any further purification procedure.
TLC: Rf = 0.76 (hexane/ethyl acetate 10:1 v/v); IR (ATR)
/ cm-1 3286, 3025, 2964, 2938, 2116, 1436, 1351,
1173, 1012, 974, 938, 832, 656, 528; 1H NMR (300 MHz,
CDCl3) d 1.93 (quint, 2H, J 6.1 Hz), 1.99 (t, 1H, J 2.7 Hz),
2.33 (dt, 2H, J1 6.1 Hz, J2 2.7 Hz), 3.00 (s, 3H), 4.32 (t,
2H, J 6.1 Hz); 13C NMR (75 MHz, CDCl3) d 14.6, 27.7,
37.1, 68.2, 69.7, 82.0; MS-EI, m/z (%): 162 (0) C6H10O3S
[M+•], 122 (3), 109 (5), 97 (4), 83 (29), 79 (51), 66 (100),
55 (19), 40 (22).
of sodium ascorbate and 144 mg (0.750 mmol) of
compound 7. Then, it was added 38.0 mg (0.150 mmol) of
CuSO4⋅5H2O. The reaction mixture was vigorously stirred
at room temperature for 24 h. After this time, saturated
aqueous solution of Na2CO3 was added and the resulting
aqueous layer was extracted with ethyl acetate (3 × 5 mL).
The organic extracts were combined and the resulting
organic layer was dried over anhydrous MgSO4, filtered and
concentrated under reduced pressured. The crude product
was purified by silica gel column chromatography eluted
with hexane/ethyl acetate/dichloromethane (3:1:3 v/v).
Compound 9a was obtained as yellow oil in 53% yield
(106 mg, 0.330 mmol) along with 25 mg of unreacted
compound 7. TLC: Rf = 0.48 (hexane/ethyl acetate/
Synthesis of (Z)-3,7-dimethyl-1-(pent-4-yn-1-yloxy)octa-
2,6-diene (8)
A 125 mL round-bottom flask was charged with sodium
hydride (480 mg, 20.0 mmol) and 10 mL of anhydrous
THF. The mixture was warmed to 40 °C followed by slow
addition of (2Z)-3,7-dimethylocta-2,6-dien-1-ol (nerol,
compound 6 in Scheme 1) (1.54 g, 10.0 mmol) dissolved
in anhydrous THF (2 mL). The system was maintained
at 40 °C and magnetically stirred for 15 h. After that, a
solution of compound 5 (2.43 g, 15.0 mmol) in THF (2 mL)
was added slowly. The resulting reaction mixture was
maintained at 40 °C and magnetically stirred for additional
8 h. Upon completion of the reaction as revealed by TLC
analysis, 20 mL of 2 mol L-1 HCl aqueous solution were
added. The aqueous layer was extracted with ethyl acetate
(3 × 20 mL). The organic extracts were combined and the
resulting organic phase was washed with water (20 mL),
brine (20 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
silica gel column chromatography eluted with hexane/ethyl
acetate (10:1 v/v). Compound 8 was obtained as brown oil
in 72% yield (1.60 g, 7.20 mmol). TLC: Rf = 0.55 (hexane/
ethyl acetate/dichloromethane 10:1:3 v/v); IR (ATR)
/ cm-1 3305, 2963, 2924, 2856, 2117, 1668, 1445,
1376, 1104, 1072, 828, 631; 1H NMR (300 MHz, CDCl3)
d 1.60 (s, 3H), 1.67 (s, 3H), 1.74 (s, 3H), 1.78 (quint, 2H,
J 6.6 Hz), 1.92 (t, 1H, J 2.6 Hz), 2.07 (s, 4H), 2.28 (dt, 2H,
J1 6.6 Hz, J2 2.6 Hz), 3.49 (t, 2H, J 6.6 Hz), 3.94 (d, 2H,
J 6.6 Hz), 5.09 (brs, 1H), 5.35 (t, 1H, J 6.6 Hz); 13C NMR
(75 MHz, CDCl3) d 15.3, 17.6, 23.4, 25.7, 26.7, 28.7, 32.2,
67.1, 68.3, 68.4, 121.9, 123.8, 131.9, 140.3; MS-EI, m/z
(%): 220 (1) C15H24O [M+•], 205 (4), 177 (3), 163 (8), 149
(17), 135 (19), 121 (60), 107 (21), 93 (100), 80 (51), 69
(90), 41 (99).
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3135,
3030, 2963, 2924, 2856, 1737, 1667, 1555, 1454, 1376,
1
1330, 1047, 720, 582, 460; H NMR (300 MHz, CDCl3)
d 1.57 (s, 3H), 1.66 (s, 3H), 1.73 (s, 3H), 2.04 (s, 4H),
4.02 (d, 2H, J 6.9 Hz), 4.58 (s, 2H), 5.06 (brs, 1H), 5.34 (t,
1H, J 6.8 Hz), 5.49 (s, 2H), 7.24-7.27 (m, 2H), 7.33-7.36
(m, 3H), 7.44 (s, 1H); 13C NMR (75 MHz, CDCl3) d 17.6,
23.4, 25.6, 26.6, 32.2, 54.1, 63.5, 66.7, 121.3, 122.2, 123.7,
128.1, 128.7, 129.0, 131.9, 134.5, 141.0, 145.9; MS-EI,
m/z (%): 325 (0.3) C20H27N3O [M+•], 296 (1), 256 (32), 190
(21), 173 (34), 144 (25), 117 (5), 91 (100), 69 (25), 43 (8).
Compounds 9b-9k and 10a-10k were synthesized using
similar methodology to that described for compound 9a.
The identities of these compounds are in agreement with
the following data.
(Z)-4-(((3,7-Dimethylocta-2,6-dien-1-yl)oxy)methyl)-
1-(4-fluorobenzyl)-1H-1,2,3-triazole (9b)
Compound 9b was obtained as a yellow oil in 54%
yield (140.0 mg, 0.40 mmol) from 4-fluorobenzylazide
(3b) (113.2 mg, 0.750 mmol) and compound 7 (144.0 mg,
0.750 mmol). TLC: Rf = 0.40 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3133,
2963, 2924, 2856, 1667, 1606, 1511, 1453, 1376, 1224,
1
1159, 1095, 1048, 1015, 824, 788, 534, 492; H NMR
(300 MHz, CDCl3) d 1.56 (s, 3H), 1.64 (s, 3H), 1.71 (s,
3H), 2.03 (s, 4H), 4.01 (d, 2H, J 6.9 Hz), 4.57 (s, 2H), 5.04
(brs, 1H), 5.33 (t, 1H, J 6.9 Hz), 5.46 (s, 2H), 7.00-7.05 (m,
2H), 7.22-7.26 (m, 2H), 7.43 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 17.6, 23.5, 25.7, 26.6, 32.2, 53.3, 63.5, 66.8,
116.0 (d, JC-F 21.6 Hz), 121.3, 122.1, 123.7, 129.9 (d, JC-F
8.3 Hz), 130.4 (d, JC-F 3.2 Hz), 132.0, 141.1, 146.0, 162.8
(d, JC-F 246.5 Hz); MS-EI, m/z (%): 343 (0.3) C20H26FN3O
[M+•], 314 (1), 274 (16), 261 (3), 208 (16), 191 (34), 162
(20), 121 (10), 109 (100), 93 (29), 83 (19), 69 (50), 53
(16), 41 (79).
Synthesis of (Z)-1-benzyl-4-(((3,7-dimethylocta-2,6-dien-
1-yl)oxy)methyl)-1H-1,2,3-triazole (9a)
Benzyl azide (3a, 100 mg, 0.750 mmol) was added
to a 10 mL round-bottom flask containing 1.50 mL of
dichloromethane, 1.50 mL of water, 60.0 mg (0.300 mmol)

546
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
(Z)-1-(4-Chlorobenzyl)-4-(((3,7-dimethylocta-2,6-dien-1-yl)
oxy)methyl)-1H-1,2,3-triazole (9c)
J 8.3 Hz), 7.44 (s, 1H), 7.66 (d, 2H, J 8.3 Hz); 13C NMR
(75 MHz, CDCl3) d 17.6, 23.4, 25.6, 26.6, 32.1, 53.4, 63.4,
66.7, 94.4, 121.2, 122.2, 123.7, 129.8, 131.9, 134.2, 138.1,
141.0, 146.1; MS-EI, m/z (%): 451 (0.09) C20H26IN3O [M+•],
382 (10), 299 (7), 217 (56), 143 (13), 90 (22), 69 (42), 53
(14), 41 (100).
Compound 9c was obtained as a yellow oil in 68%
yield (152 mg, 0.400 mmol) from 4-chlorobenzylazide
(3c) (125.2 mg, 0.750 mmol) and compound 7 (144 mg,
0.750 mmol). 25 mg of unreacted compound 7 was
also recovered. TLC: Rf = 0.50 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3134,
(Z)-4-(((3,7-Dimethylocta-2,6-dien-1-yl)oxy)methyl)-
1-(4-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole (9f)
Compound 9f was obtained as a yellow oil in 41% yield
(127 mg, 0.310 mmol) from 4-trifluoromethoxybenzylazide
(3f) (163 mg, 0.750 mmol) and compound 7 (144.0 mg,
0.750 mmol). TLC: Rf = 0.28 (hexane/ethyl acetate/
3027, 2963, 2923, 2855, 1737, 1666, 1597, 1492, 1456,
1
1376, 1220, 1090, 1050, 786, 502; H NMR (300 MHz,
CDCl3) d 1.57 (s, 3H), 1.65 (s, 3H), 1.73 (s, 3H), 2.04 (s,
4H), 4.02 (d, 2H, J 6.9 Hz), 4.58 (s, 2H), 5.06 (brs, 1H),
5.34 (t, 1H, J 6.9 Hz), 5.46 (s, 2H), 7.19 (d, 2H, J 8.4 Hz),
7.33 (d, 2H, J 8.4 Hz), 7.44 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 17.6, 23.4, 25.6, 26.6, 32.2, 53.3, 63.5, 66.8,
121.2, 122.1, 123.7, 129.3, 129.4, 131.9, 133.1, 134.7,
141.1, 146.1; MS-EI, m/z (%): 359 (0.1) C20H26ClN3O [M+•],
330 (0.4), 290 (4), 224 (9), 207 (14), 178 (5), 125 (100),
93 (15), 69 (24), 53 (9), 41 (76).
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3133,
2965, 2925, 2858, 1668, 1597, 1510, 1453, 1377, 1260,
1221, 1166, 1048, 1019, 922, 664, 628; 1H NMR (300 MHz,
CDCl3) d 1.57 (s, 3H), 1.65 (s, 3H), 1.72 (s, 3H), 2.04 (s,
4H), 4.03 (d, 2H, J 6.9 Hz), 4.58 (s, 2H), 5.05 (brs, 1H),
5.34 (t, 1H, J 6.9 Hz), 5.50 (s, 2H), 7.19 (d, 2H, J 8.4 Hz),
7.28 (d, 2H, J 8.4 Hz), 7.47 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 17.6, 23.4, 25.6, 26.6, 32.2, 53.2, 63.5, 66.8,
120.3 (q, JC-F 256.0 Hz), 121.2, 121.5, 122.2, 123.6, 129.5,
132.0, 133.3, 141.2, 146.2, 149.4; MS-EI, m/z (%): 409 (1)
C21H26F3N3O2 [M+•], 340 (9), 327 (7), 274 (27), 257 (52),
228 (32), 188 (10), 175 (100), 136 (9), 121 (22), 109 (29),
93 (57), 80 (35), 69 (69), 53 (18), 41 (74).
(Z)-1-(4-Bromobenzyl)-4-(((3,7-dimethylocta-2,6-dien-1-yl)
oxy)methyl)-1H-1,2,3-triazole (9d)
Compound 9d was obtained as a yellow oil in 67%
yield (168 mg, 0.400 mmol) from 4-bromobenzylazide
(3d) (159 mg, 0.750 mmol) and compound 7 (144 mg,
0.750 mmol). 25 mg of unreacted compound 7 were
also recovered. TLC: Rf = 0.36 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3135, 3026,
(Z)-4-(((3,7-Dimethylocta-2,6-dien-1-yl)oxy)methyl)-
1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazole (9g)
2963, 2922, 2855, 1737, 1667, 1593, 1556, 1489, 1446, 1376,
1220, 1070, 1012, 784, 490; 1H NMR (300 MHz, CDCl3)
d 1.57 (s, 3H), 1.65 (s, 3H), 1.73 (s, 3H), 2.04 (s, 4H), 4.02
(d, 2H, J 6.9 Hz), 4.58 (s, 2H), 5.06 (brs, 1H), 5.34 (t, 1H,
J 6.9 Hz), 5.45 (s, 2H), 7.13 (d, 2H, J 8.4 Hz), 7.44 (s, 1H),
7.47 (d, 2H, J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.6,
23.4, 25.6, 26.6, 32.2, 53.4, 63.5, 66.8, 121.2, 122.2, 122.8,
123.7, 129.6, 131.9, 132.2, 133.6, 141.1, 146.1; MS-EI, m/z
(%): 404 (0.04) C20H26BrN3O [M+•], 336 (4), 270 (3), 251 (8),
169 (36), 121 (7), 93 (14), 90 (16), 69 (32), 53 (12), 41 (100).
Compound 9g was obtained as a yellow oil in 48% yield
(142 mg, 0.360 mmol) from 4-trifluoromethylbenzylazide
(3g) (151 mg, 0.750 mmol) and compound 7 (144 mg,
0.750 mmol). TLC: Rf = 0.29 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3135, 2965,
2926, 2857, 1703, 1668, 1621, 1448, 1325, 1251, 1166, 1127,
1
1067, 1018, 824, 790, 622; H NMR (300 MHz, CDCl3)
d 1.56 (s, 3H), 1.64 (s, 3H), 1.72 (s, 3H), 2.03 (s, 4H), 4.03
(d, 2H, J 6.9 Hz), 4.59 (s, 2H), 5.04 (brs, 1H), 5.33 (t, 1H,
J 6.9 Hz), 5.56 (s, 2H), 7.35 (d, 2H, J 8.4 Hz), 7.48 (s, 1H),
7.60 (d, 2H, J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.6,
23.5, 25.7, 26.6, 32.2, 53.4, 63.5, 66.8, 121.2, 122.4, 123.7,
124.6 (q, JC-F 270.0 Hz), 126.0 (q, JC-F 3.7 Hz), 128.2, 130.9
(q, JC-F 32.4 Hz), 132.0, 138.6, 141.2, 146.3; MS-EI, m/z (%):
393 (0.9) C21H26F3N3O [M+•], 364 (2), 324 (34), 311 (5), 258
(33), 241 (14), 212 (45), 172 (24), 159 (100), 121 (23), 109
(41), 93 (60), 80 (33), 69 (78), 53 (24), 41 (99).
(Z)-4-(((3,7-Dimethylocta-2,6-dien-1-yl)oxy)methyl)-
1-(4-iodobenzyl)-1H-1,2,3-triazole (9e)
Compound 9e was obtained as a yellow oil in 52%
yield (150 mg, 0.330 mmol) from 4-iodobenzylazide (3e)
(194.2 mg, 0.750 mmol) and compound 7 (144.0 mg,
0.750 mmol). TLC: Rf = 0.55 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3135,
3022, 2963, 2923, 2855, 1704, 1690, 1667, 1556, 1485,
1
1446, 1375, 1220, 1048, 1008, 783, 474; H NMR
(Z)-4-(((3,7-Dimethylocta-2,6-dien-1-yl)oxy)methyl)-
1-(4-methoxybenzyl)-1H-1,2,3-triazole (9h)
Compound 9h was obtained as a yellow oil in 65%
yield (140 mg, 0.390 mmol) from 4-methoxybenzylazide
(300 MHz, CDCl3) d 1.56 (s, 3H), 1.65 (s, 3H), 1.72 (s,
3H), 2.04 (s, 4H), 4.02 (d, 2H, J 6.9 Hz), 4.57 (s, 2H), 5.05
(brs, 1H), 5.33 (t, 1H, J 6.9 Hz), 5.42 (s, 2H), 6.98 (d, 2H,

Vol. 30, No. 3, 2019
Teixeira et al.
547
(3h) (122 mg, 0.750 mmol) and compound 7 (144 mg,
0.750 mmol). 28 mg of unreacted compound 7 was
also recovered. TLC: Rf = 0.49 (hexane/ethyl acetate/
(m), 121.2, 122.2, 123.7, 124.1-124.3 (m), 131.5-131.6 (m),
132.0, 146.3, 148.7-148.9 (m), 152.0-152.2 (m); MS-EI,
m/z (%): 361 (0.17) C20H25F2N3O [M+•], 344 (0.07), 292 (9),
226 (9), 209 (20), 180 (15), 140 (7), 127 (100), 107 (8), 93
(24), 80 (11), 69 (49), 53 (17), 41 (98).
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3134,
3067, 2962, 2928, 2856, 1667, 1612, 1585, 1514, 1453,
1
1375, 1249, 1177, 1047, 814, 786, 554, 516; H NMR
(300 MHz, CDCl3) d 1.56 (s, 3H), 1.65 (s, 3H), 1.72 (s,
3H), 2.03 (s, 4H), 3.78 (s, 3H), 4.01 (d, 2H, J 6.6 Hz), 4.56
(s, 2H), 5.05 (brs, 1H), 5.33 (t, 1H, J 6.6 Hz), 5.42 (s, 2H),
6.87 (d, 2H, J 8.7 Hz), 7.21 (d, 2H, J 8.7 Hz), 7.40 (s, 1H);
13C NMR (75 MHz, CDCl3) d 17.6, 23.5, 25.7, 26.6, 32.2,
53.6, 55.3, 63.5, 66.7, 114.4, 121.3, 122.0, 123.7, 126.5,
129.7, 131.9, 141.0, 145.8, 159.9; MS-EI, m/z (%): 355
(0.18) C21H29N3O2 [M+•], 326 (0.3), 286 (6), 273 (1), 220
(3), 203 (4), 134 (3), 121 (100), 107 (3), 91 (12), 77 (17),
69 (27), 53 (10), 41 (60).
(Z)-1-(2,5-Dichlorobenzyl)-4-(((3,7-dimethylocta-2,6-dien-
1-yl)oxy)methyl)-1H-1,2,3-triazole (9k)
Compound 9k was obtained as a yellow oil in 76%
yield (118 mg, 0.300 mmol) from 2,5-dichlorobenzylazide
(3k) (101 mg, 0.500 mmol) and compound 7 (96.0 mg,
0.500 mmol). 25.0 mg of unreacted compound 7 was
also recovered. TLC: Rf = 0.66 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3138,
3088, 2964, 2925, 2857, 1720, 1668, 1466, 1376, 1223,
1099, 1048, 816, 562; 1H NMR (300 MHz, CDCl3) d 1.57
(s, 3H), 1.65 (s, 3H), 1.73 (s, 3H), 2.05 (s, 4H), 4.04 (d,
2H, J 6.9 Hz), 4.61 (s, 2H), 5.06 (brs, 1H), 5.35 (t, 1H,
J 6.9 Hz), 5.60 (s, 2H), 7.15 (d, 1H, J 2.1 Hz), 7.27 (dd,
1H, J1 8.5 Hz, J2 2.1 Hz), 7.35 (d, 1H, J 8.5 Hz), 7.57 (s,
1H); 13C NMR (75 MHz, CDCl3) d 17.6, 23.5, 25.7, 26.6,
32.2, 50.9, 63.5, 66.8, 121.2, 122.6, 123.7, 130.1, 131.0,
131.6, 132.0, 133.5, 134.0, 141.2, 146.1; MS-EI, m/z (%):
394 (0.2) C20H25Cl2N3O [M+•], 364 (0.8), 324 (14), 258
(16), 241 (31), 212 (11), 177 (5), 160 (4), 121 (11), 93 (27),
53 (11), 41 (100).
(Z)-4-(((3,7-Dimethylocta-2,6-dien-1-yl)oxy)methyl)-
1-(4-nitrobenzyl)-1H-1,2,3-triazole (9i)
Compound 9i was obtained as a yellow oil in 40%
yield (96.0 mg, 0.260 mmol) from 4-nitrobenzylazide
(3i) (134 mg, 0.750 mmol) and compound 7 (144 mg,
0.750 mmol).An amount of 40 mg of unreacted compound
7 was also recovered. TLC: Rf = 0.34 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3137,
3079, 2964, 2925, 2856, 1667, 1523, 1494, 1346, 1222,
1
1047, 804, 726; H NMR (300 MHz, CDCl3) d 1.57 (s,
3H), 1.65 (s, 3H), 1.73 (s, 3H), 2.05 (s, 4H), 4.04 (d, 2H,
J 6.9 Hz), 4.61 (s, 2H), 5.05 (brs, 1H), 5.34 (t, 1H, J 6.9 Hz),
5.62 (s, 2H), 7.39 (d, 2H, J 8.4 Hz), 7.53 (s, 1H), 8.20 (d,
2H, J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.6, 23.5,
25.7, 26.7, 32.2, 53.1, 63.5, 66.9, 121.1, 122.5, 123.7,
124.3, 126.6, 132.0, 141.3, 141.6, 146.6, 147.9; MS-EI,
m/z (%): 370 (0.12) C20H26N4O3 [M+•], 301 (5), 235 (4),
218 (14), 189 (3), 136 (12), 121 (6), 106 (20), 93 (17), 78
(28), 69 (41), 53 (16), 41 (100).
(Z)-1-Benzyl-4-(3-((3,7-dimethylocta-2,6-dien-1-yl)oxy)
propyl)-1H-1,2,3-triazole (10a)
Compound 10a was obtained as a yellow oil in 76%
yield (203 mg, 0.570 mmol) from compounds 3a (100 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 35 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.47
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3133, 3064, 3031, 2959, 2924, 2855, 1714,
1667, 1552, 1454, 1376, 1217, 1102, 726, 460; 1H NMR
(300 MHz, CDCl3) d 1.57 (s, 3H), 1.64 (s, 3H), 1.71 (s,
3H), 1.90 (quint, 2H, J 6.3 Hz), 2.04 (s, 4H), 2.75 (t, 2H,
J 6.3 Hz), 3.41 (t, 2H, J 6.3 Hz), 3.90 (d, 2 H, J 6.9 Hz), 5.06
(brs, 1H), 5.31 (t, 1H, J 6.9 Hz), 5.46 (s, 2H), 7.18 (s, 1H),
7.21-7.23 (m, 2H), 7.32-7.34 (m, 3H); 13C NMR (75 MHz,
CDCl3) d 17.5, 22.3, 23.4, 25.6, 26.6, 29.3, 32.1, 53.9, 66.9,
69.1, 120.7, 121.8, 123.8, 127.8, 128.5, 128.9, 131.8, 134.9,
140.1, 148.1; MS-EI, m/z (%): 353 (0.15) C22H31N3O [M+•],
310 (0.11), 285 (3), 218 (30), 200 (16), 187 (2), 173 (55),
121 (4), 91 (100), 69 (35), 53 (15), 41 (75).
(Z)-1-(3,4-Difluorobenzyl)-4-(((3,7-dimethylocta-2,6-dien-
1-yl)oxy)methyl)-1H-1,2,3-triazole (9j)
Compound 9j was obtained as a yellow oil in 45%
yield (123 mg, 0.340 mmol) from 3,4-difluorobenzylazide
(3j) (127 mg, 0.750 mmol) and compound 7 (144 mg,
0.750 mmol). TLC: Rf = 0.36 (hexane/ethyl acetate/
dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3135,
2964, 2925, 2857, 1715, 1669, 1611, 1521, 1439, 1376,
1
1286, 1214, 1116, 1048, 781, 576, 526, 452; H NMR
(300 MHz, CDCl3) d 1.56 (s, 3H), 1.64 (s, 3H), 1.71 (s, 3H),
2.03 (s, 4H), 4.02 (d, 2H, J 6.9 Hz), 4.58 (s, 2H), 5.04 (brs,
1H), 5.33 (t, 1H, J 6.9 Hz), 5.44 (s, 2H), 6.98-7.18 (m, 3H),
7.48 (s, 1H); 13C NMR (75 MHz, CDCl3) d 17.6, 23.5, 25.7,
26.6, 32.2, 52.9, 63.5, 66.8, 117.1-117.3 (m), 117.8-118.1
(Z)-4-(3-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)propyl)-
1-(4-fluorobenzyl)-1H-1,2,3-triazole (10b)
Compound 10b was obtained as a yellow oil in 42%
yield (96.0 mg, 0.260 mmol) from compounds 3b (113 mg,

548
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
0.750 mmol) and 8 (165 mg, 0.750 mmol). 50 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.32
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v). IR (ATR)
/ cm-1 3133, 2955, 2923, 2854, 1715, 1667, 1606, 1511,
1454, 1376, 1225, 1158, 1101, 1046, 824, 784, 534, 490;
1H NMR (300 MHz, CDCl3) d 1.57 (s, 3H), 1.65 (s, 3H),
1.72 (s, 3H), 1.91 (quint, 2H, J 6.3 Hz), 2.04 (s, 4H), 2.76 (t,
2H, J 6.3 Hz), 3.42 (t, 2H, J 6.3 Hz), 3.90 (d, 2H, J 6.9 Hz),
5.06 (brs, 1H), 5.31 (t, 1H, J 6.9 Hz), 5.44 (s, 2H), 7.00-7.06
(m, 2H), 7.19-7.24 (m, 3H); 13C NMR (75 MHz, CDCl3)
d 17.6, 22.4, 23.4, 25.7, 26.7, 29.4, 32.2, 53.2, 67.0, 69.1,
116.0 (d, JC-F 21.6 Hz), 120.6, 121.9, 123.8, 129.7 (d, JC-F
8.2 Hz), 130.8 (d, JC-F 3.2 Hz), 131.9, 140.2, 148.3, 162.8
(d, JC-F 246.4 Hz); MS-EI, m/z (%): 371 (0.04) C22H30FN3O
[M+•], 302 (0.6), 236 (9), 218 (5), 191 (20), 162 (1), 121
(2), 109 (100), 93 (7), 83 (11), 69 (31), 53 (11), 41 (61).
J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.6, 22.4, 23.5,
25.7, 26.7, 29.4, 32.2, 53.2, 67.0, 69.1, 120.7, 121.9, 122.7,
123.8, 129.5, 131.9, 132.2, 134.0, 140.2, 148.4; MS-EI, m/z
(%): 432 (0.04) C22H30BrN3O [M+•], 363 (0.6), 296 (9), 280
(5), 253 (15), 169 (53), 121 (4), 90 (26), 80 (8), 69 (54),
53 (17), 41 (100).
(Z)-4-(3-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)propyl)-
1-(4-iodobenzyl)-1H-1,2,3-triazole (10e)
Compound 10e was obtained as a yellow oil in 81%
yield (230 mg, 0.480 mmol) from compounds 3e (194 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 35 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.30
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR
(ATR)
/ cm-1 3132, 3075, 2958, 2923, 2854, 1715,
1667, 1590, 1550, 1485, 1446, 1376, 1217, 1102, 1007,
812, 474; 1H NMR (300 MHz, CDCl3) d 1.58 (s, 3H), 1.65
(s, 3H), 1.72 (s, 3H), 1.91 (quint, 2H, J 6.3 Hz), 2.05 (s,
4H), 2.77 (t, 2H, J 6.3 Hz), 3.42 (t, 2H, J 6.3 Hz), 3.91 (d,
2H, J 6.9 Hz), 5.07 (brs, 1H), 5.31 (t, 1H, J 6.9 Hz), 5.41
(s, 2H), 6.96 (d, 2H, J 8.4 Hz), 7.19 (s, 1H), 7.67 (d, 2H,
J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.6, 22.3, 23.4,
25.7, 26.7, 29.4, 32.2, 53.3, 67.0, 69.1, 94.3, 120.7, 121.9,
123.8, 129.6, 131.8, 134.6, 138.1, 140.2, 148.4; MS-EI,
m/z (%): 479 (0.3) C22H30IN3O [M+•], 411 (2), 344 (14),
326 (5), 299 (17), 217 (76), 121 (6), 90 (26), 69 (43), 53
(16), 41 (100).
(Z)-1-(4-Chlorobenzyl)-4-(3-((3,7-dimethylocta-2,6-dien-
1-yl)oxy)propyl)-1H-1,2,3-triazole (10c)
Compound 10c was obtained as a yellow oil in 81%
yield (195 mg, 0.500 mmol) from compounds 3c (125 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 30 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.33
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3135, 2956, 2924, 2854, 1720, 1667, 1597, 1552,
1492, 1453, 1376, 1217, 1099, 1047, 807, 501; 1H NMR
(300 MHz, CDCl3) d 1.59 (s, 3H), 1.66 (s, 3H), 1.73 (s,
3H), 1.92 (quint, 2H, J 6.3 Hz), 2.05 (s, 4H), 2.77 (t, 2H,
J 6.3 Hz), 3.43 (t, 2H, J 6.3 Hz), 3.92 (d, 2H, J 6.9 Hz),
5.08 (brs, 1H), 5.32 (t, 1H, J 6.9 Hz), 5.45 (s, 2H), 7.17
(d, 2H, J 8.4 Hz), 7.19 (s, 1H), 7.34 (d, 2H, J 8.4 Hz);
13C NMR (75 MHz, CDCl3) d 17.6, 22.4, 23.5, 25.7, 26.7,
29.4, 32.2, 53.2, 67.0, 69.1, 120.6, 121.9, 123.8, 129.2,
131.9, 133.4, 134.6, 140.2, 148.4; MS-EI, m/z (%): 388
(0.2) C22H30ClN3O [M+•], 318 (0.6), 252 (12), 234 (7), 207
(22), 125 (100), 89 (10), 69 (29), 53 (11), 41 (75).
(Z)-4-(3-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)propyl)-
1-(4-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole (10f)
Compound 10f was obtained as a yellow oil in 91%
yield (299 mg, 0.680 mmol) from compounds 3f (163 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). TLC: Rf = 0.26
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3133, 3074, 2961, 2928, 2857, 1713, 1667, 1510,
1446, 1372, 1260, 1221, 1166, 1104, 819, 610; 1H NMR
(300 MHz, CDCl3) d 1.56 (s, 3H), 1.64 (s, 3H), 1.71 (s,
3H), 1.91 (quint, 2H, J 6.3 Hz), 2.03 (s, 4H), 2.76 (t, 2H,
J 6.3 Hz), 3.42 (t, 2H, J 6.3 Hz), 3.90 (d, 2H, J 6.9 Hz), 5.06
(brs, 1H), 5.31 (t, 1H, J 6.9 Hz), 5.47 (s, 2H), 7.17-7.27 (m,
5H); 13C NMR (75 MHz, CDCl3) d 17.6, 22.3, 23.4, 25.6,
26.6, 29.4, 32.2, 53.0, 67.0, 69.1, 120.3 (q, J 256.0 Hz),
120.8, 121.4, 121.8, 123.8, 129.3, 131.9, 133.7, 140.2,
148.4, 149.3; MS-EI, m/z (%): 437 (0.1) C23H30F3N3O2
[M+•], 369 (1), 302 (22), 284 (14), 257 (40), 175 (100), 121
(7), 109 (24), 93 (19), 80 (10), 69 (52), 53 (14), 41 (73).
(Z)-1-(4-Bromobenzyl)-4-(3-((3,7-dimethylocta-2,6-dien-
1-yl)oxy)propyl)-1H-1,2,3-triazole (10d)
Compound 10d was obtained as a yellow oil in 68%
yield (168 mg, 0.390 mmol) from compounds 3d (159 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 40 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.31
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3136, 2959, 2926, 2856, 2358, 1713, 1667, 1592,
1552, 1489, 1445, 1376, 1218, 1070, 1012, 804, 668, 622,
1
478; H NMR (300 MHz, CDCl3) d 1.57 (s, 3H), 1.64
(s, 3H), 1.71 (s, 3H), 1.91 (quint, 2H, J 6.3 Hz), 2.04 (s,
4H), 2.75 (t, 2H, J 6.3 Hz), 3.41 (t, 2H, J 6.3 Hz), 3.90 (d,
2H, J 6.9 Hz), 5.06 (brs, 1H), 5.31 (t, 1H, J 6.9 Hz), 5.42
(s, 2H), 7.10 (d, 2H, J 8.4 Hz), 7.19 (s, 1H), 7.46 (d, 2H,
(Z)-4-(3-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)propyl)-
1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazole (10g)
Compound 10g was obtained as a yellow oil in 75%
yield (239 mg, 0.560 mmol) from compounds 3g (151 mg,

Vol. 30, No. 3, 2019
Teixeira et al.
549
0.750 mmol) and 8 (165 mg, 0.75 mmol). TLC: Rf = 0.31
5.59 (s, 2H), 7.28 (s, 1H), 7.35 (d, 2H, J 8.4 Hz), 8.18 (d,
2H, J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.6, 22.4,
23.5, 25.7, 26.7, 29.4, 32.2, 52.9, 67.0, 69.1, 121.0, 121.8,
123.8, 124.2, 128.4, 131.9, 140.3, 142.1, 147.9, 148.8; MS-
EI, m/z (%): 398 (0.2) C22H30N4O3 [M+•], 330 (0.3), 263 (8),
245 (12), 218 (22), 199 (5), 136 (10), 121 (4), 106 (19), 89
(15), 78 (34), 69 (58), 53 (18), 41 (100).
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR
(ATR)
/ cm-1 3132, 2962, 2928, 2856, 1667, 1620,
1446, 1325, 1218, 1166, 1127, 1067, 1018, 823; 1H NMR
(300 MHz, CDCl3) d 1.55 (s, 3H), 1.63 (s, 3H), 1.69 (s,
3H), 1.90 (quint, 2H, J 6.3 Hz), 2.02 (s, 4H), 2.76 (t, 2H,
J 6.3 Hz), 3.41 (t, 2H, J 6.3 Hz), 3.90 (d, 2H, J 6.9 Hz),
5.05 (brs, 1H), 5.29 (t, 1H, J 6.9 Hz), 5.52 (s, 2H), 7.24
(s, 1H), 7.31 (d, 2H, J 8.4 Hz), 7.58 (d, 2H, J 8.4 Hz);
13C NMR (75 MHz, CDCl3) d 17.6, 22.3, 23.4, 25.6, 26.6,
29.3, 32.2, 53.2, 67.0, 69.1, 120.9, 121.8, 123.8, 124.8 (q,
JC-F 270.0 Hz), 126.0 (q, JC-F 3.6 Hz), 128.0, 130.8 (q, JC-F
32.4 Hz), 131.8, 139.0, 140.2, 148.5; MS-EI, m/z (%): 421
(0.2) C23H30F3N3O [M+•], 353 (2), 286 (40), 268 (44), 241
(77), 212 (3), 159 (100), 140 (5), 121 (11), 109 (33), 93
(30), 80 (17), 69 (62), 53 (21), 41 (96).
(Z)-1-(3,4-Difluorobenzyl)-4-(3-((3,7-dimethylocta-2,6-dien-
1-yl)oxy)propyl)-1H-1,2,3-triazole (10j)
Compound 10j was obtained as a yellow oil in 96%
yield (276 mg, 0.710 mmol) from compounds 3j (126.8 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 5 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.35
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3133, 2960, 2926, 2856, 1715, 1668, 1611,
1519, 1439, 1376, 1286, 1214, 1115, 1047, 782, 574, 524,
452; 1H NMR (300 MHz, CDCl3) d 1.56 (s, 3H), 1.63 (s,
3H), 1.70 (s, 3H), 1.91 (quint, 2H, J 6.3 Hz), 2.03 (s, 4H),
2.76 (t, 2H, J 6.3 Hz), 3.41 (t, 2H, J 6.3 Hz), 3.90 (d, 2H,
J 6.9 Hz), 5.05 (brs, 1H), 5.30 (t, 1H, J 6.9 Hz), 5.42 (s,
2H), 6.99-7.17 (m, 3H), 7.23 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 17.6, 22.3, 23.4, 25.6, 26.6, 29.3, 32.2, 52.8,
67.0, 69.1, 116.9-117.1 (m), 117.7-118.0 (m), 120.8, 121.8,
123.8, 123.9-124.0 (m), 131.9, 140.2, 148.5, 148.6-148.9
(m), 151.9-152.0 (m), 152.1-152.2 (m); MS-EI, m/z (%):
389 (0.20) C22H29F2N3O [M+•], 321 (3), 262 (5), 254 (50),
236 (39), 209 (74), 180 (3), 127 (100), 93 (36), 80 (20), 69
(58), 53 (22), 41 (80).
(Z)-4-(3-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)propyl)-
1-(4-methoxybenzyl)-1H-1,2,3-triazole (10h)
Compound 10h was obtained as a yellow oil in 76%
yield (186 mg, 0.480 mmol) from compounds 3h (122 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 25 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.34
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR (ATR)
/ cm-1 3131, 3072, 2959, 2929, 2854, 1714, 1667, 1550,
1514, 1445, 1375, 1249, 1178, 1102, 1034, 823, 783, 514;
1H NMR (300 MHz, CDCl3) d 1.56 (s, 3H), 1.63 (s, 3H),
1.70 (s, 3H), 1.88 (quint, 2H, J 6.3 Hz), 2.03 (s, 4H), 2.72
(t, 2H, J 6.3 Hz), 3.40 (t, 2H, J 6.3 Hz), 3.76 (s, 3H), 3.89
(d, 2H, J 6.9 Hz), 5.05 (brs, 1H), 5.29 (t, 1H, J 6.9 Hz),
5.38 (s, 2H), 6.84 (d, 2H, J 8.4 Hz), 7.15 (s, 1H), 7.18 (d,
J 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 17.5, 22.2, 23.3,
25.6, 26.6, 29.3, 32.1, 53.4, 55.2, 66.9, 69.1, 114.3, 120.4,
121.8, 123.7, 126.8, 129.4, 131.8, 140.1, 147.9, 159.7;
MS-EI, m/z (%): 383 (0.3) C23H33N3O2 [M+•], 315 (4), 262
(2), 248 (13), 231 (5), 203 (20), 121 (100), 110 (16), 93
(15), 77 (18), 69 (27), 53 (11), 41 (58).
(Z)-1-(2,5-Dichlorobenzyl)-4-(3-((3,7-dimethylocta-2,6-dien-
1-yl)oxy)propyl)-1H-1,2,3-triazole (10k)
Compound 10k was obtained as a yellow oil in 70%
yield (174 mg, 0.410 mmol) from compounds 3k (152 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 35 mg of
unreacted compound 8 was also recovered. TLC: Rf = 0.51
(hexane/ethyl acetate/dichloromethane 3:1:3 v/v); IR
(ATR)
/ cm-1 3134, 3071, 2959, 2926, 2855, 1722,
(Z)-4-(3-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)propyl)-
1-(4-nitrobenzyl)-1H-1,2,3-triazole (10i)
1667, 1552, 1464, 1376, 1272, 1219, 1099, 1045, 815,
522; H NMR (300 MHz, CDCl3) d 1.57 (s, 3H), 1.65
1
Compound 10i was obtained as a yellow oil in 71%
yield (200 mg, 0.500 mmol) from compounds 3i (134 mg,
0.750 mmol) and 8 (165 mg, 0.750 mmol). 20 mg of
unreacted compound 8 was also recovered. Yellow oil,
TLC: Rf = 0.26 (hexane/ethyl acetate/dichloromethane
(s, 3H), 1.71 (s, 3H), 1.93 (quint, 2H, J 6.3 Hz), 2.04 (s,
4H), 2.79 (t, 2H, J 6.3 Hz), 3.43 (t, 2H, J 6.3 Hz), 3.92 (d,
2H, J 6.9 Hz), 5.08 (brs, 1H), 5.32 (t, 1H, J 6.9 Hz), 5.56
(s, 2H), 7.06 (d, 1H, J 2.1 Hz), 7.24 (dd, 1H, J1 8.4 and
J2 2.1 Hz), 7.32 (s, 1H), 7.34 (d, 1H, J 8.4 Hz); 13C NMR
(75 MHz, CDCl3) d 17.6, 22.4, 23.5, 25.7, 26.7, 29.4, 32.2,
50.7, 67.0, 69.1, 121.2, 121.9, 123.8, 129.8, 130.0, 130.9,
131.3, 131.9, 133.5, 134.4, 140.2, 148.3; MS-EI, m/z (%):
422 (0.1) C22H29Cl2N3O [M+•], 353 (1), 286 (11), 268 (13),
241 (38), 204 (4), 159 (47), 123 (13), 93 (15), 69 (58), 53
(15), 41 (100).
3:1:3 v/v); IR (ATR)
/ cm-1 3133, 3078, 2961, 2926,
2855, 1668, 1606, 1522, 1446, 1346, 1218, 1105, 1046,
858, 804, 734; 1H NMR (300 MHz, CDCl3) d 1.56 (s, 3H),
1.64 (s, 3H), 1.71 (s, 3H), 1.92 (quint, 2H, J 6.3 Hz), 2.03
(s, 4H), 2.78 (t, 2H, J 6.3 Hz), 3.43 (t, 2H, J 6.3 Hz), 3.91
(d, 2H, J 6.9 Hz), 5.05 (brs, 1H), 5.30 (t, 1H, J 6.9 Hz),

550
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
Cell culture
Wound healing assay
Human leukemia cell lines HL60 (acute myelogenous
leukemia, AML), Nalm6 (B-cell acute lymphoblastic
leukemia, ALL-B), and Jurkat (T-cell acute lymphoblastic
leukemia, ALL-T) were kindly provided by Dr Jose
Andrés Yunes (Centro Infantil Boldrini, Campinas, São
Paulo, Brazil). Mouse NIH3T3 and B16F10 cells were
kindly provided by Dr Anésia Aparecida dos Santos
(Departamento de Biologia Geral, Universidade Federal
de Viçosa, Minas Gerais, Brazil). Human embryonic
kidney HEK293 cell was kindly provided by Dr Jörg
Kobarg (Instituto de Biologia, Universidade Estadual de
Campinas, Campinas, São Paulo, Brazil). Cell lines were
grown in Roswell Park Memorial Institute (RPMI)-1640
medium (Sigma, Darmstadt, Gemany) supplemented with
10% (v/v) fetal bovine serum (FBS) (LGC Biotecnologia,
Cotia, São Paulo, Brazil), 100 g mL-1 streptomycin, and
100 units per mL penicillin at pH 7.2 and 37 °C under 5%
CO2 atmosphere.
B16F10 cells were seeded on 24-well plates and grown
for 24 h to 80-90% confluence. Cells were washed twice
with phosphate-buffered saline (PBS) and the monolayers
were scraped with a micropipette tip to create a uniform
scratch. After that, cells were washed with PBS again to
remove the detached cells. Then, compound 9f was added
in the RPMI medium at different concentrations (50, 75
and 100 µmol L-1). DMSO-vehicle treatment (0.4% v/v)
was used as control. Digital images of the wounded
monolayers were obtained by photomicroscope EVOS fl
(Life Technologies, Cotia, São Paulo, Brazil) at 0, 12, 24,
and 48 h. The unfilled scratched zones were quantified by
Java’s Image J software.31
Statistical analysis
All numeric data were obtained from three independent
experiments and are shown as means standard deviation.
Analyses were performed using Microsoft Excel (Microsoft
Office Software) and GraphPad Prism.32 Statistical analyses
were conducted by one-way analysis of variance (ANOVA)
followed by Tukey’s test. p < 0.05 was considered
significant.
Cell viability assay
HL60, Nalm6, and Jurkat cells (7 × 104 cells well-1),
B16F10, NIH3T3, and HEK293 cells (104 cells well-1) were
seeded in 96-well plates. Each well contained 100 µL of
complete RPMI medium and 100 µL of each compound
solution at different concentrations. Cytarabine, vincristine
sulfate, and etoposide (Sigma-Aldrich, Darmstadt, Gemany)
were used as positive controls. The compounds were
diluted in RPMI medium with 10% FBS and 0.4% DMSO
(v/v, Sigma, Darmstadt, Gemany). After 48 h of culture,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT, 5 mg mL-1, Sigma, Darmstadt, Gemany)
was added to the wells.After 3 h at 37 °C, the MTT solution
was removed and it was added 100 µL well-1 of DMSO
to solubilize the formazan. Absorbance was measured at
540 nm in a microplate reader (SpectraMax M5, Molecular
Devices, San Jose, USA).
Calculation of physicochemical and pharmacokinetic
properties
SMILES representations for compounds 9a-k and
10a-k were obtained from 2D structures drawn in
MarvinSketch.33 Ligands were then prepared with the
LigPrep software,34 and relevant protonation states at pH 7.0
were calculated with Epik. Forty four physicochemical and
pharmacokinetic properties were calculated by the normal
mode of QikProp.35
3D-QSAR study
Trypan blue exclusion assay
Three-dimensional structures were built in HyperChem 7
(Hyper Co.), using as reference the Nerol structure retrieved
from the ZINC Database (code 12405252).36 All geometries
were initially optimized by molecular mechanics (MM+),
in cycles alternated with molecular dynamic studies (1 ps,
300 K), until the energy obtained in MM+ no longer varied,
indicating a possible minimum energy structure. Next, these
obtained structures were optimized by quantum mechanics,
initially at AM1 semi-empirical level, in the same
software. The geometries were exported to the software
Gaussian 0937 and new optimizations were carried out at
Trypan blue exclusion assays were performed as
previously described.30 Jurkat cells were seeded at the
density of 104 cells per well in 96-well plates. The
compound 9f was added at 25 or 50 µmol L-1, and DMSO
(0.4% v/v) or RPMI medium were used as control. The
effect of these treatments on cell growth were determined
by trypan blue (Invitrogen, Carlsbad, USA) dye exclusion.
After 24, 48, and 72 h, a hemocytometer was loaded with
cells to obtain the viable cell count.

Vol. 30, No. 3, 2019
Teixeira et al.
551
Hartree-Fock level (HF/6-31Gd,p) and, in the last step, by
density functional theory (DFT) (B3LYP/Def2TZVPP).
The B3LYP functional was chosen because it leads to
quite satisfactory results for the analysis of geometries and
energies.38,39 Besides, the balanced basis set Def2-TZVPP
was chosen because it produces similar errors along all the
elements from the periodic table.40
cross-validation (RMSECV). The robustness was tested by
the leave-N-out (LNO) cross validation test, where N = 1 to
5 for all models, and each N was repeated six times (in each
replicate the rows from the data matrix were randomized).
For a robust model, it is expected an average value of
coefficients of determination obtained in each step of the
45
LNO cross-validation (or average Q2LNO) close to Q2LOO
.
Using the optimized geometry, 3D descriptors were
calculated in Pentacle software.41 The GRIND approach
that calculates 3D maps of interaction energies between the
molecule and chemical probes (GRIND based molecular
interaction fields, MIFs), in an alignment-independent
procedure, was used.42 The molecular probes involved
were: DRY, representing hydrophobic interactions, O
(sp2 carbonyl oxygen) as a hydrogen bond acceptor, N1
as hydrogen bond donor (NH like amide) and TIP that
represents the shape of the molecule in terms of steric hot
spots. The maximum field intensity at relative distances (in
angstroms) was computed using the AMANDA algorithm
and the pre-filtered nodes were encoded using the MACC2
algorithm.
Finally, the y-randomization test was applied to confirm
that the models did not suffer from chance correlation. For
this test, the vector y (containing the biological activities)
was scrambled 40 times, in accordance with the approach
suggested by Eriksson et al.46 The selected descriptors that
were included in the final models were interpreted in order
to have some insight on which properties (structural, MIF,
physiochemical and pharmacokinetic) could be related to
the cytotoxic activities. Besides, molecular graphics of
the selected descriptors and hierarchical cluster analysis
(HCA) in Pirouette software47 were compared to explore
some relationship among the cell lines.
Results and Discussion
Experimental biological activities were converted into
their corresponding pIC50 (or –logIC50, where IC50 is the
concentration in mol L-1 that inhibited cell proliferation
by 50% when compared to untreated controls). A total
of 629 GRIND descriptors were calculated for nerol and
derivatives. The data generated was organized in a data
matrix X(N × 629), where N is the number of active
compounds. Four quantitative regression models, based
on the experimental biological activities measured against
cancer cell lines, were built.
Feature selection was initially carried out by using the
fractional factorial design method (FDD), also available
in Pentacle.41 The following step was to eliminate those
descriptors that had the absolute value of Pearson’s
correlation coefficient (|r|) with biological activity
lower than 0.2. Finally, the ordered predictors selection
algorithm (OPS),43 implemented in the public domain
QSAR modeling software,44 was used to define the final
set of descriptors to be kept in the models. Descriptors
and biological activities were autoscaled (column wise
mean-centered and scaled to unity variance) prior to
chemometric analysis.
Synthesis of nerol derivatives
The steps involved in the synthesis of nerol derivatives
9a-k and 10a-k, containing a triazole moiety, are
summarized in Scheme 1.
The alkylation of nerol (6) with propargyl bromide
and pent-4-yn-1-yl methanesulfonate (5) gave alkylated
compounds 7 and 8, respectively. Azides 3 were prepared
from eleven benzylic alcohols.29 The CuAAC, also known
as click reaction, between azides 3 and compounds 7
and 8 yielded the corresponding nerol derivatives with
1,2,3-triazole appendages. The reaction conditions
used in the CuAAC were similar to those that we have
utilized for the preparation of other 1,2,3-triazoles.16,48
As previously described, the main goal of the present
investigation was to assess the cytotoxic potential of
nerol 1,2,3-triazolic derivatives. As a consequence, an
optimization of the reaction conditions was not carried out
and some triazolic products were obtained with moderate
yields. Moreover, in some click reactions it was recovered
unreacted alkyne starting material. Compound structures
were confirmed based on IR and NMR (1H and 13C)
spectroscopies. The 1H NMR spectra of nerol derivatives
exhibited signals for the aryl group attached to triazole
ring within 6.17-8.22 ppm range. In addition, the hydrogen
of the heterocyclic ring was observed at 7.18-7.57 ppm.
Once synthesized, compounds 9a-k and 10a-k as well
as compounds 7 and 8 were biologically evaluated with
respect to their cytotoxicity. It should be mentioned that it
Quantitative models were built using the partial least
squares regression method (PLS) implemented in QSAR
modeling software.44 The quality of the models was
assessed based on their coefficient of determination (R2)
and the root mean square error of calibration (RMSEC),
the F-ratio test with 95% confidence interval (F, α = 0.05),
the coefficient of determination in the leave-one-out (LOO)
cross-validation (Q2LOO), and the root mean square error of

552
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
was varied the pattern of substitution of the benzyl ring as
well as the length of the aliphatic chain in order to verify
the influence of these factors on the biological activity.
84.2 µmol L-1 against HL60, from 36.0 to 98.7 µmol L-1
against Nalm6 and from 30.9 to 84.4 µmol L-1 against Jurkat
(Table 1). Melanoma B16F10 cells were less sensitive, but
four compounds (9d, 9f, 10f, and 10i) present moderate
activity presenting IC50 values ranging from 74.7 to
98.2 µmol L-1.
Cytotoxic activity
The HL60 cell line commonly responds to potential
antitumor agents with high sensitivity.49 Thus, this cell
line was chosen to initially select nerol derivatives with
potential cytotoxic effect. With exception of nerol (6)
and compound 8, the remaining substances were able
to reduce cell viability at 100 µmol L-1, the highest
concentration evaluated (Figure 2). The most cytotoxic
compounds identified were 9e, 9f, and 10e, which reduced
the HL60 viability to approximately 20% at 25 µmol L-1.
This finding is in close agreement with previous work,
which have already reported cytotoxic activity for some
terpenoids and other compounds related to nerol.11,50
Cytarabine (Ara-C), vincristine (VCR), and etoposide
(VP-16), components of many multi-drug pediatric and
adult leukemia treatments were used as positive control,51
which decreased cell viability to 31.4, 27.7, and 11.1%,
respectively (Figure 2).
Among all evaluated substances, the derivative 9f was,
overall, the most active, as the determined IC50 values against
HL60, Nalm6, Jurkat, and B16F10 were, respectively,
12.3, 38.5, 30.9, and 74.7 µmol L-1. In addition, most of
the derivatives showed lower cytotoxicity against the non-
tumor cell NIH3T3. Nine out of twenty-three evaluated
compounds did not present any cytotoxic activity against
this cell lineage, and another nine nerol derivatives presented
IC50 values higher than 100 µmol L-1 (Table 1). Also, the
most cytotoxic 9f compound showed some cytotoxicity
(IC50 37.33 µmol L-1) against the human non-cancerous cell
line HEK293, but still lower than leukemic cells such as
HL60 and Jurkat (see Supplementary Information).
Effects of compound 9f on cancer cell viability and migration
The most active compound 9f was used in additional
experiments in order to gain insights on how it might acts in
tumor cells. In the trypan blue exclusion assays, derivative
9f significantly impaired viability of Jurkat cells in a time-
and concentration-dependent manner (Figure 3). This
compound inhibited up to 70% of cell growth after 72 h
in comparison to controls (DMSO and RPMI), suggesting
Compounds presenting cytotoxic activity against
HL60 were selected for the determination of half
maximal inhibitory concentration (IC50) against other
leukemias (Nalm6 and Jurkat) as well as melanoma
(B16F10) and embryonic non-tumor cells (NIH3T3). The
selected derivatives presented IC50 ranging from 9.84 to
Figure 2. The effect of nerol and its derivatives on leukemia cell viability. HL60 cells were treated with different concentrations (25, 50 and 100 µmol L-1)
of nerol and its derivatives for 48 h. Cytarabine (Ara-C), vincristine (VCR), and etoposide (VP-16) (8 µmol L-1) were used as positive control. Cell viability
was determined using the MTT assay. The percentage of inhibition was calculated considering the cells treated with the vehicle (DMSO).

Vol. 30, No. 3, 2019
Teixeira et al.
553
Table 1. Half-maximal inhibitory concentration (IC50) values for nerol derivatives. HL60, Nalm6 and Jurkat leukemic cells, B16F10 metastatic melanoma
and NIH3T3 mouse embryonic cell line were treated with increasing concentrations (0-200 µmol L-1) of each compound for 48 h. Cell viability was
determined using the MTT assay. IC50 values are expressed as the means standard deviation of three independent experiments
IC50 / (µmol L-1)
Compound
HL60
(AML)
Nalm6
(ALL-B)
Jurkat
(ALL-T)
B16F10
NIH3T3
7
41.7 2.94
75.7 10.0
44.9 2.97
33.1 2.58
36.4 3.51
26.0 1.56
12.3 4.33
42.3 1.03
57.9 6.84
59.2 4.86
84.2 14.8
36.6 2.79
52.5 4.11
66.4 6.97
45.3 9.58
42.3 4.60
9.84 0.84
40.3 2.19
48.3 8.75
45.2 0.26
44.5 0.49
63.0 10.6
32.5 1.70
91.1 7.13
98.7 1.89
42.8 2.28
78.2 15.8
52.3 0.11
39.9 4.14
38.5 0.39
61.0 0.66
NA
80.2 2.90
NA
149.7 12.3
NA
NA
9a
NA
9b
84.4 31.0
55.4 3.33
61.6 2.51
41.6 0.39
30.9 18.8
52.4 3.55
75.1 20.9
69.5 7.09
NA
NA
101.0 0.88
110.6 4.68
113.3 16.6
65.5 4.69
58.2 2.21
115.7 15.5
102.4 0.45
102.5 1.09
NA
9c
154.7 1.38
97.2 2.28
144.5 2.49
74.7 7.26
124.4 5.4
NA
9d
9e
9f
9g
9h
9i
65.0 2.85
96.2 5.26
50.6 4.96
78.2 4.73
NA
147.4 1.22
NA
9j
9k
51.6 2.65
NA
NA
NA
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
NA
NA
NA
NA
NA
53.0 5.89
42.2 0.92
53.2 1.60
45.2 0.82
45.9 6.63
NA
65.1 4.91
52.3 6.55
49.9 18.9
73.6 31.5
58.5 1.52
78.7 2.30
37.1 16.3
NA
125.3 6.15
140.5 0.66
131.7 0.73
92.4 2.00
134.1 4.58
NA
117.6 10.2
NA
142.3 12.7
NA
105.7 3.78
84.8 13.2
NA
36.0 0.15
72.4 6.68
43.2 3.67
98.2 0.28
174.8 16.9
145.3 4.41
97.2 16.8
84.2 8.20
51.9 9.96
AML: acute myelogenous leukemia; ALL-B: B-cell acute lymphoblastic leukemia; ALL-T: T-cell acute lymphoblastic leukemia; NA: not active.
assays were carried out to evaluate the anti-migratory
effect. Indeed, representative micrographies show that
compound 9f efficiently inhibits B16F10 migration in
comparison with DMSO in a time-dependent manner
(Figure 4). These data suggests that adherent cells would
be targeted in their migratory capacity by compound 9f,
potentially affecting the ability of colonization activity of
these tumors.
Analysis of estimated physicochemical and pharmacokinetic
properties
Figure 3. The effect of compound 9f on cell viability over time. Jurkat
cells were treated with 25 and 50 µmol L-1 of 9f. Cells treated with vehicle
(DMSO) and culture medium (RPMI) were used as control. Cell growth
was determined with trypan blue exclusion at 0, 24, 48, and 72 h after
incubation. Data are shown as means standard deviation of triplicate
In addition to anti-cancer activity, it is important
to consider several other properties relevant for drug
experiments (*p < 0.05).
development. Therefore, aiming to evaluate if compounds
are suitable for further steps of lead optimization, a set of
44 properties were estimated for the compounds herein
reported, employing the software QikProp.35
that pathways affecting cell death and proliferation might
be affected by the treatments.
Although melanoma B16F10 is commonly resistant to
potential anticancer agents in cytotoxic assays, evaluation
of other phenotypes would render additional information on
the biological activity of compound 9f. Thus, wound healing
Especially for orally available drugs, most often
compounds obey Lipinski’s and Veber’s rules.52,53
According to Lipinski’s rule of five, the following drug-
like physicochemical properties presents no more than one

554
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
Figure 4. The effect of derivative 9f on cell migration. B16F10 cells were treated with 50, 75, and 100 µmol L-1 of 9f. Cells treated with vehicle (DMSO)
and culture medium (RPMI) were used as control. (Top) Cell migration was determined by photographs of wound healing assay at 0, 12, 24, and 48 h
after incubation; (bottom) wound healing assay for percentage of inhibition of cell migration caused by 9f in these three different concentrations. Error
bars represent the means standard deviation from triplicate experiment (*p < 0.05).
violation: molecular weight (≤ 500 g mol-1), clogP (≤ 5),
number of hydrogen bond donors (≤ 5) and number of
hydrogen bond donors (≤ 10). Besides,Veber’s rules indicate
that the number of rotatable bonds (≤ 10) and total polar
surface area (TPSA, ≤ 75 Å3) are important as drug-like
properties. Among the compounds studied here, 9i obeys
all Lipinski’s rules, while the remaining compounds violate
one rule, clogP (Table 2). Considering Veber’s rules, eleven
compounds or approximately half of the total have 10 or
fewer rotatable bonds. Except for compound 10i, all other
nerol derivatives present TPSA within the suggested limit.
Therefore, overall the compounds herein investigated obey
most physicochemical drug-like properties. The most
promising compound in this study, derivative 9f, violates
only the clogP limit (clogP = 6.4).
Caco-2 (QPPCaco) and MDCK cells (QPPMDCK) and
skin (QPlogKp) and the number of predicted metabolic sites
(No. metab), were also calculated. This analysis indicated
properties which should be improved when optimizing this
class of compounds, such as the affinity for HERG. Binding
to HERG K+ channel is a common cause of cardiac toxicity,
and therefore it is important to minimize interaction with
this protein. Another aspect that deserves attention is the
predicted number of metabolic sites, which is slightly
higher than the range observed for 95% of drugs. While
most drugs have at most 8 metabolic sites, compounds
reported herein have 9 or 10. To verify if this compromises
the potential efficacy of these compounds, in vivo studies
would be necessary.
On the other hand, the compounds described in this
study are predicted to have very good cell permeability,
which is an essential pharmacokinetic property. Except
for compound 10i, all molecules were predicted to have
Several other properties which could be applicable for
drug development (Table 3), such as the estimated affinity
to HERG K+ channels (QPlogHERG), permeability through

Vol. 30, No. 3, 2019
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555
Table 2. Calculated molecular properties for compounds 9a-k and 10a-k. Estimated properties are considered relevant for drug-likeness according to the
Lipinski’s and Veber’s rules
Molecular weight /
(g mol-1)
No. H-bond
donors
No. H-bond
acceptorsa
No. Lipinski’s
rule violations
No. of rotatable
bonds
Compound
clogP
TPSA / Å3
9a
9b
9c
9d
9e
9f
9g
9h
325.5
343.4
359.9
404.3
451.3
409.5
393.5
355.5
370.5
361.4
394.3
353.5
371.5
388.0
432.4
497.4
437.5
421.5
383.5
398.5
389.5
422.4
5.3
5.5
5.8
5.9
5.6
6.4
6.3
5.3
4.5
5.7
6.2
6.0
6.3
6.6
6.7
6.7
7.2
7.1
6.1
5.4
6.5
6.9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4.2
4.2
4.2
4.2
4.2
4.2
4.2
4.95
5.2
4.2
4.2
4.2
4.2
4.2
4.2
4.2
4.2
4.2
4.95
5.2
4.2
4.2
1
1
1
1
1
1
1
1
0
1
1
1
1
1
1
1
1
1
1
1
1
1
9
9
9
9
9
10
9
10
10
9
40.9
40.9
40.8
40.8
41.8
48.6
40.8
49.1
85.7
40.8
40.5
41.8
41.8
41.7
41.8
41.8
49.5
41.8
50.1
86.7
41.8
41.4
9i
9j
9k
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
11
11
11
11
11
12
11
12
12
11
11
aThe number of hydrogen bond acceptors represents an average calculated based on a set of configurations, and therefore can be non-integer. TPSA: total
polar surface area.
Table 3. Additional predicted pharmacokinetic properties for compounds 9a-k and 10a-k
Compound
Rangef or reference
values
QPlogHERGa
> –5
QPPCacob / (nm s-1)
> 500
QPPMDCKc / (nm s-1)
> 500
QPlogKpd
No. metabe
1 to 8
–8.0 to –1.0
9a
–6.4
–6.2
–6.3
–6.3
–5.4
–6.0
–6.3
–5.8
–6.2
–6.1
–6.1
–6.4
–6.4
–6.6
–6.4
–6.5
–6.5
–6.4
–6.4
–6.6
–6.3
–6.2
3118
3135
3138
3146
3229
3375
3146
3374
376
1691
3079
4204
4533
5043
8602
7452
1842
172
–0.75
–8.79
–9.12
–9.13
–9.76
–8.11
–9.77
–7.89
–2.64
–9.94
–1.04
–4.81
–6.15
–6.47
–6.51
–6.54
–6.06
–7.16
–5.87
–2.38
–7.32
–7.54
9
9
9b
9c
9
9d
9
9e
9
9f
10
9
9g
9h
10
10
9
9i
9j
3147
3120
3492
3497
3504
3497
3493
3494
3496.
3476
420
5241
8121
1912
3465
4737
5082
5491
8930
8351
1902
194
9k
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
9
9
9
9
9
10
9
10
10
9
3506
3533
5889
9264
9
aPredicted logIC50 for HERG K+ blockage; bpredicted apparent Caco-2 cell permeability for non-active transport; cpredicted apparent MDCK cell permeability
for non-active transport; dpredicted skin permeability, log Kp; enumber of likely metabolic sites; frange observed for 95% of known drugs.

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Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
great permeability through Caco-2 cells, a model for the
gut-blood barrier, and MDCK cells, which model the
blood brain barrier. Additionally, fourteen of the twenty
compounds reported have skin permeability within the
range observed for 95% of known drugs.
leukemia cells and metastatic melanoma. On the other
hand, there exists a small negative correlation between
QPlogHERG and activities from Jurkat (–0.31) and B16F10
(–0.35). These negative correlations mean that biological
activity increases as the QPlogHERG values decrease.
Therefore, most of the evaluated parameters
seemed favorable for drug development, principally for
compound 9f. These data certainly would favor next
optimization steps in order to obtain more selective
and potent substances against cancer. Together with the
cytotoxicity results against cancer cells lines, these findings
enforce nerol derivatives containing triazolic portion
as a new class of therapeutic agents to be exploited and
optimized.
Correlation coefficient between each property included
in Tables 2 and 3 and –logIC50 was calculated to better
understand their real influence in the measured activities.
The results are shown in Table 4.
As expected, the embryonic non-tumor cells NH3T3
presents a completely different behavior, compared to
others. Permeability through skin (QPlogKp) is the only
pharmacokinetic property that shows some correlation
(–0.46) with biological activity of this cell line. Lower
values of QPlogKp favor biological activity. Molecular
weight shows a good correlation with activity of leukemia
cells and metastatic melanoma (0.71, 0.55, 0.60 and 0.55
for HL60, Nalm6, Jurkat and B16F10 cells, respectively).
In general, the higher the molecular weight better is the
activity. The number of H-bond acceptors and donors, the
number of rotatable bonds, TPSA and QPPCaco seems not
to be significant to any of the biological activities measured.
Low positive correlation was observed between clogP and
activities from HL60, Nalm6, and B16F10 cells. The same
can be stated regarding QPPMDCK and activities from
3D-QSAR analysis
In order to gain information about the structure of
nerol derivatives and their ability to inhibit cancer cell
lines, QSAR analyses were carried out. Only those
compounds that showed activity against leukemia and
metastatic melanoma cells (HL60: n = 23; Jurkat: n = 18;
Nalm6: n = 20; B16F10: n = 15) were considered. Even
though the number of compounds is small for a QSAR
study, it is assumed as reasonable in terms of the number
of molecules for an exploratory analysis, and that is the
reason why data splitting-based model validations (external
validation, bootstrapping) were not applied. Variable
selection was carried out in two steps: firstly using the
FDD and then OPS algorithm implemented in QSAR
modeling. Four regression models were obtained and
the regression coefficients (autoscaled) together with the
models performance are presented in Table 5.
The model basic statistics (R2 and Q2) satisfies the
minimal requirements for QSAR studies (R2 > 0.6, Q2 > 0.5).
Standard errors (RMSEC and RMSECV) are below 5% of
the mean value for pIC50. The number of latent variables
varied from 2 to 5. The models were validated using a set
of procedures suggested in the literature. The robustness of
each optimized model was confirmed by leave-N-out cross-
validation (LNO). Mean values of Q2LNO oscillate around
Q2LOO within a narrow range, whilst the respective standard
deviations are small for up to five of the samples taken
Table 4. Correlation coefficient between biological activities (–logIC50) and molecular/pharmacokinetic propertiesa
HL60
0.71
Nalm6
0.55
Jurkat
0.60
B16F10
0.55
NH3T3
0.15
Molecular weight
clogP
0.33
0.29
0.15
0.32
–0.04
0.07
H-Bond acceptors
No. of rotatable bonds
TPSA
–0.21
0.04
–0.23
0.01
0.08
–0.02
0.21
–0.01
0.24
–0.14
–0.02
–0.01
0.13
–0.10
–0.20
0.27
0.13
0.28
QPlogHERG
QPPCaco
–0.03
–0.11
0.38
–0.31
0.09
–0.35
0.10
QPPMDCK
QPlogKp
0.39
0.36
0.41
0.17
–0.21
0.07
–0.05
–0.09
–0.09
0.21
–0.16
0.34
–0.46
0.22
Metab
aThe number of H-bond donors was not included since all values were equal to zero. TPSA: total polar surface area; QPlogHERG: predicted logIC50
for HERG K+ blockage; QPPCaco: predicted apparent Caco-2 cell permeability for non-active transport; QPPMDCK: predicted apparent MDCK cell
permeability for non-active transport; QPlogKp: predicted skin permeability, log Kp.

Vol. 30, No. 3, 2019
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557
Table 5. Regression models obtained for each cell line and their internal statistics
Model
Cell line
Regression equationa
Statistics
pIC50 = –0.803 × (16_DRY-DRY)
+ 0.363 × (57_DRY-DRY)
– 0.192 × (202_TIP-TIP)
– 0.414 × (207_TIP-TIP)
+ 0.390 × (221_TIP-TIP)
+ 0.909 × (326_DRY-N1)
+ 0.286 × (362_DRY-N1)
+ 0.429 × (401_DRY-TIP)
R2 = 0.938; RMSEC = 0.053; F = 42.361;
Q2LOO = 0.853; RMSECV = 0.081;
average Q2LNO = 0.799; intercept R2 = 0.244;
intercept Q2LOO = –1.282;
1
HL60
cumulated information: 75.12%;
latent variables: 5
pIC50 = +0.205 × (208_TIP-TIP)
+ 0.220 × (238_TIP-TIP)
+ 0.242 × (334_DRY-N1)
+ 0.375 × (362_DRY-N1)
– 0.564 × (386_DRY-TIP)
+ 0.194 × (597_N1-TIP)
R2 = 0.872; RMSEC = 0.049; F = 57.906;
Q2LOO = 0.774; RMSECV = 0.064;
average Q2LNO = 0.767; intercept R2 = 0.167;
intercept Q2LOO = –0.813;
2
3
4
Nalm6
Jurkat
cumulated information: 62.05%;
latent variables: 2
pIC50 = +0.434 × (23_DRY-DRY)
+ 0.331 × (29_DRY-DRY)
– 0.292 × (199_TIP-TIP)
+ 0.366 × (211_TIP-TIP)
– 0.594 × (396_DRY-TIP)
+ 0.604 × (407_DRY-TIP)
R2 = 0.909; RMSEC = 0.035; Q2LOO = 0.804;
RMSECV = 0.052; F = 32.464;
average Q2LNO = 0.784; intercept R2 = 0.281;
intercept Q2LOO = –0.929;
cumulated information: 83.64%;
latent variables: 4
R2 = 0.923; RMSEC = 0.027; Q2LOO = 0.774;
RMSECV = 0.042; F = 29.967;
average Q2LNO = 0.796; intercept R2 = 0.200;
intercept Q2LOO = –1.361;
pIC50 = –0.184 × (213_TIP-TIP)
+ 0.964 × (362_DRY-N1)
– 0.149 × (386_DRY-TIP)
– 0.684 × (415_DRY-TIP)
+ 0.047 × (573_N1-TIP)
B16F10
cumulated information: 92.17%;
latent variables: 4
aRegression coefficients for descriptors in auto scaled form. R2: coefficient of determination; RMSEC: root mean square error of calibration; Q2LOO: coefficient
of determination in the leave-one-out (LOO) cross-validation; RMSECV: root mean square error of cross-validation; F: F-ratio test with 95% confidence
interval; average Q2LNO: average value of coefficients of determination obtained in each step of the LNO cross-validation.
out during the cross validation. The possibility of chance
correlation was tested using y-randomization analysis.
Comparing randomized models (i.e., models with scrambled
pIC50 values) with the final QSAR model, it is visible that
the statistical parameters satisfy minimum criteria for the
absence of chance correlation in all the four models.45,46
The number and type of MIF descriptors were different
for each PLS regression models (Table 5). Comparing
the four models based on their regression vector, it can
be seen that O type probe (i.e., a carbonyl oxygen with
hydrogen bond acceptor, HBA, properties) is not significant
for cytotoxic activity. Being an HBA probe, it identifies
hydrogen bond donor groups in the ligands (HBD) and this
is in perfect agreement with the previous analysis on the
physicochemical properties, since the molecules described
do not have HBD groups (Table 4). From the eight selected
descriptors in model 1, the most important describes a
hydrogen bond acceptor effect in the molecules combined
to hydrophobic interaction (DRY-N1). One should have
in mind that the N1 probe (which is HBD) identifies
HBA groups in the ligands. The second most important
descriptor has purely hydrophobic features (DRY-DRY). In
this model, descriptors with combination of hydrophobic-
steric (DRY-TIP) and purely steric descriptors (TIP-TIP)
are also important. Regression model 2 is based on six
MIF descriptors, where hydrophobic-steric (DRY-TIP)
is the most significant feature. Pure hydrophobic effects
(DRY-DRY) do not seem to be significant for model 2.
The hydrogen bond acceptor-hydrophobic (DRY-N1)
feature appears in other descriptors selected for this
model. On the other hand, no N1 fields were selected in
model 3, only DRY-DRY, TIP-TIP and DRY-TIP features
appear to be important in this model. But in model 4, the
DRY-N1 descriptor is the most important. As for model 2,
pure hydrophobic effects (DRY-DRY) do not seem to be
significant.
Models 1 and 3 present physicochemical information
similar to each other because they present mainly purely
hydrophobic (DRY-DRY), purely steric (TIP-TIP), and
combination of both (DRY-TIP) features. The pairs of
descriptors 199_TIP-TIP (HL60)/202_TIP-TIP (Jurkat),
and 221_TIP-TIP (HL60)/211_TIP-TIP (Jurkat) highlight
this similarity, which can be visualized in Figure 5 when
each pair occupies equivalent regions in space. On the
other hand, models 2 and 4 have two pairs of descriptors
that are common, 362_DRY-N1 and 386_DRY-TIP.

558
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
Despite their relative contribution in each equation is
different, in both of them the signal is the same, positive for
362_DRY-N1 and negative for 386_DRY-TIP. Furthermore,
as can be seen in Figure 6, both descriptors have the same
behaviors, occupying similar regions in space, as would be
expected in such situation.
calculating the Pearson’s correlation coefficient, r, between
cell lines activities from Table 1 (rHL60/Jurkat = 0.8 and
rNalm6/B16F10 = 0.7).
These results may indicate that, from the structural
modification of nerol, it would be possible to develop agents
useful for the treatment of more than one type of cancer.
These results suggest that the activities described may
be occurring by similar mechanisms of action for the HL60
and Jurkat cell lines, and the same for Nalm6 and B16F10
cell lines. For a better understanding, an HCA based on the
original IC50 values of all the compounds in the data set,
was carried out. This approach was used to compare the
behavior of the compounds as a whole, not just between
the active compounds of each subset. For this, inactive
compounds (NA) activities were taken to be the ones
presenting IC50 = 250 µmol L-1. The dendrogram obtained
(Figure 7) helps to justify the similarities between models
1 and 3, and between models 2 and 4. By also inserting the
data concerning the NH3T3 cell line, it also appears that
the mechanism of toxicity against normal cells probably
has no relation to cytotoxic activity. As a basis for these
results, it may be proposed that the cytotoxic effects of
sub-sets 1 and 3 may occur by some similar mechanism
between the two cell lines, and the same can be proposed for
sub-sets 2 and 4. Another information to be extracted from
the dendrogram is that the similarity (approximately 0.54)
between the sub-sets 1 and 3 is greater than that of sub-sets
2 and 4 (approximately 0.40), what can be confirmed by
Conclusions
In summary, a series of nerol derivatives containing
triazolic functionalities was designed and synthesized
using the CuAAC (click reaction) as the key step.
The compounds were evaluated against four different
cancer cell lines types. The occurrence of a remarkable
variability among the compounds suggests that the
presence of various substituents in the aryl group in the
triazolic portion, and their position as well, interfere
with cell viability. In addition, the length of the aliphatic
chain linking the nerol moiety to the triazolic portion
also impacts the biological activity. The most cytotoxic
compound 9f was also able to impair cell viability over
time and migration. Overall, considering the biological
activity results along with the calculated physicochemical
properties, the triazolic nerol derivatives described herein
seem favorable for further drug development procedures.
The 3D-QSAR investigation points to the fact that two
different mechanisms of action can be associated with
the four types of cell lines used in the biological assays.
Figure 5. Graphical representations of similar GRIND descriptors in models 1 and 3 superimposed on the most active compounds of each subset. Blue
line represents a descriptor with negative influence under activity and red line a descriptor with positive influence. Green spheres: TIP fields.

Vol. 30, No. 3, 2019
Teixeira et al.
559
Figure 6. Graphical representations of similar GRIND descriptors in models 2 and 4 superimposed on the most active compounds of each subset. Blue line
represents a descriptor with negative influence under activity, and red line a descriptor with positive influence. Green spheres: TIP fields; yellow spheres:
DRY fields; blue spheres: N1 fields.
functionalities seem to be a scaffold to be explored toward
the development of new agents against cancer.
Supplementary Information
Supplementary information (IR, NMR (1H and 13C) and
MS spectra of the compounds, tables related to the QSAR
study and the result of the effect compound 9f on the human
non-cancerous cell line HEK293) is available free of charge
at http://jbcs.sbq.org.br as PDF file.
Acknowledgments
The authors are grateful to the following Brazilian
agencies: Fundação deAmparo à Pesquisa de Minas Gerais
(FAPEMIG), Fundação de Amparo à Pesquisa de São
Paulo (FAPESP), Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES),
Figure 7. Dendrogram of biological activities (autoscaled data, flexible
linkage) showing their similarity.
Fundação de Amparo à Pesquisa do Rio Grande do Sul
(FAPERGS), and Fundação Araucária (FAPPR) for
financial support. FundaçãoArthur Bernardes (FUNARBE)
is also acknowledged for a fellowship to G. C. B.
Taken the data described in the present investigation,
it is assumed that nerol derivatives containing triazolic

560
Synthesis of Nerol Derivatives Containing a 1,2,3-Triazole Moiety and Evaluation of Their Activities
J. Braz. Chem. Soc.
23. Demchuk, D. V.; Samet, A. V.; Chernysheva, N. B.; Ushkarov,
V. I.; Stashina, G. A.; Konyushkin, L. D.; Raihstat, M. M.;
Firgang, S. I.; Philchenkov,A.A.; Zavelevich, M. P.; Kuiava, L.
M.; Chekhun, V. F.; Blokhin, D.Y.; Kiselyov, A. S.; Semenova,
M. N.; Semenov, V. V.; Bioorg. Med. Chem. 2014, 22,
738.
References
1. Butler, M. S.; J. Nat. Prod. 2004, 67, 2141.
2. Paterson, I.; Anderson, E. A.; Science 2005, 310, 451.
3. Koehn, F. E.; Carter, G. T.; Nat. Rev. Drug Discovery 2005, 4,
206.
24. Praveena, K. S. S.; Durgadas, S.; Babu, N. S.; Akkenapally, S.;
Kumar, C. G.; Deora, G. S.; Murthy, N. Y. S.; Mukkanti, K.;
Pal, S.; Bioorg. Chem. 2014, 53, 8.
4. Newman, D. J.; Cragg, G. M.; J. Nat. Prod. 2007, 70, 461.
5. Li, J. W. L.; Vederas, J. C.; Science 2009, 325, 161.
6. Harvery, A. L.; Edrada-Ebel, R.; Quinn, R. J.; Nat. Rev. Drug
Discovery 2015, 14, 111.
25. Khazir, J.; Hyder, I.; Gayatri, L.; Yandrati, L. P.; Nalla, N.;
Chasoo, G.; Mahajan, A.; Saxena, A. K.; Alam, M. S.; Qazi,
G. N.; Kumar, H. M. S.; Eur. J. Med. Chem. 2014, 82, 255.
26. Allam, M.; Bhavani, A. K. D.; Mudiraj, A.; Ranjan, N.;
Thipanna, M.; Babu, P. P.; Eur. J. Med. Chem. 2018, 156, 43.
27. Tsai, Y.; Etichetti, C. M. B.; Di Benedetto, C.; Girardini, J. E.;
Martins, F. T.; Spanevello, R. A.; Suárez, A. G.; Sarotti, A. M.;
J. Org. Chem. 2018, 83, 3516.
7. Newman, D. J.; Cragg, M. G.; J. Nat. Prod. 2016, 79, 629.
8. Bhanot,A.; Sharma, R.; Noolvi, M. N.; Int. J. Phytomed. 2011,
3, 09.
9. Djilani, A.; Dicko, A.; Nutrition, Well-Being and Health;
Bouayed, J., ed.; IntechOpen: India, 2012, ch. 7, p. 155-178.
10. Marques, T. H. C.; Marques, B. G. C. B.; Lima, D. S.; Siqueira,
H. D. S.; Neto, J. D. N.; Branco, S. B. G.; Souza, A. A.; Souza,
D. P.; Freitas, R. M.; World J. Neurosci. 2013, 3, 32.
11. Yamamoto, Y.; Hosokawa, M.; Kurihara, H.; Maoka, T.;
Miyashita, K.; Bioorg. Med. Chem. Lett. 2008, 18, 4004.
12. Teixeira, R. R.; Bressan, G. C.; Pereira, W. L.; Ferreira, J. G.;
Oliveira, F. M.; Thomaz, D. C.; Molecules 2013, 18, 1881.
13. Siqueira, R. P.; Barbosa, E. A. A.; Polêto, M. D.; Righetto, L.
M.; Seraphim, T. V.; Salgado, R. L.; Ferreira, J. G.; Barros, M.
V.A.; Oliveira, L. L.; Laranjeira,A. B.A.;Almeida, M. R.; Silva
Júnior, A.; Fietto, J. L. R.; Kobarg, J.; Oliveira, E. B.; Teixeira,
R. R.; Borges, J. C.; Yunes, J. A.; Bressan, G. C.; PLoS One
2015, 10, e0134882.
28. Hou, W.; Luo, Z.; Zhang, G.; Cao, D.; Li, D.; Ruan, H.; Ruan,
B. H.; Su, L.; Xu, H.; Eur. J. Med. Chem. 2017, 138, 1042.
29. Borgati, T. F.; Alves, R. B.; Teixeira, R. R.; Freitas, R. P.;
Perdigão, T. G.; Silva, S. F.; Santos, A. A.; Bastidas, A. J. O.;
J. Braz. Chem. Soc. 2013, 24, 953.
30. Siqueira, R. P.; Barros, M. V. A.; Barbosa, E. A. A.; Onofre, T.
S.; Gonçalves, V. H. S.; Pereira, H. S.; Júnior, A. S.; Oliveira,
L. L.; Oliveira, M. R.; Fietto, J. L. R.; Teixeira, R. R.; Bressan,
G. C.; Eur. J. Med. Chem. 2017, 134, 97.
31. Rasband, W. S.; ImageJ, version 1.8.0; U. S. National Institutes
of Health, Bethesda, Maryland, USA, 1997-2018. Available at
https://imagej.nih.gov/ij/, accessed in October 2018.
32. GraphPad Prism, version 5.00 for Windows; GraphPad
Software, Inc., La Jolla California, USA. Available at www.
graphpad.com, accessed in October 2018.
14. Silva, M. R.; Moreira, G. A.; Silva, R. A. G.; Barbosa, E. A.
A.; Siqueira, R. P.; Teixeira, R. R.; Almeida, M. R.; Júnior, A.
S. J.; Fietto, J. L. R.; Bressan, G. C.; Biomed. Res. Int. 2015,
article ID 150514.
33. MarvinSketch, version 15.4.6.0; ChemAxon, Budapest,
Hungary, 2015.
15. Maia, A. F. S.; Siqueira, R. P.; Oliveira, F. M.; Ferreira, J. G.;
Silva, S. F.; Cauiby, C. A.; Oliveira, L. L.; Paula, S. O.; Souza,
R. A. C.; Guilardi, S.; Bressan, G. C.; Teixeira, R. R.; Bioorg.
Med. Chem. Lett. 2016, 26, 2810.
34. LigPrep, version 3.6; Schrödinger, LLC, NewYork, NY, USA,
2015.
35. QikProp, version 4.6; Schrödinger, LLC, NewYork, NY, USA,
2015.
16. Lima, G. D.A.; Rodrigues, M. P.; Mendes, T.A. O.; Moreira, G.
A.; Siqueira, R. P.; da Silva, A. M.; Vaz, B. G.; Fietto, J. L. R.;
Bressan, G. C.; Machado-Neves, M.; Teixeira, R. R.; Toxicol.
In Vitro 2018, 53, 1.
36. Irwin, J. J.; Sterling, T.; Mysinger, M. M.; Bolstad, E. S.;
Coleman, R. G.; J. Chem. Inf. Model. 2012, 52, 1757.
37. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Petersson, G.A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich,
A.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.;
Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg,
J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.;
Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe,
D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang,
W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Throssell, K.; Montgomery Jr., J. A.; Peralta, A.
17. Kolb, H. C.; Sharpless, K. B.; Drug Discovery Today 2003, 8,
1128.
18. Tron, G. C.; Pirali, T.; Billington, R.A.; Canonico, P. L.; Sorba,
G.; Genazzani, A. A.; Med. Res. Rev. 2008, 28, 278.
19. Thirumurugan, P.; Matosiuk, D.; Jozwiak, K.; Chem. Rev. 2013,
113, 4905.
20. Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Angew. Chem., Int.
Ed. 2001, 40, 2004.
21. Dheer, D.; Singh, V.; Shankar, R.; Bioorg. Chem. 2017, 71, 30.
22. Ma, N.; Wang,Y.; Zhao, B.-X.;Ye, W.-C.; Jiang, S.; Drug Des.,
Dev. Ther. 2015, 9, 1585.

Vol. 30, No. 3, 2019
Teixeira et al.
561
E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
46. Eriksson, L.; Jaworska, J.; Worth, A. P.; Cronin, M. T.;
McDowell, R. M.; Gramatica, P.; Environ. Health Perspect.
2003, 111, 1361.
K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand,
J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, J.;
Tomasi, S. S.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo,
C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Farkas, O.; Foresman, J. B.; Fox, D. J.; Gaussian 09; Gaussian,
Inc., Wallingford, 2009.
47. Pirouette, version 4; Infometrix Inc., Woodinville, WA, USA,
2003.
48. Gazolla, P. A. R.; Teixeira, R. R.; da Silva, A. M.; Vaz, B. G.;
Vasconcelos, G.A.; Siqueira, R. P.; Gonçalves,V. H. S.; Pereira,
H. S.; Bressan, G. C.; Quim. Nova 2018, 41, 497.
38. Molfetta, F.A.; Bruni,A. T.; Rosseli, F. P.; Silva,A. B. F.; Struct.
Chem. 2007, 18, 49.
49. Tatman, D.; Mo, H.; Cancer Lett. 2002, 175, 129.
50. Carnesecchi, S.; Schneider,Y.; Ceraline, J.; Duranton, B.; Gosse,
F.; Seiler, N.; Raul, F.; J. Pharmacol. Exp. Ther. 2001, 298, 197.
51. Taga, T.; Shimomura, Y.; Horikoshi, Y.; Ogawa, A.; Itoh, M.;
Okada, M.; Ueyama, J.; Higa, T.; Watanabe, A.; Kanegane, H.;
Iwai,A.; Saiwakawa,Y.; Kogawa, K.;Yamanaka, J.; Tsurusawa,
M.; Pediatr. Blood Cancer 2011, 57, 36.
39. Kawasuji, T.; Fuji, M.; Yoshinaga, T.; Sato, A.; Fujiwara, T.;
Kiyama, R.; Bioorg. Med. Chem. 2006, 14, 8420.
40. Weigend, F.; Ahlrichs, R.; Phys. Chem. Chem. Phys. 2005, 7,
3297.
41. Pentacle, version 1.05; Molecular Discovery Ltd., Barcelona,
Spain, 2010.
42. Pastor, M.; Cruciani, G.; McLay, I.; Pickett, S.; Clementi, S.;
J. Med. Chem. 2000, 43, 3233.
52. Lipinski, C. A.; J. Pharm. Toxicol. Methods 2000, 44, 235.
53. Veber, D. F.; Johnson, S. R.; Cheng, H.Y.; Smith, B. R.; Ward,
W.; Kopple, K. D.; J. Med. Chem. 2002, 45, 2615.
43. Teófilo, R. F.; Martins, J. P.; Ferreira, M. M. C.; J. Chemom.
2009, 23, 32.
44. Martins, J. P.A.; Ferreira, M. M. C.; Quim. Nova 2013, 36, 554.
45. Kiralj, R.; Ferreira, M. M. C.; J. Braz. Chem. Soc. 2009, 20,
770.
Submitted: August 2, 2018
Published online: October 10, 2018
This is an open-access article distributed under the terms of the Creative Commons Attribution License.