Synthesis and in vitro antibacterial evaluation of novel 4-substituted 1-menthyl-1,2,3-triazoles

Article abstract of DOI:10.1248/cpb.c16-00463

Menthyl 1,4-disubstituted 1,2,3-triazole derivatives of hydroxybenzaldehydes, phenols and bile acids were synthesized via click chemistry. The novel synthesized compounds were evaluated for their in vitro antibacterial activity against Enterococcus faeciu

Full text of DOI:10.1248/cpb.c16-00463

Vol. 64, No. 11
Chem. Pharm. Bull. 64, 1589–1596 (2016)
1589
Regular Article
Synthesis and in Vitro Antibacterial Evaluation of Novel 4-Substituted
1-Menthyl-1,2,3-triazoles
,a
Pooneh Khaligh,a Peyman Salehi,* Morteza Bararjanian,a Atousa Aliahmadi,b
Hamid Reza Khavasi,c and Samad Nejad-Ebrahimia
a Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University; Evin,
b
G.C., Tehran 1983969411, Iran: Department of Biology, Medicinal Plants and Drugs Research Institute, Shahid
c
Beheshti University; Evin, G.C., Tehran 1983969411, Iran: and Department of Chemistry, Faculty of Chemistry,
Shahid Beheshti University; G.C., Evin, Tehran 1983963113, Iran.
Received June 5, 2016; accepted August 9, 2016
Menthyl 1,4-disubstituted 1,2,3-triazole derivatives of hydroxybenzaldehydes, phenols and bile acids
were synthesized via click chemistry. The novel synthesized compounds were evaluated for their in vitro anti-
bacterial activity against Enterococcus faecium, and Staphylococcus aureus as Gram-positive bacteria. Some
derivatives illustrated strong inhibitory effect against E. faecium with the minimum inhibitory concentration
(MIC) values ranged from 1–3µM, where cefixime as a positive control revealed MIC value of 35µM. The
structures of the synthesized compounds were confirmed by different spectroscopic techniques including
1H-NMR, 13C-NMR, high resolution (HR)-MS, IR and X-ray crystallographic analysis.
Key words menthol; 1,2,3-triazole; click chemistry; antibacterial activity
Menthol is a natural compound with three asymmetric car- although this moiety and its derivatives are a significant cate-
bon atoms which among the optical isomers, (−)-menthol with gory of nitrogen-containing aromatic heterocyclic compounds,
the 1R, 2S, 5R configuration found widely in nature.1) In vitro and have been considered because of their various biologi-
and in vivo researches demonstrated that menthol as a simple cal properties such as antibacterial, antifungal, anti-human
monoterpene exhibits significant biological properties such as immunodeficiency virus (HIV), antitubercular, anticancer,
anticancer, antibacterial, antifungal, antiviral, anti-inflamma- anti-inflammatory and analgesic, anticonvulsant, antipara-
tory, antipruritic, analgesic and antitussive.2,3) It is also used in sitic, antidiabetic, antihistaminic and antihypertensive activi-
lots of pharmaceutical remedies such as chest rubs, analgesic ties.20–22) Triazole derivatives have increasingly been used as
balm, nose drop and spray, cough drops and lotion.3) It has clinical remedies or candidates for the treatment of various
been reported that menthol acts as an enhancer for transder- types of diseases with powerful pharmacological activities,
mal delivery of variety of drugs and it is one of the major ago- less side effects, fewer multidrug resistances, high bioavail-
nists of transient receptor potential melastatin 8 (TRPM8).3,4) ability, good pharmacokinetic properties and drug targeting,
There are reports based on synthesis of menthol derivatives diversity of drug administration and better curative effects.
and evaluation of their effects such as antitumor, antimicrobial These evidences can be realized broad potential of triazole-
and antifungal activity as well as on penetration of drugs, based compounds as medicinal agents. A large number of dis-
percutaneous absorption, inhibition of plasminogen activator coveries illustrated that triazole compounds showed enormous
inhibitor-1 (PAI-1), cooling effect and insecticidal activity.5–12) potential as antibacterial drugs. Some triazole derivatives ex-
Previous in vitro antibacterial investigations of menthol have hibited potent activity against the clinical drug resistant bacte-
proved strong antibacterial activity of this compound against a ria. Therefore researches on triazole antibacterial aspects have
range of bacterial strains.13–15)
been considered and have become one of the directions in the
Bacterial infections progressively avoid standard treatment exploitation of antibacterial agents.21) Because of importance
as resistance to multiple antibiotics is extending throughout of disubstituted 1,2,3-triazole in drug discovery, there is an in-
the world, as a result there is an urgent medical need for terest to develop new methods for synthesis of this function.23)
a sustainable supply of novel, effective, and nontoxic anti-
Nowadays, click chemistry, especially the Huisgen 1,3-di-
bacterial drugs without cross-resistance to currently used polar cycloaddition of azides and alkynes has become a
antibiotics.16) Among all the medicines currently approved as powerful methodology to produce 1,2,3-triazole moiety with
antibacterial new chemical entities, a significant percentage of high reliability and selectivity.24) Click chemistry is an attrac-
them are either natural products or were derived from a natu- tive trend in various research fields especially in biomedical
ral product base.17) As a result, it is not surprising that natural investigations and drug discovery because of its high yield,
products are hopeful lead structures particularly for anti- high selectivity, simple purification methods, safe and green
bacterial drugs.16) Structural and chemical diversity of natural reaction conditions and the tolerance of various kinds of func-
products is more than synthetic compounds, so they have been tional groups. As a result, click chemistry have been used by
the major sources of bioactive factors and the main target for researchers as a synthetic tool for the creation of pharmaco-
discovering and designing new drugs.18)
logically valuable drugs.25,26)
Nitrogen-containing heterocycles demonstrate outstanding
In the present study, several menthyl tethered 1,4-disub-
biological potency.19) 1,2,3-Triazole is not produced in nature stituted 1,2,3-triazole derivatives of hydroxybenzaldehydes,
*To whom correspondence should be addressed. e-mail: p-salehi@sbu.ac.ir
© 2016 The Pharmaceutical Society of Japan

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Reagents and conditions: a) MsCl, Et3N, CH2Cl2, r.t., 2h, 2: 90%; b) NaN3, DMF, 40°C, 48h, 3: 70%; c) CuSO4·5H2O (0.2eq), sodium ascorbate (0.4eq), MeOH, r.t.,
30min, 10a–c, 11a–i and 12a–c: 90–98%.
Chart 1. Methods for Preparation of Azide (3) and Menthyl 1,4-Disubstituted 1,2,3-Triazole Derivatives (10a–c, 11a–i, 12a–c)
Table 1. Structures of Hydroxybenzaldehydes (4a–c), Phenols (5a–i) and Bile Acids (6a–c) and the Synthesis Pathway of Propargyl Ethers (7a–c, 8a–i,
9a–c)
phenols and bile acids have been synthesized and their anti- alkyne building blocks 7a–c, 8a–i and 9a–c with different
bacterial activities were evaluated and compared with parent substituents were subjected to synthesis of novel derivatives
compounds.
10a–c, 11a–i and 12a–c via 1,3-dipolar cycloaddition in high
yields and purity in the presence of Cu(I) sulfate and sodium
ascorbate as catalysts in methanol at room temperature (Chart
Results and Discussion
Chemistry In this study, our main strategy was the prepa- 1, Fig. 1).
ration of menthyl azide (3) from menthol and synthesis of
The use of ortho-salicylaldehyde and para-hydroxybenzal-
1,4-disubstituted 1,2,3-triazoles by the regioselective copper(I) dehyde derivatives, ended up with the formation of the cor-
(Cu(I))-catalyzed Huisgen 1,3-dipolar cycloaddition reaction responding 1,2,3-triazoles (10a–c) in 90–98% yields. Other
with terminal alkynes. Therefore, in the first step (−)-menthol phenolic compounds with different functional groups such as
(1) was mesylated in the presence of mesyl chloride followed halide, alkyl and acyl (11a–i) were synthesized and sensitive
by reaction with sodium azide which afforded the proper key groups survived under the mild reaction condition. Deoxycho-
azide 3 as the building block of all of the target molecules27,28) lic acid, cholic acid and ursodeoxycholic acid were linked to
(Chart 1). The next step was preparation of the desired alkyne the 4 position of 1-menthyl-1,2,3-triazol moiety with a meth-
library, therefore three drug-like structures including ortho- ylene spacer in excellent yields (12a–c).
salicylaldehyde and para-hydroxybenzaldehyde derivatives
The structures of synthesized compounds were confirmed
(4a–c), phenols (5a–i) and bile acids like deoxycholic acid, by different spectroscopic techniques including 1H-NMR,
cholic acid and ursodeoxycholic acid (6a–c) were selected to 13C-NMR, distortionless enhancement by polarization transfer
1
increase the diversity of the propargyl building blocks. O-Al- (DEPT)-135 and HR-MS analyses. In evaluation of H-NMR
kylation of these compounds with propargyl bromide provided and 13C-NMR spectra of derivatives 10a–c, 11a–i and 12a–c
the alkyne components 7a–c, 8a–i and 9a–c (Table 1).
characteristic peaks were clearly evident which indicating
Library generation of the menthyl 1,4-disubstituted certain positions of the molecules. One of these peaks was
1,2,3-triazoles was a paramount part of the research. As a related to H-1″ as a proton in menthyl ring which carbon is
result, functionalizations of the azide and alkyne components attached to the nitrogen of the triazole moiety and it was
were extremely important in increasing the diversity of the found that in all derivatives this peak was appeared in the
desired library. Thus compound 3 as a key azide29,30) and range of δ=4.93–5.07ppm. Also, evaluation of 1H-NMR

Vol. 64, No. 11 (2016)
Chem. Pharm. Bull.
1591
Fig. 1. Structures of 1,2,3-Triazole Derivatives of Menthol (10a–c, 11a–i, 12a–c)
spectra of products demonstrated chemical shift in the range
of δ=7.14–8.34ppm for H-5′ as a proton of the triazole ring,
one of the main scaffolds of all derivatives. Additionally,
investigation of spectra revealed chemical shifts in the range
of δ=5.09–5.44 and δ=59.3–66.7ppm for Ha,b-6′ and C-6′ as
protons and carbon of the methylene group attached to the
oxygen, respectively. And finally, C-1 as a quaternary aro-
matic carbon connected to the oxygen in the molecules with
the aromatic scaffold, illustrated chemical shift in the range
of δ=150.1–163.3ppm. In assessments, differences in chemical
Fig. 2. Atom Numbering of Compound 11d
shifts of some of these certain areas in compound 11d (Fig. 2)
compared with others attracted our attention. Differences were
Conclusive evidence for the structure of compound 11g
related to chemical shifts of protons and carbon in position was obtained from single-crystal X-ray diffraction. Single
6′ with δ=3.04, 3.08 and 37.5ppm, respectively, and C-1 with crystal of compound 11g was obtained by dissolving it in hot
δ=186.3ppm. The reason for these differences is justified by n-hexane followed by slow evaporation of the solvent. Crys-
the type of substituents of this compound. In this analogue, tallographic data (excluding structure factors) for the struc-
aryl moiety is functionalized by two bulky tert-butyl groups ture in this paper have been deposited with the Cambridge
in the ortho positions. These results were probably caused by Crystallographic Data Center, the deposition number is CCDC
the influence of bulky substituents on benzene ring which led 1447884. Its ORTEP view is shown in Fig. 3.
to a nonplanar mode.31)
Antibacterial Activity Inhibitory effect of menthol on the

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Chem. Pharm. Bull.
Vol. 64, No. 11 (2016)
Table 2. In Vitro Antibacterial Activity of Compounds 10a–c, 11a–i and
12a–c
Strains MICa) (µM)
Compounds
Enterococcus faecium Staphylococcus aureus
10a
2
22
94
21
42
23
1
10
345
10b
10c
375
11a
670
11b
670
11c
750
11d
582
11e
24
22
26
22
11
3
782
11f
704
11g
817
11h
86
11i
90
12a
209
12b
1
204
12c
7
209
13
109
410
20
157
10
35
868
(−)-Menthol
Deoxycholic acid
Cholic acid
Ursodeoxycholic acid
Cefiximeb)
>1638
>652
>626
>652
2
Fig. 3. ORTEP Drawing of Compound 11g
growth of various strains of bacteria encouraged us to choose
this compound as a starting point to optimize biological pro-
file as well as discovering and improving new antibacterial
a) Minimum inhibitory concentration. b) Positive control.
analogues by linking various scaffolds to this lead compound. tion of the number, position and stereochemistry of hydroxyl
The synthesized novel triazole derivatives of menthol (10a–c, groups and linking proper substituents that increase either the
11a–i, 12a–c) were evaluated for their in vitro antibacterial ac- hydrophilicity or the hydrophobicity of these building blocks
tivity using standard techniques by determining the minimum depending on the nature of the organic group.33)
inhibitory concentrations (MICs, µM), defined as the lowest
As indicated from the data, for S. aureus, while compounds
concentration of the compound required to give complete in- 10a with MIC of 10µM along with 11h and i with MIC values
hibition of visible bacterial growth.32) Evaluations were carried of 86 and 90µM, respectively, exhibited promising activity
out against Enterococcus faecium (ATCC 35667) and Staphy- compared to menthol, others did not show comparable activity
lococcus aureus (ATCC 25923) as Gram-positive bacteria via than cefixime with MIC of 2µM. Also, derivatives activity was
comparing the results with cefixime as a standard antibiotic investigated against two other strain namely Bacillus subtilis
and those of parent compounds. MIC values of 10a–c, 11a–i and Escherichia coli, but was not observed significant effect.
and 12a–c against strains along with cefixime, menthol and It was especially noteworthy that menthol as the precursor of
bile acids are listed in Table 2. Obtained data demonstrated the target compounds showed moderate inhibitory activity
strong antibacterial activity of derivatives in comparison with against all tested strains, while the incorporation of 1,2,3-tri-
menthol against E. faecium strain, however all of the syn- azole ring, dramatically enhanced the antibacterial activity of
thesized compounds except 10c and 11b showed even much all the derivatives against E. faecium and some derivatives
stronger effect than cefixime as a standard antibiotic. In the against S. aureus.
meantime, compounds 12b, 11d, 10a and 12a with the lowest
A survey in the literature revealed the same trend for in-
MIC values of 1, 1, 2 and 3µM, respectively, were more potent creasing the antibacterial activity of some lead compounds by
than the positive control cefixime with MIC of 35µM. Com- linking a triazole ring.20,34–36) This could be due to enhance-
pounds 12a–c which were derived from triterpenic building ment of hydrogen bonding and dipole–dipole interaction of the
blocks (9a–c) demonstrated stronger effect than their parent molecules with the biological targets or improvement of their
compounds deoxycholic acid, cholic acid and ursodeoxycholic solubility.21,37,38) 1,2,3-Triazoles are attractive linker units and
acid with MIC values of 20, 157 and 10µM, respectively, in have become useful and important in creating bioactive and
which 12b showed a remarkable change. A similar trend for functional molecules via linking two pharmacophores to give
considerable differences in the antibacterial and antifungal ac- an innovative bifunctional drug.20)
tivities of some derivatives of cholic acid and deoxycholic acid
To investigate the role of menthyl group on antibacterial
has already been reported in the literature.22) Also, the phys- activities of the products, we have synthesized compound 13
iochemical and biological properties of bile acids have been which is the methyl analogue of compound 10a (Fig. 4).
related to the balance between hydroxyls at positions 3, 7 and/
While 10a was one of the strongest antibacterial com-
or 12 and the carboxylic side chain as hydrophilic groups and pounds, the MIC values of 109 and 868µM were observed
hydrophobic methyl groups in their structures. This balance for 13 against E. faecium and S. aureus, respectively. These
and consequently properties can be modified by the distribu- findings clearly show the importance of menthyl moiety on the

Vol. 64, No. 11 (2016)
Chem. Pharm. Bull.
1593
strument equipped with a flame ionization detector (FID) and
Rtx®-5 fused silica column.
Preparation of Mesylate 2 and Azide 3 Menthyl meth-
anesulfonate (2) and menthyl azide (3) were synthesized ac-
cording to the known methods reported in the literature.27,28)
Preparation of Propargylic Compounds 7a–c, 8a–i and
9a–c Compounds 7a–c, 8a–i and 9a–c22,31,40–47) were synthe-
sized by propargylation of compounds 4a–c, 5a–i and 6a–c,
respectively, according to a known procedure.48)
Fig. 4. Structure of Compound 13
Table 3. Drug Likeness of the Synthesized Derivatives 10a–c, 11a–i and
12a–c
General Procedure for Preparation of Menthyl 1,4-Di-
substituted 1,2,3-Triazole Derivatives (10a–c, 11a–i, 12a–c)
Synthesis of the target compounds 10a–c, 11a–i and 12a–c
was carried out via alkyne-azide Huisgen cycloaddition re-
action. Accordingly, propargyl ethers 7a–c, 8a–i and 9a–c
(1eq) were treated with compound 3 (200mg, 1.1mmol) in
the presence of sodium ascorbate (0.087mg, 0.44mmol) and
copper sulfate (0.055mg, 0.22mmol) in MeOH (5mL) at room
temperature for 30min to give exclusively 1,4-disubstituted
1,2,3-triazoles (10a–c, 11a–i, 12a–c). After completion of
the reaction confirmed by TLC, aqueous ammonia (10mL)
was added to remove the excess of copper. In the following
H2O (50mL) was added to the suspension and extracted with
EtOAc (3×50mL). The organic layers were washed with H2O
(3×150mL) and dried over Na2SO4. Solvent was removed
under reduced pressure. Final purification by flash chroma-
tography on silica gel (25% EtOAc–n-hexane) afforded pure
products in 90–98% yields.
Compound
cLogPa) H-Acceptor H-Donor tPSAb) MWc)
10a
5.77
4.54
4.87
5.90
6.54
6.15
9.30
5.65
6.33
5.15
3.47
4.89
8.64
6.55
8.64
3.23
4.51
2.43
5
6
5
4
4
4
4
4
4
4
5
5
6
7
6
1
3
4
3
8
0
0
0
0
0
0
0
0
0
0
1
0
2
3
2
1
3
4
3
4
54.26 420.35
63.49 371.48
54.26 341.46
37.19 382.33
37.19 382.33
37.19 341.50
37.19 439.69
37.19 327.47
37.19 363.50
37.19 313.44
80.28 370.50
54.26 355.48
94.72 611.91
114.95 627.91
94.72 611.91
20.23 156.27
77.76 392.58
97.99 408.58
77.76 392.58
183.98 453.44
10b
10c
11a
11b
11c
11d
11e
11f
11g
11h
11i
12a
12b
12c
Menthol
Deoxycholic acid
Cholic acid
Preparation of Compound 13 One-pot synthesis of com-
pound 13 was performed using a known method with some
modifications by the reaction of methyl iodide (MeI) (1.5eq),
NaN3 (1.5eq) and 7a (1.0eq) in MeOH–H2O (1:1) as solvent
in the presence of CuSO4·5H2O (0.2eq) and sodium ascorbate
(0.4 eq).49)
Ursodeoxycholic acid 4.51
Cefixime 0.25
a) Logarithm of compound partition coefficient between n-octanol and water. b)
Molecular Polar Surface Area. c) Molecular weight.
5-Bromo-2-((1-(2-isopropyl-5-methylcyclohexyl)-1H-1,2,3-
triazol-4yl)methoxy)benzaldehyde (10a)
antibacterial activity of the synthesized compounds.
White solid. mp 72–74°C. Yield 98%. IR (KBr) cm−1: 3119,
1
The drug-likeness properties of synthesized compounds 3077, 2936, 2861, 1702, 1590, 1450, 1385, 1286, 685. H-NMR
evaluated by physicochemical properties calculation based (CDCl3) δ: 10.36 (s, 1H, Haldehyde), 7.91 (d, 1H, HAr, J=2.1Hz),
on Lipinski’s rule of five using ChemBio3D package ver- 7.77 (s, 1H, Htriazole), 7.63 (dd, 1H, J=8.7, 2.1Hz), 7.15 (d, 1H,
sion 14.0.0.117 (Perkin Elmer, Inc. (United States)). The HAr, J=8.7Hz), 5.32 (s, 2H, CH2–O), 5.05 (brs, 1H, CH–N),
calculation results showed that all compounds except 12a–c 1.81–2.00 (m, 4H), 1.64–1.81 (m, 1H), 1.33–1.56 (m, 2H),
meet the Lipinski rules of the five, suggesting that these 1.00–1.14 (m, 2H), 0.88 (d, 3H, CH3, J=5.8Hz), 0.82 (d,
compounds theoretically would not have problems with oral 3H, CH3, J=6.4Hz), 0.76 (d, 3H, CH3, J=6.4Hz). 13C-NMR
bioavailability39) (Table 3).
(CDCl3) δ: 188.3, 159.5, 138.4, 138.2, 131.5, 131.1, 126.4,
115.4, 114.1, 63.0, 59.6, 46.6, 40.6, 34.6, 29.1, 26.4, 24.9, 22.2,
21.0, 20.4. NMR purity: >95%. HR-MS (ESI) m/z: Calcd
Experimental
General Melting points were measured on an Electrother- for C20H27BrN3O2: 420.1287; Found: 420.1335 [M+H]+. [α]D20
mal 9200 apparatus and were not corrected. HR-electrospray +0.18 (c=0.5, MeOH).
ionization (ESI)-MS spectra in positive mode were recorded
2-((1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3-triazol-4-
on a Bruker micro time-of-flight (TOF) ESI-MS system with yl)methoxy)-3-methoxybenzaldehyde (10b)
a scan range of m/z 150–1500. Fourier transform (FT)-IR
White solid. mp 129–131°C. Yield 90%. IR (KBr) cm−1:
spectra were recorded on a Bruker Tensor 27 spectrometer. 3118, 3070, 2940, 2861, 1692, 1589, 1474, 1260. 1H-NMR
1H- and 13C-NMR spectra were recorded on a Bruker Avance (CDCl3) δ: 10.21 (s, 1H, Haldehyde), 7.58 (s, 1H, Htriazole), 7.35
DRX 300 spectrometer operating at 300.13 and 75.47MHz, (dd, 1H, HAr, J=7.2, 1.9Hz), 7.10–7.19 (m, 2H, HAr), 5.37
respectively, or on a Bruker Avance III 400 spectrometer (s, 2H, CH2–O), 5.01 (brs, 1H, CH–N), 3.95 (s, 3H, OCH3),
operating at 400.1 and 100.6MHz, respectively. The spectra 1.79–1.95 (m, 4H), 1.55–1.72 (m, 1H), 1.28–1.50 (m, 2H),
were obtained in chloroform (CDCl3) and dimethyl sulfox- 0.93–1.08 (m, 2H), 0.86 (d, 3H, CH3, J=6.2Hz), 0.79 (d,
ide (DMSO)-d6 using tetramethylsilane (TMS) as internal 3H, CH3, J=6.9Hz), 0.76 (d, 3H, CH3, J=6.9Hz). 13C-NMR
standard. X-Ray data were collected on a STOE IPDS-II dif- (CDCl3) δ: 190.2, 153.0, 150.1, 142.1, 139.8, 130.4, 125.1, 124.3,
fractometer with graphite monochromated MoKα radiation. 124.1, 66.7, 59.2, 56.2, 46.5, 40.7, 34.6, 29.0, 26.4, 24.9, 22.3,
GC analysis was carried out on a Thermoquest Finnigan in- 21.0, 20.6. NMR purity: >95%. HR-MS (ESI) m/z: Calcd for

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Chem. Pharm. Bull.
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C21H30N3O3: 372.2287; Found: 372.2271 [M+H]+. [α]D20 +0.10 J=2.9Hz), 4.92–4.97 (m, 1H, CH–N), 3.08 (d, 1H, CH2–O,
(c=0.2, MeOH). J=14.4Hz), 3.04 (d, 1H, CH2–O, J=14.4Hz), 1.77–1.92 (m,
4-((1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3-triazol-4- 3H), 1.68–1.77 (m, 1H), 1.58–1.67 (m, 1H), 1.38–1.44 (m, 1H),
yl)methoxy)benzaldehyde (10c) 1.27–1.35 (m, 4H, CH & CH3), 1.19 (s, 9H, 3CH3), 1.18 (s,
White solid. mp 139–141°C. Yield 98%. IR (KBr) cm−1: 9H, 3CH3), 0.96–1.04 (m, 2H), 0.83 (d, 3H, CH3, J=6.4Hz),
3124, 3070, 2932, 2864, 1699, 1602, 1454, 1251. 1H-NMR 0.80 (d, 3H, CH3, J=6.4Hz), 0.77 (d, 3H, CH3, J=6.8Hz).
(CDCl3) δ: 9.91 (s, 1H, Haldehyde), 7.86 (d, 2H, HAr, J=8.5Hz), 13C-NMR (CDCl3) δ: 186.3, 146.8, 146.7, 145.9, 145.8, 142.3,
7.75 (s, 1H, Htriazole), 7.15 (d, 2H, HAr, J=8.5Hz), 5.31 (s, 2H, 122.0, 59.0, 46.5, 40.8, 40.3, 37.5, 34.6, 34.5, 29.4, 29.3, 29.0,
CH2–O), 5.07 (brs, 1H, CH–N), 1.84–2.03 (m, 4H), 1.66–1.83 27.0, 26.3, 25.2, 22.1, 21.1, 20.6. HPLC purity: 95%. HR-MS
(m, 1H), 1.35–1.56 (m, 2H), 1.01–1.15 (m, 2H), 0.89 (d, 3H, (ESI) m/z: Calcd for C28H46N3O: 440.3641; Found: 440.3627
CH3, J=6.0Hz), 0.85 (d, 3H, CH3, J=6.5Hz), 0.78 (d, 3H, [M+H]+. [α]D20 +0.10 (c=0.3, MeOH).
CH3, J=6.5). 13C-NMR (CDCl3) δ: 190.8, 163.3, 142.0, 132.0,
130.2, 123.9, 115.2, 62.3, 59.4, 46.6, 40.7, 34.6, 29.1, 26.3, 24.9, methyl)-1H-1,2,3-triazole (11e)
1-(2-Isopropyl-5-methylcyclohexyl)-4-((m-tolyloxy)-
22.2, 21.1, 20.5. NMR purity: >95%. HR-MS (ESI) m/z: Calcd
Pale yellow needle crystal. mp 80–82°C. Yield 90%.
for C20H28N3O2: 342.2182; Found: 342.2151 [M+H]+. [α]D20 IR (KBr) cm−1: 3191, 3070, 2945, 2849, 1603, 1454, 1252.
+0.14 (c=0.5, MeOH).
4-((2,3-Dichlorophenoxy)methyl)-1-(2-isopropyl-5- J=7.6Hz), 6.78–6.87 (m, 3H, HAr), 5.21 (s, 2H, CH2–O),
methylcyclohexyl)-1H-1,2,3-triazole (11a) 5.05 (brs, 1H, CH–N), 2.34 (s, 3H, CH3), 1.67–2.02 (m,
1H-NMR (CDCl3) δ: 7.70 (s, 1H, Htriazole), 7.19 (t, 1H, HAr,
White solid. mp 123–125°C. Yield 91%. IR (KBr) cm−1: 5H), 1.33–1.53 (m, 2H), 1.01–1.71 (m, 2H), 0.89 (d, 3H, CH3,
3119, 3072, 2950, 1638, 1453, 1281, 763. 1H-NMR (CDCl3) J=6.1Hz), 0.85 (d, 3H, CH3, J=6.6Hz), 0.79 (d, 3H, CH3,
δ: 7.75 (s, 1H, Htriazole), 7.04–7.19 (m, 3H, HAr), 5.33 (s, 2H, J=6.6Hz). 13C-NMR (CDCl3) δ: 158.3, 143.2, 139.6, 129.3,
CH2–O), 5.04 (brs, 1H, CH–N), 1.66–2.00 (m, 5H), 1.33–1.53 123.7, 122.1, 115.8, 111.8, 62.2, 59.5, 46.7, 40.7, 34.6, 29.1,
(m, 2H), 1.00–1.12 (m, 2H), 0.88 (d, 3H, CH3, J=5.8Hz), 26.3, 25.0, 22.2, 21.5, 21.1, 20.6. NMR purity: >95%. HR-MS
0.83 (d, 3H, CH3, J=6.5Hz), 0.76 (d, 3H, CH3, J=6.5Hz). (ESI) m/z: Calcd for C20H30N3O: 328.2389; Found: 328.2361
13C-NMR (CDCl3) δ: 155.1, 142.2, 133.8, 127.4, 123.9, 122.9, [M+H]+. [α]D20 +0.16 (c=0.5, MeOH).
122.2, 112.6, 63.9, 59.3, 46.6, 40.8, 34.6, 29.1, 26.3, 24.9, 22.2,
1-(2-Isopropyl-5-methylcyclohexyl)-4-((naphthalen-1-yloxy)-
21.0, 20.5. NMR purity: >95%. HR-MS (ESI) m/z: Calcd methyl)-1H-1,2,3-triazole (11f)
for C19H26Cl2N3O: 382.1453; Found: 382.1454 [M+H]+. [α]D20
+0.08 (c=0.5, MeOH).
White solid. mp 143–145°C. Yield 90%. IR (KBr) cm−1:
3194, 3128, 2942, 2862, 1584, 1455, 1270. H-NMR (CDCl3)
1
4-((2,5-Dichlorophenoxy)methyl)-1-(2-isopropyl-5- δ: 8.29 (d,1H, HAr, J=7.1Hz), 7.83 (d, 1H, HAr, J=6.5Hz),
methylcyclohexyl)-1H-1,2,3-triazole (11b)
7.75 (s, 1H, Htriazole), 7.35–7.56 (m, 4H, HAr), 7.02 (d, 1H,
White solid. mp 112–114°C. Yield 96%. IR (KBr) cm−1: HAr, J=6.9Hz), 5.44 (s, 2H, CH2–O), 5.05 (brs, 1H, CH–N),
1
3080, 2951, 1582, 1480, 1262, 799. H-NMR (CDCl3) δ: 7.74 1.75–2.04 (m, 5H), 1.37–1.55 (m, 2H), 1.01–1.17 (m, 2H), 0.90
(s, 1H, Htriazole), 7.30 (d, 1H, HAr, J=8.4Hz), 7.13 (d, 1H, HAr, (d, 3H, CH3, J=5.5Hz), 0.86 (d, 3H, CH3, J=6.2Hz), 0.79 (d,
J=2.2Hz), 6.93 (dd, 1H, HAr, J=8.4, 2.2Hz), 5.30 (s, 2H, 3H, CH3, J=6.2Hz). 13C-NMR (CDCl3) δ: 154.1, 143.1, 134.5,
CH2–O), 5.05 (brs, 1H, CH–N), 1.67–2.03 (m, 5H), 1.36–1.54 127.4, 126.4, 125.9, 125.8, 125.2, 124.1, 121.9, 120.9, 105.7,
(m, 2H), 1.03–1.13 (m, 2H), 0.89 (d, 3H, CH3, J=5.9Hz), 62.8, 59.3, 46.7, 40.9, 34.7, 29.1, 26.2, 24.9, 22.3, 21.1, 20.5.
0.84 (d, 3H, CH3, J=6.5Hz), 0.78 (d, 3H, CH3, J=6.5Hz). NMR purity: >95%. HR-MS (ESI) m/z: Calcd for C23H30N3O:
13C-NMR (CDCl3) δ: 154.3, 142.1, 133.1, 130.8, 130.6, 122.0, 364.2389; Found: 364.2386 [M+H]+. [α]D20 +0.10 (c=0.5,
121.7, 115.2, 63.8, 59.3, 46.6, 40.8, 34.7, 29.1, 26.2, 25.0, 22.2, MeOH).
21.1, 20.5. NMR purity: >95%. HR-MS (ESI) m/z: Calcd
for C19H26Cl2N3O: 382.1453; Found: 382.1441 [M+H]+. [α]D20 1,2,3-triazole (11g)
+0.10 (c=0.5, MeOH).
Beige crystal. mp 97–99°C. Yield 92%. IR (KBr) cm−1:
4-((3,5-Dimethylphenoxy)methyl)-1-(2-isopropyl-5- 3081, 2950, 2860, 1594, 1490, 1238. H-NMR (CDCl3) δ: 7.71
methylcyclohexyl)-1H-1,2,3-triazole (11c) (s, 1H, Htriazole), 7.29–7.36 (m, 2H, HAr), 6.96–7.06 (m, 3H,
1-(2-Isopropyl-5-methylcyclohexyl)-4-(phenoxymethyl)-1H-
1
White solid. mp 110–112°C. Yield 91%. IR (KBr) cm−1: HAr), 5.23 (s, 2H, CH2–O), 5.06 (brs, 1H, CH–N), 1.84–2.02
3100, 2947, 2861, 1603, 1459, 1225. 1H-NMR (CDCl3) δ: (m, 4H), 1.67–1.81 (m, 1H), 1.33–1.54 (m, 2H), 1.01–1.15 (m,
7.69 (s, 1H, Htriazole), 6.65 (s, 3H, HAr), 5.20 (s, 2H, CH2–O), 2H), 0.89 (d, 3H, CH3, J=6.1Hz), 0.86 (d, 3H, CH3, J=6.5Hz),
5.05 (brs, 1H, CH–N), 2.30 (s, 6H, 2CH3), 1.72–2.03 (m, 0.79 (d, 3H, CH3, J=6.5Hz). 13C-NMR (CDCl3) δ: 158.3, 143.1,
5H), 1.33–1.54 (m, 2H), 1.01–1.18 (m, 2H), 0.89 (d, 3H, CH3, 129.5, 123.7, 121.2, 114.9, 62.2, 59.3, 46.6, 40.7, 34.6, 29.0,
J=6.1Hz), 0.86 (d, 3H, CH3, J=6.6Hz), 0.79 (d, 3H, CH3, 26.3, 25.0, 22.3, 21.1, 20.6. NMR purity: >95%. HR-MS (ESI)
J=6.6Hz). 13C-NMR (CDCl3) δ: 158.4, 143.3, 139.2, 123.7, m/z: Calcd for C19H28N3O: 314.2232; Found: 314.2205 [M+H]+.
123.0, 112.7, 62.3, 59.2, 46.6, 40.8, 34.7, 29.1, 26.2, 25.0, 22.2, [α]D20 +0.16 (c=0.5, MeOH).
21.06, 21.3, 20.6. NMR purity: >95%. HR-MS (ESI) m/z:
2-(4-((1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3-
Calcd for C21H32N3O: 342.2467; Found: 342.2516 [M+H]+. triazol-4-yl)methoxy)phenyl)acetamide (11h)
[α]D20 +0.16 (c=0.5, MeOH).
White solid. mp 182–184°C. Yield 90%. IR (KBr) cm−1:
4-((2,6-Di-tert-butyl-4-methylphenoxy)methyl)-1-(2- 3424, 3132, 3076, 2950, 2862, 1636, 1513, 1447, 1246.
isopropyl-5-methylcyclohexyl)-1H-1,2,3-triazole (11d)
1H-NMR (DMSO-d6) δ: 8.35 (s, 1H, Htriazole), 7.43 (s, 1H, NH),
Yellow solid. mp 79–81°C. Yield 94%. IR (KBr) cm−1: 7.19 (d, 2H, HAr, J=8.4Hz), 6.97 (d, 2H, HAr, J=8.4Hz), 6.86
1
3136, 2954, 2871, 1644, 1457, 1247. H-NMR (CDCl3) δ: 7.16 (s, 1H, NH), 5.09 (s, 2H, CH2–O), 5.06 (brs, 1H, CH–N), 3.40
(s, 1H, Htriazole), 6.56 (d, 1H, HAr, J=2.9Hz), 6.53 (d, 1H, HAr, (s, 2H, CH2), 1.72–1.92 (m, 5H), 1.35–1.54 (m, 2H), 0.90–1.06

Vol. 64, No. 11 (2016)
Chem. Pharm. Bull.
1595
(m, 2H), 0.83 (d, 3H, CH3, J=6.2Hz), 0.78 (d, 3H, CH3, (m, 33H, 2OH, CH, CH2), 0.92 (s, 3H, CH3) 0.88 (d, 3H, CH3,
J=6.4Hz), 0.70 (d, 3H, CH3, J=6.4Hz). 13C-NMR (DMSO- J=6.1Hz), 0.85 (d, 3H, CH3, J=6.7Hz), 0.82 (d, 3H, CH3,
d6) δ: 173.0, 157.0, 141.9, 130.6, 129.3, 126.3, 114.9, 61.5, 58.5, J=6.6Hz), 0.75 (d, 3H, CH3, J=6.6Hz), 0.64 (s, 3H, CH3).
46.0, 41.9, 34.7, 29.2, 26.1, 24.8, 22.6, 21.3, 20.7. NMR purity: 13C-NMR (CDCl3) δ: 174.2, 141.8, 124.8, 71.4, 71.3, 59.4, 57.5,
>95%. HR-MS (ESI) m/z: Calcd for C21H31N4O2: 371.2447; 55.7, 54.9, 46.6, 43.7, 42.5, 40.7, 40.1, 39.2, 37.3, 36.9, 35.3,
Found: 371.2441 [M+H]+. [α]D20 +0.14 (c=0.5, MeOH).
35.0, 34.6, 34.1, 31.2, 30.9, 30.3, 29.1, 28.6, 26.9, 26.3, 24.9,
1-(4-((1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3- 23.4, 22.2, 21.1, 21.2, 20.5, 18.8, 12.1. NMR purity: >95%.
triazol-4-yl)methoxy)phenyl)ethan-1-one (11i) HR-MS (ESI) m/z: Calcd for C37H62N3O4: 612.4740; Found:
Pale yellow needle crystal. mp 154–156°C. Yield 94%. IR 612.4573 [M+H]+. [α]D20 +0.46 (c=0.5, MeOH).
(KBr) cm−1: 3124, 3077, 2940, 2861, 1677, 1602, 1453, 1253.
5-Bromo-2-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-
1H-NMR (CDCl3) δ: 7.94 (d, 2H, HAr, J=8.7Hz), 7.74 (s, 1H, benzaldehyde (13)
Htriazole), 7.05 (d, 2H, J=8.7Hz), 5.27 (s, 2H, CH2–O), 5.05
Pale yellow solid. mp 130–132°C. Yield 85%. IR (KBr)
(brs, 1H, CH–N), 2.56 (s, 3H, COCH3), 1.83–2.00 (m, 4H), cm−1: 3152, 2927, 2861, 1676, 1590, 1479, 1400, 1276, 623.
1.65–1.81 (m, 1H), 1.33–1.53 (m, 2H), 1.00–1.13 (m, 2H), 0.87 1H-NMR (CDCl3) δ: 10.36 (s, 1H, Haldehyde), 7.92 (d, 1H, HAr,
(d, 3H, CH3, J=6.0Hz), 0.83 (d, 3H, CH3, J=6.5Hz), 0.77 (d, J=2.5Hz), 7.67 (s, 1H, Htriazole), 7.64 (dd, 1H, J=8.9, 2.5Hz),
3H, CH3, J=6.5Hz). 13C-NMR (CDCl3) δ: 196.8, 162.2, 142.2, 7.13 (d, 1H, HAr, J=8.9Hz), 5.33 (s, 2H, CH2–O), 4.14 (s, 3H,
130.7, 130.6, 123.9, 114.5, 62.2, 59.4, 46.6, 40.7, 34.5, 29.0, CH3). 13C-NMR (CDCl3) δ: 188.2, 159.3, 143.1, 138.3, 131.1,
26.4, 26.3, 24.9, 22.2, 21.1, 20.5. NMR purity: >95%. HR-MS 126.3, 124.0, 115.2, 114.1, 62.6, 38.5. NMR purity: >95%.
(ESI) m/z: Calcd for C21H30N3O2: 356.2338; Found: 356.2322 HR-MS (ESI) m/z: Calcd for C11H11BrN3O2: 296.0035; Found:
[M+H]+. [α]D20 +0.14 (c=0.5, MeOH).
(1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3-triazol-4-yl)-
296.0065 [M+H]+.
Determination of MICs Broth micro-dilution method
methyl 4-(3,12-Dihydroxy-10,13-dimethylhexadecahydro-1H- was carried out according to the standard protocols recom-
cyclopenta[a]phenanthren-17-yl)pentanoate (12a)
mended by Clinical Laboratory Standard Institute (CLSI) to
White solid. mp 97–99°C. Yield 96%. IR (KBr) cm−1: 3465, determine the minimum concentration of each antimicrobial
1
2933, 2868, 1731, 1455, 1251. H-NMR (CDCl3) δ: 7.67 (s, 1H, agent required for inhibition (MIC) of visible growth of tested
Htriazole), 5.19 (s, 2H, CH2–O), 5.02 (brs, 1H, CH–N), 3.94 bacterium. In brief, two-fold serial dilutions of each com-
(brs, 1H, CH–OH), 3.50–3.65 (m, 1H, CH–OH), 2.18–2.44 (m, pound were made in a concentration range from 0.125–256µg/
4H), 0.98–1.99 (m, 33H, 2OH, CH, CH2), 0.92 (d, 3H, CH3, mL in sterile plastic micro-dilution trays containing Mueller–
J=5.8Hz), 0.89 (s, 3H, CH3), 0.86 (d, 3H, CH3, J=6.2Hz), Hinton broth (MHB). Thereafter, bacterial suspension of each
0.82 (d, 3H, CH3, J=6.6Hz), 0.76 (d, 3H, CH3, J=6.6Hz), bacterial strain was prepared from freshly cultured bacteria in
0.64 (s, 3H, CH3). 13C-NMR (CDCl3) δ: 174.2, 141.8, 124.8, sterile normal saline that were adjusted to 0.5 McFarland stan-
73.1, 71.7, 59.4, 57.5, 48.2, 47.2, 46.7, 46.5, 42.1, 40.7, 36.4, dard turbidity. The suspension was further diluted (1:100) by
36.0, 35.2, 35.1, 34.6, 34.1, 33.6, 31.1, 30.8, 30.5, 29.1, 28.7, sterile MHB just before adding to the trays containing a serial
27.5, 27.1, 26.3, 26.1, 24.9, 23.7, 23.2, 22.2, 21.1, 20.5, 17.3, dilution of each compound. MICs were recorded after 22h
12.7. NMR purity: >95%. HR-MS (ESI) m/z: Calcd for incubation at 37°C. Cefixime was used as standard antibiotic
C37H62N3O4: 612.4740; Found: 612.4573 [M+H]+. [α]D20 +0.44 and all experiments were done in triplicate.
(c=0.5, MeOH).
(1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3-triazol-4-yl)-
methyl 4-(3,7,12-Trihydroxy-10,13-dimethylhexadecahydro-1H-
cyclopenta[a]phenanthren-17-yl)pentanoate (12b)
Conclusion
A facile and efficient method for the synthesis of hydroxy-
benzaldehydes, phenols and bile acids based 1,4-disubstituted
White solid. mp 85–87°C. Yield 95%. IR (KBr) cm−1: 1,2,3-triazole library have been developed as part of the ongo-
1
3395, 2940, 2870, 1734, 1457, 1241. H-NMR (CDCl3) δ: 7.68 ing efforts to identify their synergistic potential with menthol.
(s, 1H, Htriazole), 5.19 (s, 2H, CH2–O), 5.02 (brs, 1H, CH–N), The preliminary activity of menthol and the 1,2,3-triazole
3.92 (brs, 1H, CH–OH), 3.82 (brs, 1H, CH–OH), 3.35–3.55 analogues provide a platform that elevate the plausibility of
(m, 4H, CH–OH, 3OH), 2.17–2.45 (m, 4H), 1.17–2.00 (m, finding derivatives with enhanced antibacterial activity. Fif-
25 H), 0.98–1.14 (m, 4H), 0.93 (d, 3H, CH3, J=5.2Hz) 0.86 teen derivatives were synthesized via 1,3-dipolar cycload-
(s, 3H, CH3), 0.85 (d, 3H, CH3, J=5.2Hz), 0.82 (d, 3H, CH3, dition reactions and were evaluated for their antibacterial
J=6.6Hz), 0.76 (d, 3H, CH3, J=6.6Hz), 0.63 (s, 3H, CH3). activity against Enterococcus faecium and Staphylococcus
13C-NMR (CDCl3) δ: 174.3, 141.8, 124.8, 73.1, 71.9, 68.5, 59.3, aureus bacteria. All derivatives exhibited stronger inhibitory
57.6, 46.9, 46.7, 46.4, 41.6, 41.5, 40.7, 39.5, 35.3, 34.8, 34.7, activity than lead compounds towards E. faecium and even
34.6, 31.2, 30.8, 30.3, 29.1, 28.2, 27.5, 26.9, 26.3, 25.3, 24.9, almost all were more powerful than cefixime as a positive
23.2, 22.5, 22.3, 21.1, 20.6, 17.3, 12.5. NMR purity: >95%. control. The results showed that 1,2,3-triazole ring could be a
HR-MS (ESI) m/z: Calcd for C37H62N3O5: 628.4689; Found: good linkage for enhancing the antibacterial activity of lead
628.5099 [M+H]+. [α]D20 +0.28 (c=0.5, MeOH).
(1-(2-Isopropyl-5-methylcyclohexyl)-1H-1,2,3-triazol-4-yl)- physicochemical properties of the target compounds based on
methyl 4-(3,7-Dihydroxy-10,13-dimethylhexadecahydro-1H- Lipinski’s rule of five demonstrated that almost all compounds
compounds through different mechanisms. Also evaluation of
cyclopenta[a]phenanthren-17-yl)pentanoate (12c)
had desirable profile to be new lead candidates.
White solid. mp 78–80°C. Yield 95%. IR (KBr) cm−1:
1
3401, 2937, 2866, 1736, 1456, 1238. H-NMR (CDCl3) δ: 7.67
Acknowledgment We are grateful to Shahid Beheshti
(s, 1H, Htriazole), 5.19 (s, 2H, CH2–O), 5.01 (brs, 1H, CH–N), University research and technology council for financial sup-
3.50–3.63 (m, 2H, 2CH–OH), 2.14–2.45 (m, 4H), 0.97–2.01 port of this work, Grant No. D-600-3765.

1596
Chem. Pharm. Bull.
cycles, 84, 1033–1044 (2012).
Vol. 64, No. 11 (2016)
Conflict of Interest The authors declare no conflict of
interest.
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