Journal of Agricultural and Food Chemistry
Article
propargyl thymol 2a was obtained as the precursor of triazole
derivatives 3d−l, and strategically speaking, a noteworthy
perspective must be given to compound 2b because it is easily
obtained, in one step, with the molecular hybridization
approach. This useful concept in medicinal chemistry employs
a combination of pharmacophoric portions of bioactive
compounds with improved affinity and efficacy.
The greatest synthetic success encountered during our
efforts was fabricating nine triazole heterocyclic compounds’
thymol derivatives. In brief, the facile one-pot CuAAC
methodology was used to prepare 3d−l, through Huisgen’s
1,3-dipolar cycloaddition between alkyne and azide, which can
be performed in water with an organic cosolvent. The
microwave-assisted technique had become a landmark and
substantial contribution to mantain the environment by
decreasing the waste as well, as it gives a useful internal heat
transfer that shortens the reaction time and increases the rate
of reaction and yield.50−53
characteristic absorption bands for azide scaffold were revealed
at 2102 cm−1 (3d−f and 3k) and 2106 cm−1 (3h and 3i), and
for compound 3l, the corresponding band appeared at 2108
cm−1.
Mass spectrometry analysis validated the structure of the
examined derivatives (Tables 1 and 2).
Fungicidal Activity. All the target compounds were
screened for their inhibitory activity against Fusarium solani
ATCC 40099. Fusarium species show reduced sensitivity to
azole compounds because of an intrinsic resistance as observed
in previous works.48,54 The low sensitivity is reflected in
susceptibility assays characterized by high minimum inhibitory
concentration values or absence of activity observed for the
compound tebuconazole (Table 3), a triazole pesticide
Table 3. Antifungal Activity for New Compounds and
Commercial Pesticides against Fusarium solani ATCC
a
40099
O-Propargyl thymol (2a) was then used to optimize the 1,3-
dipolar cycloaddition with 4 molar equiv of azides’ derivatives,
under microwave conditions to shorten reaction times, in the
presence of CuSO4/sodium ascorbate in DMF to yield the
triazole derivatives. The solids obtained were washed with
water/ethyl acetate, and the organic phase was dried in a rotary
evaporator. The crude products were purified by column
chromatography using hexane:ethyl acetate or hexane:ether as
eluent to afford the desired compounds (Table 2).
During the procedure to prepare the triazol derivatives, the
following conditions were tested: changing temperature, 70 or
80 °C; ratio of azide reagents, 3 and 4 molar equiv; and time,
10, 15, and 20 min. The complete consumption of compound
2a was observed only using the ratio of 4 molar equiv, under
microwave conditions, which made the purification easier and
faster. However, using this ratio, some yields were not
satisfactory.
Fusarium solani ATCC 40099
entry
MIC (μg mL−1
)
b
2a
2b
2c
2d
2e
2f
3d
3e
3f
3g
3h
3i
3j
3k
3l
-
14
-
-
-
-
57
-
57
57
57
57
57
-
57
7
-
Spectral data of the 15 successful derivatives prepared were
1
confirmed from H NMR, 13C NMR, FTIR, and HRMS. The
thiabendazole
tebuconazole
1H NMR spectrum exhibited four sets of aromatic hydrogen
signals characteristic of the expected moiety of 1. In addition,
isopropyl and methyl hydrogens of the natural product also
appeared at δ 1.12−1.25 (CH3-8 and CH3-9) as a doublet and
2.11−2.34 (CH3-10) as a singlet in 2a−f, while δ 0.94−1.08
(CH3-8 and CH3-9) and 2.20−2.26 (CH3-10) appeared in
3d−l. Furthermore, the methylenic group (CH2−1″), in whole
derivatives except 2b, is shown in the range δ 4.69−5.64 as a
singlet (doublet for 2a), and the substituent signals are in
agreement with the nature of an aromatic moiety. The
hydrogen of the triazole ring appears in the range δ 7.98−
9.05 as a singlet and plays a crucial role in identifying of thymol
triazolic derivatives 3d−l.
a
Results were validated with strain A. fumigatus ATCC 40014 and
b
showed MIC values of 115 μg mL−1 for all compounds tested.
-
absence of activity.
commonly used in crops. The new triazolic compounds 3d−
l described here in this work are present in structural groups
such as halogenated, carboxylic acid, and nitro with broad
biological properties. The Fusarium strain showed moderate
sensitivity to the new triazole compounds, characterized by the
MIC 57 μg/mL. The literature reports that triazole
compounds with alkyl chains and/or aromatic substituents
containing halogenated radical have important antimicrobial
activities, and therefore, they have been widely used in
medicinal chemistry research to produce molecules with
specificity to the target enzyme, potency, and a broad spectrum
of action.55 The compound thiabendazole is a benzimidazole
that acts as an inhibitor of nuclear division by binding to the
tubulin protein. Its mechanism of action different from triazole
compounds explains the lower MIC value observed for the
Fusairum strain in the present work.56
Infrared spectroscopy confirmed the presence of character-
istic absorption bands for the derivatives prepared. The IR
spectra showed the following for compounds 2: two bands
related to the ether group linked to CC bond at 1246 and
1029 cm−1 (2a), 1237 and 1073 cm−1 (2b), 1257 and 1052
cm−1 (2d), 1239 and 1048 cm−1 (2e), and 1254 and 1034
cm−1 (2f). An absorption band at 2119 cm−1 verified
compound 2a and corresponded to the triple bond C−C,
while 720 cm−1 was detected to the C−Cl bond for compound
2b. Two vibration bands were observed at 1502 and 1330
cm−1 and related to the nitro group (compound 2d), and two
bands at 1315 and 1150 cm−1 corresponded to the sulfonyl
group (compound 2f). In the IR spectra for compounds 3, the
In this study, most azole compounds tested showed a
moderate MIC, 57 μg mL−1, or low sensitivity, in comparison
with thiabendazole, 7 μg mL−1, although they are more active
than tebuconazole (absence of activity), which leads to an
important perspective of molecular hybridization by coupling
6963
J. Agric. Food Chem. 2021, 69, 6958−6967