Synthesis, antifungal activity and 3D-QSAR study of novel nopol-based 1,3,4-thiadiazole–thioether compounds

Article abstract of DOI:10.1007/s11164-021-04510-x

A series of novel nopol derivatives containing 1,3,4-thiadiazole–thioether moiety were synthesized from β-pinene, which is a natural, abundant and renewable biomass resource. Their structures were characterized by FT-IR, ¹H NMR, ¹³C NMR, ESI–MS and elemental analysis. In vitro antifungal activity of the target compounds was preliminarily evaluated against eight tested plant pathogens, including Fusarium oxysporum f. sp. cucumerinum, Cercospora arachidicola, Physalospora piricola, Alternaria solani, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis and Colleterichum orbicalare. The bioassay results revealed that, at the concentration of 50?μg/mL, all the target compounds showed certain inhibition activity against the eight tested fungi. Compounds 5f (R = m–OCH₃), 5i (R = m–F) and 5r (R = m–I) had excellent inhibition rates of 77.8%, 88.9% and 77.8%, respectively, against P. piricola, showing much better antifungal activity than that of the positive control chlorothalonil. Meanwhile, compound 5?m (R = p–Cl) displayed antifungal activity of 80.7% against R. solani. Furthermore, the analysis of three-dimensional quantitative structure–activity relationship (3D-QSAR) was performed for the relationship between the structures of the target compounds and their antifungal activity against P. piricola by CoMFA method. A reasonable CoMFA model (n = 6; q² = 0.597; r² = 0.985) was established.

Full text of DOI:10.1007/s11164-021-04510-x

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04510-x
Synthesis, antifungal activity and 3D‑QSAR study of novel
nopol‑based 1,3,4‑thiadiazole–thioether compounds
Xiu Wang1 · Wen‑Gui Duan1 · Gui‑Shan Lin1 · Ming Chen1 · Fu‑Hou Lei2
Received: 3 February 2021 / Accepted: 5 June 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
A series of novel nopol derivatives containing 1,3,4-thiadiazole–thioether moiety
were synthesized from β-pinene, which is a natural, abundant and renewable bio-
1
mass resource. Their structures were characterized by FT-IR, H NMR, 13C NMR,
ESI–MS and elemental analysis. In vitro antifungal activity of the target compounds
was preliminarily evaluated against eight tested plant pathogens, including Fusar-
ium oxysporum f. sp. cucumerinum, Cercospora arachidicola, Physalospora piri-
cola, Alternaria solani, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis and
Colleterichum orbicalare. The bioassay results revealed that, at the concentration
of 50 μg/mL, all the target compounds showed certain inhibition activity against
the eight tested fungi. Compounds 5f (R=m–OCH3), 5i (R=m–F) and 5r (R=m–I)
had excellent inhibition rates of 77.8%, 88.9% and 77.8%, respectively, against P.
piricola, showing much better antifungal activity than that of the positive control
chlorothalonil. Meanwhile, compound 5 m (R=p–Cl) displayed antifungal activity
of 80.7% against R. solani. Furthermore, the analysis of three-dimensional quantita-
tive structure–activity relationship (3D-QSAR) was performed for the relationship
between the structures of the target compounds and their antifungal activity against
P. piricola by CoMFA method. A reasonable CoMFA model (n=6; q2 =0.597;
r2 =0.985) was established.
Keywords β-pinene · nopol · 1,3,4-thiadiazole–thioether · antifungal activity ·
3D-QSAR
*
Wen-Gui Duan
wgduan@gxu.edu.cn
1
2
School of Chemistry and Chemical Engineering, Guangxi University, Nanning, China
Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Nanning, China
Vol.:(0123456789)
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X. Wang et al.
Introduction
Turpentine oil is a terpenic non-wood forest product, as well as a natural, abundant
and renewable biomass resource in nature. It is obtained by the steam distillation of
the oleoresin exudate from living pine trees, and its major constituents are α-pinene
and β-pinene [1]. The content of β-pinene in turpentine oil of Pinus elliottii can be
as high as 25–35% [2], but compared with α-pinene, the study on the development
and utilization of β-pinene is relatively fewer, indicating that conversion of β-pinene
into high value-added fne chemicals is worthy of further investigation.
Nopol, 2-(6,6-dimethyl-2-bicyclo [3.1.1] hept-2-enyl) ethanol, contains three
reactive functional groups, namely a hydroxyl group, a carbon–carbon double
bond and a four-membered ring. It can be readily prepared by the Prins reaction of
β-pinene with paraformaldehyde [3, 4]. Nopol and its derivatives exhibited a broad
spectrum of biological activities, such as antifungal [5–9], antifeedant [10], repellent
[11] and treatment of gastrointestinal irritable syndrome activities [12]. Thus, nopol
deserves further study for agrochemical or pharmaceutical use based on its bioactive
property and chemical reactivity.
1,3,4-Thiadiazole, as the representative of fve-membered unsaturated hetero-
cycles, showed a great deal of biological activities, including antifungal [13–15],
antibacterial [16, 17], anticancer [18, 19], herbicidal [20–22], insecticidal [23, 24],
antiviral [25] and anti-infammatory activities [26]. Bismerthiazol and thiodiazole-
copper are an important class of fungicides containing 1,3,4-thiadiazole moiety,
which show lower toxicity, less residue, safer to the environment and stronger bioac-
tive properties [27–30]. In recent years, our research group reported several classes
of natural product-based 1,3,4-thiadiazole derivatives and found that some of the
target compounds exhibited excellent to good antifungal and herbicidal activities
(Fig. 1) [31–34].
In continuation of our interest in the investigation of natu-
ral product-based bioactive compounds [35–40], a series of nopol-based
(A)
(B)
(C)
(D)
Fig. 1 Structures of the 1,3,4-thiadiazole derivatives reported by our research group
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Synthesis, antifungal activity and 3D-QSAR study of novel…
1,3,4-thiadiazole–thioether compounds were designed and synthesized by introduc-
ing 1,3,4-thiadiazole–thioether moiety into the skeleton of nopol converted from
β-pinene. Structural characterization, antifungal evaluation and 3D-QSAR study
were carried out as well.
Results and discussion
Synthesis and characterization
The synthetic route of nopol-based 1,3,4-thiadiazole–thioether compounds 5a-
5w is illustrated in Scheme 1. At frst, nopol (2) was prepared by Prins reaction
of β-pinene (1) with paraformaldehyde in the presence of ZnCl2 as a catalyst [41].
Then, nopyl chloride (3) was prepared by Appel reaction of nopol (2) in a good
yield [42], followed by nucleophilic substitution reaction of nopyl chloride (3) with
self-prepared 5-substituted phenyl-1,3,4-thiadiazole-2-thiones (4) to aford a series
of novel nopol-based 1,3,4-thiadiazole–thioether compounds 5a-5w [43].
The structures of all the title compounds and the key intermediates (2) and (3)
1
were confrmed by FT-IR, H NMR, 13C NMR, ESI–MS and elemental analysis,
and the related spectra can be found in Supporting Information. In the IR spec-
tra of the target compounds, the weak absorption bands at about 3025 cm−1 were
attributed to the stretching vibrations of the unsaturated C-H in the nopol moiety.
The weak absorption bands at 1585–1614 cm−1 and the strong absorption bands
at 1429–1477 cm−1 were assigned to the vibrations of C=C in the nopol moiety
and C=N in 1,3,4-thiadiazole moiety, respectively. Also, the absorption bands at
1
605–712 cm−1 revealed the presence of C-S-C in thioether moiety. In the H-NMR
spectra, the olefnic protons of nopol scafold showed signals at about 5.37 ppm, and
the other protons bonded to the saturated carbons of the nopol moiety displayed sig-
nals in the range of 0.87–2.51 ppm. The protons on the saturated carbon bonded to
the S atom displayed the signals at about 3.40 ppm. The 13C NMR spectra of all the
Scheme 1 Synthetic route of nopol-based 1,3,4-thiadiazole–thioether compounds 5a-5w
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X. Wang et al.
target compounds showed peaks for the two olefnic carbons of the nopol moiety
at about 145 ppm and 118 ppm, respectively, and the unsaturated carbons in the
thiadiazole heterocycle and the benzene ring showed signals at 165–168 ppm and
95–160 ppm, respectively. The saturated carbon bonded to the S atom displayed the
signals at 30–32 ppm. Their molecular weights were confrmed by ESI–MS.
Antifungal activity
Antifungal activity of the target compounds 5a-5w was evaluated preliminarily by
in vitro method against Fusarium oxysporum f. sp. cucumerinum, Cercospora ara-
chidicola, Physalospora piricola, Alternaria solani, Gibberella zeae, Rhizoeotnia
solani, Bipolaris maydis and Colleterichum orbicalare at 50 µg/mL. The results
are listed in Table 1. Compounds 5a-5w were found to exhibit certain antifungal
activity against the eight tested fungi, especially against P. piricola. Compounds
5i (R=m–F), 5f (R=m–OCH3) and 5q (R=m–I) had excellent inhibition rates of
88.9%, 77.8% and 77.8%, respectively, against P. piricola, showing much better than
that of the positive control chlorothalonil with inhibition rate of 75%. In addition,
compound 5 m (R=p–Cl) displayed antifungal activity of 80.7% against R. solani.
CoMFA analysis
The CoMFA method has become one of the important computer simulation meth-
ods in drug design and medicinal chemistry. In this work, CoMFA was employed
to study the structure–activity relationship of the synthesized compounds against P.
piricola. The partial least squares (PLS) relevant results of the CoMFA models are
listed in Table 2. The cross-validated coefcient q2 of 0.597 (q2 >0.5) with six opti-
mal number of component (ONC), non-cross-validated correlation coefcient (r2)
between the experimental and predicted activities was 0.985(r2 >0.8), and stand-
ard error of estimate (SEE) and Fisher ratio (F) value were calculated as 0.046 and
100.925, respectively. As shown in Table 3, the experimental ED values were in
good agreement with the predicted ED values, and the scatter diagram is shown in
Fig. 2. The data signifed the generated CoMFA model was reliable.
The CoMFA steric and electrostatic contour maps are shown in Fig. 3. The
results of the CoMFA model also included contributions of steric and electro-
static felds of 72.6% and 27.4%, respectively. Based on these feld contributions,
the steric feld was the most important in the CoMFA model. In the steric map
of CoMFA (Fig. 3A), the green contour near the 3-position of the benzene ring
indicated that the introduction of bulky groups in these positions was favorable to
increase the antifungal activity. For instance, compounds 5a-5w bearing methyl
(5c), methoxy (5f) or trifuoromethyl (5u) substituents at the 3-position of phenyl
ring had better antifungal activity. In contrast, the yellow blocks (Fig. 3A), nearby
the 2-position of the phenyl ring, indicated that steric bulky substituents in these
positions were associated with worse antifungal activities. For example, the com-
pounds 5b bearing substituents at the 2-position of the phenyl ring showed worse
antifungal activity than the unsubstituted compound 5a. In the electrostatic map
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X. Wang et al.
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Synthesis, antifungal activity and 3D-QSAR study of novel…
Table 2 Experimental and
Statistical parameters
CoMFA
predictive activities of CoMFA
q2a
0.597
6
0.985
0.046
100.925
ONCb
r2c
SEd
F-valuee
Field contribution (%)
Steric
Electrostatic
72.6
27.4
aCross-validated correlation coefcient after the leave-one-out pro-
cedure
bOptiml number of components
cNon-cross-validated correlation coefcient
dStandard error of estimate
eF-test value
Table 3 The ED values of
experimental and predicted
activities
Compound
ED
ED"
Residue
5c
5d
5f
5 g
5 h
5j
5 k
5 l
5n
5p
5r
5 s
5t
5u
5v
5w
−2.339
−2.666
−1.979
−2.9
−2.368
−2.723
−2.001
−2.919
−2.378
−2.445
−2.924
−2.393
−2.996
−2.799
−2.826
−2.558
−2.658
−2.449
−3
0.029
0.057
0.022
0.019
0.033
−0.051
−0.062
−0.028
0.054
−0.046
−0.008
−0.045
0.007
−2.345
−2.496
−2.986
−2.421
−2.942
−2.845
−2.834
−2.603
−2.651
−2.449
−2.976
−2.941
0
0.024
−0.004
−2.937
ED=experimental value, ED′′=predictive value of ED
of CoMFA (Fig. 3B), red block meant that an increase in the negative charge will
lead to increase the antifungal activity, while the blue contour defnes the oppo-
site. In fact, the electron-donating group substituted at the 3-position of the phenyl
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X. Wang et al.
Fig. 2 Scatter plot of predicted ED vs experimental ED for CoMFA model
Fig. 3 A Contours of steric contribution: green contour favors steric or bulky group, and yellow contour
denotes disfavored region. B Contours of electrostatic contribution: blue contour indicates electropositive
charge and red contour electronegative charge. (Color fgure online)
ring, such as the antifungal activity of 5c (R = m–CH3) and 5f (R = m–OCH3), had
better than or equal to that of the unsubstituted compound 5a (R = H).
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Synthesis, antifungal activity and 3D-QSAR study of novel…
Experimental
Materials and methods
The GC analysis was performed on an Agilent 6890 GC (Agilent Technologies Inc.,
Santa Clara, CA, USA) equipped with an HP-1 (30 m, 0.530 mm, 0.88 µm) column.
The 1H NMR and 13C NMR spectra were recorded using tetramethylsilane (TMS) as
the internal standard on a Bruker Avance III HD spectrometer at 600 and 150 MHz,
respectively. The IR spectra were recorded by employing a Nicolet iS50 FT-IR
spectrometer (Thermo Scientifc Co., Ltd., Madison, WI, USA) using the KBr pel-
let method. Mass spectra were obtained by means of the electrospray ionization
(ESI) method on TSQ Quantum Access MAX HPLC–MS instrument (Thermo Sci-
entifc Co., Ltd., Waltham, MA, USA). Elemental analyses were measured using a
PE 2400 II elemental analyzer (PerkinElmer Instruments Co., Ltd., USA). β-Pinene
(GC purity 98%) was provided by Jiangxi Xuesong Natural Medicinal Oil Co.,
Ltd. (Ji’an, Jiangxi, China). All other materials and reagents were purchased from
commercial suppliers and used as received. 5-Substituted phenyl-1,3,4-thiadiazole-
2-thiones (4) were prepared by our laboratory according to the literature [44].
General procedure for the synthesis of nopol (2)
A mixture of paraformaldehyde (85.68 g, 0.95 mol), β-pinene (300 mL, 1.90 mol)
was magnetically stirred under solvent-free condition. When the mixture was
heated to 75 ℃, a catalytic quantity of anhydrous ZnCl2 was added to the reaction
system. Afterward, the reaction mixture was stirred for 1 h at 75 ℃ and then con-
tinuously heated to 110 ℃ for 10 h. When the reaction was completed, the reac-
tion mixture was cooled to room temperature. Then, the organic layer was separated,
washed three times with deionized water and dried over anhydrous Na2SO4. The
crude product was further purifed by vacuum distillation to obtain nopol (2) as a
colorless transparent liquid at 60–70 ℃/1333 Pa (GC purity 94.5%). Yield 70%. IR
(KBr, v/cm−1): 3370 (s, OH), 3025 (w, C=C–H), 2991, 2914, 2831 (s, C–H), 1468
1
(m, CH2), 1381, 1368 (m,CMe2), 1046 (s, C–O); H NMR (600 MHz, CDCl3): δ
(ppm) 5.36–5.35 (m, 1H, H-3), 3.62–3.58 (m, 2H, H-11), 2.40 (dt, J=8.6, 5.6 Hz,
1H, H-1), 2.32–2.21 (m, 4H, H-7, H-10), 2.14–2.10 (m, 1H, H-5), 2.05 (td, J=5.6,
1.4 Hz, 1H, H-4), 1.51 (s, 1H, H-12), 1.29 (s, 3H, H-8), 1.16 (d, J=8.6 Hz, 1H,
H-4), 0.86 (s, 3H, H-9); 13C NMR (150 MHz, CDCl3): δ (ppm) 144.72, 119.38,
59.98, 45.61, 40.72, 40.22, 37.90, 31.76, 31.39, 26.25, 21.19.
General procedure for the synthesis of nopyl chloride (3)
Under stirring, a solution of triphenylphosphine (25.3 g, 0.09 mol) and nopol
(14.6 g, 15 mL, 0.09 mol) dissolved in carbon tetrachloride (52 mL) was refuxed
for 3 h. After cooling to room temperature, a white precipitate was removed by fl-
tration. The fltrate was evaporated to give a yellowish oil, which was subsequently
1 3

X. Wang et al.
washed with petroleum ether and further purifed by vacuum distillation to obtain
nopyl chloride (3) as a pale yellow liquid at 80–90 ℃/1333 Pa (GC purity 94.0%).
Yield 80%, IR (KBr, v/cm−1): 3029(w, C=C–H), 2987,2916, 2981, 2831(s, C–H),
1
1470(m, CH2), 1383, 1368(m,CMe2),741(w, C–Cl); H NMR (600 MHz, CDCl3):
δ (ppm) 5.38–5.33 (m, 1H, H-3), 3.59–3.44 (m, 2H, H-11), 2.47–2.37 (m, 3H, H-1,
H-10), 2.32–2.20 (m, 2H, H-7), 2.11–2.10 (m, 1H, H-5), 2.05 (td, J=4.8, 2.3 Hz,
1H, H-4), 1.30 (s, 3H, H-9), 1.19 (d, J=8.6 Hz, 1H, H-4), 0.86 (s, 3H, H-8); 13C
NMR (150 MHz, CDCl3): δ (ppm) 144.41, 119.27, 45.57, 42.64, 40.71, 40.16,
38.06, 31.64, 31.32, 26.27, 21.21.
General procedure of 2‑((2‑(6,6‑dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑1,3,4‑thiadiazole derivatives (5a‑5w)
Nopyl chloride (3) was added dropwise to a solution of compounds (4) (3 mmol),
K2CO3 (0.41 g, 3 mmol) and PEG-400 (0.34 g, 0.5 mmol) in acetone (20 mL),
and the reaction mixture was refuxed for 6 h. Upon completion of the reaction
(monitored by TLC), the mixture was concentrated in vacuum. Then, the crude
product was poured into saturated sodium bicarbonate solution, and the mixture
was extracted with ethyl acetate (3 × 20 mL). The combined organic layer was
washed with saturated salt water three times, dried over anhydrous sodium sul-
fate and purifed by silica gel column chromatography (petroleum ether/ethyl ace-
tate = 20:1 ~ 10:1, v/v) to aford the target compounds (5a-5w).
Spectral data of all the target compounds
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑phenyl‑1,3,4‑thiadiazole (5a)
Pale yellow liquid, yield: 61.2%; IR (KBr, v/cm−1): 3027 (w, = C–H), 2985,
1
2912, 2831 (s, C–H), 1462,1433 (s, C=N), 687 (s, C–S–C); H NMR (600 MHz,
CDCl3): δ (ppm) 7.93–7.88 (m, 2H, Ar–H), 7.51–7.46 (m, 3H, Ar–H), 5.37 (dq,
J = 4.3, 1.4 Hz, 1H, H-3), 3.45–3.39 (m, 2H, H-11), 2.50 (td, J = 7.5, 1.4 Hz,
2H, H-10), 2.41 (dt, J = 8.6, 5.6 Hz, 1H, H-1), 2.34–2.21 (m, 2H, H-7), 2.12 (d,
J = 5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J = 8.6 Hz, 1H, H-4), 0.88
(s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 168.12, 165.66, 145.58,
130.95, 130.02, 129.17, 127.70, 118.71, 45.54, 40.76, 38.08, 36.34, 32.23, 31.72,
31.32, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H22N2S2 [M + H]+ 343.12,
found 343.01 [M + H]+. Anal. Calcd. for C19H22N2S2: C, 66.63; H, 6.47; N, 8.18;
Found: C, 66.62; H, 6.45; N, 8.16.
1 3

Synthesis, antifungal activity and 3D-QSAR study of novel…
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(2‑methylphenyl)‑1,3,4‑thiadiazole (5b)
Pale yellow liquid, yield: 66.3%; IR (KBr, v/cm−1): 3022 (w, = C–H), 2983, 2916,
1
2831 (s, C–H), 1468, 1431 (s, C=N), 718 (m, C–S–C); H NMR (600 MHz,
CDCl3): δ (ppm) 7.63 (d, J = 7.7 Hz, 1H, Ar–H), 7.39 (td, J = 7.5, 1.1 Hz, 1H,
Ar–H), 7.35 (d, J = 7.1 Hz, 1H, Ar–H), 7.30 (t, J = 7.7 Hz, 1H, Ar–H), 5.38 (dd,
J = 2.7, 1.3 Hz, 1H, H-3), 3.48–3.42 (m, 2H, H-11), 2.60 (s, 3H, H-20), 2.50 (td,
J = 7.5, 1.4 Hz, 2H, H-10), 2.41 (dt, J = 8.6, 5.6 Hz, 1H, H-1), 2.32–2.23 (m, 2H,
H-7), 2.12 (d, J = 5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J = 8.6 Hz,
1H, H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.34,
166.17, 145.58, 137.22, 131.61, 130.62, 130.30, 129.02, 126.26, 118.70, 45.53,
40.75, 38.08, 36.33, 32.03, 31.73, 31.32, 26.29, 21.58, 21.27; ESI–MS m/z:
Calcd. for C20H24N2S2 [M + H]+ 357.14, found 357.02 [M + H]+. Anal. Calcd. for
C20H24N2S2: C, 67.37; H, 6.79; N, 7.86; Found: C, 67.36; H, 6.78; N, 7.85.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3‑methylphenyl)‑1,3,4‑thiadiazole (5c)
Pale yellow liquid, yield: 71.9%; IR (KBr, v/cm-1): 3025 (w,=C–H), 2983, 2916,
1
2879, 2831 (s, C–H), 1470, 1445 (s, C=N), 691 (s, C–S–C); H NMR (600 MHz,
CDCl3): δ (ppm) 7.74 (s, 1H, Ar–H), 7.68 (d, J=7.7 Hz, 1H, Ar–H), 7.36 (t,
J=7.6 Hz, 1H, Ar–H), 7.30 (d, J=7.6 Hz, 1H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz,
1H, H-3), 3.45–3.37 (m, 2H, H-11), 2.50 (td, J=7.6, 1.3 Hz, 2H, H-10), 2.44 (s,
3H, H-20), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12 (d,
J=5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s,
3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 168.35, 165.46, 145.60, 139.02,
131.77, 129.89, 129.05, 128.20, 124.95, 118.69, 45.52, 40.75, 38.08, 36.35, 32.23,
31.72, 31.32, 26.28, 21.34, 21.27; ESI–MS m/z: Calcd. for C20H24N2S2 [M+H]+
357.14, found 357.01 [M+H]+. Anal. Calcd. for C20H24N2S2: C, 67.37; H, 6.79; N,
7.86; Found: C, 67.35; H, 6.78; N, 7.84.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(4‑methylphenyl)‑1,3,4‑thiadiazole (5d)
Pale yellow liquid, yield: 72.2%; IR (KBr, v/cm−1): 3020 (w,=C–H), 2981, 2918,
2879, 2833 (s, C–H), 1456 (s, C=N), 712 (w, C–S–C); 1H NMR (600 MHz, CDCl3):
δ (ppm) 7.79 (d, J=8.1 Hz, 2H, Ar–H), 7.30–7.26 (m, 2H, Ar–H), 5.37 (dq, J=4.3,
1.4 Hz, 1H, H-3), 3.45–3.36 (m, 2H, H-11), 2.50 (td, J=7.6, 1.3 Hz, 2H, H-10),
2.42 (s, 3H, H-20), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12
(d, J=5.5 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88
(s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 168.29, 165.11, 145.61, 141.41,
129.84, 127.62, 127.30, 118.67, 45.52, 40.75, 38.08, 36.36, 32.21, 31.72, 31.31,
26.28, 21.51, 21.27; ESI–MS m/z: Calcd. for C20H24N2S2 [M+H]+ 357.14, found
357.01 [M+H]+. Anal. Calcd. for C20H24N2S2: C, 67.37; H, 6.79; N, 7.86; Found:
C, 67.35; H, 6.77; N, 7.85.
1 3

X. Wang et al.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(2‑methoxyphenyl)‑1,3,4‑thiadiazole (5e)
Pale yellow liquid, yield: 69.3%; IR (KBr, v/cm−1): 3022 (w,=C–H), 2981, 2916,
1
2875, 2831 (s, C–H), 1600, 1500(s, C=C), 1466 (s, C=N), 681 (s, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 8.45 (dd, J=7.9, 1.6 Hz, 1H, Ar–H), 7.50–7.44
(m, 1H, Ar–H), 7.12 (t, J=7.6 Hz, 1H, Ar–H), 7.04 (d, J=8.3 Hz, 1H, Ar–H),
5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 4.01 (s, 3H, H-20), 3.44–3.36 (m, 2H, H-11),
2.50 (td, J=7.6, 1.3 Hz, 2H, H-10), 2.40 (dt, J=8.5, 5.6 Hz, 1H, H-1), 2.32–2.22
(m, 2H, H-7), 2.12 (d, J=5.5 Hz, 2H, H-4, H-5), 1.30 (s, 3H, H-9), 1.20 (d,
J=8.6 Hz, 1H, H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm)
166.32, 161.97, 155.62, 145.75, 131.92, 128.27, 121.34, 119.17, 118.52, 111.33,
55.71, 45.54, 40.76, 38.07, 36.49, 32.00, 31.72, 31.32, 26.29, 21.27; ESI–MS m/z:
Calcd. for C20H24N2OS2 [M+H]+ 373.13, found 373.01 [M+H]+. Anal. Calcd. for
C20H24N2OS2: C, 64.48; H, 6.49; N, 7.52; Found: C, 64.47; H, 6.48; N, 7.51.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3‑methoxyphenyl)‑1,3,4‑thiadiazole (5f)
Pale yellow liquid, yield: 72.6%; IR (KBr, v/cm−1):3029 (w,=C–H), 2987, 2914,
1
2877, 2831 (s, C–H), 1604(s, C=C), 1477 (s, C=N), 687 (s, C–S–C); H NMR
(600 MHz, CDCl3): δ (ppm) 7.54–7.51 (m, 1H, Ar–H), 7.42–7.35 (m, 2H, Ar–H),
7.03 (ddd, J=8.0, 2.5, 1.1 Hz, 1H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.89
(s, 3H, H-20), 3.45–3.37 (m, 2H, H-11), 2.50 (td, J=7.5, 1.2 Hz, 2H, H-10), 2.41
(dt, J=8.6, 5.6 Hz, 1H, H-1), 2.41–2.22 (m, 2H, H-7), 2.12 (d, J=5.5 Hz, 2H,
H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s, 3H, H-8); 13C
NMR (150 MHz, CDCl3): δ (ppm) 168.01, 165.76, 160.05, 145.58, 131.16, 130.20,
120.48, 118.71, 117.35, 111.99, 55.49, 45.52, 40.74, 38.08, 36.35, 32.21, 31.72,
31.32, 26.28, 21.27; ESI–MS m/z: Calcd. for C20H24N2OS2 [M+H]+ 373.13, found
373.02 [M+H]+. Anal. Calcd. for C20H24N2OS2: C, 64.48; H, 6.49; N, 7.52; Found:
C, 64.47; H, 6.47; N, 7.51.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(4‑methoxyphenyl)‑1,3,4‑thiadiazole (5 g)
Pale yellow liquid, yield: 81.4%; IR (KBr, v/cm−1): 3024 (w,=C–H), 2985, 2916,
1
2880, 2832 (s, C–H), 1603, 1520(s, C=C), 1453 (s, C=N), 662 (m, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 7.85–7.82 (m, 2H, Ar–H), 6.98 (d, J=8.8 Hz, 2H,
Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.88 (s, 3H, H-20), 3.43–3.35 (m, 2H),
2.50 (td, J=7.5, 1.2 Hz, 2H, H-10), 2.40 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.31–2.22 (m,
2H, H-7), 2.11 (d, J=5.5 Hz, 2H, H-4, H-5), 1.30 (s, 3H, H-9), 1.19 (d, J=8.6 Hz,
1H, H-4), 0.87 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.96, 164.56,
161.79, 145.62, 129.23, 122.71, 118.65, 114.54, 55.46, 45.52, 40.75, 38.07, 36.38,
32.23, 31.71, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C20H24N2OS2 [M+H]+
373.13, found 373.01 [M+H]+. Anal. Calcd. for C20H24N2OS2: C, 64.48; H, 6.49;
N, 7.52; Found: C, 64.46; H, 6.48; N, 7.50.
1 3

Synthesis, antifungal activity and 3D-QSAR study of novel…
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(2‑fuorophenyl)‑1,3,4‑thiadiazole (5 h)
Pale yellow liquid, yield: 80.8%; IR (KBr, v/cm−1): 3025 (w,=C–H), 2983, 2916,
2879, 2831 (s, C–H), 1614, 1583 (m, C=C), 1458 (s, C=N), 670 (s, C–S–C);
1H NMR (600 MHz, CDCl3): δ (ppm) 8.36 (td, J=7.6, 1.7 Hz, 1H, Ar–H), 7.49
(ddd, J=15.5, 5.4, 1.7 Hz, 1H, Ar–H), 7.34–7.29 (m, 1H, Ar–H), 7.26- 7.19 (m,
1H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.47–3.39 (m, 2H, H-11), 2.50 (td,
J=7.5, 1.3 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H,
H-7), 2.12 (d, J=5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H,
H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.36, 160.25,
159.32, 145.55, 132.37, 128.66, 124.92, 118.73, 118.17, 116.14, 45.52, 40.74, 38.08,
36.35, 32.17, 31.72, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H21FN2S2
[M+H]+ 361.11, found 360.99 [M+H]+. Anal. Calcd. for C19H21FN2S2: C, 63.30;
H, 5.87; N, 7.77; Found: C, 63.29; H, 5.86; N, 7.75.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3‑fuorophenyl)‑1,3,4‑thiadiazole (5i)
Pale yellow liquid, yield: 65.8%; IR (KBr, v/cm−1): 3025 (w,=C–H), 2983, 2916,
1
2879, 2829 (s, C–H), 1610, 1591(s, C=C), 1472 (s, C=N), 683 (s, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 7.66 (dt, J=17.0, 4.8 Hz, 2H, Ar–H), 7.45 (td,
J=8.1, 5.8 Hz, 1H, Ar–H), 7.22–7.17 (m, 1H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz,
1H, H-3), 3.47–3.39 (m, 2H, H-11), 2.50 (td, J=7.5, 1.3 Hz, 2H, H-10), 2.41 (dt,
J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12 (dd, J=5.5, 1.0 Hz, 2H,
H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s, 3H, H-8); 13C
NMR (150 MHz, CDCl3): δ (ppm) 166.66, 166.39, 162.9, 145.49, 131.93, 130.84,
123.56, 118.79, 117.88, 114.41, 45.51, 40.74, 38.08, 36.28, 32.23, 31.72, 31.31,
26.27, 21.27; ESI–MS m/z: Calcd. for C19H21FN2S2 [M+H]+ 361.11, found 361.00
[M+H]+. Anal. Calcd. for C19H21FN2S2: C, 63.30; H, 5.87; N, 7.77; Found: C,
63.28; H, 5.86; N, 7.76.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(4‑fuorophenyl)‑1,3,4‑thiadiazole (5j)
Pale yellow liquid, yield: 68.5%; IR (KBr, v/cm−1): 3027 (w,=C–H), 2989, 2918,
1
2879, 2833 (s, C–H), 1602, 1516(s, C=C), 1454 (s, C=N), 664 (m, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 7.93–7.87 (m, 2H, Ar–H), 7.21–7.14 (m, 2H,
Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.46–3.37 (m, 2H, H-11), 2.50 (dd,
J=15.0, 1.0 Hz, 2H, H-10), 2.40 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H,
H-7), 2.12 (dd, J=5.5, 1.0 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz,
1H, H-4), 0.87 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 166.88, 165.74,
164.29, 145.53, 129.67, 126.32, 118.75, 116.46, 116.31, 45.51, 40.74, 38.08, 36.31,
32.23, 31.71, 31.31, 26.27, 21.26; ESI–MS m/z: Calcd. for C19H21FN2S2 [M+H]+
361.11, found 360.99 [M+H]+. Anal. Calcd. for C19H21FN2S2: C, 63.30; H, 5.87;
N, 7.77; Found: C, 63.29; H, 5.85; N, 7.76.
1 3

X. Wang et al.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(2‑chlorophenyl)‑1,3,4‑thiadiazole (5 k)
Pale yellow liquid, yield: 74.2%; IR (KBr, v/cm−1): 3029 (w,=C–H), 2983, 2914,
2879, 2831 (s, C–H), 1433 (s, C=N), 662 (w, C–S–C); 1H NMR (600 MHz, CDCl3):
δ (ppm) 8.31- 8.26 (m, 1H, Ar–H), 7.55–7.51 (m, 1H, Ar–H), 7.46–7.40 (m, 2H,
Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.47–3.41 (m, 2H, H-11), 2.51 (td,
J=7.5, 1.2 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H,
H-7), 2.12 (d, J=5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H,
H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.57, 163.41,
145.55, 132.38, 131.49, 130.83, 130.55, 128.94, 127.37, 118.74, 45.52, 40.75, 38.08,
36.36, 32.15, 31.72, 31.32, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H21ClN2S2
[M+H]+ 377.08, found 376.97 [M+H]+. Anal. Calcd. for C19H21ClN2S2: C, 60.54;
H, 5.62; N, 7.43; Found: C, 60.53; H, 5.61; N, 7.42.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3‑chlorophenyl)‑1,3,4‑thiadiazole (5 l)
Pale yellow liquid, yield: 74.7%; IR (KBr, v/cm−1): 3027 (w,=C–H), 2985, 2916,
2877, 2829 (s, C–H),1595, 1572(s, C=C), 1458, 1427 (s, C=N), 681 (s, C–S–C); 1H
NMR (600 MHz, CDCl3): δ (ppm) 7.91 (t, J=1.7 Hz, 1H, Ar–H), 7.77 (dd, J=7.6,
1.2 Hz, 1H, Ar–H), 7.48–7.44 (m, 1H, Ar–H), 7.41 (t, J=7.8 Hz, 1H, Ar–H), 5.37
(dq, J=4.3, 1.4 Hz, 1H, H-3), 3.47–3.38 (m, 2H, H-11), 2.50 (td, J=7.5, 1.1 Hz,
2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12 (d,
J=5.3 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s,
3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 166.49, 166.45, 145.48, 135.22,
131.60, 130.89, 130.43, 127.52, 125.81, 118.80, 45.51, 40.74, 38.08, 36.28, 32.26,
31.72, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H21ClN2S2 [M+H]+ 377.08,
found 376.98 [M+H]+. Anal. Calcd. for C19H21ClN2S2: C, 60.54; H, 5.62; N, 7.43;
Found: C, 60.53; H, 5.60; N, 7.41.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(4‑chlorophenyl)‑1,3,4‑thiadiazole (5 m)
Pale yellow liquid, yield: 70.8%; IR (KBr, v/cm−1): 3022 (w,=C–H), 2987, 2935,
1
2912, 2833 (s, C–H), 1595 (s, C=C), 1450 (s, C=N), 652 (s, C–S–C); H NMR
(600 MHz, CDCl3): δ (ppm) 7.84 (d, J=8.5 Hz, 2H, Ar–H), 7.46 (d, J=8.5 Hz,
2H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.46–3.37 (m, 2H, H-11), 2.50 (td,
J=7.5, 1.1 Hz, 2H, H-10), 2.40 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H,
H-7), 2.11 (d, J=4.9 Hz, 2H, H-4, H-5), 1.30 (s, 3H, H-9), 1.19 (d, J=8.6 Hz, 1H,
H-4), 0.87 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 166.82, 166.08,
145.51, 137.03, 129.46, 128.83, 128.49, 118.77, 45.51, 40.73, 38.08, 36.29, 32.24,
31.72, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H21ClN2S2 [M+H]+ 377.08,
found 376.96 [M+H]+. Anal. Calcd. for C19H21ClN2S2: C, 60.54; H, 5.62; N, 7.43;
Found: C, 60.52; H, 5.61; N, 7.41.
1 3

Synthesis, antifungal activity and 3D-QSAR study of novel…
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(2‑bromophenyl)‑1,3,4‑thiadiazole (5n)
Pale yellow liquid, yield: 65.8%; IR (KBr, v/cm−1): 3025 (w,=C–H), 2985, 2916,
2879, 2831 (s, C–H), 1431 (s, C=N), 637 (w, C–S–C); 1H NMR (600 MHz, CDCl3):
δ (ppm) 8.13 (dd, J=7.9, 1.6 Hz, 1H, Ar–H), 7.73 (dd, J=8.0, 0.9 Hz, 1H, Ar–H),
7.46 (td, J=7.8, 1.1 Hz, 1H, Ar–H), 7.35 (td, J=7.9, 1.7 Hz, 1H, Ar–H), 5.37 (dq,
J=4.3, 1.4 Hz, 1H, H-3), 3.48–3.40 (m, 2H, H-11), 2.51 (dd, J=15.0, 1.0 Hz,
2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12 (d,
J=5.5 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s,
3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.51, 164.83, 145.54, 133.97,
131.63, 130.96, 127.85, 122.30, 118.75, 45.52, 40.75, 38.09, 36.35, 32.17, 31.72,
31.32, 26.29, 21.27; ESI–MS m/z: Calcd. for C19H21BrN2S2 [M+H]+ 421.03, found
420.94 [M+H]+. Anal. Calcd. for C19H21BrN2S2: C, 54.15; H, 5.02; N, 6.65; Found:
C, 54.14; H, 5.01; N, 6.64.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3‑bromophenyl)‑1,3,4‑thiadiazole (5o)
Pale yellow liquid, yield: 67.4%; IR (KBr, v/cm−1): 3027 (w,=C–H), 2983, 2914,
1
2875, 2831 (s, C–H), 1595, 1566 (m, C=C), 1427 (s, C=N), 681 (s, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 8.07 (t, J=1.7 Hz, 1H, Ar–H), 7.82 (d, J=7.8 Hz,
1H, Ar–H), 7.62 (dd, J=8.0, 0.8 Hz, 1H, Ar–H), 7.36 (t, J=7.9 Hz, 1H, Ar–H),
5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.47–3.38 (m, 2H, H-11), 2.50 (td, J=7.5,
1.2 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12
(d, J=4.8 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88
(s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 166.41, 166.35, 145.48, 133.81,
131.82, 130.66, 130.41, 126.25, 123.19, 118.81, 45.51, 40.74, 38.09, 36.28, 32.27,
31.72, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H21BrN2S2 [M+H]+ 421.03,
found 420.93 [M+H]+. Anal. Calcd. for C19H21BrN2S2: C, 54.15; H, 5.02; N, 6.65;
Found: C, 54.13; H, 5.01; N, 6.64.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(4‑bromophenyl)‑1,3,4‑thiadiazole (5p)
Pale yellow liquid, yield: 71.6%; IR (KBr, v/cm−1): 3022 (w,=C–H), 2981, 2918,
1
2879, 2831 (s, C–H), 1585(m, C=C), 1445 (s, C=N), 658 (s, C–S–C); H NMR
(600 MHz, CDCl3): δ (ppm) 7.79–7.75 (m, 2H, Ar–H), 7.63–7.60 (m, 2H, Ar–H),
5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.45–3.39 (m, 2H, H-11), 2.50 (td, J=7.5,
1.3 Hz, 2H, H-10), 2.40 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.11
(d, J=5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.19 (d, J=8.6 Hz, 1H, H-4), 0.87
(s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 166.90, 166.13, 145.50, 132.42,
129.01, 128.93, 125.36, 118.78, 45.51, 40.73, 38.08, 36.29, 32.24, 31.72, 31.31,
26.28, 21.27; ESI–MS m/z: Calcd. for C19H21BrN2S2 [M+H]+ 421.03, found 420.94
[M+H]+. Anal. Calcd. for C19H21BrN2S2: C, 54.15; H, 5.02; N, 6.65; Found: C,
54.13; H, 5.01; N, 6.63.
1 3

X. Wang et al.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3‑iodophenyl)‑1,3,4‑thiadiazole (5q)
Pale yellow liquid, yield: 70.5%; IR (KBr, v/cm−1): 3029 (w,=C–H), 2983, 2914,
1
2877, 2829 (s, C–H), 1589,1558 (s, C=C), 1433 (s, C=N), 683 (s, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 8.27 (t, J=1.7 Hz, 1H, Ar–H), 7.85 (dd, J=7.8,
1.1 Hz, 1H, Ar–H), 7.83–7.79 (m, 1H, Ar–H), 7.21 (t, J=7.9 Hz, 1H, Ar–H), 5.37
(dq, J=4.3, 1.4 Hz, 1H, H-3), 3.45–3.38 (m, 2H, H-11), 2.50 (td, J=7.5, 1.4 Hz,
2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.12 (d,
J=6.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s,
3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 166.41, 166.19, 145.49, 139.75,
136.21, 131.83, 130.72, 126.85, 118.80, 94.64, 45.51, 40.74, 38.09, 36.28, 32.28,
31.72, 31.32, 26.28, 21.28; ESI–MS m/z: Calcd. for C19H21IN2S2 [M+H]+ 469.02,
found 468.95 [M+H]+. Anal. Calcd. for C19H21IN2S2: C, 48.72; H, 4.52; N, 5.98;
Found: C, 48.70; H, 4.51; N, 5.97.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(4‑iodophenyl)‑1,3,4‑thiadiazole (5r)
Pale yellow liquid, yield: 68.1%; IR (KBr, v/cm−1): 3027 (w,=C–H), 2983, 2935,
1
2918, 2831 (s, C–H), 1585(s, C=C), 1445 (s, C=N), 656 (s, C–S–C); H NMR
(600 MHz, CDCl3): δ (ppm) 7.84–7.81 (m, 2H, Ar–H), 7.64–7.61 (m, 2H, Ar–H),
5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.46–3.37 (m, 2H, H-11), 2.50 (td, J=7.5,
1.3 Hz, 2H, H-10), 2.40 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7),
2.12 (d, J=6.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.19 (d, J=8.6 Hz, 1H, H-4),
0.87 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.08, 166.14, 145.50,
138.36, 129.47, 129.02, 118.78, 97.34, 45.51, 40.74, 38.08, 36.29, 32.24, 31.72,
31.32, 26.28, 21.28; ESI–MS m/z: Calcd. for C19H21IN2S2 [M+H]+469.02, found
468.94 [M+H]+. Anal. Calcd. for C19H21IN2S2: C, 48.72; H, 4.52; N, 5.98; Found:
C, 48.71; H, 4.50; N, 5.97.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3,4‑dimethoxyphenyl)‑1,3,4‑thiadiazole (5 s)
Pale yellow liquid, yield: 64.7%; IR (KBr, v/cm−1): 3026 (w,=C–H), 2981, 2912,
1
2877, 2831 (s, C–H), 1603, 1521(s, C=C), 1433 (s, C=N), 644 (m, C–S–C); H
NMR (600 MHz, CDCl3): δ (ppm) 7.59 (d, J=2.0 Hz, 1H, Ar–H), 7.33 (dd, J=8.3,
2.0 Hz, 1H, Ar–H), 6.92 (d, J=8.3 Hz, 1H, Ar–H), 5.36 (dq, J=4.3, 1.4 Hz, 1H,
H-3), 3.96 (d, J=13.9 Hz, 6H), 3.40–3.37 (m, 2H, H-11), 2.50 (dd, J=10.9, 4.3 Hz,
2H, H-10), 2.40 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m, 2H, H-7), 2.11 (d,
J=5.5 Hz, 2H, H-4, H-5), 1.30 (s, 3H, H-9), 1.19 (d, J=8.6 Hz, 1H, H-4), 0.87 (s,
3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 168.05, 164.74, 151.48, 149.42,
145.62, 122.91, 121.52, 118.66, 111.11, 109.57, 56.10, 56.05, 45.52, 40.74, 38.07,
36.39, 32.24, 31.71, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C21H26N2O2S2
[M+H]+403.14, found 403.05 [M+H]+. Anal. Calcd. for C21H26N2O2S2: C, 62.66;
H, 6.51; N, 6.96; Found: C, 62.65; H, 6.50; N, 6.94.
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Synthesis, antifungal activity and 3D-QSAR study of novel…
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(3,5‑dimethoxyphenyl)‑1,3,4‑thiadiazole (5t)
Pale yellow liquid, yield: 73.6%; IR (KBr, v/cm−1): 2983, 2917, 2876, 2831 (s, C–H),
1591(s, C=C), 1465 (s, C=N), 1347 (s, C=S), 680 (s, C–S–C); 1H NMR (600 MHz,
CDCl3): δ (ppm) 7.16 (d, J=2.3 Hz, 2H, Ar–H), 6.62 (t, J=2.3 Hz, 1H, Ar–H),
5.38 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.87 (s, 6H), 3.35- 3.33 (m, 2H, H-11), 2.51
(td, J=7.5, 1.3 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22 (m,
2H, H-7), 2.12 (d, J=6.4 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz,
1H, H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 165.61, 164.67,
161.16, 145.28, 125.20, 119.00, 104.38, 104.31, 55.64, 45.46, 40.72, 38.08, 36.40,
31.70, 31.31, 30.68, 26.26, 21.25; ESI–MS m/z: Calcd. for C21H26N2O2S2 [M+H]+
403.14, found 403.04 [M+H]+. Anal. Calcd. for C21H26N2O2S2: C, 62.66; H, 6.51;
N, 6.96; Found: C, 62.64; H, 6.49; N, 6.95.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)thio)‑5‑(3‑(trifuoromethyl)
phenyl)‑1,3,4‑thiadiazole (5u)
Pale yellow liquid, yield: 74.8%; IR (KBr, v/cm−1): 3025 (w,=C–H), 2987, 2918,
2877, 2831 (s, C–H), 1472 (s, C=N), 695 (s, C–S–C); 1H NMR (600 MHz, CDCl3):
δ (ppm) 8.17 (s, 1H, Ar–H), 8.08 (d, J=7.8 Hz, 1H, Ar–H), 7.75 (d, J=7.8 Hz, 1H,
Ar–H), 7.63 (t, J=7.8 Hz, 1H, Ar–H), 5.38 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.48–3.41
(m, 2H, H-11), 2.51 (td, J=7.5, 1.3 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H,
H-1), 2.32–2.22 (m, 2H, H-7), 2.12 (d, J=5.5 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9),
1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ
(ppm) 166.76, 166.38, 145.46, 131.90, 131.68, 130.76, 129.80, 127.42, 124.41,
122.68, 118.84, 45.51, 40.73, 38.09, 36.26, 32.29, 31.72, 31.31, 26.27, 21.26;
ESI–MS m/z: Calcd. for C20H21F3N2S2 [M+H]+ 411.11, found 411.01 [M+H]+.
Anal. Calcd. for C20H21F3N2S2: C, 58.52; H, 5.16; N, 6.82; Found: C, 58.51; H,
5.15; N, 6.80.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)thio)‑5‑(4‑(tert‑butyl)
phenyl)‑1,3,4‑thiadiazole (5v)
Pale yellow liquid, yield: 75.9%; IR (KBr, v/cm−1): 3026 (w,=C–H), 2964, 2916,
1
2874, 2832 (s, C–H), 1607(w, C=C), 1455 (s, C=N), 695 (s, C–S–C); H NMR
(600 MHz, CDCl3): δ (ppm) 7.83 (d, J=8.4 Hz, 2H, Ar–H), 7.50 (d, J=8.4 Hz,
2H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.43–3.37 (m, 2H, H-11), 2.50
(dd, J=10.9, 4.3 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22
(m, 2H, H-7), 2.12 (d, J=5.5 Hz, 2H, H-4, H-5), 1.37 (s, 9H), 1.31 (s, 3H, H-9),
1.20 (d, J=8.6 Hz, 1H, H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ
(ppm) 168.17, 165.14, 154.53, 145.62, 127.49, 127.24, 126.13, 118.67, 45.52,
40.75, 38.08, 36.37, 34.99, 32.20, 31.72, 31.32, 31.15, 26.28, 21.27; ESI–MS m/z:
Calcd. for C23H30N2S2 [M+H]+ 399.19, found 399.05 [M+H]+. Anal. Calcd. for
C23H30N2S2: C, 69.30; H, 7.59; N, 7.03; Found: C, 69.28; H, 7.58; N, 7.02.
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X. Wang et al.
2‑((2‑(6,6‑Dimethylbicyclo[3.1.1]hept‑2‑en‑2‑yl)ethyl)
thio)‑5‑(2‑chloro‑4‑fuorophenyl)‑1,3,4‑thiadiazole (5w)
Pale yellow liquid, yield: 60.9%; IR (KBr, v/cm−1): 3027 (w,=C–H), 2983, 2916, 2879,
1
2831 (s, C–H),1600, 1500(s, C=C), 664 (w, C–S–C); H NMR (600 MHz, CDCl3):
δ (ppm) 8.30 (dd, J=8.9, 6.1 Hz, 1H, Ar–H), 7.30–7.26 (m, 1H, Ar–H), 7.16 (ddd,
J=8.9, 7.6, 2.6 Hz, 1H, Ar–H), 5.37 (dq, J=4.3, 1.4 Hz, 1H, H-3), 3.47–3.40 (m, 2H,
H-11), 2.50 (td, J=7.5, 1.3 Hz, 2H, H-10), 2.41 (dt, J=8.6, 5.6 Hz, 1H, H-1), 2.32–2.22
(m, 2H, H-7), 2.12 (d, J=5.6 Hz, 2H, H-4, H-5), 1.31 (s, 3H, H-9), 1.20 (d, J=8.6 Hz,
1H, H-4), 0.88 (s, 3H, H-8); 13C NMR (150 MHz, CDCl3): δ (ppm) 167.55, 163.43,
162.50, 145.51, 133.37, 132.41, 125.47, 118.77, 117.82, 115.18, 45.52, 40.74, 38.08,
36.34, 32.16, 31.72, 31.31, 26.28, 21.27; ESI–MS m/z: Calcd. for C19H20ClFN2S2
[M+H]+ 395.07, found 394.95 [M+H]+. Anal. Calcd. for C19H20ClFN2S2: C, 57.78;
H, 5.10; N, 7.09; Found: C, 57.76; H, 5.09; N, 7.07.
In vitro antifungal activity test
The biological activity of the nopol-based 1,3,4-thiadiazole–thioether compounds was
evaluated in vitro through the agar dilution method according to the literature [45]. The
strains were incubated in petri dishes with potato–sugar–agar (PSA) culture medium
to culture new mycelia for the antifungal assay. The tested compound was dissolved in
acetone. As an emulsifer, Sorporl-144 (200 mg/L) was added to dilute the solution of
each sample to 500 mg/L. Then, 50 mg/L of the test compounds were made by mixing
1 mL 500 mg/L stock solution with 9 mL of PSA culture medium. A bacterium tray of
5-mm-diameter cut along the external edge of the mycelium was transferred to the fat
containing the tested compound and put in equilateral triangular style in triplicate. After
culturing 48 h at (24 1) ℃ in the incubator, the expanded colony diameters of strains
were measured and compared with that treated with aseptic distilled water. Aseptic dis-
tilled water without the test samples was served as a blank control, and the commercial
protective fungicide chlorothalonil was used as a positive control. All the experiments
were performed in three replicates to calculate the relative inhibition percentage.
3D‑QSAR analysis
3D-QSAR model was performed to fnd the correlation between the structure and
activity of the target molecules according to previously reported procedures [46]. All
the molecular modeling calculations were constructed using SYBYL-X 2.0. According
Fig. 4 Asterisk skeleton of the
target compounds
1 3

Synthesis, antifungal activity and 3D-QSAR study of novel…
Fig. 5 Alignment superposition of molecules based on compound 5f
to reported literature [47], ED value of the antifungal activity against P. piricola was
expressed by the formula:
ED = log {I∕[(100 − I) × MW]}
where I is the percent inhibition at 50 µg/mL and MW is the molecular weight of
the target compounds. Complete conformational optimization of each structure was
performed using a conjugate gradient procedure based on the Tripos force feld with
termination convergence energy of 0.005 kcal/(mol*Å) and a maximum of 1000
iterations and Gasteiger–Hückel charges. The steric and electrostatic felds were cal-
culated using a sp3 hybridized carbon atom as a probe with+1.0 charge. Compound
5f was selected as the template, in which the atoms marked with an asterisk con-
stituted the common superimposed skeleton (Fig. 4), and sixteen test compounds
as training set were superimposed (Fig. 5). CoMFA descriptors are independent
variables, and ED values are dependent variables. The cross-validation with the
leave-one-out method was carried out to obtain the cross-validated q2 and the opti-
mal number of components. Then, a non-cross-validation analysis under the optimal
number of components was performed. The modeling capability was indicated by
the correlation coefcient squared r2, and the prediction capability was judged by
the r2 and q2.
Conclusion
In conclusion, twenty-three novel nopol-based 1,3,4-thiadiazole–thioether com-
pounds were synthesized, characterized and evaluated for their antifungal activity
by using the natural product β-pinene as starting material. It was found by prelimi-
nary bioassay that, at the concentration of 50 μg/mL, some of the target compounds
exhibited excellent antifungal activity against P. piricola, in which compound 5i
(R=m–F) held the highest inhibition rate of 88.9% against P. piricola, better than
that of the commercial fungicide chlorothalonil (75%). Besides, compound 5 m
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X. Wang et al.
(R=p–Cl) showed antifungal activity of 80.7% against R. solani. In order to design
more efective antifungal molecules against P. piricola, 3D-QSAR analysis was per-
formed by CoMFA method. A reasonable 3D-QSAR model (q2 =0.597; r2 =0.985)
was established.
Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1007/s11164-021-04510-x.
Acknowledgements The authors are grateful to the State Key Laboratory of Element-organic Chemistry,
Nankai University, China, for the bioassay test.
Funding The authors declare that this study was funded by the National Natural Science Foundation of
China (No. 31870556) and the Open Fund of Guangxi Key Laboratory of Chemistry and Engineering of
Forest Products (No. GXFG2010).
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