Design, synthesis, fungicidal activities and structure–activity relationship studies of (?)-borneol derivatives containing 2-aryl-thiazole scaffold

Article abstract of DOI:10.1016/j.bmcl.2021.128006

A series of (-)-borneol derivatives containing 2-aryl-thiazole scaffold were designed, synthesized, and characterized by ¹H NMR, ¹³C NMR, and HRMS. The fungicidal activities of these novel compounds against Fusarium oxysporum, Magnaporthe grisea, Botrytis cinerea, and Penicillium digitatum were evaluated. The results indicated that (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(Z)-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)amino)but-2-enoate (6a) displayed potential fungicidal activities with broad spectrum. Especially, 6a exhibited an IC₅₀ value of 48.5 mg/L against P. digitatum, which has higher fungicidal activity than commercial products hymexazol and amicarthiazol. Moreover, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)amino)butanoate (5a) possesses an IC₅₀ value of 24.3 mg/L against B. cinerea, comparable to hymexazol and far superior to amicarthiazol. Furthermore, the superficial structure–activity relationship was discussed, which might be helpful for discovering novel fungicides.

Full text of DOI:10.1016/j.bmcl.2021.128006

Bioorg. Med. Chem. Lett. 45 (2021) 128006
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, fungicidal activities and structure–activity relationship
studies of (ꢀ )-borneol derivatives containing 2-aryl-thiazole scaffold
Danling Huang, Shumin Zheng, Tianyuan Zhang, Yong-Xian Cheng*
School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A series of (-)-borneol derivatives containing 2-aryl-thiazole scaffold were designed, synthesized, and charac-
terized by 1H NMR, 13C NMR, and HRMS. The fungicidal activities of these novel compounds against Fusarium
oxysporum, Magnaporthe grisea, Botrytis cinerea, and Penicillium digitatum were evaluated. The results indi-
Borneol derivatives
Thiazole
Synthesis
cated
that
(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(Z)-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)
Fungicidal activity
Structure-activity relationship
amino)but-2-enoate (6a) displayed potential fungicidal activities with broad spectrum. Especially, 6a exhibited
an IC50 value of 48.5 mg/L against P. digitatum, which has higher fungicidal activity than commercial products
hymexazol and amicarthiazol. Moreover, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-4-oxo-4-(((2-
phenylthiazol-4-yl)methyl)amino)butanoate (5a) possesses an IC50 value of 24.3 mg/L against B. cinerea,
comparable to hymexazol and far superior to amicarthiazol. Furthermore, the superficial structure–activity
relationship was discussed, which might be helpful for discovering novel fungicides.
Plant diseases cause crops reduction, further leading to inadequacy
of food supply. Thus, crops protection is a crucial element in human
survival and development. Reasonable application of fungicides is one of
the crops protection strategy, which is an effective method for protecting
crops from fungi infection. However, with the abuse of fungicides, most
fungi show resistance or cross-resistance against the commercial fungi-
cides more or less.1,2 Therefore, to develop and discovery novel fungi-
cides are a matter of great urgency.
derivatives have been largely explored against fungi by the research
group of prof. Secci,15–18 which enlighten us on fungicides design. In our
previous work,19,20 we has demonstrated that the 2-phenyl-thiazole
derivatives exhibited distinct and broad spectrum fungicidal activities,
which inspired us to make further efforts in hunting for potential
fungicide molecules. In pursuit of discovering novel compounds with
excellent fungicidal activities, taking above-mentioned discussion into
account, molecular hybridization between (-)- borneol scaffold and
thiazole skeleton via succinic or butenedioic acid linker was carried out
(Fig. 1). Here we reported several (-)-borneol derivatives bearing 2-
phenyl-thiazole (5a-5e, 6a-6e, and 7a-7e) and their fungicidal activ-
ities. Furthermore, the apparent structure–activity relationship was
given according to the bioactivities assay results.
Borneol, a bicyclic monoterpenoid alcohol, is the a component of
essential oil found naturally in multitudinous families of plants such as
Asteraceae, Lamiaceae, and Valerianaceae,3 which is has been used as
traditional Chinese medicine for the treatment of convulsion, stroke,
sore throat, aphtha, etc.4 Moreover, borneol was usually consider as a
bioactive fragment introduced to drug molecules in drug design because
of its diversiform bioactivity such as antitumor, anti-inflammatory, and
antiviral activity.5–7 Recently, Wang8–11 group reported some sub-
stances modified with borneol segment exhibited antifungal and anti-
bacterial activities, which inspired us building borneol fragment as an
bioactive skeleton in fungicide molecule design. On the other hand,
thiazole ring plays a key role on the structure of fungicides design
because it possesses high flexibility in location of substituents and
moreover developed commercial products of ethaboxam,12 tri-
fluzamide,13 and amicarthiazole.14 In past decade, thiazole and its
The synthetic pathway of the target compounds was in Scheme 1 and
the synthetic procedure was described in detail in Supporting Informa-
tion. The key intermediates 3a-3e were synthesized according to our
previous reported method.20 The thiazole ring was established via
Hantzsch reaction.21 Reaction between 1,3-dichloroacetone and phenyl
thioamide via refluxing in ethanol give 2-aryl-4-chloromethyl thiazole
derivatives (1a-1e). Gabriel reaction22 was proceeded to convert 1a-1e
to the key intermediates 3a-3e. Briefly, 1a-1e were subjected to the
nucleophilic reaction with potassium phthalimide in N,N-dime-
◦
thylformamide (DMF) at 80 C for over 6 h. Further hydrazinolysis of
* Corresponding author.
E-mail addresses: leonchemistry@szu.edu.cn (D. Huang), yxcheng@szu.edu.cn (Y.-X. Cheng).
https://doi.org/10.1016/j.bmcl.2021.128006
Received 24 December 2020; Received in revised form 18 February 2021; Accepted 26 March 2021
Available online 31 March 2021
0960-894X/© 2021 Published by Elsevier Ltd.

D. Huang et al.
Bioorganic & Medicinal Chemistry Letters 45 (2021) 128006
Fig. 1. The design strategy for the target compounds.
Scheme 1. The synthetic route of the target compounds. Reagents and conditions: (i) 1,3-dichloroacetone, EtOH, reflux; (ii) potassium phthalimide, DMF, 80 ◦C; (iii)
hydrazine hydrate, EtOH, reflux, then 37% HCl, 0 ◦C; (iv) succinic anhydride, Et3N, DCM, 0 ◦C and then room temperature; (v) 3a-3e, HATU, DIEA, DCM, 0 ◦C and
then room temperature; (vi) maleic anhydride, Et3N, DCM, 0 ◦C and then room temperature; (vii) 3a-3e, HATU, DIEA, DCM, 0 ◦C and then room temperature; viii)
DMF, 140 ◦C.
phthalimide derivates 2a-2e was performed via refluxing in ethanol and
hydrazine hydrate to obtain the corresponding (2-aryl-thiazol-4-yl)
methanamine. Then precipitation of amine hydrochloride derivatives
3a-3e were given by adding concentrated hydrochloric acid to a solution
of (2-aryl-oxazol-4-yl)methanamine in acetone.
(Table 1, entry 3), while the reaction did not occur in any other solvents
(Table 1, entries 1, 2, 4, 6). To our delight, further optimization of the
reaction conditions showed that the thermodynamic product 7a was
obtained in a considerable yield when the reaction was kept at 140 ◦C for
8 h in the presence of DMF as the solvent (Table 1, entry 16), while poor
yields were provided when reaction conducted in dioxane, DMSO,
toluene or DMF at 100 ◦C (Table 1, entries 12–15).
Mono-bornyl succinate (4a) and mono-bornyl maleate (4b) were
prepared from (-)-borneol by stirring succinic anhydride and maleic
anhydride respectively with triethylamine in dichloromethane (DCM).
Afterwards, condensation reaction between amine hydrochloride de-
rivatives (3a-3e) and 4a or 4b was carried out in the presence of 2-(7-
Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosp
hate (HATU) to get target compounds 5a-5e or 6a-6e.
The title compounds 5a-5e, 6a-6e, 7a-7e, and (-)- borneol were
evaluated for fungicidal activities against F. oxysporum, M. grisea,
B. cinerea, and P. digitatum using the method we have reported.20 The
bioactivity assay results were shown in Table 2. hymexazol and ami-
carthiazol were used as positive controls. Combination of (ꢀ )-borneol
and 4-aminomethyl thiazole derivatives indeed enhanced the fungicidal
activity of the compounds, while (-)- borneol only displays weak
fungicidal activity. For F. oxysporum, the inhibition rates of 5a (37.0%),
6a (41.2%), and 6d (37.9%) were higher than that of hymexazol
(12.8%) at 20 mg/L. At 50 mg/L, most target compounds exhibit satis-
factory fungicidal activity against M. grisea, whose the inhibition rates
were higher than that of hymexazol. In particular, 6c and 6e still display
Finally, cis–trans isomerization conversion between cis-isomer 6a-6e
and trans-isomer 7a-7e were carried out. We chose 6a as a representa-
tive to screen the optimum isomerization condition. Given that lewis
acid was often used as the catalyst for shift maleic acid to fumaric
acid,23,24 AlCl3 was attempted to catalyze the isomerization initially. As
a result, a trace amount of the desired product 7a was acquired when the
reaction was performed with lewis acid AlCl3 (1.0 equiv) in DMF
2

D. Huang et al.
Bioorganic & Medicinal Chemistry Letters 45 (2021) 128006
IC50 value against M. grisea than that of hymexazol. 5a possesses 24.3
mg/L IC50 value against B. cinerea, which is similar to that of hymexazol
and far superior to that of amicarthiazol. To our delight, the IC50 of 5a is
48.5 mg/L against P. digitatum, which is more active than hymexazol and
amicarthiazol (see Table 3).
Table 1
Exploration of the cis–trans isomerization.
With the biological data in hand, the apparent structure–activity
relationship was briefly discussed. Comparing 6a-6e with 7a-7e, it is
obvious that cis configuration of these compounds give more contribu-
tion to the fungicidal activities against F. oxysporum, B. cinerea, and
Entry
solvent
Additive (mol %)
Temp. (oC)
Time (h)
Yield (%)
1
dioxane
toluene
DMF
AlCl3 (10)
RT
4
4
4
4
4
4
4
4
4
4
4
8
8
8
8
8
8
NR a
2
AlCl3(10)
RT
NR
3
AlCl3(10)
RT
trace
4
DMSO
MeOH
MeCN
AcOH
dioxane
toluene
DMF
AlCl3(10)
RT
NR
5
AlCl3(10)
RT
alcoholysis b
6
AlCl3(10)
RT
NR
NR
trace
9
7
–
–
–
–
–
–
–
–
–
–
–
RT
8
100
100
100
100
100
100
100
100
140
140
9
10
11
12
13
14
15
16
17
10
DMSO
dioxane
toluene
DMF
trace
12
23
18
DMSO
DMF
9
87
21
DMSO
a
b
NR means no reaction.
alcoholysis was occurred to obtain methyl (Z)-4-oxo-4-(((2-phenylthiazol-4-
yl)methyl)amino)but-2-enoate.
about 50% inhibition rate against M. grisea at lower concentration (20
mg/L). Both compounds 6a and 6d show over 40% inhibition rate
against B. cinerea at 20 mg/L, while the fungicidal activities exceed that
of hymexazol and were similar to that of amicarthiazol. Moreover, 5a
was found to be better against B. cinerea than micarthiazol and
hymexazol at 20 mg/L. Most target compounds show negligible activity
at 20 mg/L against P. digitatum while both micarthiazol and hymexazol
are inactive. It is satisfactory that 6a still exhibits 43.9% inhibition rate
against P. digitatum at 20 mg/L. In general, all the title compounds
display antifungal activities against M. grisea selectively. Significantly,
6a has broad fungicidal activities against F. oxysporum, M. grisea,
B. cinerea, and P. digitatum (Fig. 2), while amicarthiazol only responds to
M. grisea and hymexazol only inhibit the growth of F. oxysporum. Finally,
the 50% inhibitory concentration (IC50) values of the better fungicidal
active compounds (5a, 5d, 6a, and 6d) were given in Table 2. It
demonstrated that 5d (45.3 mg/L) and 6a (55.3 mg/L) display lower
Fig. 2. The antifungal efficacy of 6a.
Table 3
The IC50 values of active compounds.
Compound
IC50 (mg/L)
FO
MG
BC
PD
5a
>150
>150
133.4
>150
>150
26.6
94.6
45.3
55.3
68.2
2.5
24.3
>150
38.9
82.0
Nb
>150
>150
48.5
>150
N
5d
6a
6d
amicarthiazol
hymexazol
62.8
27.9
N
aFO means F. oxysporum, MG means M. grisea, BC means B. cinerea, PD means
P. digitatum.
bN means no effect.
Table 2
Fungicidal activities of the target compounds.
Compound
Structure
Inhibition rate (%)
F. oxysporum
M. grisea
B. cinerea
P. digitatum
R
Linker
20 mg/L
50 mg/L
20 mg/L
50 mg/L
20 mg/L
50 mg/L
20 mg/L
50 mg/L
5a
H
Succinyl
Succinyl
Succinyl
Succinyl
Succinyl
Fumaryl
Fumaryl
Fumaryl
Fumaryl
Fumaryl
Maleoyl
Maleoyl
Maleoyl
Maleoyl
Maleoyl
37.0 ± 0
24.4 ± 0.0
17.7 ± 0.8
32.0 ± 0
N
37.9 ± 0.8
27.8 ± 0.8
18.6 ± 0.8
34.5 ± 1.5
17.7 ± 0.8
42.9 ± 0.8
24.4 ± 0
26.4 ± 1.4
25 ± 0.0
34.7 ± 2.7
45.8 ± 2.4
37.5 ± 0
41.7 ± 2.4
37.5 ± 2.4
50.0 ± 2.4
38.9 ± 1.4
47.2 ± 1.4
36.1 ± 1.4
31.9 ± 1.4
40.3 ± 1.4
33.3 ± 2.4
N
45.8 ± 2.4
40.3 ± 1.4
45.8 ± 2.4
58.3 ± 2.4
41.7 ± 0
53.9 ± 0.8
35.9 ± 2.1
25.8 ± 2.1
33.7 ± 0.8
23.5 ± 5.5
42.2 ± 0.8
29.7 ± 1.4
21.9 ± 0.8
43.0 ± 0.8
14.9 ± 0.8
26.6 ± 1.6
16.5 ± 1.6
12.6 ± 0.8
29.0 ± 0.8
N
55.5 ± 0
34.8 ± 1.5
25.8 ± 4.8
N
39.4 ± 1.5
27.3 ± 1.3
19.7 ± 2.0
31.8 ± 2.6
17.4 ± 2.7
56.8 ± 2.3
29.5 ± 1.3
28.0 ± 2.0
38.6 ± 1.3
25.0 ± 1.3
34.1 ± 1.3
9.1 ± 3.9
43.2 ± 2.6
25.0 ± 4.7
11.2 ± 2.3
12.9 ± 2.0
N
5b
CH3
Cl
33.7 ± 1.6
32.9 ± 0.8
36.0 ± 0.8
26.6 ± 0.8
54.7 ± 0.8
43.0 ± 8.7
31.3 ± 0.8
46.9 ± 0.8
18.1 ± 0
5c
5d
F
35.6 ± 2.0
15.9 ± 1.3
43.9 ± 1.5
25.0 ± 2.6
28.1 ± 2.0
40.9 ± 1.3
19.7 ± 3.3
27.3 ± 1.3
15.9 ± 3.5
39.4 ± 2.0
25.7 ± 3.3
N
5e
CF3
H
6a
41.2 ± 0.8
21.9 ± 1.5
25.3 ± 0.8
37.9 ± 0.8
N
45.8 ± 0
6b
CH3
Cl
45.7 ± 0
6c
26.1 ± 0.8
40.3 ± 0.8
18.6 ± 0.8
13.5 ± 0.8
17.7 ± 0.8
18.6 ± 0.8
12.7 ± 0.8
10.1 ± 0.3
N
51.4 ± 3.7
40.3 ± 1.4
55.6 ± 1.4
50.0 ± 0
6d
F
6e
CF3
H
7a
N
21.9 ± 0.8
16.5 ± 0.8
19.6 ± 0.8
30.5 ± 3.4
17.8 ± 0.7
14.1 ± 2.0
17.8 ± 0.2
51.5 ± 0.3
7b
CH3
Cl
N
48.6 ± 1.4
33.3 ± 2.4
37.5 ± 0
7c
13.5 ± 0.8
7d
F
Na
7f
CF3
N
40.2 ± 1.2
31.9 ± 2.8
100 ± 0
(-)-borneol
amicarthiazol
hymexazol
N
N
N
N
12.8 ± 0.4
51.9 ± 0.1
25.0 ± 0.5
55.6 ± 1.1
93.1 ± 0.5
38.5 ± 0.8
13.4 ± 0.3
39.4 ± 1.5
N
46.2 ± 2.3
N
12.7 ± 2.1
a
N means no effect.
3

D. Huang et al.
Bioorganic & Medicinal Chemistry Letters 45 (2021) 128006
P. digitatum than trans configuration. Beside, to change the linker from
fumaryl to succinyl, the fungicidal activities become weak apparently.
Basically, the linkers have impact on the activity as follows: fumaryl >
succinyl > maleoyl. Taking 20 mg/L concentration for instance, the
antifungal activities of 6a (41.2% against F. oxysporum, 41.7% against
M. grisea, and 43.9% against P. digitatum), 5a (37.0% against
F. oxysporum, 26.4% against M. grisea, and 34.8% against P. digitatum),
and 7a (invalidation against F. oxysporum, 36.1% against M. grisea, and
27.3% against P. digitatum) processed a decline trend progressively,
while the correlative compounds followed a similar rule. In addition, the
substituents R of the benzene ring influence the activities of the com-
pounds regularly. For F. oxysporum, B. cinerea, and P. digitatum, when
benzene substituted without any groups, the target compounds show
more encouraging activities than those of the compounds introduced
other substituents. Meanwhile, trifluoromethyl makes most inferior
contribution to the activity against F. oxysporum, B. cinerea, and
P. digitatum. For example, the activitiy against F. oxysporum of 5a is
better than those of 5b, 5c, 5d and 5e. Superficially, to keep the linker
constant, the influence of R moiety on improved activity against
F. oxysporum, B. cinerea, and P. digitatum, might be concluded as follows:
H ≈ F > CH3 ≈ Cl > CF3. On the other hand, the fungicidal tendency
affected by R of the compounds against M. grisea is dissimilar from the
three other test fungi. When keep the linker as fumaryl or maleoyl, R
substituted in phenyl ring remains Cl atom could be fateful for
increasement of the fungicidal efficacy of the target compound against
M. grisea. It is clear that both 6c and 7c show the best antifungal ac-
tivities against M. grisea among 6a-6e and 7a-7e, respectively. However,
when keep the linker as succinyl, introduction of F atom to phenyl ring
improves the fungicidal potency against M. grisea crucially.
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The authors declare that they have no known competing financial
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