Synthesis and biological activities of novel 5-substituted-1,3,4-oxadiazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.08.059

A series of novel 5-substituted-1,3,4-oxadiazole Mannich bases and bis-Mannich bases have been conveniently synthesized in good yields. Their structures were characterized by IR,¹H NMR,¹³C NMR and elemental analysis. The preliminary bioassay results indicated that some of the compounds showed promising in vitro fungicidal activities towards several test plant fungi; some of them exhibited significant herbicidal activities against Brassica campestris and excellent in vitro inhibitory activities against rice ketol-acid reductoisomerase (KARI). Among 14 novel compounds, 8c, 8d and 8m showed potent KARI inhibitory activities with K_ivalue of (0.96?±?0.42), (3.86?±?0.49) and (3.10?±?0.71) μmol/L, respectively, and were comparable with IpOHA. These compounds could be novel KARI inhibitors for further investigation. The density functional theory (DFT) calculations and molecular docking were carried out to study the structure–activity relationship (SAR) of the active inhibitors in this Letter.

Full text of DOI:10.1016/j.bmcl.2016.08.059

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activities of novel 5-substituted-1,3,4-
oxadiazole Mannich bases and bis-Mannich bases as ketol-acid
reductoisomerase inhibitors
a
b
a
a
a
a
Yan Zhang , Xing-Hai Liu , Yi-Zhou Zhan , Li-Yuan Zhang , Zheng-Ming Li , Yong-Hong Li ,
a
a,
⇑
Xiao Zhang , Bao-Lei Wang
a
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Enginnering (Tianjin), NanKai University, Tianjian 300071, PR China
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 5-substituted-1,3,4-oxadiazole Mannich bases and bis-Mannich bases have been conve-
Received 2 April 2016
Revised 4 August 2016
Accepted 19 August 2016
Available online xxxx
1
13
niently synthesized in good yields. Their structures were characterized by IR, H NMR, C NMR and ele-
mental analysis. The preliminary bioassay results indicated that some of the compounds showed
promising in vitro fungicidal activities towards several test plant fungi; some of them exhibited signifi-
cant herbicidal activities against Brassica campestris and excellent in vitro inhibitory activities against rice
ketol-acid reductoisomerase (KARI). Among 14 novel compounds, 8c, 8d and 8m showed potent KARI
Keywords:
i
inhibitory activities with K value of (0.96 ± 0.42), (3.86 ± 0.49) and (3.10 ± 0.71) lmol/L, respectively,
1
,3,4-Oxadiazole
and were comparable with IpOHA. These compounds could be novel KARI inhibitors for further investi-
gation. The density functional theory (DFT) calculations and molecular docking were carried out to study
the structure–activity relationship (SAR) of the active inhibitors in this Letter.
Ó 2016 Elsevier Ltd. All rights reserved.
Mannich base
Ketol-acid reductoisomerase inhibitors
Herbicidal activity
Fungicidal activity
It is well known that the application of agrochemicals has led to
numerous benefits and made a significant contribution to the life-
styles we have come to expect for over many years. In view of the
emergence of resistance and pollution problems associated with
conventional agrochemicals, there is an urgent need to research
and develop more agrochemicals with novel structures, super
activity, high selectivity and eco-friendly properties.1
pathway. Ketol-acid reductoisomerase (KARI, EC 1.1.1.86) is
another key enzyme that catalyzes the second step of the pathway.
There are only a few KARI inhibitors with potent in vitro activities
reported in literatures, such as 2-dimethylphosphinoyl-2-hydroxy
7
8
acetic acid (Hoe 704), N-hydroxy-N-isopropyloxamate (IpOHA),
9
cyclopropane-1,1-dicarboxylate (CPD), and thiadiazole com-
–3
10
pounds. Regrettably, the in vivo activities of all these inhibitors
Plants and microorganisms contain numerous enzymes that are
potential targets for the bioactive compounds. Enzymes involved
in the biosynthesis of branched chain amino acids (BCAA) leucine,
valine and isoleucine are one such example. Some organisms—
plants, bacteria and fungi possess the BCAA pathway, while all
the mammals including human do not possess this pathway.
Therefore, the design and development for novel herbicidal and
fungicidal compounds based on the BCAA pathway could be in
accord with the research orientation of green agrochemicals. Ace-
tohydroxyacid synthase (AHAS) is the first enzyme in the BCAA
pathway, it has already been a successful target for development
of herbicides and antifungal reagents, such as sulfonylurea and
imidazolinone compounds.4 The success of AHAS inhibitors has
stimulated research into inhibitors of other enzymes in the BCAA
as herbicides are weak. Therefore, more inhibitors of KARI with
novel structures and high biological activities remain as a potential
source of novel herbicidal or fungicidal compounds.
Due to the interesting structural and versatile biological proper-
ties, heterocyclic compounds have attracted much attention not
only in organic chemistry but also in medicinal, pharmaceutical
and agrochemical chemistry. In particular, they are very important
part in almost all kinds of agrochemicals. For examples, Pefura-
1
1
zoate is a kind of fungicides with furan moiety; Pyroxsulam, dis-
covered by the DOW chemical company, and Pyribencarb,
discovered by KUMIAI chemical industry Co., LTD are heterocyclic
herbicide and fungicide containing pyridine ring, respectively.1
Likewise, oxadiazole compounds are also associated with various
2,13
–6
1
4–16
agrochemical activities.
Moreover, heterocyclic Mannich bases that are derived from the
corresponding heterocyclic intermediates also possess various use-
ful properties, however most of which were embodied in their
⇑
Corresponding author. Tel.: +86 22 23499404; fax: +86 22 23505948.
E-mail address: nkwbl@nankai.edu.cn (B.-L. Wang).
http://dx.doi.org/10.1016/j.bmcl.2016.08.059
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Zhang, Y.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.08.059

2
Y. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
pharmacological activities, such as anticancer, antimicrobial,18
1
7
The title compounds were identified by IR, 1H NMR, and 13
C
1
9
20
antitumor and antituberculous activities. Overall, the researches
of heterocyclic Mannich bases in agrochemical area are relatively
few, so further exploration for this topic might provide novel agro-
chemical candidates. In our early work, we reported the synthesis
and biological activities of some interesting 1,2,4-triazole Mannich
base structures containing piperazine and (substituted)benzylide-
NMR spectra. The measured elemental analyses were also consis-
1
tent with the corresponding calculated values. In H NMR, the
chemical shift at d 14.07–14.65 for intermediates 3 and 7 as a sin-
glet indicates that the compounds existed as the oxadiazole thiol
form. For the title compounds, the signal of CH
ing to the oxadiazole ring was observed at d 5.04–5.17 as a singlet.
The piperazine ring proton (CH ) in 8a–8l appeared at d 2.82–3.95
2
protons neighbor-
3
,21
neamino groups.
Some of those compounds displayed favorable
2
herbicidal and in vitro KARI inhibitory activities. Especially, those
compounds possessed significant fungicidal activities against some
plant fungi such as Pseudoperonospora cubensis and Corynespora
cassiicola. Recently, some phenylpyrazole-containing triazole Man-
nich bases were also found to be effective for inhibiting the growth
of Rhizoctonia cerealis and Cercospora arachidicola in our lab.2 Those
previous results provided an important initiative to undertake fur-
ther structural modifications.
and d 2.37–3.10 as multiplets, respectively. Whereas in the case of
bis-Mannich bases 8m and 8n, the piperazine ring proton appeared
13
at d ꢀ2.90 as a singlet due to their symmetric structure. In the
C
NMR spectra of the title compounds, the typical carbon signal at d
177.4–178.3 was derived from the resonance of thiocarbonyl group
(C@S), and such signals in pyridine-3-yl substituted compounds (d
178.2–178.3) shifted downfield compared with those of furan-2-yl
substituted compounds (d 177.4–177.5).
2
Considering all that mentioned above and with our pursuit to
look for novel heterocyclic compounds with promising KARI inhi-
bitory and pesticidal potential, a series of novel 1,3,4-oxadiazole
Mannich bases and bis(1,3,4-oxadiazole) Mannich bases with var-
ious substituted piperazine moieties were designed. Herein,
regarding to the structure of lead compound 1,2,4-triazole
The piperazine carbons of compounds 8m and 8n also appeared
as one signal at d ꢀ50.10 as opposed to two signals at d 50.11–
52.90 and d 43.46–50.27 in compounds 8a–8l. The IR spectra of
À1
the compounds showed bands at 1499–1576 cm for C@N and
À1
1161–1175 cm for C@S stretching.
The in vitro fungicidal results of the oxadiazole Mannich bases
3
,21
Mannich bases,
the 4-(substituted)benzylideneamino-1,2,4-tri-
8a–8l and bis-Mannich bases 8m and 8n in inhibiting the mycelial
2
7
azole group was replaced by a 1,3,4-oxadiazole ring, meanwhile
furan/pyridine motif was introduced into the 5-position of 1,3,
growth of six test fungi are listed in Table 1. The commercial
fungicides Triadimefon, Carbendazim and Chlorothalonil were
used as controls. The known KARI inhibitor CPD was also tested
the fungicidal activities at the first time in our lab. As indicated
4
-oxadiazole ring. These novel compounds have been synthesized
successfully via Mannich reaction in this Letter. Their fungicidal,
herbicidal and KARI inhibitory activities were investigated and
the structure–activity relationships was discussed.
in Table 1, the compounds at the concentration of 50 lg/mL
showed obvious in vitro fungicidal activities against several tested
fungi, especially for Physalospora piricola and Rhizoctonia cerealis.
For examples, compounds 8d, 8e, 8g and 8m possessed inhibition
rates of 42–50% against Physalospora piricola, which were near to
that of Triadimefon, and those of the representative triazole Man-
The synthetic routes for the intermediates are shown in
Schemes 1 and 2 and for the title compounds—in Scheme 3.
According to the reported procedures,2
3–26
The intermediates 5-
substituted-1,3,4-oxadiazole-2-thiol 3 and 7 were synthesized via
2
1
multi-step reactions. Just as the thioamide structure (C(@S)A
nich bases TM1 and TM2 we reported before; 8m also showed
72.8% inhibition towards Rhizoctonia cerealis. In addition, 8m held
an inhibition rate of 44.8% against Cercospora arachidicola and was
more effective than Triadimefon (34.5%). Interestingly, the potent
in vitro KARI inhibitor CPD was found to exhibit weak fungicidal
activities against almost all the test fungi. In comparison with
TM1 and TM2, these oxadiazole Mannich bases overall showed less
fungicidal effects against most of test fungi in this study.
NHA) in 1,2,4-triazole-5-thiol-type compounds,3
,21,22
the interme-
diate 3 or 7 can exist in either thiol or thione tautomeric forms.
Based on the results of our experiment, it was found that the oxa-
diazole thione isomer undergoes subsequent Mannich reaction via
N–H at
tion of 1,3,4-oxadiazole-2-thiol 3 or 7 with formaldehyde and
-(substituted benzyl)piperazine, or 4-(substituted pyrimidyl)/
a-position of thiocarbonyl (C@S). As a result, the condensa-
4
phenyl/pyridylpiperazine in ethanol at room temperature resulted
in novel Mannich bases—1,3,4-oxadiazole thiones 8a–8l in satis-
factory yields (57–94%). Under the similar reaction conditions,
bis-Mannich bases, that is, bis(1,3,4-oxadiazole thione) 8m and
The herbicidal activity data based on the rape (Brassica
campestris) root and barnyardgrass (Echinochloa crusgalli) cup
2
8
tests, and in vitro inhibitory activity data by the continuous
9
assay against rice KARI of the compounds are listed in Table 2.
8
n were successfully synthesized in 76% and 65% yield, respec-
The commercial herbicide Chlorsulfuron, and known potent
in vitro KARI inhibitors IpOHA and CPD were used as controls. It
was found that at the test concentration of 100 lg/mL, most of
the compounds exhibited remarkable herbicidal activities with
the inhibition rates of 58.2–81.4% against Brassica campestris, while
some of these results were comparable with those of the controls,
tively, using excess formaldehyde and 2:1 molar ratio of interme-
diate 3 or 7 and piperazine. In general, this approach towards the
synthesis of the title compounds possesses noticeable advantages,
such as, mild reaction conditions, high yield and short reaction
time (2 h).
O
COCH
O
N
O
N
(
i)
(ii)
(iii)
COOH
2
CH
3
CNHNH2
O
O
1
O
2
O
3
SH
Scheme 1. The synthesis of the intermediate 5-(furan-2-yl)-1,3,4-oxadiazole-2-thiol (3). Reagents and conditions: (i) CH
3
CH
2
OH, H
2
SO
4
, reflux,7 h, (ii) NH
2
NH
2 2
ÁH O,
3
CH CH
2
OH, reflux, 6 h, (iii) CS
2
, KOH, CH CH
3 2
OH, reflux,7 h.
N
(
i)
(ii)
(iii)
(iv)
N
COOH
COCl
COOCH CH
2 3
CONHNH2
N
N
N
N
N
O
SH
4
5
6
7
Scheme 2. The synthesis of the intermediate 5-(pyridin-3-yl)-1,3,4-oxadiazole-2-thiol (7). Reagents and conditions: (i) SOCl
iii) NH NH O, CH CH OH, reflux, 6 h, (iv) CS , KOH, CH CH OH, reflux, 7 h.
ÁH
2 3 2 3 2 2
, 77 °C, 3 h, (ii) CH CH OH, Et N, CH Cl , rt, 18 h,
(
2
2
2
3
2
2
3
2
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Y. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
R1
Table 2
N
N
The herbicidal and in vitro KARI inhibitory activities of the compounds (%, inhibition)
O
N
R2
EtOH
r.t.
EtOH
N
N N
O
S
N R2
Compd
Brassica
campestris
Echinochloa
crusgalli
KARI (180
mL)
lg/
+
HCHO + HN
8a-8l
R1
SH
r.t.
N
N
100
lg/mL
100 lg/mL
R1=
3
:
7:
O
N
N N
O
N N
8
8b
a
69.0
81.4
65.1
68.4
62.3
66.9
58.2
52.7
49.4
30.7
39.0
45.4
77.2
62.7
50.2
48.0
71.1
71.6
76.8
3.0
5.0
10.0
5.0
10.0
4.0
0
0
0
0
0
0
15.0
0
5.1
20.4
9.8
14.4
7.0
29.9
79.53
28.86
99.31
98.69
99.78
84.43
91.32
77.38
86.58
33.64
40.82
51.58
96.96
79.78
22.8 (100
30.0 (100
R1=
R1
S
S
R1
O
8m 8n
-
8c
Cl
8c: R1= O ; R2=
8d: R1= O ; R = N
2
8
a: R1= O ; R2=
8b: R1= O ; R2=
N
8d
Me
Cl
Cl
8
8
e
f
e: R1=
2
8f: R1= O ; R2=
8g: R1= N
R2=
8h: R1= N ;R2=
Cl
8
; R =N
Me
N
N
;
O
8g
Me
Cl
Cl
8h
2
8l: R1=
;R2=
8
i: R1=
;R2=
8j: R1=
; R =N
2
N
8k: R1= N ;R = N
N
N
8i
N
O
N
N
Me
Me
Me
8
8
8
8
8
j
k
l
m
n
m: R1=
2
R =H
;
8n: R1= N
R
2
=H
8
;
Scheme 3. The synthesis of the title compounds 8a–8n.
2
1
TM1
l
l
g/mL)
g/mL)
TM22
1
such as 8b (81.4%) and 8m (77.2%), especially 8b was even more
effective than the best active control Chlorsulfuron (80.4%). Inter-
estingly, furan-2-yl substituted compounds displayed strikingly
better herbicidal activities (>62%) against Brassica campestris than
pyridin-3-yl substituted ones, such as, 8a versus 8g, 8b versus
TM33
27
IpOHA
CPD
100
100
Chlorsulfuron 80.4
8
h, 8c versus 8i, 8d versus 8j, 8e versus 8k, 8f versus 8l and 8m
versus 8n. It seemed that 4-chloro or 2,4-dichlorobenzyl-contain-
ing compounds exhibited favorable activities than aryl-containing
ones in piperazine part. However, when R1 is furan-2-yl, no big
herbicidal activity difference was shown for compounds with
different aryl substituents in piperazine ring—phenyl, 4-
methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, and pyridin-
Table 3
Inhibitory constant K
i
of compounds against rice KARI
Compd
K
i
(lmol/L)
Compd
i
K (lmol/L)
8c
0.96 ± 0.42
3.86 ± 0.49
10.16 ± 2.04
2.75 ± 0.7227
8g
8i
8m
11.68 ± 2.26
45.86 ± 7.10
3.10 ± 0.71
8d
8e
IpOHA
2
-yl. It can also be found that all of the compounds showed rather
weak herbicidal activities against Echinochloa crusgalli, just as
those situations in all the controls, which indicates that the title
compounds may be more effective against dicotyledonous weeds.
As shown in Table 2, at a 180
lg/mL concentration most of the
effective than the control IpOHA (2.75 ± 0.72
lmol/L) in the pre-
compounds exhibited excellent in vitro inhibitory activities
towards rice KARI, such as 8c, 8d, 8e, 8f, 8g, 8i and 8m, whose inhi-
bition rates against KARI enzyme were all over 84%, in particular,
liminary studies. There are some relativity reflected between
in vitro KARI inhibitory and in vivo Brassica campestris herbicidal
activities to a certain extent—most of the compounds that had
excellent KARI inhibitory activities showed favorable Brassica
campestris herbicidal activities (8a, 8c, 8d, 8e, 8f, 8g, 8m and 8n),
and the furan-2-yl compounds exhibited the superiority to pyri-
dine-3-yl compounds for the activities.
8
c, 8d, 8e and 8m held a value of >96%, respectively. Therefore,
these compounds were further tested. From Table 3, among the
tested compounds, 8c, 8d and 8m held inhibitory activities against
KARI with K
i
values of (0.96 ± 0.42), (3.86 ± 0.49) and (3.10 ± 0.71)
l
mol/L, respectively, and were comparable with the control. Pleas-
In addition, it was found that most of these oxadiazole Mannich
bases showed favorable KARI inhibitory activities than those of
ingly, 8c (inhibition regression curve shown in Fig. 1) was more
Table 1
In vitro fungicidal activities of the compounds at the concentration of 50 lg/mL (%, inhibition)
Compd
Fusarium oxysporum
Cercospora arachidicola
Physalospora piricola
Rhizoctonia cerealis
Alternaria solani
Gibberella sanbinetti
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
10.0
5.0
7.5
10.0
7.5
2.5
7.5
0.0
5.0
5.0
17.2
17.2
17.2
13.8
10.3
10.3
24.1
10.3
13.8
13.8
13.8
10.3
44.8
10.3
70.4
63.6
25.0
34.5
12.5
35.9
12.5
43.8
42.2
4.7
50.0
18.8
34.4
12.5
15.6
12.5
45.3
35.9
30.5
41.6
30.2
53.1
100
38.3
49.4
39.5
35.8
30.9
27.2
25.9
29.6
30.9
30.9
25.9
23.5
72.8
35.8
17.6
23.5
23.5
23.5
17.6
23.5
17.6
17.6
17.6
17.6
5.9
23.5
17.6
23.5
51.8
30.2
15.8
52.9
9.1
18.2
18.2
13.6
9.1
13.6
13.6
9.1
9.1
27.3
9.1
5.0
2.5
9.1
9.1
17.5
7.5
70.8
60.8
19.4
50.0
18.2
50.3
30.5
14.6
45.5
100
21
TM1
TM221
CPD
26.8
93.8
Triadimefon
Carbendazim
Chlorothalonil
100
75.0
72.2
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Y. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
The DFT-derived graphic results are presented in Figure 2. The
red and green parts represent the cloud density of frontier orbitals
at HOMO or LOMO states. The total energies of the compounds 8c
and 8m are À1425.89094662 a.u. and À2121.93230262 a.u.,
respectively. The energy gap between HOMO and LUMO for both
of 8c and 8m is rather small (0.119 a.u. and 0.138 a.u., respectively)
suggesting that the stability of these two compounds is limited,
especially in the case of 8c. As seen from Figure 2 of 8c in the
HOMO, electrons are mainly delocalized on the piperazine ring
and phenyl ring; in the case of 8m, besides the piperazine ring
(
2
major), there are also methylene group (CH ) and a small part of
oxadiazole and furan rings contributing to the HOMO electrons.
However, when electron transitions take place, some electrons in
HOMO will enter into the LUMO, then, in the LUMOs of 8c and
8
m, the electrons will mainly be delocalized on the oxadiazole ring
and furan ring (both cases are alike), as shown in Figure 2. It is
known that the frontier molecular orbitals are located on the main
groups which atoms can easily bind with the receptor. Thus, it can
be concluded that the oxadiazole ring, furan ring and piperazine
ring of 8c and 8m probably make major contributions to the activ-
ity towards KARI and these are largely through
bic interactions.
p–p and hydropho-
Figure 1. Inhibition regression curve of compound 8c against rice KARI.
Based on the 1.65 Å high resolution crystal structure of KARI
complex (PDB ID: 1YVE), molecular docking calculations were per-
formed on Discovery Studio software. The binding mode of the best
active compound 8c was studied using classical docking procedure.
From Figure 3, it was found that there is a strong H bond interac-
tion between the oxadiazole moiety of 8c and KARI amino acid
residue Gln205; piperazine ring, oxadiazole ring and furan ring
are surrounded by residues Leu501, Ser518, Leu323, Glu319,
Glu496, Glu492, Asp315, Lys252, Pro251 and His226, which indi-
triazole Mannich bases TM1, TM2 and TM3,21,3 and also herbicidal
activity in some cases (Tables 2 and 3).
According to the frontier molecular orbital theory, HOMO has
the priority to provide electrons, while LUMO accept electrons in
2
9
the first place; these two frontier orbitals are the most important
30
factors that affect the bioactivity of compounds. Thus a study of
the frontier orbital energy can provide some useful information for
the active mechanism. We therefore calculated the frontier molec-
ular orbital of compounds 8c and 8m that have different structural
characteristics (Mannich base and bis-Mannich base) and good
inhibitory activity against KARI by means of DFT/B3LYP.
cates there are probably hydrophobic and/or
p–p interactions
existed between them. These results are in accord with those of
DFT calculations.
In summary, a series of novel furan/pyridyl and piperazine-
containing 1,3,4-oxadiazole Mannich bases and bis-Mannich bases
Figure 2. HOMO and LUMO maps for compounds 8c and 8m from DFT calculations. The green parts represent positive molecular orbital, and the red parts represent negative
molecular orbital.
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Y. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
5
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.08.
0
59.
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This work was supported by the National Natural Science Foun-
dation of China (No. 21372133), Zhejiang Province National Natu-
ral Science Foundation of China (No. LY16C140007) and China
Scholarship Council. We thank Dr. Cong-Wei Niu of Nankai
University (China) for kind biological testing assistance.
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Please cite this article in press as: Zhang, Y.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.08.059