Synthesis and fungicidal activity of 1,3,4-oxadiazol-2-yl thioether derivatives containing a phenazine-1-carboxylic acid scaffold

Article abstract of DOI:10.1080/14786419.2018.1489389

To find new higher fungicidal activities lead compounds and develop new eco-friendly agrochemicals, natural product phenazine-1-carboxylic acid (PCA) as scaffold, a series of 1,3,4-oxadiazol-2-yl thioether derivatives was synthesized and bio-assayed. The results reveal that most target compounds possessed moderate to good fungicidal activities against R. solani, S. sclerotioru and P. oryzac Cavgra. Compounds 6n and 6o exhibit more than 90% bioactivity against S. sclerotioru. The EC₅₀ value of compounds 6n and 6o are 11.16 and 30.47 μM respectively, in particular, compound 6n show equal activity against S. sclerotioru to PCA (10.49 μM). This result provides a valuable lead compound for further studies.

Full text of DOI:10.1080/14786419.2018.1489389

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis and fungicidal activity of 1,3,4-
oxadiazol-2-yl thioether derivatives containing a
phenazine-1-carboxylic acid scaffold
Lu Xingliang, Zhu Xiang, Zhang Min, Wu Qinglai, Zhou Xudong & Li Junkai
To cite this article: Lu Xingliang, Zhu Xiang, Zhang Min, Wu Qinglai, Zhou Xudong & Li
Junkai (2018): Synthesis and fungicidal activity of 1,3,4-oxadiazol-2-yl thioether derivatives
containing a phenazine-1-carboxylic acid scaffold, Natural Product Research, DOI:
10.1080/14786419.2018.1489389
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2018.1489389
Synthesis and fungicidal activity of 1,3,4-oxadiazol-2-yl
thioether derivatives containing a phenazine-1-carboxylic
acid scaffold
a
a,b
a,b
a,b
c
Lu Xingliang , Zhu Xiang , Zhang Min , Wu Qinglai , Zhou Xudong and
Li Junkai
a,b
a
b
School of Agriculture, Yangtze University, Jingzhou, China; Institute of Pesticides, Yangtze
c
University, Jingzhou, China; School of Pharmaceutical Sciences, Wenzhou Medical University,
Wenzhou, China
ABSTRACT
ARTICLE HISTORY
Received 2 April 2018
Accepted 12 June 2018
To find new higher fungicidal activities lead compounds and
develop new eco-friendly agrochemicals, natural product phena-
zine-1-carboxylic acid (PCA) as scaffold, a series of 1,3,4-oxadiazol-
2-yl thioether derivatives was synthesized and bio-assayed. The
KEYWORDS
Phenazine-1-carboxylic acid
results reveal that most target compounds possessed moderate
to good fungicidal activities against R. solani, S. sclerotioru and P.
oryzac Cavgra. Compounds 6n and 6o exhibit more than 90%
bioactivity against S. sclerotioru. The EC50 value of compounds 6n
and 6o are 11.16 and 30.47 lM respectively, in particular, com-
pound 6n show equal activity against S. sclerotioru to PCA
(
PCA); 1,3,4-oxadiazol-2-yl
thioether; fungicidal
activity; deriva-
tives; synthesis
(
10.49 lM). This result provides a valuable lead compound for
further studies.
1. Introduction
1
,3,4-oxadiazoles and 1,3,4-oxadiazol-2-yl thioethers (Figure 1) have excellent pesticidal
and pharmaceutical biological actives, especially widely used in the field of pesticide
Liu et al. 2014; Rajput and Kankhare 2015; Shi, Huo, et al. 2016), such as commercial
herbicide oxadiazon (Figure 1, A), insecticide Metoxadiazone (Figure 1, B), compound
(
CONTACT Qinglai Wu
wql106@163.com; Xudong Zhou
xudongzhou999@163.com; Junkai Li
junkaili@sina.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2018.1489389.
ß 2018 Informa UK Limited, trading as Taylor & Francis Group

2
X. LU ET AL.
Figure 1. The structures of 1,3,4-oxdiazoles and 1,3,4-oxdiazol-2-yl sulfur ethers.
Ia (Figure 1, C) and compound Ib (Figure 1, D) which showed remarkable antiviral
activities (Gan et al. 2016; Shi, Li, et al. 2016; Wu et al. 2016), Compounds IIa (Figure 1,
E) showed the equivalent fungicidal activity against Sclerotinia sclerotiorum to
Azoxystrobin and compounds IIb–IIe (Figure 1, F) have better fungicidal activities-
than Azoxystrobin against Rhizotonia cerealis (Liu et al. 2017).
Phenazine-1-carboxylic acid (PCA) and its derivatives, such as phenazine-1-carboxa-
mide, Phenazine-1-carbohydrazide (Figure 2) et al, are important natural products
which have antileukemia, antitumor and antifungal effects (Laursen and Nielsen 2004;
Hu et al. 2005), which existed widely in microbial metabolites from Streptomycetes and
Pseudomonads. Particularly, PCA has been registered in China as the biofungicide
“
Shenqinbactin” (Su et al. 2010; Zhou et al. 2010), because of its excellent inhibition
effects against many soil-borne fungal phytopathogens in agricultural application,
friendliness to environment, and low toxicity to human and animals (Arseneault et al.
2
013; Padaria et al. 2016). In our previous studies, we have synthesized several series
PCA derivatives and found that some compounds, such as phenazine-1-carboxamide
EC50 = 6.66 mg/L), N-methylphenazine-1-carboxamide and some PCA-amino acid ester
(
conjugates (Figure 2, G) (EC50 = 7.09mg/L) et al, which showed better fungicidal activ-
ity against Rhizoctonia solani than PCA (Niu et al. 2016; Xiong et al. 2017).
To find novel lead compounds with high fungicidal activities and develop effective
agrochemicals, we introduced 1,3,4-oxadiazol-2-yl thioether moiety into natural scaf-
fold PCA, a series of 2-substituted mercapto-5-(phenazin-1-yl)-1,3,4-oxadiazoles were
designed and synthesized. Structures of the target compounds were characterized by
1
H NMR, high resolution mass spectrum (HR-MS) and X-ray crystallography. Results of
bioassays indicate that all target compounds showed moderate fungicidal activities
against all the tested pathogenic fungi. It is worth mentioning that the compounds 6n
and 6o exhibit the excellent fungicidal activity against S. sclerotioru with the EC50 val-
ues of 11.16 and 30.47 lM respectively, and compound 6n shows equal activity
against S. sclerotioru to PCA (10.49 lM).

NATURAL PRODUCT RESEARCH
3
Figure 2. The structures of PCA and its analogues.
2. Results and discussion
2.1. Chemistry
The synthetic route of 2-substituted mercapto-5-(phenazin-1-yl)-1,3,4-oxadiazoles is
shown in Figure 3. PCA reacted with oxalyl chloride in CH Cl2 solution at reflux
2
temperature to afford phenazine-1-carbonyl chloride 2 which was used in next step
without purification. Treatment of intermediate 2 with CH OH gave methyl phenazine-
3
1-carboxylate 3 and the yield of two steps was 86.0%. Subsequent reaction of inter-
mediate 3 and hydrazine hydrate give phenazine-1-carbohydrazide 4 in 88.4% yields,
which was reacted with carbon disulphide led to intermediate 5 in 72.9% yields.
Finally, the target compounds were obtained conveniently by treating of intermediate
5
with the corresponding chlorine substituted compounds having yields of
1
2
0.9–75.3%. The structures of 6a–6p were confirmed by H-NMR, HR-MS (Analysis data
of all the target compounds are presented in Supplementary Information).
To determine the stereo structure of the target compounds, a single crystal of the
target compound 6j (R = p-ClC H ) was prepared by slow evaporation of a solution of
6
4
compound 6j in dichloromethane at room temperature. As shown in Figure S50, the
crystal data for 6j: triclinic, space group P-1, a = 6.1460(11) Å, b = 10.7524(19) Å, c =
ꢀ ꢀ ꢀ
3
1
2
(
4.154(3) Å, a = 78.263(2) , b = 84.303(3) , g = 78.884(3) , V = 896.9(3) Å , Z = 2, T =
À1
3
97(2) K, l(Mo) = 0.350 mm , Dcalcd. = 1.499 Mg/m , 6731 reflections measured
ꢀ
1.472 ꢁ 2Ɵ ꢁ 25.998 ), 3489 unique (R(int) = 0.0261) which were used in all calcula-
tions. The final R was 0.0410 (I > 2 sigma (I)) and wR was 0.1420. Crystallographic
1
2
data have been deposited with the Cambridge Crystallographic Data Centre, and the
deposition number was CCDC 1563917.
2.2. Fungicidal activities
The in vitro fungicidal activities of all the target compounds have been determined
against five pathogenic fungi at a concentration of 200 lM, using a plate method
(PDA medium) (Shentu et al. 2014). The commercial fungicide Shenqinbactin (PCA)
was assessed under the same conditions as positive control. The results were shown
in Table S1. The results of preliminary bioassay show that all compounds exhibit

4
X. LU ET AL.
Figure 3. Synthetic route of target compounds.
certain fungicidal activities against the pathogenic fungi, in which the target com-
pounds show more than moderate level fungicidal activities against R. solani, S. sclero-
tioru and P. oryzacCavgra at the concentration of 200 lM (This concentration of PCA
equal to 44.8 mg/L). In particular, compounds 6n and 6o exhibit more than 90% bio-
activity against S. sclerotioru (93.2 and 90.6%, respectively). The structure-activity rela-
tionship of the target compounds reveal that when R is methyl substituent benzyl
group, the fungicidal activities against R. solani display m-CH < p-CH and o-CH (6b
3
3
3
<
6a and 6c), but the fungicidal activities against P. oryzacCavgra display m-CH > p-
3
CH and o-CH (6b > 6a and 6c). When R is para-position alkyl and alkoxy substituted
3
3
benzyl group, the fungicidal activities against R. solani and P. oryzacCavgra depend on
the ability of alkyl and alkoxy giving electrons, as shown in Figure S51. Introduction of
halogen to R group, the fungicidal activities have no obvious change. When R replaces
benzyl group with heterocyclic group, such as pyridinyl, show the better fungicidal
activities against R. solani and S. sclerotioru, in particular, the fungicidal activities
against S. sclerotioru increase much remarkably, the result suggests that the introduc-
tion of heterocyclic group would be considered in future work.
Compounds 6n and 6o were chosen to determine EC50 values against S. sclerotioru
(Shentu et al. 2014), because 6n and 6o showed fungicidal activities with the inhibi-
tory rate over 90% against S. sclerotioru at the concentration of 200 lM. The results
were shown in Table S2. Compounds 6n and 6o exhibit the inhibitory against S. sclero-
tioru with the EC50 value of 11.16 and 30.47 lM respectively. In particularly, compound
6
n shows equal activity against S. sclerotioru to PCA (10.49 lM).

NATURAL PRODUCT RESEARCH
5
3
. Conclusion
In summary, a series of 1,3,4-oxadiazol-2-yl thioether derivatives containing phenazine-
-carboxylic group were designed and synthesized. Their structures were confirmed by
1
1
HNMR and HRMS, The crystal structure of the representative compound 6j was deter-
mined by X-ray single crystal diffraction. The results of bioassay indicate that all the
target compounds exhibit good fungicidal activities against R. solani and S. sclerotioru
at the concentration of 200 lM. And those compounds with the heterocyclic substitu-
ents can obviously increase the fungicidal activities. Particularly, compounds 6n and
6
o exhibit more than 90% bioactivity against S. sclerotioru with their EC50 values are
11.16 and 30.47 lM, respectively. And compound 6n shows comparable activity
against S. sclerotioru to PCA (10.49 lM). This result provides a valuable lead compound
for further studies.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This study was supported by Natural Science Foundation of China [No. 31672069] and Natural
Science Foundation of Hubei Province [No. 2014CFA105].
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