b College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China;
c State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai University, Tianjin 300071, China
Plant diseases, mainly caused by fungi, bacteria, viruses and oomycetes, have resulted in severe losses to agriculture, even emerged threat to global food security, and affected our health . Although some efficient measures have been taken to resolve the above problem, it is well known that agrochemicals in reducing crop loss caused by plant diseases play an important role and cannot be ignored [2, 3].
Naturalproductsfoundinnatureandproducedbylivingorganisms have low toxicity, good compatibility, and biodegradability, so they have been widely used in the fields of medicine and agrochemistry, suchasEribulin , Paclitaxel , Artemisinin [6-8], andRotenone . Furthermore, natural products are also often used as pesticide precursor compounds in discovering new synthetic pesticides [10-13], which display better efficacies than those of natural products. (—)-(R)-Dihydroaeruginoic acid (Fig. S1 in Supporting information), as a natural product, had been found to exhibit in vitro antiproliferative activity for L1210 cell lines . Pyochelin (Fig. S1 in Supporting information was produced by Gramnegative bacteria (Burkholderia cepacia and Pseudomonas aeruginosa), and possessed a unique microbial siderophore activity . Subsequently, a variety of 2-aryl-4, 5-dihydrothiazole-4-carboxylic acid analogues were reported, and displayed anticancer reactivity [16, 17], anti-HIV , and antibiotic activity . However, there are few reports about the application of these analogues in plant disease prevention. Recently, our research groupfirstly reported the synthesis and antifungal activity of a series of (R)-2-aryl-4, 5- dihydrothiazole-4-carboxylic acid derivatives containing piperazine, piperidine, and pyrimidine moieties, and some compounds exhibited good and broad spectrum antifungal activities .
Up to now, more than 30% of agrochemicals contain at least one sulfur atom and they have played an important role in the field of modern crop protection . The introduction of sulfur into a biologically active molecule is still an important way in modifying the biological activities to discover novel agrochemical candidate with new modes of action by binding to a target receptor and blocking metabolic deactivation [22, 23]. Inspired by the above findings, herein we reported a series of (R)-2-phenyl-4, 5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety. The bioactivities of the title compounds were evaluated, and the structure-activity relationship of these compounds is studied. In addition, a CoMSIA model is built to optimize the substituents (R) on the benzene ring.
The synthetic routes are depicted in Scheme S1 (Supporting information) and Scheme 1. Intermediates 3, 6, and 9 were synthesized according to the literature  with some modifications. 2-Ammoniopropyl sulfates (2, 5, and 8) were obtained in 75%—85% yields by reactions of 2-aminopropan-1-ol (1, 4, and 7) and chloronic sulfonic acid with anhydrous 1, 2-dimethoxyethane as the solvent below 0 ℃, which further reacted with sodium methyl mercaptan (20%) to afford intermediates 3, 6, and 9 in 75%— 83% yields. The key intermediates 12a—h were synthesized referring to our previously reported method  with some improvement in Scheme 1. Subsequently, treatment of 12a—h with 1-(methylthio)propan-2-amines (3, 6, and 9) in the presence of N- (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxy-1H-benzotriazole (HOBT) and N, N-diisopropylethylamine (DIPEA) afforded the desired products 13—15. They were identified by NMR and elemental analysis (EA). Moreover, the structure of compound 13d was confirmed through single crystal X-ray diffraction analysis. (Fig. S2 in Supporting information, CCDC: 1839896).
The antifungal activities (in vitro) of title compounds 13-15 against six plant pathogenic fungi are displayed in Table 1. From it, all of the title compounds exhibited good (>50%) antifungal activities against Physalospora piricola and Phytophthora capsici, and more effective than the control carbendazim at the concentration of 50 mg/L. Furthermore, 13a, 13h, 15a, and 15h showed broad spectrum antifungal activities. For six plant pathogenic fungi mentioned above, a preliminary structure activity relationship study indicated that the antifungal activity can be affected by the different type of functional groups (R) on benzene ring and the configuration of 1-(methylthio)propan-2-amine moiety. It could be concluded that the proper electron donating groups (R = EDG) on benzene ring result in an enhancement of the antifungal activity, however, obviously decreased by electron withdrawing groups (R = EWG). For instance, the antifungal activities of title compounds 13g, 13h, 14g, 15g, and 15h (R = OCH3 or CH3) were superior to the compounds 13d, 13e, 14d 14e, 15d and 15e (R = NO2 or CF3). Meanwhile, the configuration of 1-(methylthio) propan-2-amine moiety displayed the sequence of antifungal activity as CR ≥ Cachiral ≈ CS. The EC50 values of compounds 13-15 against Phytophthora capsici were further tested and shown in Table 2, and much lower than that of carbendazim. Moreover, the EC50 value of compound 15h (6.7 mg/L) was comparable to that of chlorothalonil (5.1 mg/L).
The insecticidal activities of title compounds 13-15 against Plutella xylostella were tested and summarized in Table 1. Most of compounds exhibited apparent insecticidal activities at 100 mg/L. The insecticidal activities of compounds (13d, 13e, 14d, 14e, 15d, 15e) with electron withdrawing groups (R = EWG) were better than those of compounds (13g, 14g, 15g) with electron donating groups (R = EDG).
In order to give more information of SAR, a 3D-QSAR model was established based on the EC50 data of title compounds against Phytophthora capsici shown in Table 2. Among 21 compounds, four compounds (13c, 13g, 14e and 15d) were chosen randomly as the test set of the 3D-QSAR model. Due to the lowest EC50 value, 15a was used as the template molecule, and the superimposition of training set compounds had shown in Fig. S3 (Supporting information). A correlation coefficient of r2 = 0.977, and a cross validated coefficient of q2 = 0.876 were obtained as the best 3DQSAR model. The standard error of estimate, optimal number of components, and F value was 0.022, 9, and 132.682, respectively. The final 3D-QSAR model was satisfactory with respect to both the predictive ability and statistical significance of the training set and test set. Steric, electrostatic, hydrophobic, H-bond acceptor, and Hbond donor fields were used to build the CoMSIA model, and the order of the relative contribution of them to the full model is hydrophobic (37.5%) > electrostatic (36.6%) > H-bond acceptor (18.5%) > steric (7.4%) > H-bond donor (0%). These results revealed that the hydrophobic and electrostatic fields were the two most important factors to the antifungal activities.
As shown in Table S1 (Supporting information), the pEC50 data training set and test set compounds were predicted by the CoMSIA model, and Fig. S4 (Supporting information) displayed the correlations, which indicated that the CoMSIA model established could predict the antifungal activity.
The CoMSIA contour maps were showed in Fig. 1 to observe how hydrophobic and electrostatic fields contribute to antifungal activities. Fig. 1a is the contour of the CoMSIA hydrophobic field. The black contours around the R group of phenyl ring reveal the areas where the hydrophobic groups are favorable for the antifungal activity. The electrostatic CoMSIA contour map is shown in Fig. 1b. The black contours around the R group of the phenyl ring indicate that the increase of negative charge will play a favourable role on antifungal activity, which suggests that proper electron-donating groups at this position could improve the antifungal activity. This is consistent with experimental data (13d, 13e, 14d, 14e, 15d, 15e vs. 13g, 14g, 15g). Analysis of the CoMSIA contour maps indicates that a proper hydrophobic and electrondonating group in the R group of phenyl ring could increase the antifungal activity against Phytophthora capsici, which provides useful information for the further optimization of the structures.
|Fig. 1. The contour map of the hydrophobic field (a) and electrostatic field (b).|
On the basis of the SAR and CoMSIA model, in order to improve the antifungal activity, we rationally designed and synthesized 2 compounds 13h (R = CH3) and 15h (R = CH3). As shown in Tables 1 and 2, the antifungal activities of 13h and 15h are increased to some extent compared to other title compounds, and this is consistent with the prediction of the CoMSIA model, indicating that the CoMSIA model displayed good predictability.
In conclusion, a series of (R)-2-phenyl-4, 5-dihydrothiazole-4- carboxamide derivatives containing a sulfur ether moiety were synthesized and their chemical structures were identified. All the title compounds were evaluated for fungicidal and insecticidal activities, and most of them exhibited excellent and broad spectrum antifungal activities against Physalospora piricola and Phytophthora capsici, and more effective than the control carbendazim at 50 mg/L dosage. The preliminary SAR of the title compound was studied. The proper electron donating groups (R = EDG) on benzene ring and the configuration of CR in 1- (methylthio)propan-2-amine moiety played an important role in the antifungal activity. The built 3D-QSAR model revealed that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. According to the CoMSIA model, structure optimization was carried out to find compound 15h with excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel antiphytopathogenic fungus agent development, which indicated that the CoMSIA model established could predict the antifungal activity.Acknowledgments
This study was financially supported by the Scientific Project of Tianjin Municipal Education Commission (No. 2018KJ008), Tianjin Natural Science Foundation (No. 16JCYBJC29400).Appendix A. Supplementary data
Supplementarymaterial related to this article can befound, in the online version, at doi:https://doi.org/10.1016/j.cclet.2018.11.001.
Y.B. Bai, A.L. Zhang, J.J. Tang, et al., J. Agric. Food Chem. 61 (2013) 2789-2795. DOI:10.1021/jf3053934
A. Sessitsch, B. Mitter, Microb. Biotechnol. 8 (2015) 32-33. DOI:10.1111/1751-7915.12180
D.W. Cai, Bull. Agric. Sci. Technol. 1 (2008) 36-38.
T. Mukohara, S. Nagai, H. Mukai, et al., Invest. New Drug 30 (2012) 1926-1933. DOI:10.1007/s10637-011-9741-2
D. Lau, Semin. Oncol. 26 (1999) 12.
S. Li, G.M. Li, X.H. Yang, et al., Bioorg. Med. Chem. Lett. 28 (2018) 2275-2278. DOI:10.1016/j.bmcl.2018.05.035
S.S. Wang, Bioorg. Med. Chem. Lett. 23 (2013) 4424-4427. DOI:10.1016/j.bmcl.2013.05.057
P. Buragohain, B. Saikia, N. Surineni, et al., Bioorg. Med. Chem. Lett. 24 (2014) 237-239. DOI:10.1016/j.bmcl.2013.11.032
F. Yi, C.H. Zou, Q.B. Hu, et al., Molecules 17 (2012) 7533-7542. DOI:10.3390/molecules17067533
A.M. Rimando, S.O. Duke, Natural products for pest management, in: A.M. Rimando, S.O. Duke (Eds.), Natural Products for Pest Management, American Chemical Society, Washington, DC, 2006, pp. 2-21. https://www.researchgate.net/publication/287578513_Natural_Products_for_Pest_Management
B.A. Song, S. Yang, L.H. Jin, et al., Environment-friendly Anti-plant Viral Agents, Chemical Industry Press, Beijing, 2009, pp. 1-305. https://link.springer.com/chapter/10.1007%2F978-3-642-03692-7_6
H.Y. Sun, H. Li, J.Y. Wang, et al., Chin. Chem. Lett. 29 (2018) 977-980. DOI:10.1016/j.cclet.2017.10.015
R.G. Yang, Y. Guo, Y.Y. Zhang, et al., Chin. Chem. Lett. 29 (2018) 995-997. DOI:10.1016/j.cclet.2017.10.018
G.T. Elliot, K.F. Kelly, R.L. Bonna, et al., Cancer Chemother. Pharm. 21 (1988) 233-236.
K.L. Rinehart, A.L. Staley, S.R. Wilson, J. Org. Chem. 60 (1995) 2786-2791. DOI:10.1021/jo00114a029
V. Gududuru, E. Hurh, J.T. Dalton, et al., J. Med. Chem. 48 (2005) 2584-2588. DOI:10.1021/jm049208b
R.S. Guo, E.A. Kasbohm, P. Arora, et al., Endocrinology 147 (2006) 4883-4892. DOI:10.1210/en.2005-1635
G. Pattenden, S.T. Thom, J. Chem. Soc. Perk. Trans. 1 (1993) 1629-1636.
A. Zamri, I.J. Schalk, F. Pattus, et al., Bioorg. Med. Chem. Lett. 13 (2003) 1147-1150. DOI:10.1016/S0960-894X(03)00010-6
J.B. Liu, Y.X. Li, Y.W. Chen, et al., Chin. J. Chem. 33 (2015) 1269-1275. DOI:10.1002/cjoc.v33.11
P. Devendar, G.F. Yang, Top. Curr. Chem. 375 (2017) 1-44. DOI:10.1007/s41061-016-0088-1
T.R. Fukuto, M.A.H. Fahmy, Am. Chem. Soc. 158 (1981) 35-49.
R.M. Hollingworth, N. Kurihara, J. Miyamoto, et al., Pure Appl. Chem. 67 (1995) 1487-1532. DOI:10.1351/pac199567081487
X.W. Hua, W.T. Mao, Z.J. Fan, et al., Aust. J. Chem. 67 (2014) 1491-1503. DOI:10.1071/CH13701