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Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method Changling Liu,* Aiying Guan, Jindong Yang, Baoshan Chai, Miao Li, Huichao Li, Jichun Yang, and Yong Xie State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Company Ltd., Shenyang 110021, China ABSTRACT: Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate “what is the IDM” and “why to use” and “how to use” it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years. KEYWORDS: intermediate derivatization method, new agrochemical discovery, patentable novel structure, shorter discovery phase, lower cost
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INTRODUCTION In modern agricultural production, agrochemicals, including insecticides/acaricides, herbicides, and fungicides, play an essential role in ensuring good crop quality, high crop yield, and low labor costs.1−3 Typically, approximately 10 years and U.S. $200 million are required to bring a new agrochemical from initial lead compound synthesized to final registration.4,5 The success rate of agrochemical discovery is currently estimated at 1/140,000.6 As the stringent regulatory requirements for environmental protection and food safety increase, the agrochemical discovery process lengthens and the success rate for commercial development declines.7 Obviously, agrochemical discovery presents a downward trend in recent years. It is well-known that new agrochemical discovery is based on the exploitation of a bioactive lead compound. The existing methods for discovering bioactive lead compounds are mainly as follows: random synthesis and screening,8 modification of natural compounds,9,10 “me too chemistry” (molecules with structures similar to those of existing products),11 combinatorial chemistry,12,13 and rational design.14,15 Statistically, “me too chemistry” and random synthesis and screening have been the two most successful approaches for new agrochemical discovery. From 2000 to 2013, 126 new synthetic agrochemicals were developed: 88 by “me too chemistry” and 38 by random synthesis and screening. However, these two methods require substantial investment of funding, time, and manpower, and their success rates for new agrochemical discovery are declining. Additionally, as market competition heats up, many companies have strengthened the scope of their intellectual property to block competitors’ imitations. Because of broad claims for the known patents, it is more difficult to discover the new products simply by using “me too chemistry”, which is often based on bioisosteric replacement. Other methods, such © XXXX American Chemical Society
as combinatorial chemistry and rational design, have not yet been proven successful in the discovery of new agrochemicals. Therefore, a more practically useful and efficient strategy to discover novel bioactive compounds with excellent marketable potential is urgently needed to achieve sustainability in the agrochemical industry. In our previous papers, we had introduced intermediate derivatization methods (IDM) for new agrochemical discovery.16−19 Here, we will give a comprehensive description of its applications in new agrochemical discovery through several examples.
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INTERMEDIATE DERIVATIZATION METHOD On the basis of many years of research and evaluation of research conducted by other scientists, we proposed an innovative method for new agrochemical discovery, the intermediate derivatization method (IDM), which could greatly simplify the process of agrochemical discovery. IDM is a comprehensive strategy for discovering novel bioactive compounds falling between conventional methods used in agrochemical discovery and recent novel methods reported in the pharmaceutical field, such as chemical genetics,20 fragmentbased or molecule-based design,21 target-oriented synthesis (TOS), and diversity-oriented synthesis (DOS).22,23 The essence of IDM can be summarized as the application of various synthetic methodologies on key intermediates to generate innovative chemical structures, which, through Special Issue: 13th IUPAC Pesticide Chemistry Congress - Selected Topics Received: November 12, 2014 Accepted: December 17, 2014
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Figure 1. Discovery of diflufenican and chlorsulfuron via CIM.
appropriate biological screening, provide novel patentable leads or target compounds. The selected key raw intermediates are usually simple, cheap, and commercially available raw materials. According to the role of the key intermediate, IDM can be classified into three types. Common Intermediate Method (CIM). CIM uses modifiable key intermediates with reactive groups as raw materials to prepare a diverse set of structures, for exammple, discovery of the herbicides diflufenican and chlorsulfuron. It is a novel chemistry from simple intermediates to make novel structures that are totally different from previously known products through new chemical reactions or new synthesis routes. The discovery of the herbicide diflufenican is a typical example of CIM (Figure 1).24 The starting material, 2chloronicotinic acid, was simply amidated by aniline and Cl on the pyridine ring was replaced by a phenoxy group to yield 2-phenoxy-N-phenylnicotinamide, followed by further structure optimization and bioactive screening to afford diflufenican. Similar to diflufenican, chlorsulfuron can also be obtained after several rounds of modifications on benzenesulfonyl isocyanate (Figure 1),25 the milestone herbicide with a use rate at 10 g/ha compared to normal herbicide at 1000 g/ha at that time. Replacement Method (RM). RM uses key intermediates with reactive groups to replace partial moieties of existing agrochemicals, thus generating patentable structures with maintained or improved bioactivities, for example, the discovery of fluopicolide and carboxanilide fungicides. At first glance, RM seems to be similar to bioisosterism. However, in RM, the moieties may be replaced with groups that are not necessarily similar in size, and therefore it goes beyond the definition of bioisosters and known patent claims. Figure 2 shows some new agrochemicals discovered by replacing some moieties of various existing agrochemicals with 2,3-dichloro-5-(trifluoromethyl)pyridine via RM. Derivatization Method (DM). DM incorporates the modification of known active compounds with reactive groups
to derivatization, for example,. from acifluorfen to fomesafen. Typically, agrochemicals or noncommercial compounds with known biological activity used as intermediates have been on the decline and/or possess low biological activity, high toxicity, or some other drawback. Newly obtained compounds utilizing DM usually have structures similar to known ones, but possess improved bioactivity or a different biological activity spectrum compared to the known compounds from which they are derived. Certainly novel compounds may also be discovered. In Figure 3, the carboxyl group of acifluorfen is derivatized into amide to produce fomesafen, which has better biological activity and selectivity on early postemergence control of broad-leaved weeds in soybeans.26 Surprisingly, the same reaction happened on the herbicide dichlorprop, a fungicide for controlling rice blast; fenoxanil was discovered instead of herbicide.27 Two isomers of 2-aryl-3-oxo-3-phenylpropanenitrile with acaricideal activity, keto form and enol form, were further derived with acyl chloride respectively to obtain two new acaricides, cyenopyrafen and cyflumetofen, for controlling various mites in fruitd, teas, and vegetables.28 One more example is derivatization based on a carboxyl group from bispyribac to pyribenzoxim. Although there was little difference in herbicidal properties between them, the structure of pyribenzoxim is an innovative derivative of bispyribac.29 Combination of RM and DM. The three IDM methods mentioned above (CIM, RM, and DM) can be used singly or in combination. The combination of RM with DM also significantly contributes to the discovery of novel chemical structures. A range of pyridine and pyrimidine herbicides discovered from the known herbicide aminopyralid via the combination of RM and DM approaches is illustrated in Figure 4. Aminopyralid was used as starting material by combination utilization of RM related to 2-Cl on the pyridine ring or R group in lead-1 and DM related to bioisosterism between pyridine and pyrimidine rings to afford three novel herbicides, halauxifen, halauxifen-methyl, and aminocyclopyrachlor.30−32
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APPLICATIONS OF IDM IN SYRICI Over the past decade, we have successfully applied the IDM strategy in agrochemical discovery at Shenyang Research Institute of Chemical Industry (SYRICI). Hundreds of novel biologically active candidates, particularly agrochemicals, have been developed in our group, indicating that IDM is a useful, practical, and effective strategy for agrochemical discovery. Now, IDM has been firmly established in our research programs. In the following sections, we will provide practical examples of the application of IDM at SYRICI in the discovery of agrochemicals with the hope that it will promote the
Figure 2. Discovery of fluopicolide and other agrochemicals via RM. B
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Figure 3. Various agrochemicals discovered via DM.
and DM, we will mainly discuss the replacement method (RM) in this section because it is the most frequently used method at SYRICI. Considering their early patent stage, the exact structures of some active candidates will not be revealed. Discovery of Coumoxystrobin, Pyraoxystrobin, Pyrametostrobin, and Pyriminostrobin. Figure 5 shows a range of methoxyacrylate fungicides and acaricides prepared from highlighted key intermediates 1−3 by RM. Three key intermediates were all prepared from the same starting material, β-keto ester, by CIM. β-Keto ester was first cyclized with suitable phenols to offer key intermediate-1. Then replacement of the terminal 2methylphenyl group of the fungicide kresoxim-methyl with key intermediate-1 produced lead-1, which would lead to the fungicide coumoxystrobin (SYP-3375) after further optimiza-
Figure 4. Discovery of halauxifen, aminocyclopyrachlor, and halauxifen-methyl.
discovery of biologically active compounds. Although we have so far discussed three major approaches including CIM, RM.
Figure 5. Discovery of coumoxystrobin, pyraoxystrobin, pyrametostrobin, and pyriminostrobin. C
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Journal of Agricultural and Food Chemistry tions.33,34 The fungicide coumoxystrobin presents an excellent activity in the control of apple valsa canker (AVC), which shows an absolute advantage over the commercial fungicide azoxystrobin (Table 1).
(SYP-11277).36,37 Pyriminostrobin shows excellent efficacy against mites at various developmental stages and both good quick-acting and persistence activity. The detailed results are shown in Table 4. Patents for coumoxystrobin, pyraoxystrobin, pyrametostrobin, and pyriminostrobin have been granted in many countries, such as China, Japan, the United States, and Korea, and the corresponding discovery processes have been published in authoritative journals. Discovery of Fungicide SYP-4288. 2,6-Dichlorotoluene is another key intermediate to produce a wide variety of agrochemicals through appropriate IDM,38 including the herbicides dichlobenil,39 tembotrione,40 and florasulame,41 the insecticides methoxyfenozide42 and diflubenzuron,43,44 and the fungicide fluopicolide.45 In our research programs at SYRICI, active candidates SYP-4288 and SYP-2549 are both developed from starting material 2,6-dichlorotoluene via RM (Figure 6). Nitration of 2,6-dichlorotoluene, a cheap and commercially available raw material, was performed to achieve key intermediate. Then, the substituted phenyl group of fluazinam was replaced by this key intermediate via RM to yield lead-A, which could result in lead-B and SYP-2459 with both acaricidal and antitumor activities. Finally, a diphenylamine fungicide (SYP-4288) was developed from lead-B after further optimization. SYP-4288 shows a broad-spectrum fungicidal activity, especially against potato late blight (Table 5).46 Discovery of SYP-4380. Replacement of the terminal pyridinyl group of the known insecticide pyridalyl by substituted pyrazolyl (Q1), coumarinyl (Q2), and pyrimidinyl (Q3), which were prepared from the same raw material β-keto esters, led to a new active candidate, SYP-4380 (Figure 7). It possesses better insecticidal activity against lepidopterous pests than commercial pyridalyl (Figure 8), but a much lower cost beyond the known patent claim.47 Discovery of SYP-4575 and SYP-4576. Chlorothalonil with reactive groups to derivatization, which is commercially available and has broad-spectrum fungicidal activity and low toxicity (LD50 >5000 mg/kg), supplies us an ideal intermediate for agrochemical discovery. Through several rounds of derivatization and optimization via IDM, two active chlorothalonil analogues SYP-4575 and SYP-4576 were discovered (Figure 9), which show fungicidal activity and antitumor activity, separately.48 Besides the novel agrochemicals mentioned above, there are also many other excellent examples discovered via IDM at SYRICI, such as insecticide SYP-3409, fungicides SYP-2086 and SYP-3503, herbicide SYP-8601, acaricide SYP-4523, and antitumor agent SYP-3333 (Figure 10).
Table 1. Effect of 20% Coumoxystrobin SC on Recurrence Rate of Scar of AVC (Liaoning) compound
mg/L
recurrence rate (%)
control (%)
20% coumoxystrobin SC
1000 500 1000
1.7 7.1 16.3
97.3 88.5 73.5
25% azoxystrobin SC
The discovery of fungicides pyraoxystrobin (SYP-3343) and pyrametostrobin (SYP-4155) originated from further derivatization of the fungicide coumoxystrobin (SYP-3375), the coumarin group of which was replaced by key intermediates 2 to yield lead-2.35 Inspired by the unique structure of pyraclostrobin, phenylpyrazole moieties were introduced into lead-2, finally offering the active candidates pyraoxystrobin and pyrametostrobin after optimization and biological screening. Although they have exactly the same core structure with a fine distinction lying in the substituents on the terminal phenyl ring or pyrazole ring, they possess different fungicidal activities as shown in Tables 2 and 3. Table 2. Field Trial Results of Pyraoxystrobin against Cucumber Downy Mildew (CDM) and Rice Blast (RB) control (%) compound
concentration (g ai/ha)
CDM
RB
pyraoxystrobin (3343)
200 100 50 100 disease index
96.1 95.6 91.2 91.6 25.5
96.4 95.9 81.3 78.5 8.6
azoxystrobin blank control
Table 3. Test Results of Curative Activity of Pyrametostrobin against Wheat Powdery Mildew (WPM) (4 Days) control (%) compound
12.5 ppm
6.25 ppm
3.13 ppm
1.56 ppm
0.78 ppm
0.39 ppm
pyrametostrobin tebuconazole pyraclostrobin kresoxim-methyl
100 85 100 100
100 70 100 20
100 45 85 15
100 15 60 10
80 0 25 0
50 0 0 0
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Replacement of the pyrimidine moiety on the fluacrypyrim by key intermediate 3 through RM supplied lead-3, which was further optimized to result in the acaricide pyriminostrobin
CONCLUSION
After decades of practical application, the intermediate derivatization method has proven to be a more efficient
Table 4. Field Trial Results against Citrus Red Mite in Guilin mortality (%) compound
concentration (mg/L)
1 day
3 days
10 days
15 days
20 days
30 days
pyriminostrobin
100 50 25 48 267
92 91 90 59 90
96 95 92 72 93
96 92 83 75 92
95 89 91 76 96
97 91 92 83 94
94 77 91 82 93
spirodiclofen propargite
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Figure 6. Discovery of fungicide SYP-4288.
Table 5. Field Efficacy of SYP-4288 on Potato Late Blight at Hebei in China (2012) chemical SYP-4288
fluazinam blank control
dose (mg/L)
disease index
control (%)
disease index
control (%)
100 250 500 250
0.33 0.25 0.16 0.54 1.62
79.6 84.4 90.2 66.3
0.22 0.16 0.09 0.52 2.35
90.4 93.4 96.0 77.9
Figure 8. Insecticidal activity of SYP-4380.
method for the discovery of new biologically active molecules than traditional ones by both reducing the ever-increasing time and cost and improving the success rate of agrochemical discovery. Now, it has been established firmly at SYRICI and received international recognition. At the 2010 IUPAC International Pesticide Conference in Melbourne, Australia, IDM was introduced in an invited lecture titled “Discovery of New Strobilurin Acaricidal Compounds”. Then, a following paper “Novel Substituted Diphenylamine Fungicide” was given at the 241st National Meeting of the American Chemical Society held in Los Angeles, CA, USA, in 2011 to offer a further description and understanding of IDM. Recently, the inventor was invited to give a comprehensive summary of the application of IDM in novel agrochemical discovery, “Efficient Approach to Discover Novel Agrochemical Candidates: Intermediate Derivatization Method”, in a plenary lecture at the 13th IUPAC International Congress of Pesticide Chemistry Events in San Francisco, CA, USA. Moreover, IDM has been the subject of several papers in various journals in the agrochemical field, such as J. Agric. Food Chem., Pest Manage. Sci., and Chem. Rev..
Figure 9. Discovery of SYP-4575 and SYP-4576.
Figure 10. Some novel agrochemicals and antitumor agents discovered via IDM at SYRICI.
Figure 7. Discovery of insecticide SYP-4380. E
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(15) Lamberth, C.; Jeanmart, S.; Luksch, T.; Plant, A. Current challenges and trends in the discovery of agrochemicals. Science 2013, 341, 742−746. (16) Liu, C. L. Approach and application of novel agrochemical innovation. Chin. J. Pestic. 2011, 50, 20−23. (17) Liu, C. L. New agrochemical candidates from intermediate derivatization method based on bioisosteric replacement. In Frontiers of Modern Chemical Engineering, Metallurgy, and Material Technologies, 7th Academic Conference of Chemical, Metallurgy and Material Engineering Department; Wang, J. K., Ed.; Chemical Industry Press Publishers: Beijing, China, 2009; pp 86−94. (18) Liu, C. L. Innovation of pesticide discovery methods and candidate compounds. High-Technol. Ind. 2008, 9, 79−81. (19) Guan, A. Y.; Liu, C. L.; Yang, X. P.; Dekeyser, M. Application of the intermediate derivatization approach in agrochemical discovery. Chem. Rev. 2014, 114, 7079−7107. (20) Russel, K.; Michne, W. F. In Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective, 1st ed.; Kubinyi, H., Muller, G., Mannhold, R., Folkers, G., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 69. (21) Orita, M.; Ohno, K.; Warizaya, M.; Amano, Y.; Niimi, T. In Methods in Enzymology: Fragment-Based Drug Design-Tools, Practical Approaches, and Examples; Kuo, L. C., Ed.; Academic Press: San Diego, CA, USA, 2011; Vol. 493, p 383. (22) Hajduk, P. J.; Galloway, W. R.; Spring, D. R. Drug discovery: a question of library design. Nature 2011, 470, 42−43. (23) Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000, 287, 1964−1969. (24) Cramp, M. C.; Gilmour, J.; Hatton, L. R.; Hewett, R. H.; Nolan, C. J.; Parnell, E. W. Design and synthesis of N-(2,4-difluoropheny1)-2(3-trifluoromethylphenoxy)-3-pyridinecarboxamide (diflufenican), a novel pre- and early post-emergence herbicide for use in winter cereals. Pestic. Sci. 1987, 1815−1828. (25) Levitt, G. Pesticide chemistry: human welfare environment. In Proceedings of the International Congress on Pesticide Chemistry, 5th ed.; Miyamoto, J., Kearney, P. C., Eds.; Pergamon: Oxford, UK, 1983; Vol. 5, p 243. (26) Fennimore, S. A.; Mitich, L. W. Proceedings of the Western Society of Weed Science, Los Angeles, CA, March 8−10, 1983; Western Society of Weed Science: Las Cruces, NM, USA, 1983; p 170. (27) Sieverding, E.; Hirooka, T.; Nishiguchi, T.; Yamamoto, Y.; Spadafora, V. J.; Hasui, H. Proceedings of the Brighton Crop Protection Conference − Pests and Diseases, Brighton, UK, Nov 16−19, 1998; British Crop Protection Council: Alton, UK, 1998; p 359. (28) Yu, H. B.; Xu, M.; Cheng, Y.; Wu, H. F.; Luo, Y. M.; Li, B. Synthesis and acaricidal activity of cyenopyrafen and its geometric isomer. Arkivoc 2012, 26−34. (29) Koo, S. J.; Ahn, S. C.; Lim, J. S.; Chae, S. H.; Kim, J. S.; Lee, J. H.; Cho, J. H. Biological activity of the new herbicide LGC-40863 {benzophenone O-[2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoyl]oxime}. Pestic. Sci. 1997, 51, 109−114. (30) Clark, D. A.; Finkelstein, B. L.; Armel, G. R.; Wittenbach, V. A. Herbicidal pyrimidines. PCT Int. Appl. WO 2005063721, July 14, 2005. (31) Yerkes, C. N.; Lowe, C. T.; Eckelbarger, J. D.; Epp, J. B.; Guenthenspberger, K. A.; Siddall, T. L.; Schmitzer, P. R. Arylalkyl esters of 4-amino-6-(substituted phenyl)-picolinates and 6-amino-2(substituted phenyl)-pyrimidinecarboxylates and their use as selective herbicides for crops. U.S. Patent Appl. Publ. US 20120190551, July 26, 2012. (32) Eckelbarger, J.; Schmitzer, P.; Yerkes, C.; Boebel, T.; Satchivi, N.; Whiteker, G. N-Alkoxyamides of 6-(substituted phenyl)-4aminopicolinates and 2-(substituted phenyl)-6-amino-4-pyrimidinecarboxylates and their use as selective herbicides for crops. PCT Int. Appl. WO 2010099279, Sept 2, 2010. (33) Guan, A. Y.; Liu, C. L.; Li, M.; Zhang, H.; Li, Z. N.; Li, Z. M. Design, synthesis and structure-activity relationship of novel coumarin derivatives. Pest Manage. Sci. 2011, 67, 647−655.
OUTLOOK The intermediate derivatization method (IDM) is a useful approach for agrochemical discovery. What we are doing now is reducing the increasing time and cost in the discovery process and improving the success rate of agrochemical discovery. We are trying to improve the efficiency of IDM in agrochemical discovery via selection of intermediates with more varied functionalities and application of more robust organic synthesis routes. We believe that novel intermediates will undoubtedly lead to novel molecules, and novel molecules may lead to novel agrochemical candidates.
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AUTHOR INFORMATION
Corresponding Author
*(C.L.) Phone: 86-24-85869078. Fax: 86-24-85869137. E-mail: [email protected]. Funding
The project was supported by the National Key Technologies R&D Program of China (2011BAE06B05). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Mark Dekeyser (Canada) for assistance with manuscript preparation.
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Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method Changling Liu,* Aiying Guan, Jindong Yang, Baoshan Chai, Miao Li, Huichao Li, Jichun Yang, and Yong Xie State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Company Ltd., Shenyang 110021, China ABSTRACT: Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate “what is the IDM” and “why to use” and “how to use” it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years. KEYWORDS: intermediate derivatization method, new agrochemical discovery, patentable novel structure, shorter discovery phase, lower cost
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INTRODUCTION In modern agricultural production, agrochemicals, including insecticides/acaricides, herbicides, and fungicides, play an essential role in ensuring good crop quality, high crop yield, and low labor costs.1−3 Typically, approximately 10 years and U.S. $200 million are required to bring a new agrochemical from initial lead compound synthesized to final registration.4,5 The success rate of agrochemical discovery is currently estimated at 1/140,000.6 As the stringent regulatory requirements for environmental protection and food safety increase, the agrochemical discovery process lengthens and the success rate for commercial development declines.7 Obviously, agrochemical discovery presents a downward trend in recent years. It is well-known that new agrochemical discovery is based on the exploitation of a bioactive lead compound. The existing methods for discovering bioactive lead compounds are mainly as follows: random synthesis and screening,8 modification of natural compounds,9,10 “me too chemistry” (molecules with structures similar to those of existing products),11 combinatorial chemistry,12,13 and rational design.14,15 Statistically, “me too chemistry” and random synthesis and screening have been the two most successful approaches for new agrochemical discovery. From 2000 to 2013, 126 new synthetic agrochemicals were developed: 88 by “me too chemistry” and 38 by random synthesis and screening. However, these two methods require substantial investment of funding, time, and manpower, and their success rates for new agrochemical discovery are declining. Additionally, as market competition heats up, many companies have strengthened the scope of their intellectual property to block competitors’ imitations. Because of broad claims for the known patents, it is more difficult to discover the new products simply by using “me too chemistry”, which is often based on bioisosteric replacement. Other methods, such © XXXX American Chemical Society
as combinatorial chemistry and rational design, have not yet been proven successful in the discovery of new agrochemicals. Therefore, a more practically useful and efficient strategy to discover novel bioactive compounds with excellent marketable potential is urgently needed to achieve sustainability in the agrochemical industry. In our previous papers, we had introduced intermediate derivatization methods (IDM) for new agrochemical discovery.16−19 Here, we will give a comprehensive description of its applications in new agrochemical discovery through several examples.
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INTERMEDIATE DERIVATIZATION METHOD On the basis of many years of research and evaluation of research conducted by other scientists, we proposed an innovative method for new agrochemical discovery, the intermediate derivatization method (IDM), which could greatly simplify the process of agrochemical discovery. IDM is a comprehensive strategy for discovering novel bioactive compounds falling between conventional methods used in agrochemical discovery and recent novel methods reported in the pharmaceutical field, such as chemical genetics,20 fragmentbased or molecule-based design,21 target-oriented synthesis (TOS), and diversity-oriented synthesis (DOS).22,23 The essence of IDM can be summarized as the application of various synthetic methodologies on key intermediates to generate innovative chemical structures, which, through Special Issue: 13th IUPAC Pesticide Chemistry Congress - Selected Topics Received: November 12, 2014 Accepted: December 17, 2014
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Figure 1. Discovery of diflufenican and chlorsulfuron via CIM.
appropriate biological screening, provide novel patentable leads or target compounds. The selected key raw intermediates are usually simple, cheap, and commercially available raw materials. According to the role of the key intermediate, IDM can be classified into three types. Common Intermediate Method (CIM). CIM uses modifiable key intermediates with reactive groups as raw materials to prepare a diverse set of structures, for exammple, discovery of the herbicides diflufenican and chlorsulfuron. It is a novel chemistry from simple intermediates to make novel structures that are totally different from previously known products through new chemical reactions or new synthesis routes. The discovery of the herbicide diflufenican is a typical example of CIM (Figure 1).24 The starting material, 2chloronicotinic acid, was simply amidated by aniline and Cl on the pyridine ring was replaced by a phenoxy group to yield 2-phenoxy-N-phenylnicotinamide, followed by further structure optimization and bioactive screening to afford diflufenican. Similar to diflufenican, chlorsulfuron can also be obtained after several rounds of modifications on benzenesulfonyl isocyanate (Figure 1),25 the milestone herbicide with a use rate at 10 g/ha compared to normal herbicide at 1000 g/ha at that time. Replacement Method (RM). RM uses key intermediates with reactive groups to replace partial moieties of existing agrochemicals, thus generating patentable structures with maintained or improved bioactivities, for example, the discovery of fluopicolide and carboxanilide fungicides. At first glance, RM seems to be similar to bioisosterism. However, in RM, the moieties may be replaced with groups that are not necessarily similar in size, and therefore it goes beyond the definition of bioisosters and known patent claims. Figure 2 shows some new agrochemicals discovered by replacing some moieties of various existing agrochemicals with 2,3-dichloro-5-(trifluoromethyl)pyridine via RM. Derivatization Method (DM). DM incorporates the modification of known active compounds with reactive groups
to derivatization, for example,. from acifluorfen to fomesafen. Typically, agrochemicals or noncommercial compounds with known biological activity used as intermediates have been on the decline and/or possess low biological activity, high toxicity, or some other drawback. Newly obtained compounds utilizing DM usually have structures similar to known ones, but possess improved bioactivity or a different biological activity spectrum compared to the known compounds from which they are derived. Certainly novel compounds may also be discovered. In Figure 3, the carboxyl group of acifluorfen is derivatized into amide to produce fomesafen, which has better biological activity and selectivity on early postemergence control of broad-leaved weeds in soybeans.26 Surprisingly, the same reaction happened on the herbicide dichlorprop, a fungicide for controlling rice blast; fenoxanil was discovered instead of herbicide.27 Two isomers of 2-aryl-3-oxo-3-phenylpropanenitrile with acaricideal activity, keto form and enol form, were further derived with acyl chloride respectively to obtain two new acaricides, cyenopyrafen and cyflumetofen, for controlling various mites in fruitd, teas, and vegetables.28 One more example is derivatization based on a carboxyl group from bispyribac to pyribenzoxim. Although there was little difference in herbicidal properties between them, the structure of pyribenzoxim is an innovative derivative of bispyribac.29 Combination of RM and DM. The three IDM methods mentioned above (CIM, RM, and DM) can be used singly or in combination. The combination of RM with DM also significantly contributes to the discovery of novel chemical structures. A range of pyridine and pyrimidine herbicides discovered from the known herbicide aminopyralid via the combination of RM and DM approaches is illustrated in Figure 4. Aminopyralid was used as starting material by combination utilization of RM related to 2-Cl on the pyridine ring or R group in lead-1 and DM related to bioisosterism between pyridine and pyrimidine rings to afford three novel herbicides, halauxifen, halauxifen-methyl, and aminocyclopyrachlor.30−32
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APPLICATIONS OF IDM IN SYRICI Over the past decade, we have successfully applied the IDM strategy in agrochemical discovery at Shenyang Research Institute of Chemical Industry (SYRICI). Hundreds of novel biologically active candidates, particularly agrochemicals, have been developed in our group, indicating that IDM is a useful, practical, and effective strategy for agrochemical discovery. Now, IDM has been firmly established in our research programs. In the following sections, we will provide practical examples of the application of IDM at SYRICI in the discovery of agrochemicals with the hope that it will promote the
Figure 2. Discovery of fluopicolide and other agrochemicals via RM. B
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Figure 3. Various agrochemicals discovered via DM.
and DM, we will mainly discuss the replacement method (RM) in this section because it is the most frequently used method at SYRICI. Considering their early patent stage, the exact structures of some active candidates will not be revealed. Discovery of Coumoxystrobin, Pyraoxystrobin, Pyrametostrobin, and Pyriminostrobin. Figure 5 shows a range of methoxyacrylate fungicides and acaricides prepared from highlighted key intermediates 1−3 by RM. Three key intermediates were all prepared from the same starting material, β-keto ester, by CIM. β-Keto ester was first cyclized with suitable phenols to offer key intermediate-1. Then replacement of the terminal 2methylphenyl group of the fungicide kresoxim-methyl with key intermediate-1 produced lead-1, which would lead to the fungicide coumoxystrobin (SYP-3375) after further optimiza-
Figure 4. Discovery of halauxifen, aminocyclopyrachlor, and halauxifen-methyl.
discovery of biologically active compounds. Although we have so far discussed three major approaches including CIM, RM.
Figure 5. Discovery of coumoxystrobin, pyraoxystrobin, pyrametostrobin, and pyriminostrobin. C
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Journal of Agricultural and Food Chemistry tions.33,34 The fungicide coumoxystrobin presents an excellent activity in the control of apple valsa canker (AVC), which shows an absolute advantage over the commercial fungicide azoxystrobin (Table 1).
(SYP-11277).36,37 Pyriminostrobin shows excellent efficacy against mites at various developmental stages and both good quick-acting and persistence activity. The detailed results are shown in Table 4. Patents for coumoxystrobin, pyraoxystrobin, pyrametostrobin, and pyriminostrobin have been granted in many countries, such as China, Japan, the United States, and Korea, and the corresponding discovery processes have been published in authoritative journals. Discovery of Fungicide SYP-4288. 2,6-Dichlorotoluene is another key intermediate to produce a wide variety of agrochemicals through appropriate IDM,38 including the herbicides dichlobenil,39 tembotrione,40 and florasulame,41 the insecticides methoxyfenozide42 and diflubenzuron,43,44 and the fungicide fluopicolide.45 In our research programs at SYRICI, active candidates SYP-4288 and SYP-2549 are both developed from starting material 2,6-dichlorotoluene via RM (Figure 6). Nitration of 2,6-dichlorotoluene, a cheap and commercially available raw material, was performed to achieve key intermediate. Then, the substituted phenyl group of fluazinam was replaced by this key intermediate via RM to yield lead-A, which could result in lead-B and SYP-2459 with both acaricidal and antitumor activities. Finally, a diphenylamine fungicide (SYP-4288) was developed from lead-B after further optimization. SYP-4288 shows a broad-spectrum fungicidal activity, especially against potato late blight (Table 5).46 Discovery of SYP-4380. Replacement of the terminal pyridinyl group of the known insecticide pyridalyl by substituted pyrazolyl (Q1), coumarinyl (Q2), and pyrimidinyl (Q3), which were prepared from the same raw material β-keto esters, led to a new active candidate, SYP-4380 (Figure 7). It possesses better insecticidal activity against lepidopterous pests than commercial pyridalyl (Figure 8), but a much lower cost beyond the known patent claim.47 Discovery of SYP-4575 and SYP-4576. Chlorothalonil with reactive groups to derivatization, which is commercially available and has broad-spectrum fungicidal activity and low toxicity (LD50 >5000 mg/kg), supplies us an ideal intermediate for agrochemical discovery. Through several rounds of derivatization and optimization via IDM, two active chlorothalonil analogues SYP-4575 and SYP-4576 were discovered (Figure 9), which show fungicidal activity and antitumor activity, separately.48 Besides the novel agrochemicals mentioned above, there are also many other excellent examples discovered via IDM at SYRICI, such as insecticide SYP-3409, fungicides SYP-2086 and SYP-3503, herbicide SYP-8601, acaricide SYP-4523, and antitumor agent SYP-3333 (Figure 10).
Table 1. Effect of 20% Coumoxystrobin SC on Recurrence Rate of Scar of AVC (Liaoning) compound
mg/L
recurrence rate (%)
control (%)
20% coumoxystrobin SC
1000 500 1000
1.7 7.1 16.3
97.3 88.5 73.5
25% azoxystrobin SC
The discovery of fungicides pyraoxystrobin (SYP-3343) and pyrametostrobin (SYP-4155) originated from further derivatization of the fungicide coumoxystrobin (SYP-3375), the coumarin group of which was replaced by key intermediates 2 to yield lead-2.35 Inspired by the unique structure of pyraclostrobin, phenylpyrazole moieties were introduced into lead-2, finally offering the active candidates pyraoxystrobin and pyrametostrobin after optimization and biological screening. Although they have exactly the same core structure with a fine distinction lying in the substituents on the terminal phenyl ring or pyrazole ring, they possess different fungicidal activities as shown in Tables 2 and 3. Table 2. Field Trial Results of Pyraoxystrobin against Cucumber Downy Mildew (CDM) and Rice Blast (RB) control (%) compound
concentration (g ai/ha)
CDM
RB
pyraoxystrobin (3343)
200 100 50 100 disease index
96.1 95.6 91.2 91.6 25.5
96.4 95.9 81.3 78.5 8.6
azoxystrobin blank control
Table 3. Test Results of Curative Activity of Pyrametostrobin against Wheat Powdery Mildew (WPM) (4 Days) control (%) compound
12.5 ppm
6.25 ppm
3.13 ppm
1.56 ppm
0.78 ppm
0.39 ppm
pyrametostrobin tebuconazole pyraclostrobin kresoxim-methyl
100 85 100 100
100 70 100 20
100 45 85 15
100 15 60 10
80 0 25 0
50 0 0 0
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Replacement of the pyrimidine moiety on the fluacrypyrim by key intermediate 3 through RM supplied lead-3, which was further optimized to result in the acaricide pyriminostrobin
CONCLUSION
After decades of practical application, the intermediate derivatization method has proven to be a more efficient
Table 4. Field Trial Results against Citrus Red Mite in Guilin mortality (%) compound
concentration (mg/L)
1 day
3 days
10 days
15 days
20 days
30 days
pyriminostrobin
100 50 25 48 267
92 91 90 59 90
96 95 92 72 93
96 92 83 75 92
95 89 91 76 96
97 91 92 83 94
94 77 91 82 93
spirodiclofen propargite
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Figure 6. Discovery of fungicide SYP-4288.
Table 5. Field Efficacy of SYP-4288 on Potato Late Blight at Hebei in China (2012) chemical SYP-4288
fluazinam blank control
dose (mg/L)
disease index
control (%)
disease index
control (%)
100 250 500 250
0.33 0.25 0.16 0.54 1.62
79.6 84.4 90.2 66.3
0.22 0.16 0.09 0.52 2.35
90.4 93.4 96.0 77.9
Figure 8. Insecticidal activity of SYP-4380.
method for the discovery of new biologically active molecules than traditional ones by both reducing the ever-increasing time and cost and improving the success rate of agrochemical discovery. Now, it has been established firmly at SYRICI and received international recognition. At the 2010 IUPAC International Pesticide Conference in Melbourne, Australia, IDM was introduced in an invited lecture titled “Discovery of New Strobilurin Acaricidal Compounds”. Then, a following paper “Novel Substituted Diphenylamine Fungicide” was given at the 241st National Meeting of the American Chemical Society held in Los Angeles, CA, USA, in 2011 to offer a further description and understanding of IDM. Recently, the inventor was invited to give a comprehensive summary of the application of IDM in novel agrochemical discovery, “Efficient Approach to Discover Novel Agrochemical Candidates: Intermediate Derivatization Method”, in a plenary lecture at the 13th IUPAC International Congress of Pesticide Chemistry Events in San Francisco, CA, USA. Moreover, IDM has been the subject of several papers in various journals in the agrochemical field, such as J. Agric. Food Chem., Pest Manage. Sci., and Chem. Rev..
Figure 9. Discovery of SYP-4575 and SYP-4576.
Figure 10. Some novel agrochemicals and antitumor agents discovered via IDM at SYRICI.
Figure 7. Discovery of insecticide SYP-4380. E
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(15) Lamberth, C.; Jeanmart, S.; Luksch, T.; Plant, A. Current challenges and trends in the discovery of agrochemicals. Science 2013, 341, 742−746. (16) Liu, C. L. Approach and application of novel agrochemical innovation. Chin. J. Pestic. 2011, 50, 20−23. (17) Liu, C. L. New agrochemical candidates from intermediate derivatization method based on bioisosteric replacement. In Frontiers of Modern Chemical Engineering, Metallurgy, and Material Technologies, 7th Academic Conference of Chemical, Metallurgy and Material Engineering Department; Wang, J. K., Ed.; Chemical Industry Press Publishers: Beijing, China, 2009; pp 86−94. (18) Liu, C. L. Innovation of pesticide discovery methods and candidate compounds. High-Technol. Ind. 2008, 9, 79−81. (19) Guan, A. Y.; Liu, C. L.; Yang, X. P.; Dekeyser, M. Application of the intermediate derivatization approach in agrochemical discovery. Chem. Rev. 2014, 114, 7079−7107. (20) Russel, K.; Michne, W. F. In Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective, 1st ed.; Kubinyi, H., Muller, G., Mannhold, R., Folkers, G., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 69. (21) Orita, M.; Ohno, K.; Warizaya, M.; Amano, Y.; Niimi, T. In Methods in Enzymology: Fragment-Based Drug Design-Tools, Practical Approaches, and Examples; Kuo, L. C., Ed.; Academic Press: San Diego, CA, USA, 2011; Vol. 493, p 383. (22) Hajduk, P. J.; Galloway, W. R.; Spring, D. R. Drug discovery: a question of library design. Nature 2011, 470, 42−43. (23) Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000, 287, 1964−1969. (24) Cramp, M. C.; Gilmour, J.; Hatton, L. R.; Hewett, R. H.; Nolan, C. J.; Parnell, E. W. Design and synthesis of N-(2,4-difluoropheny1)-2(3-trifluoromethylphenoxy)-3-pyridinecarboxamide (diflufenican), a novel pre- and early post-emergence herbicide for use in winter cereals. Pestic. Sci. 1987, 1815−1828. (25) Levitt, G. Pesticide chemistry: human welfare environment. In Proceedings of the International Congress on Pesticide Chemistry, 5th ed.; Miyamoto, J., Kearney, P. C., Eds.; Pergamon: Oxford, UK, 1983; Vol. 5, p 243. (26) Fennimore, S. A.; Mitich, L. W. Proceedings of the Western Society of Weed Science, Los Angeles, CA, March 8−10, 1983; Western Society of Weed Science: Las Cruces, NM, USA, 1983; p 170. (27) Sieverding, E.; Hirooka, T.; Nishiguchi, T.; Yamamoto, Y.; Spadafora, V. J.; Hasui, H. Proceedings of the Brighton Crop Protection Conference − Pests and Diseases, Brighton, UK, Nov 16−19, 1998; British Crop Protection Council: Alton, UK, 1998; p 359. (28) Yu, H. B.; Xu, M.; Cheng, Y.; Wu, H. F.; Luo, Y. M.; Li, B. Synthesis and acaricidal activity of cyenopyrafen and its geometric isomer. Arkivoc 2012, 26−34. (29) Koo, S. J.; Ahn, S. C.; Lim, J. S.; Chae, S. H.; Kim, J. S.; Lee, J. H.; Cho, J. H. Biological activity of the new herbicide LGC-40863 {benzophenone O-[2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoyl]oxime}. Pestic. Sci. 1997, 51, 109−114. (30) Clark, D. A.; Finkelstein, B. L.; Armel, G. R.; Wittenbach, V. A. Herbicidal pyrimidines. PCT Int. Appl. WO 2005063721, July 14, 2005. (31) Yerkes, C. N.; Lowe, C. T.; Eckelbarger, J. D.; Epp, J. B.; Guenthenspberger, K. A.; Siddall, T. L.; Schmitzer, P. R. Arylalkyl esters of 4-amino-6-(substituted phenyl)-picolinates and 6-amino-2(substituted phenyl)-pyrimidinecarboxylates and their use as selective herbicides for crops. U.S. Patent Appl. Publ. US 20120190551, July 26, 2012. (32) Eckelbarger, J.; Schmitzer, P.; Yerkes, C.; Boebel, T.; Satchivi, N.; Whiteker, G. N-Alkoxyamides of 6-(substituted phenyl)-4aminopicolinates and 2-(substituted phenyl)-6-amino-4-pyrimidinecarboxylates and their use as selective herbicides for crops. PCT Int. Appl. WO 2010099279, Sept 2, 2010. (33) Guan, A. Y.; Liu, C. L.; Li, M.; Zhang, H.; Li, Z. N.; Li, Z. M. Design, synthesis and structure-activity relationship of novel coumarin derivatives. Pest Manage. Sci. 2011, 67, 647−655.
OUTLOOK The intermediate derivatization method (IDM) is a useful approach for agrochemical discovery. What we are doing now is reducing the increasing time and cost in the discovery process and improving the success rate of agrochemical discovery. We are trying to improve the efficiency of IDM in agrochemical discovery via selection of intermediates with more varied functionalities and application of more robust organic synthesis routes. We believe that novel intermediates will undoubtedly lead to novel molecules, and novel molecules may lead to novel agrochemical candidates.
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AUTHOR INFORMATION
Corresponding Author
*(C.L.) Phone: 86-24-85869078. Fax: 86-24-85869137. E-mail: [email protected]. Funding
The project was supported by the National Key Technologies R&D Program of China (2011BAE06B05). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Mark Dekeyser (Canada) for assistance with manuscript preparation.
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