ROUTE DEVELOPMENT, ANTIVIRAL STUDIES, FIELD EVALUATION AND TOXICITY OF AN ANTIVIRAL PLANT PROTECTANT NK0238

doi:10.15302/J-FASE-2021390

Front. Agr. Sci. Eng.

2022, Vol. 9

Issue (1) : 110-119 https://doi.org/10.15302/J-FASE-2021390

RESEARCH ARTICLE

ROUTE DEVELOPMENT, ANTIVIRAL STUDIES, FIELD EVALUATION AND TOXICITY OF AN ANTIVIRAL PLANT PROTECTANT NK0238

Wentao XU¹, Hao TIAN¹, Hongjian SONG¹(

), Yuxiu LIU¹, Yongqiang LI¹, Qingmin WANG²(

)

¹. State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
². Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China.

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Abstract

• Developed a two-step synthetic route to anti-plant-virus candidate NK0238.

• NK0238 exhibited a broad antivirus spectrum in greenhouse.

• NK0238 showed comparable antivirus activities as controls in field trials.

• NK0238 was safe to birds, fish, bees and silkworms.

• NK0238 has a very good prospect in commercial development.

It has previously been shown that tryptophan, the biosynthesis precursor of Peganum harmala alkaloids, and its derivatives have anti-TMV activity both in vitro and in vivo. Further exploration of this led to the identification of NK0238 as a highly effective agent for the prevention and control of diseases caused by plant viruses, but the existing routes are unsuitable for its large-scale synthesis. This study optimized a route for two-step synthesis of this virucide candidate via reaction of l-tryptophan with triphosgene to produce l-tryptophan-N-carboxylic anhydride, which then reacts with n-octylamine to give NK0238 at up to 94% yield and nearly 97% HPLC purity. In addition, the route was used for the preparation of NK0238 on a>40 g scale permitting further assessment of its antivirus activity in the greenhouse and field experiments, and toxicity tests. NK0238 exhibited useful antiviral activities against a variety of viruses both in greenhouse and field experiments. The toxicity tests showed that NK0238 was not acutely toxic to birds, fish, honey bees and silkworms. The optimized route provides a solid foundation for its large-scale synthesis and subsequent efficacy and toxicity studies, its excellent activity and safety make NK0238 a promising drug candidate for further development.

Keywords antiviral plant protectant antiviral in the greenhouse field evaluation l-trp-NCA synthesis optimization toxicity tests

Corresponding Author(s): Hongjian SONG,Qingmin WANG

Just Accepted Date: 26 March 2021 Online First Date: 26 April 2021 Issue Date: 17 January 2022

Cite this article:

Wentao XU,Hao TIAN,Hongjian SONG, et al. ROUTE DEVELOPMENT, ANTIVIRAL STUDIES, FIELD EVALUATION AND TOXICITY OF AN ANTIVIRAL PLANT PROTECTANT NK0238[J]. Front. Agr. Sci. Eng. , 2022, 9(1): 110-119.

URL:

https://academic.hep.com.cn/fase/EN/10.15302/J-FASE-2021390
https://academic.hep.com.cn/fase/EN/Y2022/V9/I1/110

Fig.1 Route for synthesis of the antiviral plant protectant, NK0238.

Fig.2 Previously reported routes for the synthesis of the anti-plant-virus candidate, NK0238.

Fig.3 Proposed new route for the synthesis of the anti-plant-virus candidate, NK0238.

Tab.1 Synthesis of L-trp-NCA with triphosgene as the cyclocarbonylation agent in various solvents^a

Tab.2 Optimization of conditions for the first step^a

Tab.3 Optimization of reaction conditions for the second step^a

Fig.4 Solvent screening for the synthesis of L-Trp-NCA with triphosgene as the cyclocarbonylation agent

Fig.5 Optimization of conditions for the first step.

Fig.6 Optimization of reaction conditions for the second step.

Fig.7 Scaled-up synthesis of the anti-plant-virus candidate, NK0238.

Tab.4 Inactivation effect against plant viruses, SCMV, PMMoV and TMV^a

Tab.5 Protective effect and curative effect against plant virus, TMV^a

Tab.6 Anti-TMV effects at different treatment dates^a

Tab.7 Field experiments

Tab.8 Ecotoxicology assessment of the anti-plant-virus candidate, NK0238

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